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CHAPTER 4
Phlebothrombosis (venous thrombosis):
Mostly occur in superficial or deep veins of the leg. Superficial usually occur in
varicosities (abnormally dilated and tortuous veins that usually appear in the lower
extremities) but rarely embolize , can be painful and cause congestion. DVT occurs in
larger leg vein or above the knee only has local pain while others recognise it after it
has embolized in the lung.
Gas/air embolism:
Gas bubbles within circulation can obstruct vascular flow and cause distal ischemic
injury.
Decompression sickness: caused by sudden changes in atmospheric pressure. (When
air is breathed at high pressure (e.g., during a deep sea dive), increased amounts of
gas (particularly nitrogen) become dissolved in the blood and tissues. If the diver then
ascends (depressurizes) too rapidly, the nitrogen expands in the tissues and bubbles
out of solution in the blood to form gas emboli)
AE in the lung causes hemorrhages, atelectasis ( complete or partial collapse of the
entire lung or area (lobe) of the lung), respiratory distress. In CNS coma
Fat embolism:
Usually occurs in crush injuries and severe skeletal injuries.
Caused by release of fat globulins from narrow vascular sinusoids or soft tissue into
circulation.
Fat microemboli occlude pulmonary and cerebral microvasculature, both directly and by
triggering platelet aggregation. This deleterious effect is exacerbated by fatty acid
release from lipid globules, which causes local toxic endothelial injury.
Clinical signs appear 1-3 days after injury with sudden Tachypnea, dyspnea,
tachycardia, irritability, restlessness then delirium and coma.
Amniotic fluid embolism:
The underlying cause is the entry of amniotic fluid (and its contents) into the maternal
circulation via tears in the placental membranes and/or uterine vein rupture
Characteristics: sudden severe dyspnea, cyanosis, hypotensive shock, followed by
seizure and coma.
If she survives, usually pulmonary edema and intravascular coagulation (main cause of
death) occur due increased activation of innate immunity and coagulation bec of
biochemical substances in amniotic fluid.
What will we see under the microscope if someone has amniotic fluid
embolization:4
Squamous cells shed from fetal skin, lanugo hair, mucin derived from fetus respiratory
and GI tract in maternal pulmonary microcirculation and collagen.
Septic infarction:
occur when infected cardiac valve vegetations embolize, or when microbes seed
necrotic tissue. In these cases the infarct is converted into an abscess, with a
correspondingly greater inflammatory response and healing by organization and fibrosis
Red and white infarcts:
Red infarcts- caused by venous occlusion, happens in loose tissue e.g lungs where
blood can accumulate, tissues with dual blood supply e.g lungs and intestine, or
previously congested tissues. Excavated RBC are phagocytosed by macrophages
White infarcts: occur with arterial occlusions in solid organs with end arterial circulation
like heart, spleen and kidney.
Waterhouse-fredrichson
Bleeding into the adrenal glands.
Massive release of glucocorticoids happens followed by adrenal insufficiency
associated with Waterhouse fredrichson syndrome. Can be associated with DIC.
Neisseria meningitis can cause this syndrome. Vasodilation and hypotension happens.
Mural thrombi
Thrombi occurring in heart chambers or in the aortic lumen.
Abnormal myocardial contraction (arrhythmias, dilated cardiomyopathy, or myocardial
infarction) or endocardial injury (myocarditis, catheter trauma) promote cardiac mural
thrombi
Anti phospholipid antibody syndrome
Has different clinical manifestations like recurrent thromboses, repeated miscarriages
due antibody against trophoblasts, cardiac valve vegetations and thrombocytopenia .
antibody targets include B2-glycoprotein I on prothrombin & trophoblasts
It provides false positives for syphilis bec it's in cardiolipin.
Therapy with anticoagulants and immunosuppression.
Pulmonary congestion
acute pulmonary congestion is marked by blood-engorged alveolar capillaries and
variable degrees of alveolar septal edema and intra alveolar hemorrhage.
In chronic pulmonary congestion, the septa become thickened and fibrotic, and the
alveolar spaces contain numerous macrophages laden with hemosiderin
Types of shock
Cardiogenic shock results from low cardiac output as a result of myocardial pump
failure. Failure of myocardial pump resulting from intrinsic myocardial damage, extrinsic
pressure, or obstruction to outflow. Ex. Myocardial infarction, Ventricular rupture
Arrhythmia Cardiac tamponade Pulmonary embolism Hypovolemic shock results from
low cardiac output due to loss of blood or plasma volume. Inadequate blood or plasma
volume ex. Hemorrhage, fluid loss Septic shock is triggered by microbial infections and
is associated with severe systemic inflammatory response. Peripheral vasodilation ex.
Gram negative sepsis, superantigens like toxic shock syndrome happens from
streptococcus pyogenes.
Hemostasis:
Primary hemostasis(formation of platelet plug): the disrupted epithelium uncovers sub
endothelium that contains von-willebrand growth factor and collagen ,platelet activation
and adherence is mediated by collagen and vWF which act as bridge between receptor
glycoprotein Ib(GpIb) Platelet activation: done by collagen and vWF make them flatter
with spiky protrusion that inc surface area and release secretory granules containing
ADP that recruit platelets & prostaglandin thromboxane A2 (Tax2) induce platelet
aggregation. Note: aspirin inhibits cyclooxygenase, a platelet enzyme required for TAX2
synthesis.
Secondary hemostasis (deposition of fibrin): Tissue factor(membrane bound
procoagulant glycoprotein) is exposed at site of injury expressed in sub endothelium.
Tissue factor(TF) activates factor VII(7) starting a cascade that results in thrombin
generation. • Thrombin cleaves fibrinogen into fibrin that helps in formation of fibrin
meshwork which is also a potent platelet activator. Entrapped blood cells are due P
selectin
Coagulation cascade
It is a series of amplifying reactions that lead to deposition of insoluble fibrin clots. Each
reaction requires an enzyme and cofactor. • Assembly of reaction complexes depends
on calcium which binds to y-glutamic acid residues present in factor II,VII, IX and X.
They also use vitamin K as cofactor and are antagonized by the drug Coumadin.
Prothrombin time (PT)
The assay assesses the function of the proteins in the extrinsic pathway (factors II, V,
X,VII)(prothrombin), and fibrinogen). In brief, tissue factor, phospholipids, and calcium
are added to plasma and the time for a fibrin clot to form is recorded.
Partial thromboplastin time (PTT)
assay screens the function of the proteins in the intrinsic pathway (factors XII, XI, IX,
VIII, X, V, II, and fibrinogen). In this assay, clotting of plasma is initiated by the addition
of negative- charged particles (e.g., ground glass) that activate factor XII (Hageman
factor) together with phospholipids and calcium, and the time to fibrin clot formation is
recorded.
Factor deficiencies
F 5,7,8,9,10 cause moderate bleeding disorders. Prothrombin is incompatible with life.
F11 is mild. F12 doesn't bleed or may be susceptible to thrombosis because it's involved
in the fibrinolysis pathway.
Factor VIIa/Tissue
Factor complex is the most important activator of Factor 9 and Factor 9a/Factor 8a
complex is the most important activator of Factor 5. Mild bleeding in Factor 11
deficiency bec of ability of thrombin to activate Factor 11 as well as F5&F13 to amplify
coagulation cascade
Anticoagulant effects:
Thrombomodulin and protein C(PC) Thrombomodulin bind to thrombin which activate
protein C. PC is a vitamin K dependent protease that requires a cofactor Protein S.
Activated protein C/S complex is potent inhibitor of coagulation factor 5a and 7a.
Anti-coagulators. Tissue factor pathway inhibitor (TFPI) requires protein S as cofactor; it
binds to TF/factor VIIa complexes.
Heparin-like molecules bind to antithrombin 3 and this complex will inactivate thrombin.
An abnormal PT may indicate an issue with the clotting factors involved in the extrinsic
pathway.
Causes of thrombosis: hypercoagulability, stasis or turbulent blood flow and endothelial
injury.
Txa2 function:
An activator of platelet aggregation and causes Vasoconstriction
TPA (Tissue Plasminogen Activator) function:
Conversion of plasminogen to plasmin
Fibrinolysis of excess fibrin
What is DIC (disseminated intravascular coagulation):
The widespread microvascular thrombosis that consumes platelets and coagulation
proteins (hence the synonym consumptive coagulopathy), and at the same time,
fibrinolytic mechanisms are activated.
Sepsis:
Various microbial cell wall constituents engage receptors on cells of the innate immune
system, triggering proinflammatory response
Libman-sacks endocarditis:
a form of endocarditis that is associated with autoimmune diseases such as systemic
lupus erythematosus, where there are vegetations (abnormal mass) on both sides of the
valves of the heart. These vegetations can cause valve dysfunction and increase the
risk of embolism.
Note:*vegetation: where platelets and stuff accumulate as a response to bacteria then
they get dislodged obstructing blood vessels, causing the septic emboli*
Function of antithrombin 3:
inhibits thrombin and factors 9a, 10a, 11a, and 12a.
What causes immunosuppression for septic shock
The use IL-10
What is D-dimer:
D-dimers are fibrinogen residues. An elevated level of D-dimer can indicate that there is
an ongoing clotting process in the body, but it cannot identify the location or cause of
the clot.
Complement cascade:
Complement cascade set of events that activates different plasma proteins which will
lead to killing the affected cell (c3b most important one)
What are lines of zahn:
The lines of Zahn are layers of platelet-fibrin thrombi intercalated with layers of red
blood cells
can help to distinguish between postmortem clot formation and thrombi formed before
death (present in thrombi formed before death).
What causes septic embolism?
Septic embolism is a condition in which bacteria or other infectious agents spread
through the bloodstream and form small clumps or emboli that can block blood vessels
in various parts of the body. These emboli can cause tissue damage and inflammation,
and can lead to serious complications such as organ failure or sepsis.
It can be caused by a variety of underlying infections, such as bacterial endocarditis,
which is an infection of the heart valves, or osteomyelitis, which is an infection of the
bone. Other infections that can lead to septic embolism include skin infections,
pneumonia, and urinary tract infections.
CHAPTER 3
C1 inhibitor deficiency
Hereditary angioedema:face swelling,hands,stomach,bowel, and genitals
c1 inhibitor defects cause excessive activation of the kinin system, increase bradykinin
>increased vascular permeability and edema.
CD59 Deficiency:
Paroxysmal nocturnal hemoglobinuria:sudden/onset,night, blood in urine.
Function of cd59: inhibits MAC pore formation
If there is defect:increase MAC production> and induces intravascular hemolysis
Kinins
Kinins are proteins in the blood that cause inflammation and affect blood pressure
Bradykinin increases vascular permeability and causes contraction of smooth muscle,
dilation of blood vessels, and pain when injected into the skin. These effects are similar
to those of histamine.
Complement system:
function:protection of the host from infection/inflammation by recruiting chemotaxis and
enhancing phagocytosis by innate immune cells (opsonization) leading to lysis of
targeted cells.
Cleavage of C3 can occur by one of three pathways:
● The classical pathway, which is triggered by fixation of C1 to antibody (IgM or
IgG) that has combined with antigen
● The alternative pathway, which can be triggered by microbial surface molecules
(e.g., endotoxin, or LPS), complex polysaccharides, and other substances, in the
absence of antibody •The lectin pathway, in which plasma mannose-binding
lectin binds to carbohydrates on microbes and directly activates C1
Function of leukotrienes
Leukotrienes are produced in leukocytes and mast cells by the action of lipoxygenase
(leukotrienes biosynthesis requires 5 lipoxygenase.) and are involved in vascular and
smooth muscle reactions, and leukocyte recruitment. The synthesis of leukotrienes
involves multiple steps, the first of which generates leukotriene A4 (LTA4), which in turn
gives rise to LTB4 or LTC4. LTB4 is produced by neutrophils and some macrophages
The cysteinyl-containing leukotriene LTC4 and its metabolites, LTD4 and LTE4, are
produced mainly in mast cells and cause intense vasoconstriction, bronchospasm
(important in asthma), and increased permeability of venules.
Types of leukotrienes:
1. leukotriene A4 (LTA4), which in turn gives rise to LTB4 or LTC4. LTB4 is produced by
neutrophils and some macrophages, and is a potent chemotactic agent and activator of
neutrophils, causing aggregation and adhesion of the cells to venular endothelium,
generation of ROS, and release of lysosomal enzymes.
2. The cysteinyl-containing leukotriene LTC4 and its metabolites, LTD4 and LTE4, are
produced mainly in mast cells and cause intense vasoconstriction, bronchospasm
(important in asthma), and increased permeability of venules. They’re dangerous in
case of asthma because leukotrienes are potent Bronchoconstrictors.
