Content is related to immunology

1. Immune Deficiency
Hypersensitivity
Autoimmunity
Classification of Immune Disorder

2. Overview
• Diseases of the immune system take many forms,
including hypersensitivity reactions, autoimmune
disorders and immunodeficiency states.
• Autoimmune diseases are the result of a failure in the
immune system to recognize self-antigens, resulting in the
production of antibodies that react against the normal
components of cells.
• Immunodeficiency states can be hereditary or acquired.
Severe combined immunodeficiency disorder (SCID)
is a genetic disorder.

3. Immune Deficiency
• Immune deficiency is a state in which immune
system ability to fight infectious disease and
cancer become compromised or entirely
absent.

8. Hypersensitivity
• A state of exaggerated or abnormal response to an
antigen with resulting injury/damage to the host tissue
instead of protection.
Four Types of Hypersensitivity Reactions:
• Type I (Anaphylactic) Reactions
• Type II (Cytotoxic) Reactions
• Type III (Immune Complex) Reactions
• Type IV (Delayed or Cell-Mediated) Reactions

9. Type-I (Atopic or Anaphylactic) Reactions
It occurs within minutes of exposure to antigen. Also known as IgE
mediated or immediate hypersensitivity
o Mechanism
• First Exposure or Sensitization phase: The antigen is taken by
antigen presenting cells (i.e. dendritic cells and macrophages) to
the CD4+ (T helper) cells that differentiate to Th2 cells.
• Th2 cells release IL-4 & IL-5. IL-4 activates B-cells to undergo
class switching or isotype switching to produce IgE antibodies,
while IL-5 stimulates production and activation of eosinophils.
• Mast cells in the mucosal tissues or under the skin have high
affinity to Fcε RI ( Fc epsilon region of immunoglobulin E)
receptor which binds IgE even in absence of allergen. IgE are also
called cytotropic antibodies since they can bind to cell surfaces.
• IgE binds to mast cells.

10. Mechanism of Type I Cont…
• Second Exposure/Activation Phase: Subsequent exposure to the
same antigen results in binding of the antigen to IgE bound to mast
cells.
• Two or more antigens required to crosslink IgE antibodies, causing the
mast cells to degranulate and thus release several pro-inflammatory
molecules called mediators which cause the allergic effects.
o Types of Mediators Released
• Histamine: Causes vasodilation and increases vascular permeability
(swelling & redness), increases mucus secretion (runny nose), attract
neutrophils and eosinophils (chemotactic factor) contracts smooth
muscles (in bronchi).
• Prostaglandins: Cause vasodilation, contract bronchial smooth
muscles and increase mucus secretion.
• Leukotrienes: Cause bronchial spasms and attract more immune
cells.
• Proteases: Causes tissue damage (due to protein breakdown)

11. Mediators Involved
Primary inflammatory mediators
Histamine: Vascular permeability, smooth muscle contraction
Serotonin: Neurotransmitter – smooth muscle contraction
ECF-A: Eosinophil chemotactic factor of anaphylaxis causes
Eosinophil chemotaxis.
NCF-A: Neutrophil chemotactic factor of anaphylaxis causes
Neutrophil chemotaxis.
Proteases: mucus secretion, connective tissue degradation by protein
breakdown
Tryptase: It is an enzyme that is released, along with histamine and
other chemicals, from mast cells when they are activated as part of a
normal immune response as well as in allergic (hypersensitivity)
responses. Serum tryptase concentration servers as a marker of
mast cell activation.
Heparin: Initiates bradykinin production causing swelling,
anaphylaxis.