Lipoxins:
Lipoxins also are generated from arachidonic acid by the lipoxygenase pathway, but
unlike prostaglandins and leukotrienes, the lipoxins suppress inflammation by inhibiting
the recruitment of leukocytes. They inhibit neutrophil chemotaxis and adhesion to
endothelium
Opsonization
C3b and its cleavage product iC3b (inactive C3b), when fixed to a microbial cell wall, act
as opsonins and promote phagocytosis by neutrophils and macrophages, which bear
cell surface receptors for these complement fragments
What Opsonins do you know?
opsonins: coat the cell with antibodies promoting their phagocytosis
C3B & Fc portion of IgG , & IgM
Inflamazoms
Explanation 1: NLRP3 inflammasome is a multiprotein complex that plays a role in
regulating the innate immune system and inflammatory signaling.activation by PAMPs
and DAMPs, NLRP3 oligomerizes and activates caspase-1 which initiates the
processing and release of pro-inflammatory cytokines IL-1β and IL-18.
Explanation 2: The inflammasome is a protein complex that recognizes products of
dead cells and some microbes and induces the secre- tion of biologically active
interleukin-1. It is a complex of multiple copies of a sensor protein (a leucine-rich
protein called NLRP3), an adapter, and the enzyme caspase-1, which is
converted from an inactive to an active form.
Study whichever you feel is easier for you to memorize, both are right…
What are PAMPS & DAMP’S:
(Pathogen associated molecular pattern) & (Damage associated molecular patterns)
PAMPs are found on microorganisms and recognized by Pattern Recognition Receptors
(PRRs) on immune cells. Examples of PAMPs are LPS, viral nucleic acids, and fungal
cell wall components. DAMPs are released from damaged or dying cells and can also
activate the immune system by binding to PRRs on immune cells. Examples of DAMPs
include heat shock proteins, uric acid
IL10 inhibits what
TH1 cells: INFy is the main Th1 cytokine > is inhibited by IL10 to stop production of
proinflammatory substances and responses.
IL10 function: limiting the host's immune response to pathogens, thereby preventing
damage to the host and maintaining normal tissue homeostasis.``anti-inflammatory”. It
suppresses NK and T cells by preventing APCs (Antigen Presenting Cells) from
producing cytokines.
What is C1 inhibitory function:
Binds to C1s and C1r
To inhibit recessive complement system, we use it if it’s indirect and it inhibits in the
classical pathway, which is triggered by fixation of C1 to antibody (IgM or IgG) that has
combined with antigen, The lectin pathway, in which plasma mannose-binding lectin
binds to carbohydrates on microbes and directly activates C1.
(What does it bind to c1q, c1r, c1s and write how do they bind to it)
What are acute phase interleukines/reactants?
The acute phase response is a facet of the innate immune system that occurs in
response to infection, trauma, or other insults. They are inflammation markers that
exhibit significant changes in serum concentration during inflammation.These
changes are reactions to cytokines whose production is stimulated by bacterial
products.
Positive acute phase reactants are those whose concentration increases with
inflammation. For example: C-reactive protein is an acute phase protein that is involved
in innate immunity, and is responsible for activating the complement pathway.
Negative acute phase reactant:are those whose concentrations decrease in an acute
phase response. For example: serum albumin
What are chemokines?
CXC chemokines, CC chemokines, C chemokines, CX3C chemokines
These are the different chemokines arranged according to their cysteine residue
Chemokines are proteins that work by attracting leukocytes
.
CXC attracts neutrophils. IL-8 is part of this group
CC attracts monocytes, lymphocytes, basophils and eosinophils. Example is MCP-1
(MCP-1 activates the respiratory burst of monocytes and induces the expression of the
pro-inflammatory cytokines IL-6 and IL-1β,which in turn may regulate the expression of
TGF-β.)
C chemokines are for lymphocytes. Example lymphotactin
A CX3C example is fractalkine. They attract monocytes and T cells and exist in two
forms: cell surface bound protein and soluble protein form
P & E selectins:
P and e selectins are adhesion molecules on the endothelium to which leukocytes bind
to in case of chemotaxis
Function: rolling to slow down cells
ligand sialylated lewis binds to P&E selectins
Function of thrombomodulin:
Thrombomodulin activates protein c which inhibits factors 5a 8a
Leukocytes rolling:
Leukocytes rolling is just the attachment and detachment of leukocytes on the
endothelium when they become activated, it's just a movement
What does CD59 do and how does it inhibit MAC formation:
CD59 inhibits MAC formation which perforates the affected cell and disrupts the osmotic
gradient leading to rupture of the affected cell.
Myeloperoxidase deficiency:
deficiency or absence of myeloperoxidase enzyme in phagocytes that are unable to
form hypochlorous acid (HClO) but have preserved respiratory burst (since NADPH
oxidase is intact).
Recurrent candida infections
Autoinflammatory syndrome:
Autoinflammatory syndrome occurs when there is a gain of function mutation in the
inflammasomes, they increase the release of IL-1 for inflammation
Deficiency of decay accelerating factor (CD55):
results in the over-activation of the complement system due to the inability to properly
regulate it.
When DAF is deficient, the complement system activates too much and RBC dies
causing paroxysmal nocturnal hemoglobinuria.
What is Fc complex/receptors:
The Fc region of an antibody molecule is the part that binds to various Fc receptors on
the surface of cells such as B cells, macrophages, natural killer cells, and dendritic cells.
When an antibody molecule binds to its target antigen, the Fc region of the antibody
becomes exposed and can interact with Fc receptors on immune cells. This interaction
triggers a variety of immune responses, depending on the specific Fc receptor and the
type of immune cell involved.
Function of protein C:
Protein C is needed for fibrinolysis function, breaking down the clot. It is activated by
thrombomodulin and then protein c with the help of protein S inactivating factors Va and
VIIIa.
Function of IL-17:
IL-17 is a cytokine-induced production of chemokines like CXCL1. They produce
defensin which is an antimicrobial protein. It just helps with inflammation.
Chronic granulomatous disorder why do they come with catalase + bacteria are
causing recurrent infections:
Bacteria that are catalase positive break down hydrogen peroxide that they produce and
don’t allow our body to break it down and so free radicals cannot be formed to kill the
bacteria. That’s why the infection becomes recurrent. With catalase negative, the
bacteria wouldn’t break down H2O2 and the body will do so and form free radicals to kill
the bacteria
Deficiency in phagocyte oxidase (enzyme that converts NADPH to NADP+)
Chronic granulomatous disease is just an immune disease where granuloma is formed
and bacteria like Staph Aureus and Strep Pyogenes invade the body since the immune
system is unable to produce ROS in response to bacterial and fungal infections.
What are neuropeptides:
play a role in the initiation and regulation of inflammatory responses. These small
peptides, including substance P and neurokinin A, are produced in the central and
peripheral nervous systems. Nerve fibers containing substance P are prominent in the
lung and gastrointestinal tract. Substance P has many biologic functions, including the
transmission of pain signals, regulation of blood pressure, stimulation of hormone
secretion by endocrine cells, and in increasing vascular permeability.
How alternative pathway gets activated:
Alternative pathway is triggered by endotoxins or LPS of gram negative bacteria or also
could be polysaccharides and they then form MAC which kills bacteria
Decay accelerating factor:
DAF is a protein that prevents C3 convertase enzyme from forming
Tissue plasminogen activation:
t-PA is synthesized by endothelium. tPA works by converting plasminogen into plasmin,
an active enzyme that can break down fibrin.
What’s anaphylactic shock:
Anaphylactic shock, also known as anaphylaxis, is a severe and potentially
life-threatening allergic reaction that occurs rapidly after exposure to an allergen
Causes fall in blood pressure (shock) caused by vascular dilation by release of
histamine from mast cells; airway obstruction due to laryngeal edema caused by
increased permeability which allows fluid to leak out of the blood vessels and into the
surrounding tissues, causing edema.
Why don’t we give aspirin to people who have asthma?
Because aspirin will inhibit cyclooxygenase pathway (COX), so arachidonic acid can’t
be metabolized to cyclooxygenase so it will not produce PSG which causes vasodilation
What are M1 & M2 macrophages:
What are TH1 cells:
CD4+ T cell differentiates into Th1 which secrete IFN-y
TH2 cells:
Differentiated T cells
Cells secrete IL-4 (class switching in B cells), IL-5 (recruit and activate eosinophils), and
IL-13 (mucous prod. And IgE prod.)
TH17 cells:
CD4+ T cell differentiates into Th17 which secrete IL-17 and other cytokines, which
induce the secretion of chemokines responsible for recruiting neutrophils promoting
inflammation.
Foreign body granulomas:
Response to foreign bodies in the absence of T cell mediated immune response. FBG
forms around materials such as talc, sutures or other fibers that are large enough to
preclude phagocytosis by a macrophage (not immunogenic). On the surface of FBG we
can see epithelioid cells and giant cells. They can be identified in the center of the
granuloma using polarized light (appears refractile).
Function of IL-12:
IL-12 is a cytokine primarily produced by activated macrophages and dendritic cells that
plays a key role in the differentiation of CD4+ T cells into the Th1 subset. It stimulates
the production of IFN-γ and enhances the cytotoxic activity of natural killer cells and T
cells.
Function of IL-6:
Has macrophages, systemic effects (acute phase response)
What releases IL-6?
Macrophages, endothelial cells, mast cells
IL-1:
including the activation of immune cells, the induction of fever, and the stimulation of the
acute phase response.
Produced by Macrophages, endothelial cells, mast cells
How do we activate mannose pathway:
The mannose pathway of complement activation is activated by the binding of
mannose-binding lectin (MBL) to microbial cell surface carbohydrates containing
mannose
What are immune granulomas:
They are caused by agents that can induce persistent T cell mediated immune
response. This immune response produces granulomas when the agent can’t be readily
eliminated such as persistent microbes or self antigen. Responses such as
macrophages activate T cells to produce cytokines.
Function of interferon gamma:
Activation of macrophages (increased ability to kill microbes and tumor cells)
produced by activated T cells, natural killer (NK) cells,
What is the nuclear factor kappa light chain?
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein
complex that controls transcription of DNA, cytokine production and cell survival. NF-κB
is found in almost all animal cell types and is involved in cellular responses to stimuli
such as stress, cytokines, free radicals, heavy metals, ultraviolet irradiation, oxidized
LDL, and bacterial or viral antigens. NF-κB plays a key role in regulating the immune
response to infection. Incorrect regulation of NF-κB has been linked to cancer,
inflammatory and autoimmune diseases, septic shock, viral infection, and improper
immune development. NF-κB has also been implicated in processes of synaptic
plasticity and memory
Which cytokines are produced by Th2 lymphocytes?
IL-4, IL5, IL13
Function of IL-10?
an anti-inflammatory cytokine that inhibits the activation and function of T cells,
monocytes, and macrophages. It also suppresses the expression of pro-inflammatory
cytokines, chemokines, and adhesion molecules.
IL-10 inhibit which cell?
Th1 cells, NK, dendritic cells and macrophages.
What are thromboxane and prostaglandins, their function and why they’re
dangerous?
TXA2: is a potent vasoconstrictor and platelet aggregator that helps to promote blood
clotting and wound healing. However, excessive production of thromboxanes can lead
to the formation of blood clots in the arteries, which can cause heart attacks, strokes,
and other serious cardiovascular diseases.
Prostaglandins (PGD2 PGE2 ): promotes vasodilation and increased vascular
permeability. Excessive production of PGs is associated with many inflammatory
disorders, including rheumatoid arthritis, osteoarthritis, and inflammatory bowel disease.
PGD2 and PGE2 can cause bronchoconstriction, mucus secretion, and airway
inflammation, leading to breathing difficulties in asthma patients.
Diapedesis
The process in which white blood cells come out of the blood vessels into the
surrounding area in case of injuries
The steps of the inflammatory response? five Rs: (1) recognition of the injurious
agent, (2) recruitment of leukocytes, (3) removal of the agent, (4) regulation (control) of
the response, and (5) resolution (repair).
How leukocytes go to site of inflammation?
TNF alpha and IL-1 released by macrophages can activate endothelial cells to express
adhesion molecules such as P and E-selectins, which help leukocytes to adhere to the
endothelium and roll along the vessel wall. However, leukocytes do not go through
endothelial cells to reach the site of inflammation. They cross the endothelial barrier
through a process called transmigration, facilitated by integrins, adhesion molecules,
chemokines, and cytokines.
What happens in acute inflammation?
Vasodilation: The arterioles in the affected tissue dilate, causing an increase in blood
flow to the area.
Increased vascular permeability: The increased blood flow causes the capillaries in the
area to become leaky, allowing fluid, plasma proteins, and inflammatory cells to leave
the circulation and enter the tissue.
Leukocyte migration and activation: Inflammatory mediators, such as cytokines and
chemokines, attract and activate leukocytes (white blood cells), particularly neutrophils,
causing them to adhere to the endothelium and migrate into the tissue.
Phagocytosis: Once in the tissue, neutrophils and other phagocytic cells engulf and
destroy invading microorganisms and damaged tissue debris through phagocytosis.
Termination of the response: The acute inflammatory response is self-limited mediated
by various anti-inflammatory mediators, (IL-10)
external manifestations of inflammation as: heat (calor), redness (rubor), swelling
(tumor), pain (dolor)
OUTCOMES OF ACUTE INFLAMMATION #1: Resolution of inflammation • Removal of
microbes/debris • Tissue returns to normal #2: Healing/scar • Tissue damage too
extensive for regeneration • Connective tissue growth #3: Chronic inflammation
What can elicit inflammation?Inflammation can be elicited by a variety of stimuli,
including microbial pathogens, tissue necrosis, foreign bodies, immune reactions,
physical and chemical insults, and others.
How free radicals are produced in phagocytic cells?
NADPH oxidase catalyzes the conversion of O2 to superoxide anion (O2-). This O2- is
then rapidly converted to hydrogen peroxide (H2O2) and, by myeloperoxidase H2O2 is
in turn converted to a highly reactive OH compound, hypochlorite These ROS are then
used by the leukocytes to kill microorganisms within the phagolysosome.
Prostacyclin (PGI2)?
a potent vasodilator and inhibitor of platelet aggregation. preventing thrombosis and
inflammation. NOTE: vascular endothelium contains prostacyclin synthase, which is
responsible for the formation of prostacyclin (PGI2)
Factor H deficiency?
Factor H is a plasma protein that serves as a cofactor for the proteolysis of the C3
convertase; its deficiency results in excessive complement activation
A deficiency in Factor H can lead to uncontrolled activation of the complement pathway,
which can cause tissue damage and inflammation. This can result in several conditions,
including atypical hemolytic uremic syndrome
Factor I deficiency?
Factor I is a crucial inhibitor controlling all complement pathways due to its ability to
degrade activated complement proteins C3b and C4b in the presence of cofactors such
as factor H Patients will get Recurrent pyogenic infections and autoimmune disorders
Regulatory proteins:
• C1 inhibitor blocks the activation of C1(hereditary angioedema.) • Decay accelerating
factor (DAF) : prevents formation of C3 convertases(PN hemoglobinuria ) • CD59:
inhibits formation of the MAC (PN hemoglobinuria ) • Factor H: cofactor of the C3
convertase (in excessive complement activation) • factor i: degrade activated
complement proteins C3b and C4b(recurrent infections)
What is fibrinous inflammation?
Fibrinous inflammation is typically associated with increased vascular permeability,
which allows larger molecules such as fibrinogen to leak out of the blood vessels and
accumulate in the tissue. The presence of a procoagulant stimulus, such as tissue injury
or infection, can further promote the formation of fibrin and deposition of fibrinous
exudate.
Mediators of inflammation?
-Platelet activating factor - Products of Coagulation - Kenin system - Neuropeptides
Gaseous & non-gaseous granulomas:
Gaseous granulomas are caused by antigens that are relatively volatile or that can be
cleared by a strong cellular immune response. They are typically composed of activated
macrophages, lymphocytes, and multinucleated giant cells, and may have a central
area of necrosis. Examples of gaseous granulomas include tuberculosis, fungal
infections, and sarcoidosis.
Non-gaseous granulomas are caused by antigens that are relatively non-volatile or that
persist despite a strong cellular immune response. They are typically composed of
fibroblasts, collagen, and other connective tissue components, in addition to activated
macrophages, lymphocytes, and multinucleated giant cells. Examples of non-gaseous
granulomas include foreign body reactions, such as those caused by sutures, implants,
or other indwelling devices, as well as granulomatous diseases caused by
autoimmunity, such as Crohn's disease or granulomatosis with polyangiitis
What kind of disease does gaseous granulomas happens from?
tuberculosis, fungal infections, Leprosy, Syphilis
What kind of disease does non-gaseous granulomas happen from?
Foreign body reactions, Sarcoidosis, Crohn’s disease
CHAPTER 5
Lupus is which hypersensitivity:
In systemic lupus we get anemia this is type III hypersensitivity.
Glomerulonephritis/nephritic syndrome this is type III hypersensitivity.
CD40 deficiency?
CD40 is a receptor for CD40L It’s needed for macrophages activation and also for B cell
proliferation. So, if it’s deficient, ig those won’t activate and immunodeficiencies happen.
If we have complement cascade deficiency we get recurrent bacteria infection
which are:
Hypersensitivity I,II,III,IV.
What is goodpasture’s syndrome, which type of hypersensitivity:
Target antigen is Type IV collagen in the basement membrane of kidney and glomeruli
and lung alveoli. Antibody-mediated (type II) hypersensitivity Production of IgG, IgM →
binds to antigen on target cell or tissue → phagocytosis or lysis of target cell by
activating complement or Fc receptors mediated inflammation which causes nephritis
and lung hemorrhage in alveoli (it produces collagen type IV there which affects
membrane and that’s why we’ll have hematuria) it also causes disorders like
Autoimmune hemolytic anemia, Goodpasture syndrome etc..
What is Type I hypersensitivity:
is a tissue reaction that occurs after interacting of antigen with IgE antibody bound to
the surface of mast cells. The reaction is initiated by entry of an antigen, which is called
an allergen because it triggers allergy. TH2 cells and IgE are responsible for the clinical
and pathologic manifestations of the reaction. (e.g., seasonal rhinitis, hay fever),
(asthma), or even fatal (anaphylaxis)
What is poststreptococcal glomerulonephritis, which type of hypersensitivity:
Type III hypersensitivity, post-streptococcal glomerulonephritis, which occurs when
antibodies produced against streptococcal antigens form immune complexes that
deposit in the glomeruli of the kidneys. This can lead to inflammation and damage to the
kidney tissue, resulting in nephritis.
What’s type IV hypersensitivity:
Disorders: Contact dermatitis; multiple sclerosis; type 1 diabetes; tuberculosis.
1- CD4+ T cell-mediated
APC display peptides to naive CD4+ helper T cells which release IL-2 which proliferate
antigen responsible T cells
CD4+ helper T cells differentiate into to Th1 and Th17
CD4+ T cell differentiates into Th1 which secretes IFN-y that activate macrophages
causing inflammation
CD4+ T cell differentiates into Th17 which secrete IL-17 and other cytokines, which
induce the secretion of chemokines responsible for recruiting neutrophils promoting
inflammation.
2- CD8+ T cell-mediated
In viruses for example:
Viral peptides displaying by MHC 1 which is recognised by TCR of CD8+ which kill
infectious cells and and eliminates infection
CD8+ T cell also produce cytokines and IFN-y to promote inflammatory response
Examples of Disorders Caused by Immediate Hypersensitivity:
Allergic rhinitis, sinusitis (hay fever), Increased mucus secretion; inflammation of upper
airways and sinuses. We get allergic from pollen (flowers, trees, grasses) during spring.
Anaphylaxis; allergies; bronchial asthma. It causes vascular dilation, edema, smooth
muscle contraction, mucus production, tissue injury, inflammation.
Immediate & delayed hypersensitivity I:
In immediate hypersensitivity reactions, IgE binds to the mast cells’ Fc receptors and
recognizes antigen, and in response the cells degranulate and release mediators, such
as histamine and prostaglandins. (LONG ANSWER READ THE BOOK)
Delayed hypersensitivity: TH1 cells secrete cytokines, mainly IFN-γ, which are
responsible for many of the manifestations of delayed-type hypersensitivity.
IFNγ-activated macrophages produce substances that destroy microbes and damage
tissues, and mediators that promote inflammation. (ChronicTH1 reactions associated
with macrophage activation often lead to granuloma formation)
Examples for type IV hypersensitivity:
Contact dermatitis; multiple sclerosis; type 1 diabetes; tuberculosis, causes perivascular
cellular infiltrates; edema; granuloma formation; cell destruction
What is contact dermatitis? and which type of hypersensitivity it is.
In contact dermatitis, the environmental chemical (eg. jewelry) modifies self-proteins,
leading to the activation of T cells and the development of a DTH reaction, resulting in
skin inflammation and rash. Type IV hypersensitivity.
Main cause of contact dermatitis?
Viridans streptococcus bacterial infection
What cells do we have in hypersensitivity I and hypersensitivity IV?
IgE, TH2 cells, and mast cells activated for type I, T cytotoxic cells and TH2 for type 4
Mast cells:
During an allergic reaction, an allergen triggers the production of IgE antibodies, which
bind to the FcεRI receptor on the surface of mast cells. The cross-linking of IgE
molecules by allergens leads to the activation and degranulation of mast cells, resulting
in the release of various mediators, such as histamine, leukotrienes, and cytokines,
which cause the symptoms of allergies. Mast cells are derived from hematopoietic stem
cells in the bone marrow and mature in peripheral tissues, such as the skin, lungs, and
gut
Which immunoglobulin activates mast cells:
the Fc portion of IgE antibodies to FcεRI on their surface.
What is the acute response of mast cells activation?
Histamine is released which causes vasodilation and increased vascular permeability
and release proteolytic enzymes that kill bacteria or inactivate toxins
Which type of diseases happens when we have elevated mast cells:
All hypersensitivity 1, Allergies, asthma and anaphylactic shock for example
What are primary lymphoid organ?
- bone marrow, fetal liver (know this), thymus
What is Polyarteritis nodosa , and which type of hypersensitivity and what it
does?
hepatitis B virus antigens and antibodies produced by the host immune system result in
the formation of immune complexes and causes systemic vasculitis. It’s an example of
immune complex mediated diseases (type III).
What is myasthenia gravis, and which type of hypersensitivity?
Type II hypersensitivity, target antigen is acetylcholine receptor, mechanism of disease
is antibody inhibits acetylcholine binding, it causes muscle weakness and paralysis.
What is Hashimoto thyroiditis, and which type of Hypersensitivity?
Is an autoimmune disorder. Increase amounts of T3 and T4, The immune system
creates antibodies that attack thyroid cells as if they were bacteria, viruses or some
other foreign body. Gradual thyroid failure due to autoimmune destruction, the formation
of antithyroid antibodies that attack the thyroid tissue, causing progressive fibrosis
which causes your thyroid to not make enough thyroid hormone. Type 2 & 4
hypersensitivity.
About anaphylactic shock and which type of hypersensitivity?
Type I hypersensitivity, Fall in blood pressure (shock) caused by vascular dilation;
airway obstruction due to laryngeal edema. Anaphylaxis (may be caused by drugs, bee
sting, food)
Why could you have Edema in anaphylactic shock?
Histamines are released during allergic reaction, causing vasodilation which causes
decreased blood pressure so the fluid can leak into the lungs causing swellings so it
causes pulmonary edema, which causes anaphylactic shock.
Affinity maturation?
Production of functionally different antibodies, all with the same specificity, relies on
heavy-chain class (isotype) switching, which increases the range of functions that
antibodies serve. Some of the isotype-specific functions of antibodies include
opsonization and transplacental transfer of IgG, IgA secretion into mucosal lumens, and
binding of IgE to mast cells. Helper T cells also stimulate the production of antibodies
with higher affinity for the antigen. This process, called affinity maturation, improves the
quality of the humoral immune response.
Psoriasis?
Type IV hypersensitivity. T cell mediated disease, specificity of pathogenic T cells is
unknown, principle mechanism of tissue injury is inflammation mediated mainly by TH17
cytokine, causing destructive plaques in the skin.
Class switching?
Mechanism that changes B cells production of immunoglobulin from one type to another
like from IgM to IgG. So, NK cells and phagocytes both have fc receptors where in
phagocyte it causes opsonization and phagocytosis while NK cells cause antibody-
dependent cytotoxicity. Class switching happens in the differentiation stage.
MHC class II?
CD4 is a protein found on the surface of T helper cells. CD4 recognizes MHC class II
molecules, which are expressed by antigen-presenting cells such as dendritic cells,
macrophages, and B cells. MHC class II molecules are heterodimers composed of an
alpha and a beta chain.
What are dendritic cells?
Dendritic cells (DCs) are considered to be antigen-presenting cells (APCs). They play a
critical role in the initiation and regulation of the adaptive immune response by
presenting antigens to T cells. They also have a high expression of major
histocompatibility complex (MHC) molecules, which are necessary for the presentation
of antigens to T cells.
Di George syndrome?
DiGeorge syndrome is caused by a congenital defect in thymic development resulting in
deficient T-cell maturation. T cells are absent in the lymph nodes, spleen, and peripheral
blood, and infants with this defect are extremely vulnerable to viral, fungal, and
protozoal infections. Patients also are susceptible to infection with intracellular bacteria,
because of defective T cell–mediated immunity. B cells and serum immunoglobulins are
generally unaffected.
Graves’ disease?
Graves' disease is an autoimmune disorder that results in hyperthyroidism, a condition
where the thyroid gland produces too much thyroid hormone. In Graves' disease,
autoantibodies, known as thyroid-stimulating immunoglobulins (TSIs) or
thyroid-stimulating antibodies (TSAb), bind to and activate the thyrotropin (TSH)
receptor on thyroid follicular cells, causing excessive thyroid hormone production.
Type 2 hypersensitivity.
What is hay fever?
Type 1 hypersensitivity, it is also called allergic rhinitis. It is one of the localized allergic
reactions.