12. Mediators Involved
Secondary inflammatory mediators
Leukotrienes: Its release leads to Vascular permeability, smooth
muscle contraction
Prostaglandins: Causes vasodilation, smooth muscle contraction,
platelet activation
Bradykinin: Increases vascular permeability, smooth muscle
contraction
Cytokines: It signals the immune system to do its job. It causes
activation of vascular endothelium, eosinophil recruitment and its
activation

13. Mast Cells and the Allergic Response

14. Sequence of Events in Type-I Reaction
1- Early phase
• It occurs within 5–30 minutes of re-exposure or 2nd
exposure to an antigen.
• Characterized by vasodilation, increased vascular
permeability, edema, increased smooth muscles
contraction, and urticarial (hives, is an outbreak of swollen,
pale red bumps).
• The early phase is due to binding of antigen to IgE bound
to mast cells, with subsequent degranulation of the mast
cells and release of chemical mediators mainly histamine.
2 - Late phase
• It occurs in 24–48 hours after re-exposure to antigen.
• Characterized by infiltration of neutrophils, basophils,
eosinophils & monocytes and results in mucosal damage
due to release of mediators such as leukotrienes and
prostaglandins.

15. Forms of Type-I hypersensitivity Reactions
 Local anaphylaxis
Skin
Contact with allergen causes immediate redness, swelling
and itching (urticaria). Allergen may come in contact with
the skin directly, by injection (e.g. insect bite) and ingestion
(e.g. food or drug allergies that produce skin reactions).
Angioedema is characterized by laryngeal edema, edema of
the eyelids, lips, tongue & trunk.
Lungs
Inhalation of allergens (e.g. pollens, dust particles) results in
bronchial smooth muscles contraction, resulting in an acute
airway obstruction and wheezing (e.g. allergic bronchial
asthma).

16. Forms of Type-I hypersensitivity Reactions
 Local anaphylaxis
Nose
Inhalation of allergens (e.g. pollens, dust) leads to
vasodilation and secretion of mucous, a condition known as
hay fever and allergic rhinitis.
Intestine
Ingestion of allergens (e.g. nuts & sea foods) causes muscle
contraction and fluid secretion that produce abdominal
cramps and diarrhea, a condition called allergic
gastroenteritis.

17. Forms of Type-I hypersensitivity Reactions
 Atopy
• Genetic predisposition to allergic reactions is called atopy.
• Atopy is a tendency of an individual to produce specific
IgE antibodies after natural exposure to environmental
allergens.
• Atopic patients usually have markedly elevated total
serum IgE levels.
• The atopic trait is inherited in genes.
• Examples include allergic rhinitis, asthma
and atopic dermatitis (eczema) etc.

18. Forms of Type-I hypersensitivity Reactions
 Systemic Anaphylactic Reaction
• It is a life-threatening systemic type-1 hypersensitivity
reaction that typically results from injected allergens (e.g.
penicillin antibiotics, local anesthetics, contrast dyes) and
cutaneous allergens (e.g. bees stings).
• Release of inflammatory mediators cause vasodilation &
increased vascular permeability that leads to shock,
allergic edema and may cause fatal asphyxia.
• Asphyxia is generalized hypoxia that arises from abnormal
breathing leading to unconsciousness and death.

19. Type-II Hypersensitivity Reaction
Overview of General Mechanism
• Antibodies (IgG and IgM) are directed against target
antigens on cells or in extracellular matrix.
• The target antigens may be endogenous (e.g. normal cell
recognized by the immune system as foreign) or absorbed
exogenous antigens (e.g. a drug).
Specific Mechanisms
• There are three specific mechanisms by which type-II
hypersensitivity reactions occur.
a) Complement-dependent reactions
b) Antibody dependent cell-mediated cytotoxicity, and
c) Antibody-mediated cellular dysfunction.

20. Type-II Hypersensitivity Reaction
(a) Complement-dependent reactions
Mechanism
• Antibodies react with cell surface antigen, leading to
activation of complement system that cause the direct
lysis of the antigen-antibody complex containing the cell.
• The complement proteins can also promote phagocytosis
of the antigen by providing opsonization.
Example-1: Reaction to Penicillin
• The drug can bind to red blood cells, causing them to be
recognized as foreign antigen. IgG & IgM antibodies bind
to these antigens to form complexes that activate
complement system to eliminate cells presenting foreign
antigens.