What is Multiple sclerosis, in which type of hypersensitivity is it?
Type 4 hypersensitivity
Target antigen is Protein antigens in myelin (e.g., myelin basic protein) which causes
inflammation mediated by TH1 and TH17 cytokines, and myelin destruction by
activated macrophages. The result is demyelination in CNS with perivascular
inflammation and paralysis. MS is characterized by episodes of disease activity that
produce white matter lesions that are separated in space.
Different between type 2 and 3 hypersensitivity?
Different between type 2 and type 4 hypersensitivity?
ANSWER:
Leukocytes adhesion deficiency?
Inherited defects in adhesion molecules that impair leukocyte recruitment to sites of
infection, resulting in recurrent bacterial infections.
LAD1 is caused by defects in the β2 chain that is shared by the integrins LFA-1 and
Mac-1. LAD I caused by mutations of ITGB2 gene
LAD2 is caused by a defect in a fucosyl transferase that is required to synthesize
functional sialyl-Lewis X, the ligand for E- and P-selectins. Mutation in CD18. LAD II
caused by mutations of SLC35C1 gene
What is TLR defect?
Mutations in TLR3, a receptor for viral RNA, result in recurrent herpes simplex
encephalitis, and mutations in MYD88, an adaptor protein needed for signaling
downstream of multiple TLRs, are associated with destructive bacterial pneumonias.
Agammaglobulinemia?
A defect in B-cell development or maturation that results in an inability to produce
immunoglobulins, including IgG, IgA, IgE, and IgM. This leads to a deficiency in all types
of antibodies.
If IgG is missing then we have a problem in opsonization (antibody is not able to
undergo opsonization and phagocytosis) patients present with recurrent pyogenic
infections because of low levels of opsonizing IgG antibodies.
In IgA deficiency, patients can’t undergo protection of mucosa from microbes and it
won't be able to maintain the homeostasis so a lot of infections can happen like giardia,
lupus erythematosus, rheumatoid arthritis, myasthenia gravis, type I diabetes,
streptococcus ammonia.
Hyper IgM syndrome?
This disease is characterized by the production of normal (or even supranormal) levels
of IgM antibodies and decreased levels of the IgG, IgA, and IgE. This defect is an
inability of T cells to activate B cells. As discussed earlier, many of the functions of
CD4+ helper T cells require the engagement of CD40 on B cells, macrophages, and
dendritic cells by CD40L (also called CD154) expressed on antigen-activated T cells.
This interaction triggers Ig class switching and affinity maturation in the B cells.
What is chronic granulomatous deficiency?
Chronic granulomatous disease results from inherited defects in the genes encoding
components of phagocyte oxidase, the phagolysosomal enzyme that generates ROS
such as superoxide (O2) Decreased oxidative burst , resulting in defective bacterial
killing and susceptibility to recurrent bacterial infection. We get catalase positive
bacterial infection (streptococcus).
What is Chédiak-Higashi syndrome?
Is characterized by defective fusion of phagosomes and lysosomes, resulting in
defective phagocyte function and susceptibility to infections. The main leukocyte
abnormalities are neutropenia, defective degranulation, and delayed microbial killing.
The affected leukocytes contain giant granules, which are seen in peripheral blood
smears. There are abnormalities in melanocytes (leading to albinism), cells of the
nervous system (associated with nerve defects), and platelets (causing bleeding
disorders). The gene associated with this disorder encodes a large cytosolic protein
called LYST, which regulates lysosomal trafficking. (Decreased leukocyte functions
because of mutations affecting protein involved in lysosomal membrane traffic).
What is Graft-versus-host-disease (GvHD)?
Occurs when immunologically competent cells or their precursors are transplanted into
crippled recipients, and the transferred cells recognize alloantigens in the host and
attack host tissues. It is seen most commonly in the setting of HSC transplantation. On
receiving allogeneic HSCs, an immunologically compromised host cannot reject the
graft, but T cells present in the donor graft perceive the host’s tissue as foreign and
react against it. This results in the activation of donor CD4+ and CD8+ T cells, causing
inflammation and killing recipient cells. To try to minimize GVHD, HSC transplants are
done between donor and recipient that are carefully HLA-matched using precise DNA
sequencing–based methods.
What is ataxia telangiectasia?
Is an autosomal-recessive disorder characterized by abnormal gait (ataxia), vascular
malformations (telangiectases), neurologic deficits, increased incidence of tumors, and
immunodeficiency. It affects both B cells and T cells. Its Immune abnormalities are
defective production of isotype-switched antibodies, mainly IgA and IgG2. The T-cell
defects are associated with thymic hypoplasia. Patients experience upper and lower
respiratory tract bacterial infections, multiple autoimmune phenomena, and frequent
cancers, particularly lymphoid tumors, with advancing age. The gene responsible for
this disorder encodes a protein called ATM (ataxia telangiectasia mutated), a sensor of
DNA damage that activates cell cycle checkpoints and apoptosis in cells with damaged
DNA. Lack of ATM also leads to abnormalities in antigen gene recombination and
abnormal antibody isotype switching.
What is Sjögren Syndrome?
Chronic disease characterized by dry eyes (keratoconjunctivitis sicca) and dry mouth
(xerostomia) resulting from destruction of the lacrimal and salivary glands. It occurs as
an isolated disorder (primary form), also known as the sicca syndrome, or more often in
association with another autoimmune disease (secondary form). Rheumatoid arthritis is
the most common associated disorder, while other patients have SLE, polymyositis,
scleroderma, vasculitis, mixed connective tissue disease, or autoimmune thyroid
disease. The lacrimal and salivary glands show dense lymphocytic infiltration consisting
mainly of activated CD4+ helper T cells and some B cells, including plasma cells.
Systemic Sclerosis (Scleroderma)?
This disorder is characterized by excessive fibrosis in multiple tissues, vascular disease,
and production of multiple autoantibodies . Disease limited to the skin is also called
localized scleroderma. Systemic sclerosis is classified into two groups:
• Diffuse systemic sclerosis, characterized by initial widespread skin involvement,
with rapid progression and early visceral involvement
• Limited systemic sclerosis, with relatively mild skin involvement, often in fingers and
face. Involvement of the viscera occurs late, so the disease generally follows a fairly
benign course. This presentation also is called CREST syndrome because of its
frequent features of calcinosis, Raynaud phenomenon, esophageal dysmotility,
sclerodactyly, and telangiectasia. The disease results from three processes—
autoimmune responses, vascular damage, and collagen deposition.
Endocarditis in Systemic Lupus Erythematosus: Libman-Sacks Endocarditis?
Libman-Sacks endocarditis is characterized by the presence of vegetations on the
valves of patients with systemic lupus erythematosus. Associated with inflammation,
often with fibrinoid necrosis of the valve adjacent to the vegetation, can result in lesions
that resemble chronic rheumatic heart disease. Similar lesions can occur in the setting
of antiphospholipid antibody syndrome.
Focal lupus nephritis?
(class III) is defined by involvement of fewer than 50% of all glomeruli. The lesion
affects only a (segmental) portion of the glomerulus or (global) involving the entire
glomerulus. Affected glomeruli may exhibit swelling and proliferation of endothelial and
mesangial cells associated with leukocyte accumulation, capillary necrosis, and hyaline
thrombi. The clinical presentation ranges from mild hematuria and proteinuria to acute
renal insufficiency. Red blood cell casts in the urine are common when the disease is
active.
What is CREST syndrome?
CREST stands for (Calcinosis, Raynaud’s phenomenon, Esophageal dysfunction,
sclerodactyly, tanglectasis) It’s the limited scleroderma, with relatively mild skin
involvement, often confined to the fingers and face. Its frequent features are calcinosis,
Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia.
IPEX syndrome?
IPEX:immune dysregulation, polyendocrinopathy, enteropathy, X-linked
Mutations in the FOXP3 gene result in severe autoimmunity in humans and mice; in
humans, these mutations are the cause of a systemic autoimmune disease called IPEX.
What is peripheral tolerance?
Peripheral tolerance mechanisms prevent potentially autoreactive T and B cells from
responding to self-antigens.
Anergy occurs when the costimulatory signals required for T cell activation are absent,
leading to functional inactivation of the T cell.
Regulatory T cells prevent immune reactions against self-antigens through the secretion
of immunosuppressive cytokines and the expression of CTLA-4, which reduces APC's
ability to activate T cells via CD28.
Deletion by apoptosis may be triggered by the upregulation of pro-apoptotic proteins or
by engagement of the death receptor Fas.
Lastly, some self-antigens are hidden from the immune system, such as those located
in immune-privileged sites like the testis, eye, and brain. Unless released into
circulation, these antigens tend to be ignored by the immune system.
• The factors that lead to a failure of self-tolerance (1) inheritance of susceptibility genes
that disrupt different tolerance pathways (2) infections and tissue injury that expose self
antigens and activate APCs and lymphocytes in the tissues.
What is serum sickness?
Type III hypersensitivity, It’s a systemic immune complex disease, antigen involves
various proteins (e.g., foreign serum protein). It's when antibodies are for antibodies
like, (horse anti-thymocyte globulin). It can Cause arthritis, vasculitis, and nephritis.
Specific autoantibody for scleroderma?/
If you have limited scleroderma, CREST syndrome, which autoantibody will you have?
DNA topoisomerase 1, Centromeric proteins (CENPs) A, B, C, and RNA polymerase II
Specific autoantibodies for sjogren’s syndrome?
SSA and SSB
What is chronic rejection?
Is an indolent form of graft damage that occurs over months or years, leading to
progressive loss of graft function. It causes gradual narrowing of graft blood vessels
(graft arteriosclerosis). is dominated by vascular changes, often with intimal thickening
and vascular occlusion.
Wiskott-Aldrich syndrome?
Is an X-linked disease characterized by thrombocytopenia, eczema, and there is
progressive loss of T lymphocytes from the blood and the T cell zones (paracortical
areas) of lymph nodes, IgM levels in the serum are low, but levels of IgG are usually
normal and, IgA and IgE are often elevated. The syndrome is caused by mutations in an
X-linked gene encoding Wiskott-Aldrich syndrome protein (WASP). WASP belongs to a
family of signaling proteins that link membrane receptors, such as antigen receptors, to
cytoskeletal elements. The only treatment is HSC transplantation.
Severe combined immunodeficiency abnormalities?
MHC2 receptor, adenosine deaminase, which inhibits a specific enzyme called
ribonucleotide reductase. (When adenosine accumulates it’s going to become
deoxyadenosine, toxigenic for this enzyme where it inhibits the enzyme and it won’t be
able to produce and in order to put nucleotides in the DNA we need to make them in
deoxy forms, if you can’t do that then you can’t produce B cells, T cells etc..).
X-linked skin cytokine gamma chain? X-SCID
Failure of T cell and B cell maturation; mutation in the common γ chain of a cytokine
receptor, leading to failure of IL-7 signaling and defective lymphopoiesis./ these are
caused by mutations in the gene encoding the common γ (γc) chain shared by the
receptors for the cytokines IL-2, IL-4, IL-7, IL-9, and IL-15.
RAG 1 & RAG 2?
Immature B cells and T both express a pair of gene products, RAG1 and RAG2, that
carry out V(D)J segment recombination, After encountering antigen, mature B cells
express a specialized enzyme called activation-induced cytosine deaminase (AID).
Systemic lupus erythematosus autoantibodies/SLE?
Double-stranded DNA, UI-RNP, Smith (Sm) antigen (core protein of small RNP
particles), Ro (SS-A) nucleoprotein, Phospholipid-protein complexes (anti-PL), Multiple
nuclear antigens (“generic ANAs”). Lupus is a disease that occurs when the body’s
immune system attacks your own tissues and organs. Type II hypersensitivity.
Which drug induces lupus/SLE?
Hydralazine, procainamide, isoniazid, and D-penicillamine
IgG4 related disorders?
Rich in IgG4 antibody-producing plasma cells and lymphocytes, particularly T cells,
associated with fibrosis and obliterative phlebitis. Mikulicz syndrome (enlargement and
fibrosis of salivary and lacrimal glands), Riedel thyroiditis, idiopathic retroperitoneal
fibrosis, autoimmune pancreatitis, and inflammatory pseudotumors of the orbit, lungs,
and kidneys.
Isolated IgA Deficiency?
This is the most common primary immune deficiency disease. IgA is the major
immunoglobulin in mucosal secretions and it’s involved in defending the airways and
the gastrointestinal tract. Weakened mucosal defenses due to IgA deficiency causes
patients to recurrent sinopulmonary infections and diarrhea.
Activation-induced cytosine deaminase?
When we have hyper-IgM syndrome: Failure to produce isotypeswitched high-affinity
antibodies (IgG, IgA, IgE); mutations in genes encoding CD40L or activation-induced
cytosine deaminase.
What is central tolerance?
Mechanism of central tolerance is the antigen-induced deletion (death) of self-reactive T
lymphocytes and B lymphocytes during their maturation in central (generative) lymphoid
organs (i.e., in the thymus for T cells and in the bone marrow for B cells)./ immature T
and B lymphocytes that recognize self antigens in the central (generative) lymphoid
organs are killed by apoptosis; in the B-cell lineage, some of the self-reactive
lymphocytes switch to new antigen receptors that are not self-reactive.
Hyper-IgE syndrome?
Includes triad of eiosinophils, eczema, rash, abcess in joints and lungs, and pulmonary
infections. Mutations in STAT3 gene, and elevated IgE level.
3 year old boy brought to the physician for MRI, rash didn’t resolve, 3 months ago
he was treated for several asymptomatic soft tissues abcess on his legs he has
been to the hospital due to pneumonia, prominent forehead, widen nasal bridge,
leukocytes, eosinophils, deficiency of T helper 17 cells, patient increased
susceptibility to infections is most likely to which of the following?
Impaired chemotaxis for neutrophils, because of job syndrome, deficiency of
IL-17
Impaired DNA repair in lymphocytes
Impaired respiratory burst in neutrophils
Impaired actin assembly in lymphocytes
Impaired Ig class switching in lymphocytes

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pathology questions for studying and notes

  • 1. CHAPTER 4 Phlebothrombosis (venous thrombosis): Mostly occur in superficial or deep veins of the leg. Superficial usually occur in varicosities (abnormally dilated and tortuous veins that usually appear in the lower extremities) but rarely embolize , can be painful and cause congestion. DVT occurs in larger leg vein or above the knee only has local pain while others recognise it after it has embolized in the lung. Gas/air embolism: Gas bubbles within circulation can obstruct vascular flow and cause distal ischemic injury. Decompression sickness: caused by sudden changes in atmospheric pressure. (When air is breathed at high pressure (e.g., during a deep sea dive), increased amounts of gas (particularly nitrogen) become dissolved in the blood and tissues. If the diver then ascends (depressurizes) too rapidly, the nitrogen expands in the tissues and bubbles out of solution in the blood to form gas emboli) AE in the lung causes hemorrhages, atelectasis ( complete or partial collapse of the entire lung or area (lobe) of the lung), respiratory distress. In CNS coma Fat embolism: Usually occurs in crush injuries and severe skeletal injuries. Caused by release of fat globulins from narrow vascular sinusoids or soft tissue into circulation. Fat microemboli occlude pulmonary and cerebral microvasculature, both directly and by triggering platelet aggregation. This deleterious effect is exacerbated by fatty acid release from lipid globules, which causes local toxic endothelial injury. Clinical signs appear 1-3 days after injury with sudden Tachypnea, dyspnea, tachycardia, irritability, restlessness then delirium and coma. Amniotic fluid embolism: The underlying cause is the entry of amniotic fluid (and its contents) into the maternal circulation via tears in the placental membranes and/or uterine vein rupture Characteristics: sudden severe dyspnea, cyanosis, hypotensive shock, followed by seizure and coma. If she survives, usually pulmonary edema and intravascular coagulation (main cause of death) occur due increased activation of innate immunity and coagulation bec of biochemical substances in amniotic fluid.
  • 2. What will we see under the microscope if someone has amniotic fluid embolization:4 Squamous cells shed from fetal skin, lanugo hair, mucin derived from fetus respiratory and GI tract in maternal pulmonary microcirculation and collagen. Septic infarction: occur when infected cardiac valve vegetations embolize, or when microbes seed necrotic tissue. In these cases the infarct is converted into an abscess, with a correspondingly greater inflammatory response and healing by organization and fibrosis Red and white infarcts: Red infarcts- caused by venous occlusion, happens in loose tissue e.g lungs where blood can accumulate, tissues with dual blood supply e.g lungs and intestine, or previously congested tissues. Excavated RBC are phagocytosed by macrophages White infarcts: occur with arterial occlusions in solid organs with end arterial circulation like heart, spleen and kidney. Waterhouse-fredrichson Bleeding into the adrenal glands. Massive release of glucocorticoids happens followed by adrenal insufficiency associated with Waterhouse fredrichson syndrome. Can be associated with DIC. Neisseria meningitis can cause this syndrome. Vasodilation and hypotension happens. Mural thrombi Thrombi occurring in heart chambers or in the aortic lumen. Abnormal myocardial contraction (arrhythmias, dilated cardiomyopathy, or myocardial infarction) or endocardial injury (myocarditis, catheter trauma) promote cardiac mural thrombi Anti phospholipid antibody syndrome Has different clinical manifestations like recurrent thromboses, repeated miscarriages due antibody against trophoblasts, cardiac valve vegetations and thrombocytopenia . antibody targets include B2-glycoprotein I on prothrombin & trophoblasts It provides false positives for syphilis bec it's in cardiolipin. Therapy with anticoagulants and immunosuppression. Pulmonary congestion acute pulmonary congestion is marked by blood-engorged alveolar capillaries and variable degrees of alveolar septal edema and intra alveolar hemorrhage.
  • 3. In chronic pulmonary congestion, the septa become thickened and fibrotic, and the alveolar spaces contain numerous macrophages laden with hemosiderin Types of shock Cardiogenic shock results from low cardiac output as a result of myocardial pump failure. Failure of myocardial pump resulting from intrinsic myocardial damage, extrinsic pressure, or obstruction to outflow. Ex. Myocardial infarction, Ventricular rupture Arrhythmia Cardiac tamponade Pulmonary embolism Hypovolemic shock results from low cardiac output due to loss of blood or plasma volume. Inadequate blood or plasma volume ex. Hemorrhage, fluid loss Septic shock is triggered by microbial infections and is associated with severe systemic inflammatory response. Peripheral vasodilation ex. Gram negative sepsis, superantigens like toxic shock syndrome happens from streptococcus pyogenes. Hemostasis: Primary hemostasis(formation of platelet plug): the disrupted epithelium uncovers sub endothelium that contains von-willebrand growth factor and collagen ,platelet activation and adherence is mediated by collagen and vWF which act as bridge between receptor glycoprotein Ib(GpIb) Platelet activation: done by collagen and vWF make them flatter with spiky protrusion that inc surface area and release secretory granules containing ADP that recruit platelets & prostaglandin thromboxane A2 (Tax2) induce platelet aggregation. Note: aspirin inhibits cyclooxygenase, a platelet enzyme required for TAX2 synthesis. Secondary hemostasis (deposition of fibrin): Tissue factor(membrane bound procoagulant glycoprotein) is exposed at site of injury expressed in sub endothelium. Tissue factor(TF) activates factor VII(7) starting a cascade that results in thrombin generation. • Thrombin cleaves fibrinogen into fibrin that helps in formation of fibrin meshwork which is also a potent platelet activator. Entrapped blood cells are due P selectin Coagulation cascade It is a series of amplifying reactions that lead to deposition of insoluble fibrin clots. Each reaction requires an enzyme and cofactor. • Assembly of reaction complexes depends on calcium which binds to y-glutamic acid residues present in factor II,VII, IX and X. They also use vitamin K as cofactor and are antagonized by the drug Coumadin. Prothrombin time (PT) The assay assesses the function of the proteins in the extrinsic pathway (factors II, V, X,VII)(prothrombin), and fibrinogen). In brief, tissue factor, phospholipids, and calcium are added to plasma and the time for a fibrin clot to form is recorded. Partial thromboplastin time (PTT)
  • 4. assay screens the function of the proteins in the intrinsic pathway (factors XII, XI, IX, VIII, X, V, II, and fibrinogen). In this assay, clotting of plasma is initiated by the addition of negative- charged particles (e.g., ground glass) that activate factor XII (Hageman factor) together with phospholipids and calcium, and the time to fibrin clot formation is recorded. Factor deficiencies F 5,7,8,9,10 cause moderate bleeding disorders. Prothrombin is incompatible with life. F11 is mild. F12 doesn't bleed or may be susceptible to thrombosis because it's involved in the fibrinolysis pathway. Factor VIIa/Tissue Factor complex is the most important activator of Factor 9 and Factor 9a/Factor 8a complex is the most important activator of Factor 5. Mild bleeding in Factor 11 deficiency bec of ability of thrombin to activate Factor 11 as well as F5&F13 to amplify coagulation cascade Anticoagulant effects: Thrombomodulin and protein C(PC) Thrombomodulin bind to thrombin which activate protein C. PC is a vitamin K dependent protease that requires a cofactor Protein S. Activated protein C/S complex is potent inhibitor of coagulation factor 5a and 7a. Anti-coagulators. Tissue factor pathway inhibitor (TFPI) requires protein S as cofactor; it binds to TF/factor VIIa complexes. Heparin-like molecules bind to antithrombin 3 and this complex will inactivate thrombin. An abnormal PT may indicate an issue with the clotting factors involved in the extrinsic pathway. Causes of thrombosis: hypercoagulability, stasis or turbulent blood flow and endothelial injury. Txa2 function: An activator of platelet aggregation and causes Vasoconstriction TPA (Tissue Plasminogen Activator) function: Conversion of plasminogen to plasmin Fibrinolysis of excess fibrin What is DIC (disseminated intravascular coagulation): The widespread microvascular thrombosis that consumes platelets and coagulation proteins (hence the synonym consumptive coagulopathy), and at the same time, fibrinolytic mechanisms are activated.
  • 5. Sepsis: Various microbial cell wall constituents engage receptors on cells of the innate immune system, triggering proinflammatory response Libman-sacks endocarditis: a form of endocarditis that is associated with autoimmune diseases such as systemic lupus erythematosus, where there are vegetations (abnormal mass) on both sides of the valves of the heart. These vegetations can cause valve dysfunction and increase the risk of embolism. Note:*vegetation: where platelets and stuff accumulate as a response to bacteria then they get dislodged obstructing blood vessels, causing the septic emboli* Function of antithrombin 3: inhibits thrombin and factors 9a, 10a, 11a, and 12a. What causes immunosuppression for septic shock The use IL-10 What is D-dimer: D-dimers are fibrinogen residues. An elevated level of D-dimer can indicate that there is an ongoing clotting process in the body, but it cannot identify the location or cause of the clot. Complement cascade: Complement cascade set of events that activates different plasma proteins which will lead to killing the affected cell (c3b most important one) What are lines of zahn: The lines of Zahn are layers of platelet-fibrin thrombi intercalated with layers of red blood cells can help to distinguish between postmortem clot formation and thrombi formed before death (present in thrombi formed before death). What causes septic embolism? Septic embolism is a condition in which bacteria or other infectious agents spread through the bloodstream and form small clumps or emboli that can block blood vessels in various parts of the body. These emboli can cause tissue damage and inflammation, and can lead to serious complications such as organ failure or sepsis. It can be caused by a variety of underlying infections, such as bacterial endocarditis, which is an infection of the heart valves, or osteomyelitis, which is an infection of the bone. Other infections that can lead to septic embolism include skin infections, pneumonia, and urinary tract infections.