21. Complement-dependent Reactions
Example-2: Transfusion reactions
• RBCs from an incompatible donor are destroyed by the
antibodies normally present within the recipient. Such
antibodies are directed against blood group antigens
present on the cell membrane of RBCs.

22. Type-II Hypersensitivity Reaction
(a) Complement-dependent reactions Contd..
Example-3: Good pasture's Syndrome
Goodpasture syndrome, also known as anti-glomerular basement
membrane disease, is a rare autoimmune disease in which antibodies
attack the basement membrane in lungs and kidneys, leading to
bleeding from the lungs, glomerulonephritis, and kidney failure.
1-Glomerulonephritis
• Autoantibodies IgG are deposited along the capillaries of the
glomeruli, where they react with glycoprotein present in the
glomerular basement membrane. This results in a strong
inflammatory reaction & complement fixation leading to necrosis of
the glomerulus with impending renal failure.
2-Alveolar Basement membrane Damage
• Auto-antibodies are produced against pulmonary alveolar basement
membrane antigen, the resulting damage leads to bleeding from the
lung.

23. Type-II Hypersensitivity Reaction
Example 4: Hemolytic Disease of the Newborn
• The Rh-negative mother is sensitized from Rh-positive
baby during first pregnancy.
• Rh-specific B-cells of the mother are sensitized which
remain in the memory.
• In the 2nd pregnancy, if the fetus is Rh-positive, memory
B-cell will readily produce Rh-negative antibodies which
can cross the placenta and cause the destruction of Rh-
positive fetal red blood cells.
• The resulting syndrome is called erythroblastosis fetalis
or Hemolytic Disease of the Newborn.

24. Erythroblastosis Fetalis

25. Type-II Hypersensitivity Reaction
(b) Antibody-dependent cell-mediated cytotoxicity (ADCC)
Mechanism
• This form of antibody-mediated cell injury does not involve
fixation of the complement proteins but instead requires the
cooperation of leukocytes.
• Cell types that possess receptors for the Fc portion of IgG,
such as neutrophils, eosinophils, macrophages and natural
killer cells, mediate the destruction of antigen-antibody
complex containing the target cell. Cellular lysis proceeds
without phagocytosis.
• ADCC may be relevant to the destruction of targets too large
to be phagocytosed, such as parasites or tumor cells, and it
may also play some role in graft rejection.

27. Type-II Hypersensitivity Reaction
(c) Antibody-mediated cellular dysfunction (Non-cytotoxic)
or Stimulatory Type II Hypersensitivity Also classified as
Type V)
Mechanism
• Antibodies formed against cell surface receptors impair or
dysregulate cell function without causing cell injury (i.e.
may stimulate or inhibit cellular function).
Example
a) Stimulation
Graves disease (autoimmune hyperthyroidism) is due to the
production of autoantibodies that stimulate the thyroid-
stimulating hormone (TSH) receptor, resulting in
hyperthyroidism.

28. Type-II Hypersensitivity Reaction
Antibody-mediated cellular dysfunction
Example
b) Inhibition
Myasthenia Gravis is due to the production of auto-
antibodies that block the acetylcholine receptors at the
postsynaptic neuromuscular junction, inhibiting the
excitatory effects of the neurotransmitter acetylcholine their
receptors throughout neuromuscular junctions.

29. Effector Mechanisms of Antibody-Mediated Disease

30. Type-III (Immune Complex) Reaction
• Mediated by immune complexes (antigen-antibody complexes)
• Type-III reactions are caused by deposition of antigen-antibody
complexes in the tissue & blood vessels.
• Type-III reactions specifically occur when the antigen is in excess
and small, immune complexes circulate in blood for longer periods
and are slowly broken down.
• The immune complex activates the complement system (family of
complement proteins C1-C9) and attracts polymorpho-nuclear
lymphocytes (Neutrophil, basophil, eosinophils) and macrophages to
the site.
• These attracted cells may release proteases, reactive oxygen species
and inflammatory mediators that cause local tissue damage.
Commonly occurs in kidneys lead to Glomerulonephritis & joints
which lead to arthritis.