  • 6. CHAPTER 3 C1 inhibitor deficiency Hereditary angioedema:face swelling,hands,stomach,bowel, and genitals c1 inhibitor defects cause excessive activation of the kinin system, increase bradykinin >increased vascular permeability and edema. CD59 Deficiency: Paroxysmal nocturnal hemoglobinuria:sudden/onset,night, blood in urine. Function of cd59: inhibits MAC pore formation If there is defect:increase MAC production> and induces intravascular hemolysis Kinins Kinins are proteins in the blood that cause inflammation and affect blood pressure Bradykinin increases vascular permeability and causes contraction of smooth muscle, dilation of blood vessels, and pain when injected into the skin. These effects are similar to those of histamine. Complement system: function:protection of the host from infection/inflammation by recruiting chemotaxis and enhancing phagocytosis by innate immune cells (opsonization) leading to lysis of targeted cells. Cleavage of C3 can occur by one of three pathways: ● The classical pathway, which is triggered by fixation of C1 to antibody (IgM or IgG) that has combined with antigen ● The alternative pathway, which can be triggered by microbial surface molecules (e.g., endotoxin, or LPS), complex polysaccharides, and other substances, in the absence of antibody •The lectin pathway, in which plasma mannose-binding lectin binds to carbohydrates on microbes and directly activates C1 Function of leukotrienes Leukotrienes are produced in leukocytes and mast cells by the action of lipoxygenase (leukotrienes biosynthesis requires 5 lipoxygenase.) and are involved in vascular and smooth muscle reactions, and leukocyte recruitment. The synthesis of leukotrienes involves multiple steps, the first of which generates leukotriene A4 (LTA4), which in turn gives rise to LTB4 or LTC4. LTB4 is produced by neutrophils and some macrophages The cysteinyl-containing leukotriene LTC4 and its metabolites, LTD4 and LTE4, are
  • 7. produced mainly in mast cells and cause intense vasoconstriction, bronchospasm (important in asthma), and increased permeability of venules. Types of leukotrienes: 1. leukotriene A4 (LTA4), which in turn gives rise to LTB4 or LTC4. LTB4 is produced by neutrophils and some macrophages, and is a potent chemotactic agent and activator of neutrophils, causing aggregation and adhesion of the cells to venular endothelium, generation of ROS, and release of lysosomal enzymes. 2. The cysteinyl-containing leukotriene LTC4 and its metabolites, LTD4 and LTE4, are produced mainly in mast cells and cause intense vasoconstriction, bronchospasm (important in asthma), and increased permeability of venules. They’re dangerous in case of asthma because leukotrienes are potent Bronchoconstrictors. Lipoxins: Lipoxins also are generated from arachidonic acid by the lipoxygenase pathway, but unlike prostaglandins and leukotrienes, the lipoxins suppress inflammation by inhibiting the recruitment of leukocytes. They inhibit neutrophil chemotaxis and adhesion to endothelium Opsonization C3b and its cleavage product iC3b (inactive C3b), when fixed to a microbial cell wall, act as opsonins and promote phagocytosis by neutrophils and macrophages, which bear cell surface receptors for these complement fragments What Opsonins do you know? opsonins: coat the cell with antibodies promoting their phagocytosis C3B & Fc portion of IgG , & IgM Inflamazoms Explanation 1: NLRP3 inflammasome is a multiprotein complex that plays a role in regulating the innate immune system and inflammatory signaling.activation by PAMPs and DAMPs, NLRP3 oligomerizes and activates caspase-1 which initiates the processing and release of pro-inflammatory cytokines IL-1β and IL-18. Explanation 2: The inflammasome is a protein complex that recognizes products of dead cells and some microbes and induces the secre- tion of biologically active interleukin-1. It is a complex of multiple copies of a sensor protein (a leucine-rich protein called NLRP3), an adapter, and the enzyme caspase-1, which is converted from an inactive to an active form. Study whichever you feel is easier for you to memorize, both are right…
  • 8. What are PAMPS & DAMP’S: (Pathogen associated molecular pattern) & (Damage associated molecular patterns) PAMPs are found on microorganisms and recognized by Pattern Recognition Receptors (PRRs) on immune cells. Examples of PAMPs are LPS, viral nucleic acids, and fungal cell wall components. DAMPs are released from damaged or dying cells and can also activate the immune system by binding to PRRs on immune cells. Examples of DAMPs include heat shock proteins, uric acid IL10 inhibits what TH1 cells: INFy is the main Th1 cytokine > is inhibited by IL10 to stop production of proinflammatory substances and responses. IL10 function: limiting the host's immune response to pathogens, thereby preventing damage to the host and maintaining normal tissue homeostasis.``anti-inflammatory”. It suppresses NK and T cells by preventing APCs (Antigen Presenting Cells) from producing cytokines. What is C1 inhibitory function: Binds to C1s and C1r To inhibit recessive complement system, we use it if it’s indirect and it inhibits in the classical pathway, which is triggered by fixation of C1 to antibody (IgM or IgG) that has combined with antigen, The lectin pathway, in which plasma mannose-binding lectin binds to carbohydrates on microbes and directly activates C1. (What does it bind to c1q, c1r, c1s and write how do they bind to it) What are acute phase interleukines/reactants? The acute phase response is a facet of the innate immune system that occurs in response to infection, trauma, or other insults. They are inflammation markers that exhibit significant changes in serum concentration during inflammation.These changes are reactions to cytokines whose production is stimulated by bacterial products. Positive acute phase reactants are those whose concentration increases with inflammation. For example: C-reactive protein is an acute phase protein that is involved in innate immunity, and is responsible for activating the complement pathway. Negative acute phase reactant:are those whose concentrations decrease in an acute phase response. For example: serum albumin
  • 9. What are chemokines? CXC chemokines, CC chemokines, C chemokines, CX3C chemokines These are the different chemokines arranged according to their cysteine residue Chemokines are proteins that work by attracting leukocytes . CXC attracts neutrophils. IL-8 is part of this group CC attracts monocytes, lymphocytes, basophils and eosinophils. Example is MCP-1 (MCP-1 activates the respiratory burst of monocytes and induces the expression of the pro-inflammatory cytokines IL-6 and IL-1β,which in turn may regulate the expression of TGF-β.) C chemokines are for lymphocytes. Example lymphotactin A CX3C example is fractalkine. They attract monocytes and T cells and exist in two forms: cell surface bound protein and soluble protein form P & E selectins: P and e selectins are adhesion molecules on the endothelium to which leukocytes bind to in case of chemotaxis Function: rolling to slow down cells ligand sialylated lewis binds to P&E selectins Function of thrombomodulin: Thrombomodulin activates protein c which inhibits factors 5a 8a Leukocytes rolling: Leukocytes rolling is just the attachment and detachment of leukocytes on the endothelium when they become activated, it's just a movement What does CD59 do and how does it inhibit MAC formation: CD59 inhibits MAC formation which perforates the affected cell and disrupts the osmotic gradient leading to rupture of the affected cell. Myeloperoxidase deficiency: deficiency or absence of myeloperoxidase enzyme in phagocytes that are unable to form hypochlorous acid (HClO) but have preserved respiratory burst (since NADPH oxidase is intact). Recurrent candida infections Autoinflammatory syndrome: Autoinflammatory syndrome occurs when there is a gain of function mutation in the inflammasomes, they increase the release of IL-1 for inflammation Deficiency of decay accelerating factor (CD55):
  • 10. results in the over-activation of the complement system due to the inability to properly regulate it. When DAF is deficient, the complement system activates too much and RBC dies causing paroxysmal nocturnal hemoglobinuria. What is Fc complex/receptors: The Fc region of an antibody molecule is the part that binds to various Fc receptors on the surface of cells such as B cells, macrophages, natural killer cells, and dendritic cells. When an antibody molecule binds to its target antigen, the Fc region of the antibody becomes exposed and can interact with Fc receptors on immune cells. This interaction triggers a variety of immune responses, depending on the specific Fc receptor and the type of immune cell involved. Function of protein C: Protein C is needed for fibrinolysis function, breaking down the clot. It is activated by thrombomodulin and then protein c with the help of protein S inactivating factors Va and VIIIa. Function of IL-17: IL-17 is a cytokine-induced production of chemokines like CXCL1. They produce defensin which is an antimicrobial protein. It just helps with inflammation. Chronic granulomatous disorder why do they come with catalase + bacteria are causing recurrent infections: Bacteria that are catalase positive break down hydrogen peroxide that they produce and don’t allow our body to break it down and so free radicals cannot be formed to kill the bacteria. That’s why the infection becomes recurrent. With catalase negative, the bacteria wouldn’t break down H2O2 and the body will do so and form free radicals to kill the bacteria Deficiency in phagocyte oxidase (enzyme that converts NADPH to NADP+) Chronic granulomatous disease is just an immune disease where granuloma is formed and bacteria like Staph Aureus and Strep Pyogenes invade the body since the immune system is unable to produce ROS in response to bacterial and fungal infections. What are neuropeptides: play a role in the initiation and regulation of inflammatory responses. These small peptides, including substance P and neurokinin A, are produced in the central and peripheral nervous systems. Nerve fibers containing substance P are prominent in the lung and gastrointestinal tract. Substance P has many biologic functions, including the transmission of pain signals, regulation of blood pressure, stimulation of hormone secretion by endocrine cells, and in increasing vascular permeability.
  • 11. How alternative pathway gets activated: Alternative pathway is triggered by endotoxins or LPS of gram negative bacteria or also could be polysaccharides and they then form MAC which kills bacteria Decay accelerating factor: DAF is a protein that prevents C3 convertase enzyme from forming Tissue plasminogen activation: t-PA is synthesized by endothelium. tPA works by converting plasminogen into plasmin, an active enzyme that can break down fibrin. What’s anaphylactic shock: Anaphylactic shock, also known as anaphylaxis, is a severe and potentially life-threatening allergic reaction that occurs rapidly after exposure to an allergen Causes fall in blood pressure (shock) caused by vascular dilation by release of histamine from mast cells; airway obstruction due to laryngeal edema caused by increased permeability which allows fluid to leak out of the blood vessels and into the surrounding tissues, causing edema. Why don’t we give aspirin to people who have asthma? Because aspirin will inhibit cyclooxygenase pathway (COX), so arachidonic acid can’t be metabolized to cyclooxygenase so it will not produce PSG which causes vasodilation What are M1 & M2 macrophages: What are TH1 cells: CD4+ T cell differentiates into Th1 which secrete IFN-y TH2 cells: Differentiated T cells Cells secrete IL-4 (class switching in B cells), IL-5 (recruit and activate eosinophils), and IL-13 (mucous prod. And IgE prod.) TH17 cells: CD4+ T cell differentiates into Th17 which secrete IL-17 and other cytokines, which induce the secretion of chemokines responsible for recruiting neutrophils promoting inflammation. Foreign body granulomas: Response to foreign bodies in the absence of T cell mediated immune response. FBG forms around materials such as talc, sutures or other fibers that are large enough to preclude phagocytosis by a macrophage (not immunogenic). On the surface of FBG we
  • 12. can see epithelioid cells and giant cells. They can be identified in the center of the granuloma using polarized light (appears refractile). Function of IL-12: IL-12 is a cytokine primarily produced by activated macrophages and dendritic cells that plays a key role in the differentiation of CD4+ T cells into the Th1 subset. It stimulates the production of IFN-γ and enhances the cytotoxic activity of natural killer cells and T cells. Function of IL-6: Has macrophages, systemic effects (acute phase response) What releases IL-6? Macrophages, endothelial cells, mast cells IL-1: including the activation of immune cells, the induction of fever, and the stimulation of the acute phase response. Produced by Macrophages, endothelial cells, mast cells How do we activate mannose pathway: The mannose pathway of complement activation is activated by the binding of mannose-binding lectin (MBL) to microbial cell surface carbohydrates containing mannose What are immune granulomas: They are caused by agents that can induce persistent T cell mediated immune response. This immune response produces granulomas when the agent can’t be readily eliminated such as persistent microbes or self antigen. Responses such as macrophages activate T cells to produce cytokines. Function of interferon gamma: Activation of macrophages (increased ability to kill microbes and tumor cells) produced by activated T cells, natural killer (NK) cells, What is the nuclear factor kappa light chain? Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, heavy metals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens. NF-κB plays a key role in regulating the immune response to infection. Incorrect regulation of NF-κB has been linked to cancer,
  • 13. inflammatory and autoimmune diseases, septic shock, viral infection, and improper immune development. NF-κB has also been implicated in processes of synaptic plasticity and memory Which cytokines are produced by Th2 lymphocytes? IL-4, IL5, IL13 Function of IL-10? an anti-inflammatory cytokine that inhibits the activation and function of T cells, monocytes, and macrophages. It also suppresses the expression of pro-inflammatory cytokines, chemokines, and adhesion molecules. IL-10 inhibit which cell? Th1 cells, NK, dendritic cells and macrophages. What are thromboxane and prostaglandins, their function and why they’re dangerous? TXA2: is a potent vasoconstrictor and platelet aggregator that helps to promote blood clotting and wound healing. However, excessive production of thromboxanes can lead to the formation of blood clots in the arteries, which can cause heart attacks, strokes, and other serious cardiovascular diseases. Prostaglandins (PGD2 PGE2 ): promotes vasodilation and increased vascular permeability. Excessive production of PGs is associated with many inflammatory disorders, including rheumatoid arthritis, osteoarthritis, and inflammatory bowel disease. PGD2 and PGE2 can cause bronchoconstriction, mucus secretion, and airway inflammation, leading to breathing difficulties in asthma patients. Diapedesis The process in which white blood cells come out of the blood vessels into the surrounding area in case of injuries The steps of the inflammatory response? five Rs: (1) recognition of the injurious agent, (2) recruitment of leukocytes, (3) removal of the agent, (4) regulation (control) of the response, and (5) resolution (repair). How leukocytes go to site of inflammation? TNF alpha and IL-1 released by macrophages can activate endothelial cells to express adhesion molecules such as P and E-selectins, which help leukocytes to adhere to the endothelium and roll along the vessel wall. However, leukocytes do not go through endothelial cells to reach the site of inflammation. They cross the endothelial barrier through a process called transmigration, facilitated by integrins, adhesion molecules, chemokines, and cytokines.
  • 14. What happens in acute inflammation? Vasodilation: The arterioles in the affected tissue dilate, causing an increase in blood flow to the area. Increased vascular permeability: The increased blood flow causes the capillaries in the area to become leaky, allowing fluid, plasma proteins, and inflammatory cells to leave the circulation and enter the tissue. Leukocyte migration and activation: Inflammatory mediators, such as cytokines and chemokines, attract and activate leukocytes (white blood cells), particularly neutrophils, causing them to adhere to the endothelium and migrate into the tissue. Phagocytosis: Once in the tissue, neutrophils and other phagocytic cells engulf and destroy invading microorganisms and damaged tissue debris through phagocytosis. Termination of the response: The acute inflammatory response is self-limited mediated by various anti-inflammatory mediators, (IL-10) external manifestations of inflammation as: heat (calor), redness (rubor), swelling (tumor), pain (dolor) OUTCOMES OF ACUTE INFLAMMATION #1: Resolution of inflammation • Removal of microbes/debris • Tissue returns to normal #2: Healing/scar • Tissue damage too extensive for regeneration • Connective tissue growth #3: Chronic inflammation What can elicit inflammation?Inflammation can be elicited by a variety of stimuli, including microbial pathogens, tissue necrosis, foreign bodies, immune reactions, physical and chemical insults, and others. How free radicals are produced in phagocytic cells? NADPH oxidase catalyzes the conversion of O2 to superoxide anion (O2-). This O2- is then rapidly converted to hydrogen peroxide (H2O2) and, by myeloperoxidase H2O2 is in turn converted to a highly reactive OH compound, hypochlorite These ROS are then used by the leukocytes to kill microorganisms within the phagolysosome. Prostacyclin (PGI2)? a potent vasodilator and inhibitor of platelet aggregation. preventing thrombosis and inflammation. NOTE: vascular endothelium contains prostacyclin synthase, which is responsible for the formation of prostacyclin (PGI2) Factor H deficiency? Factor H is a plasma protein that serves as a cofactor for the proteolysis of the C3 convertase; its deficiency results in excessive complement activation
  • 15. A deficiency in Factor H can lead to uncontrolled activation of the complement pathway, which can cause tissue damage and inflammation. This can result in several conditions, including atypical hemolytic uremic syndrome Factor I deficiency? Factor I is a crucial inhibitor controlling all complement pathways due to its ability to degrade activated complement proteins C3b and C4b in the presence of cofactors such as factor H Patients will get Recurrent pyogenic infections and autoimmune disorders Regulatory proteins: • C1 inhibitor blocks the activation of C1(hereditary angioedema.) • Decay accelerating factor (DAF) : prevents formation of C3 convertases(PN hemoglobinuria ) • CD59: inhibits formation of the MAC (PN hemoglobinuria ) • Factor H: cofactor of the C3 convertase (in excessive complement activation) • factor i: degrade activated complement proteins C3b and C4b(recurrent infections) What is fibrinous inflammation? Fibrinous inflammation is typically associated with increased vascular permeability, which allows larger molecules such as fibrinogen to leak out of the blood vessels and accumulate in the tissue. The presence of a procoagulant stimulus, such as tissue injury or infection, can further promote the formation of fibrin and deposition of fibrinous exudate. Mediators of inflammation? -Platelet activating factor - Products of Coagulation - Kenin system - Neuropeptides Gaseous & non-gaseous granulomas: Gaseous granulomas are caused by antigens that are relatively volatile or that can be cleared by a strong cellular immune response. They are typically composed of activated macrophages, lymphocytes, and multinucleated giant cells, and may have a central area of necrosis. Examples of gaseous granulomas include tuberculosis, fungal infections, and sarcoidosis. Non-gaseous granulomas are caused by antigens that are relatively non-volatile or that persist despite a strong cellular immune response. They are typically composed of fibroblasts, collagen, and other connective tissue components, in addition to activated macrophages, lymphocytes, and multinucleated giant cells. Examples of non-gaseous granulomas include foreign body reactions, such as those caused by sutures, implants, or other indwelling devices, as well as granulomatous diseases caused by autoimmunity, such as Crohn's disease or granulomatosis with polyangiitis What kind of disease does gaseous granulomas happens from? tuberculosis, fungal infections, Leprosy, Syphilis
  • 16. What kind of disease does non-gaseous granulomas happen from? Foreign body reactions, Sarcoidosis, Crohn’s disease CHAPTER 5 Lupus is which hypersensitivity: In systemic lupus we get anemia this is type III hypersensitivity. Glomerulonephritis/nephritic syndrome this is type III hypersensitivity. CD40 deficiency? CD40 is a receptor for CD40L It’s needed for macrophages activation and also for B cell proliferation. So, if it’s deficient, ig those won’t activate and immunodeficiencies happen. If we have complement cascade deficiency we get recurrent bacteria infection which are: Hypersensitivity I,II,III,IV. What is goodpasture’s syndrome, which type of hypersensitivity: Target antigen is Type IV collagen in the basement membrane of kidney and glomeruli and lung alveoli. Antibody-mediated (type II) hypersensitivity Production of IgG, IgM → binds to antigen on target cell or tissue → phagocytosis or lysis of target cell by activating complement or Fc receptors mediated inflammation which causes nephritis and lung hemorrhage in alveoli (it produces collagen type IV there which affects membrane and that’s why we’ll have hematuria) it also causes disorders like Autoimmune hemolytic anemia, Goodpasture syndrome etc.. What is Type I hypersensitivity: is a tissue reaction that occurs after interacting of antigen with IgE antibody bound to the surface of mast cells. The reaction is initiated by entry of an antigen, which is called an allergen because it triggers allergy. TH2 cells and IgE are responsible for the clinical and pathologic manifestations of the reaction. (e.g., seasonal rhinitis, hay fever), (asthma), or even fatal (anaphylaxis) What is poststreptococcal glomerulonephritis, which type of hypersensitivity: Type III hypersensitivity, post-streptococcal glomerulonephritis, which occurs when antibodies produced against streptococcal antigens form immune complexes that deposit in the glomeruli of the kidneys. This can lead to inflammation and damage to the kidney tissue, resulting in nephritis. What’s type IV hypersensitivity: Disorders: Contact dermatitis; multiple sclerosis; type 1 diabetes; tuberculosis. 1- CD4+ T cell-mediated
  • 17. APC display peptides to naive CD4+ helper T cells which release IL-2 which proliferate antigen responsible T cells CD4+ helper T cells differentiate into to Th1 and Th17 CD4+ T cell differentiates into Th1 which secretes IFN-y that activate macrophages causing inflammation CD4+ T cell differentiates into Th17 which secrete IL-17 and other cytokines, which induce the secretion of chemokines responsible for recruiting neutrophils promoting inflammation. 2- CD8+ T cell-mediated In viruses for example: Viral peptides displaying by MHC 1 which is recognised by TCR of CD8+ which kill infectious cells and and eliminates infection CD8+ T cell also produce cytokines and IFN-y to promote inflammatory response Examples of Disorders Caused by Immediate Hypersensitivity: Allergic rhinitis, sinusitis (hay fever), Increased mucus secretion; inflammation of upper airways and sinuses. We get allergic from pollen (flowers, trees, grasses) during spring. Anaphylaxis; allergies; bronchial asthma. It causes vascular dilation, edema, smooth muscle contraction, mucus production, tissue injury, inflammation. Immediate & delayed hypersensitivity I: In immediate hypersensitivity reactions, IgE binds to the mast cells’ Fc receptors and recognizes antigen, and in response the cells degranulate and release mediators, such as histamine and prostaglandins. (LONG ANSWER READ THE BOOK) Delayed hypersensitivity: TH1 cells secrete cytokines, mainly IFN-γ, which are responsible for many of the manifestations of delayed-type hypersensitivity. IFNγ-activated macrophages produce substances that destroy microbes and damage tissues, and mediators that promote inflammation. (ChronicTH1 reactions associated with macrophage activation often lead to granuloma formation) Examples for type IV hypersensitivity: Contact dermatitis; multiple sclerosis; type 1 diabetes; tuberculosis, causes perivascular cellular infiltrates; edema; granuloma formation; cell destruction What is contact dermatitis? and which type of hypersensitivity it is. In contact dermatitis, the environmental chemical (eg. jewelry) modifies self-proteins, leading to the activation of T cells and the development of a DTH reaction, resulting in skin inflammation and rash. Type IV hypersensitivity.
  • 18. Main cause of contact dermatitis? Viridans streptococcus bacterial infection What cells do we have in hypersensitivity I and hypersensitivity IV? IgE, TH2 cells, and mast cells activated for type I, T cytotoxic cells and TH2 for type 4 Mast cells: During an allergic reaction, an allergen triggers the production of IgE antibodies, which bind to the FcεRI receptor on the surface of mast cells. The cross-linking of IgE molecules by allergens leads to the activation and degranulation of mast cells, resulting in the release of various mediators, such as histamine, leukotrienes, and cytokines, which cause the symptoms of allergies. Mast cells are derived from hematopoietic stem cells in the bone marrow and mature in peripheral tissues, such as the skin, lungs, and gut Which immunoglobulin activates mast cells: the Fc portion of IgE antibodies to FcεRI on their surface. What is the acute response of mast cells activation? Histamine is released which causes vasodilation and increased vascular permeability and release proteolytic enzymes that kill bacteria or inactivate toxins Which type of diseases happens when we have elevated mast cells: All hypersensitivity 1, Allergies, asthma and anaphylactic shock for example What are primary lymphoid organ? - bone marrow, fetal liver (know this), thymus What is Polyarteritis nodosa , and which type of hypersensitivity and what it does? hepatitis B virus antigens and antibodies produced by the host immune system result in the formation of immune complexes and causes systemic vasculitis. It’s an example of immune complex mediated diseases (type III). What is myasthenia gravis, and which type of hypersensitivity? Type II hypersensitivity, target antigen is acetylcholine receptor, mechanism of disease is antibody inhibits acetylcholine binding, it causes muscle weakness and paralysis. What is Hashimoto thyroiditis, and which type of Hypersensitivity? Is an autoimmune disorder. Increase amounts of T3 and T4, The immune system creates antibodies that attack thyroid cells as if they were bacteria, viruses or some other foreign body. Gradual thyroid failure due to autoimmune destruction, the formation
  • 19. of antithyroid antibodies that attack the thyroid tissue, causing progressive fibrosis which causes your thyroid to not make enough thyroid hormone. Type 2 & 4 hypersensitivity. About anaphylactic shock and which type of hypersensitivity? Type I hypersensitivity, Fall in blood pressure (shock) caused by vascular dilation; airway obstruction due to laryngeal edema. Anaphylaxis (may be caused by drugs, bee sting, food) Why could you have Edema in anaphylactic shock? Histamines are released during allergic reaction, causing vasodilation which causes decreased blood pressure so the fluid can leak into the lungs causing swellings so it causes pulmonary edema, which causes anaphylactic shock. Affinity maturation? Production of functionally different antibodies, all with the same specificity, relies on heavy-chain class (isotype) switching, which increases the range of functions that antibodies serve. Some of the isotype-specific functions of antibodies include opsonization and transplacental transfer of IgG, IgA secretion into mucosal lumens, and binding of IgE to mast cells. Helper T cells also stimulate the production of antibodies with higher affinity for the antigen. This process, called affinity maturation, improves the quality of the humoral immune response. Psoriasis? Type IV hypersensitivity. T cell mediated disease, specificity of pathogenic T cells is unknown, principle mechanism of tissue injury is inflammation mediated mainly by TH17 cytokine, causing destructive plaques in the skin. Class switching? Mechanism that changes B cells production of immunoglobulin from one type to another like from IgM to IgG. So, NK cells and phagocytes both have fc receptors where in phagocyte it causes opsonization and phagocytosis while NK cells cause antibody- dependent cytotoxicity. Class switching happens in the differentiation stage. MHC class II? CD4 is a protein found on the surface of T helper cells. CD4 recognizes MHC class II molecules, which are expressed by antigen-presenting cells such as dendritic cells, macrophages, and B cells. MHC class II molecules are heterodimers composed of an alpha and a beta chain.