31. Immune Complex Mediated Hypersensitivity

32. Disorders of Type-III Reactions
• Two types of immune complex injuries are resulted:
1) Systemic immune complex disease (serum sickness)
2) Local immune complex disease (Arthus reaction)
• Serum Sickness
Pathogenic immune complexes are formed in the circulation
that are deposited in various tissues and cause inflammatory
reactions there.
Mechanism
1. Exposure to antigen leads to antibody formation
2. Antigen-antibody complexes are formed in the
circulation.

33. Disorders of Type-III Reactions
Mechanism Cont…
3. The complexes pass through the endothelial pores of
small vessels and are deposited in the vessels wall where
they activate complement system.
This result in complement mediated necrosis and acute
inflammation of the vessel wall, a condition called
necrotizing vasculitis.
Vasculitis may occur in a single organ (e.g. post
streptococcus glomerulonephritis) or it may affect many
organs (e.g. serum sickness due to injection of foreign serum
(vaccines) or SLE)

34. Multiple Activities of the Complement System

35. Disorders of Type-III Reactions
Arthus Reaction
• This is localized immune complex injury in which tissue
necrosis occurs at the site of entry of antigen.
Mechanism
• Repeated exposure to antigen results in high levels of
antibody formation in the serum.
• Subsequent exposure to the same antigen leads to the
formation of antigen-antibody complexes that deposit
locally in the small blood vessels.
• The immune complexes activate complement & produce
severe local acute inflammatory reaction with necrosis.

36. Disorders of Type-III Reactions
Example of Arthus Reaction
• A local type-III reaction can develop in the skin, for
example, after vaccination.
Hypersensitivity Pneumonitis
• Repeated inhalation of small amounts of antigen results in
the production of large amounts of IgG and immune
complexes are formed that are deposited in the lung.
• This results in cough, dyspnea and fever after 6-8 hours of
exposure to antigen, a condition called Hypersensitivity
Pneumonitis.
• The lung disease caused by exposure to molds that grow
on hay is known as farmer’s lung.

37. Type-IV (Cell-Mediated) Hypersensitivity
• Mediated by sensitized T-cells rather than antibodies.
• First contact sensitizes the person, subsequent contacts
elicit a reaction.
• Reactions are delayed and typically occur 48-72 hours
after exposure to the antigen.
• Delay is due to migration of macrophages and T-cells to
the site of foreign antigens.
• Type-IV reactions are categorized as (1) delayed
hypersensitivity, (2) cell mediated cytotoxicity

38. Type-IV (Cell-Mediated) Hypersensitivity
Delayed Type Hypersensitivity Reaction
• First exposure leads to phagocytosis of the antigen by
macrophages and presentation to T-cells forming memory
T-cells.
• On later exposure, memory T-cells (CD4+ helper T-cells)
secrete interferon-γ, which activates macrophages.
• Activated macrophages secrete IL-12, which causes
differentiation of T-helper cells to TH1 cells that destroy
the antigen. The activated macrophages also destroy the
antigen intracellularly.

39. Type-IV (Cell-Mediated) Hypersensitivity
Delayed Type Hypersensitivity Reaction
• Microscopic morphology
Stimulation of macrophages results in granulomas (i.e
collections of epithelioid cells).
• Inciting agents
Mycobacteria, fungi, and parasites.
Examples
Tuberculin reaction
Granulomatous inflammation

40. Overview of the DTH response

41. A prolonged DTH response can lead to formation of a granuloma

42. Type-IV (Cell-Mediated) Hypersensitivity
T-cell Mediated Cytotoxicity
• Sensitized CD8+ cells (cytotoxic T-cells) kill antigen-
bearing cells.
• The CD8+ cells accomplish this by releasing perforin that
produces holes in the plasma membrane of cells, allowing
granzyme to enter the cells. Granzyme then activates
apoptosis.
Example
• Contact dermatitis