  • 20. What are dendritic cells? Dendritic cells (DCs) are considered to be antigen-presenting cells (APCs). They play a critical role in the initiation and regulation of the adaptive immune response by presenting antigens to T cells. They also have a high expression of major histocompatibility complex (MHC) molecules, which are necessary for the presentation of antigens to T cells. Di George syndrome? DiGeorge syndrome is caused by a congenital defect in thymic development resulting in deficient T-cell maturation. T cells are absent in the lymph nodes, spleen, and peripheral blood, and infants with this defect are extremely vulnerable to viral, fungal, and protozoal infections. Patients also are susceptible to infection with intracellular bacteria, because of defective T cell–mediated immunity. B cells and serum immunoglobulins are generally unaffected. Graves’ disease? Graves' disease is an autoimmune disorder that results in hyperthyroidism, a condition where the thyroid gland produces too much thyroid hormone. In Graves' disease, autoantibodies, known as thyroid-stimulating immunoglobulins (TSIs) or thyroid-stimulating antibodies (TSAb), bind to and activate the thyrotropin (TSH) receptor on thyroid follicular cells, causing excessive thyroid hormone production. Type 2 hypersensitivity. What is hay fever? Type 1 hypersensitivity, it is also called allergic rhinitis. It is one of the localized allergic reactions. What is Multiple sclerosis, in which type of hypersensitivity is it? Type 4 hypersensitivity Target antigen is Protein antigens in myelin (e.g., myelin basic protein) which causes inflammation mediated by TH1 and TH17 cytokines, and myelin destruction by activated macrophages. The result is demyelination in CNS with perivascular inflammation and paralysis. MS is characterized by episodes of disease activity that produce white matter lesions that are separated in space. Different between type 2 and 3 hypersensitivity? Different between type 2 and type 4 hypersensitivity? ANSWER:
  • 21. Leukocytes adhesion deficiency? Inherited defects in adhesion molecules that impair leukocyte recruitment to sites of infection, resulting in recurrent bacterial infections. LAD1 is caused by defects in the β2 chain that is shared by the integrins LFA-1 and Mac-1. LAD I caused by mutations of ITGB2 gene LAD2 is caused by a defect in a fucosyl transferase that is required to synthesize functional sialyl-Lewis X, the ligand for E- and P-selectins. Mutation in CD18. LAD II caused by mutations of SLC35C1 gene What is TLR defect? Mutations in TLR3, a receptor for viral RNA, result in recurrent herpes simplex encephalitis, and mutations in MYD88, an adaptor protein needed for signaling downstream of multiple TLRs, are associated with destructive bacterial pneumonias. Agammaglobulinemia? A defect in B-cell development or maturation that results in an inability to produce immunoglobulins, including IgG, IgA, IgE, and IgM. This leads to a deficiency in all types of antibodies. If IgG is missing then we have a problem in opsonization (antibody is not able to undergo opsonization and phagocytosis) patients present with recurrent pyogenic infections because of low levels of opsonizing IgG antibodies. In IgA deficiency, patients can’t undergo protection of mucosa from microbes and it won't be able to maintain the homeostasis so a lot of infections can happen like giardia,
  • 22. lupus erythematosus, rheumatoid arthritis, myasthenia gravis, type I diabetes, streptococcus ammonia. Hyper IgM syndrome? This disease is characterized by the production of normal (or even supranormal) levels of IgM antibodies and decreased levels of the IgG, IgA, and IgE. This defect is an inability of T cells to activate B cells. As discussed earlier, many of the functions of CD4+ helper T cells require the engagement of CD40 on B cells, macrophages, and dendritic cells by CD40L (also called CD154) expressed on antigen-activated T cells. This interaction triggers Ig class switching and affinity maturation in the B cells. What is chronic granulomatous deficiency? Chronic granulomatous disease results from inherited defects in the genes encoding components of phagocyte oxidase, the phagolysosomal enzyme that generates ROS such as superoxide (O2) Decreased oxidative burst , resulting in defective bacterial killing and susceptibility to recurrent bacterial infection. We get catalase positive bacterial infection (streptococcus). What is Chédiak-Higashi syndrome? Is characterized by defective fusion of phagosomes and lysosomes, resulting in defective phagocyte function and susceptibility to infections. The main leukocyte abnormalities are neutropenia, defective degranulation, and delayed microbial killing. The affected leukocytes contain giant granules, which are seen in peripheral blood smears. There are abnormalities in melanocytes (leading to albinism), cells of the nervous system (associated with nerve defects), and platelets (causing bleeding disorders). The gene associated with this disorder encodes a large cytosolic protein called LYST, which regulates lysosomal trafficking. (Decreased leukocyte functions because of mutations affecting protein involved in lysosomal membrane traffic). What is Graft-versus-host-disease (GvHD)? Occurs when immunologically competent cells or their precursors are transplanted into crippled recipients, and the transferred cells recognize alloantigens in the host and attack host tissues. It is seen most commonly in the setting of HSC transplantation. On receiving allogeneic HSCs, an immunologically compromised host cannot reject the graft, but T cells present in the donor graft perceive the host’s tissue as foreign and react against it. This results in the activation of donor CD4+ and CD8+ T cells, causing inflammation and killing recipient cells. To try to minimize GVHD, HSC transplants are done between donor and recipient that are carefully HLA-matched using precise DNA sequencing–based methods. What is ataxia telangiectasia?
  • 23. Is an autosomal-recessive disorder characterized by abnormal gait (ataxia), vascular malformations (telangiectases), neurologic deficits, increased incidence of tumors, and immunodeficiency. It affects both B cells and T cells. Its Immune abnormalities are defective production of isotype-switched antibodies, mainly IgA and IgG2. The T-cell defects are associated with thymic hypoplasia. Patients experience upper and lower respiratory tract bacterial infections, multiple autoimmune phenomena, and frequent cancers, particularly lymphoid tumors, with advancing age. The gene responsible for this disorder encodes a protein called ATM (ataxia telangiectasia mutated), a sensor of DNA damage that activates cell cycle checkpoints and apoptosis in cells with damaged DNA. Lack of ATM also leads to abnormalities in antigen gene recombination and abnormal antibody isotype switching. What is Sjögren Syndrome? Chronic disease characterized by dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) resulting from destruction of the lacrimal and salivary glands. It occurs as an isolated disorder (primary form), also known as the sicca syndrome, or more often in association with another autoimmune disease (secondary form). Rheumatoid arthritis is the most common associated disorder, while other patients have SLE, polymyositis, scleroderma, vasculitis, mixed connective tissue disease, or autoimmune thyroid disease. The lacrimal and salivary glands show dense lymphocytic infiltration consisting mainly of activated CD4+ helper T cells and some B cells, including plasma cells. Systemic Sclerosis (Scleroderma)? This disorder is characterized by excessive fibrosis in multiple tissues, vascular disease, and production of multiple autoantibodies . Disease limited to the skin is also called localized scleroderma. Systemic sclerosis is classified into two groups: • Diffuse systemic sclerosis, characterized by initial widespread skin involvement, with rapid progression and early visceral involvement • Limited systemic sclerosis, with relatively mild skin involvement, often in fingers and face. Involvement of the viscera occurs late, so the disease generally follows a fairly benign course. This presentation also is called CREST syndrome because of its frequent features of calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia. The disease results from three processes— autoimmune responses, vascular damage, and collagen deposition. Endocarditis in Systemic Lupus Erythematosus: Libman-Sacks Endocarditis? Libman-Sacks endocarditis is characterized by the presence of vegetations on the valves of patients with systemic lupus erythematosus. Associated with inflammation, often with fibrinoid necrosis of the valve adjacent to the vegetation, can result in lesions
  • 24. that resemble chronic rheumatic heart disease. Similar lesions can occur in the setting of antiphospholipid antibody syndrome. Focal lupus nephritis? (class III) is defined by involvement of fewer than 50% of all glomeruli. The lesion affects only a (segmental) portion of the glomerulus or (global) involving the entire glomerulus. Affected glomeruli may exhibit swelling and proliferation of endothelial and mesangial cells associated with leukocyte accumulation, capillary necrosis, and hyaline thrombi. The clinical presentation ranges from mild hematuria and proteinuria to acute renal insufficiency. Red blood cell casts in the urine are common when the disease is active. What is CREST syndrome? CREST stands for (Calcinosis, Raynaud’s phenomenon, Esophageal dysfunction, sclerodactyly, tanglectasis) It’s the limited scleroderma, with relatively mild skin involvement, often confined to the fingers and face. Its frequent features are calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia. IPEX syndrome? IPEX:immune dysregulation, polyendocrinopathy, enteropathy, X-linked Mutations in the FOXP3 gene result in severe autoimmunity in humans and mice; in humans, these mutations are the cause of a systemic autoimmune disease called IPEX. What is peripheral tolerance? Peripheral tolerance mechanisms prevent potentially autoreactive T and B cells from responding to self-antigens. Anergy occurs when the costimulatory signals required for T cell activation are absent, leading to functional inactivation of the T cell. Regulatory T cells prevent immune reactions against self-antigens through the secretion of immunosuppressive cytokines and the expression of CTLA-4, which reduces APC's ability to activate T cells via CD28. Deletion by apoptosis may be triggered by the upregulation of pro-apoptotic proteins or by engagement of the death receptor Fas. Lastly, some self-antigens are hidden from the immune system, such as those located in immune-privileged sites like the testis, eye, and brain. Unless released into circulation, these antigens tend to be ignored by the immune system. • The factors that lead to a failure of self-tolerance (1) inheritance of susceptibility genes that disrupt different tolerance pathways (2) infections and tissue injury that expose self antigens and activate APCs and lymphocytes in the tissues.
  • 25. What is serum sickness? Type III hypersensitivity, It’s a systemic immune complex disease, antigen involves various proteins (e.g., foreign serum protein). It's when antibodies are for antibodies like, (horse anti-thymocyte globulin). It can Cause arthritis, vasculitis, and nephritis. Specific autoantibody for scleroderma?/ If you have limited scleroderma, CREST syndrome, which autoantibody will you have? DNA topoisomerase 1, Centromeric proteins (CENPs) A, B, C, and RNA polymerase II Specific autoantibodies for sjogren’s syndrome? SSA and SSB What is chronic rejection? Is an indolent form of graft damage that occurs over months or years, leading to progressive loss of graft function. It causes gradual narrowing of graft blood vessels (graft arteriosclerosis). is dominated by vascular changes, often with intimal thickening and vascular occlusion. Wiskott-Aldrich syndrome? Is an X-linked disease characterized by thrombocytopenia, eczema, and there is progressive loss of T lymphocytes from the blood and the T cell zones (paracortical areas) of lymph nodes, IgM levels in the serum are low, but levels of IgG are usually normal and, IgA and IgE are often elevated. The syndrome is caused by mutations in an X-linked gene encoding Wiskott-Aldrich syndrome protein (WASP). WASP belongs to a family of signaling proteins that link membrane receptors, such as antigen receptors, to cytoskeletal elements. The only treatment is HSC transplantation. Severe combined immunodeficiency abnormalities? MHC2 receptor, adenosine deaminase, which inhibits a specific enzyme called ribonucleotide reductase. (When adenosine accumulates it’s going to become deoxyadenosine, toxigenic for this enzyme where it inhibits the enzyme and it won’t be able to produce and in order to put nucleotides in the DNA we need to make them in deoxy forms, if you can’t do that then you can’t produce B cells, T cells etc..). X-linked skin cytokine gamma chain? X-SCID Failure of T cell and B cell maturation; mutation in the common γ chain of a cytokine receptor, leading to failure of IL-7 signaling and defective lymphopoiesis./ these are caused by mutations in the gene encoding the common γ (γc) chain shared by the receptors for the cytokines IL-2, IL-4, IL-7, IL-9, and IL-15. RAG 1 & RAG 2?
  • 26. Immature B cells and T both express a pair of gene products, RAG1 and RAG2, that carry out V(D)J segment recombination, After encountering antigen, mature B cells express a specialized enzyme called activation-induced cytosine deaminase (AID). Systemic lupus erythematosus autoantibodies/SLE? Double-stranded DNA, UI-RNP, Smith (Sm) antigen (core protein of small RNP particles), Ro (SS-A) nucleoprotein, Phospholipid-protein complexes (anti-PL), Multiple nuclear antigens (“generic ANAs”). Lupus is a disease that occurs when the body’s immune system attacks your own tissues and organs. Type II hypersensitivity. Which drug induces lupus/SLE? Hydralazine, procainamide, isoniazid, and D-penicillamine IgG4 related disorders? Rich in IgG4 antibody-producing plasma cells and lymphocytes, particularly T cells, associated with fibrosis and obliterative phlebitis. Mikulicz syndrome (enlargement and fibrosis of salivary and lacrimal glands), Riedel thyroiditis, idiopathic retroperitoneal fibrosis, autoimmune pancreatitis, and inflammatory pseudotumors of the orbit, lungs, and kidneys. Isolated IgA Deficiency? This is the most common primary immune deficiency disease. IgA is the major immunoglobulin in mucosal secretions and it’s involved in defending the airways and the gastrointestinal tract. Weakened mucosal defenses due to IgA deficiency causes patients to recurrent sinopulmonary infections and diarrhea. Activation-induced cytosine deaminase? When we have hyper-IgM syndrome: Failure to produce isotypeswitched high-affinity antibodies (IgG, IgA, IgE); mutations in genes encoding CD40L or activation-induced cytosine deaminase. What is central tolerance? Mechanism of central tolerance is the antigen-induced deletion (death) of self-reactive T lymphocytes and B lymphocytes during their maturation in central (generative) lymphoid organs (i.e., in the thymus for T cells and in the bone marrow for B cells)./ immature T and B lymphocytes that recognize self antigens in the central (generative) lymphoid organs are killed by apoptosis; in the B-cell lineage, some of the self-reactive lymphocytes switch to new antigen receptors that are not self-reactive. Hyper-IgE syndrome? Includes triad of eiosinophils, eczema, rash, abcess in joints and lungs, and pulmonary infections. Mutations in STAT3 gene, and elevated IgE level.
  • 27. 3 year old boy brought to the physician for MRI, rash didn’t resolve, 3 months ago he was treated for several asymptomatic soft tissues abcess on his legs he has been to the hospital due to pneumonia, prominent forehead, widen nasal bridge, leukocytes, eosinophils, deficiency of T helper 17 cells, patient increased susceptibility to infections is most likely to which of the following? Impaired chemotaxis for neutrophils, because of job syndrome, deficiency of IL-17 Impaired DNA repair in lymphocytes Impaired respiratory burst in neutrophils Impaired actin assembly in lymphocytes Impaired Ig class switching in lymphocytes