The document discusses the immune system as a complex network defending against foreign antigens, including its potential failures leading to allergies, autoimmunity, alloimmunity, and immune deficiencies. It emphasizes the roles of innate and adaptive immunity, the presence of different antibodies, and mechanisms of immunological tolerance, detailing the significance of Major Histocompatibility Complex (MHC) proteins. Additionally, it explores autoimmune diseases, particularly systemic lupus erythematosus, outlining genetic and environmental factors contributing to such conditions.

2.  T he immune system is a finely tuned network that protects the
host against foreign antigens, particularly infectious agents.
Sometimes this network breaks down, causing the immune system
to react inappropriately.
 Inappropriate immune responses may be
1) exaggerated against environmental antigens (allergy);
2) misdirected against the host’s own cells (autoimmunity);
3) directed against beneficial foreign tissues, such as transfusions or
transplants (alloimmunity); or
4) insufficient to protect the host (immune deficiency).
 All of these can be serious or life threatening.
 Exaggerated immune responses (allergy) are the most common,
but usually the least life threatening.

3. • Immunity, types, role
• Immune response
• Immunological tolerance
• Autoimmune disorders
• Immune deficiency
• Allergy, types.

4. • Immunity describes the ability of an organism to resist
foreign organisms or invaders which enter its body.
• The immune system is designed to protect against
microscopic organisms (bacteria, viruses) and foreign
substances which enter an organism from outside its
body. The immune system also protects from many cancer
cells which arise within our bodies.
• An antigen is any foreign substance which invades the
body of an organism, while a pathogen is a living antigen
(such as viruses or bacteria) which invade an organism.

5. FEATURE INNATE (Natural) ADAPTIVE
Time of response Immediate (minutes/hours)
Dependent upon exposure (first:
delayed, second: immediate d/t
production antibodies)
Diversity
Limited to classes or groups of
microbes
Very large; specific for each unique
antigen
Microbe recognition
General patterns on microbes;
nonspecific
Specific to individual microbes and
antigens (antigen/antibody
complexes)
Nonself recognition Yes Yes
Response to repeated
infection
Similar with each exposure
Immunologic memory; more rapid
and efficient with subsequent
exposure
Defense
Epithelium (skin, mucous
membranes), phagocytes,
inflammation, fever
Cell killing; tagging of antigen by
antibody for removal
Cellular components
Phagocytes (monocytes/
/macrophages, neutrophils), NK
cells, DCs
T and B lymphocytes, macrophages,
DCs, NK cells
Molecular
components
Cytokines, complement proteins,
acute-phase proteins, soluble
mediators
Antibodies, cytokines, complement
system

6. INNATE IMMUNITY
CHARACTE-
RISTICS
BARRIERS INFLAMMATORY RESPONSE ADAPTIVE (ACQUIRED) IMMUNITY
Level of
defense
First line of defense against
infection and tissue injury
Second line of defense; occurs as a
response to tissue injury or infection
Third line of defense; initiated when
innate immune system signals the cells
of adaptive immunity
Timing of
defense
Constant Immediate response
Delay between primary exposure to
antigen and maximum response;
immediate against secondary exposure
to antigen
Specificity Broadly specific Broadly specific
Response is very specific toward
“antigen”
Cells Epithelial cells
Mast cells, granulocytes (neutrophils,
eosinophils, basophils), monocytes/
macrophages, natural killer (NK) cells,
platelets, endothelial cells
T lymphocytes, B lymphocytes,
macrophages, dendritic cells
Memory No memory involved No memory involved
Specific immunologic memory by T and
B lymphocytes
Peptides
Defensins, cathelicidins, collectins,
lactoferrin, bacterial toxins
Complement, clotting factors, kinins Antibodies, complement
Protection
Protection includes anatomic
barriers (i.e., skin and mucous
membranes), cells and secretory
molecules or cytokines (e.g.,
lysozymes, low pH of stomach and
urine), and ciliary activity
Protection includes vascular responses,
cellular components (e.g., mast cells,
neutrophils, macrophages), secretory
molecules or cytokines, and activation
of plasma protein systems
Protection includes activated T and B
lymphocytes, cytokines, and antibodies

7. Immunity or body defense mechanism is
divided into 2 types, each with humoral
and cellular components:
PRIMARY
REACTION:
Ag+Ab
SECONDARY
REACTION:
TISSUE DAMAGE
(in vivo)
Agglutination
Precipitation
Immobilisation
Neutralisation
Lysis
Complement
fixation
Ag-Ab complex
a) Primary lymphoid organs:
1) Thymus; 2) Bone marrow
b) Secondary lymphoid organs:
1) Lymph nodes; 2) Spleen;
3) MALT (Mucosa-Associated
Lymphoid Tissue located in the
respiratory tract and GIT).
ORGANS OF
IMMUNE
SYSTEM

8. Lymphocytes
Monocytes &
macrophages
(1st immune cells to
encounter pathogen
are macrophages &
dendritic cells
Mast cells &
basophils
Neutrophils
Eosinophils Kill virus-infected and neoplastic cells
Release IFN-γ

10. INNATE AND ADAPTIVE IMMUNITY
In response to recognition of microbes, phagocytes,
DCs, and many other cell types secrete proteins called
cytokines, which promote inflammation and microbial
killing and enhance protective immune responses. Cells
use several receptors to sense microbes; foremost
among these are the Toll-like receptors (TLRs), so
named because of homology with the Drosophila Toll
protein, that recognize bacterial and viral components
a. TLRs are membrane proteins located on the above
effector cells.
b. TLRs recognize non-self antigens (molecules)
commonly shared by pathogens.
1) Called pathogen-associated molecular patterns(PAMPs)
2) Examples of PAMPs
a) Endotoxin in gram-negative bacteria (LPS)
b) Peptidoglycan in gram-positive bacteria
c. PAMPs are not present on normal host effector cells.
d. Interaction of TLRs on effector cells with PAMPs:
1) Initiates intracellular transmission of activating signals to
nuclear factor (NF)κβ - the "master switch" to the nucleus.
2) Genes are encoded for mediator production.
3) Mediators are released into the serum or spinal fluid.
4) Innate immunity mediators:
Adhesion molecules
for neutrophils (e.g.,
selectins)
Cytokines (tumor
necrosis factor, IL 1)
Chemokines
Nitric oxide
Reactive
oxygen species
(e.g.. peroxide)
Antimicrobial
peptides

11. An antigen is any molecule that can
stimulate a specific immune response
against itself or the cell that carries it.Billions of B and T
lymphocytes are produced
during fetal development
with the potential to bind to
at least 100 million distinct
antigens.
Antigens that can bind to a
T or B lymphocyte include
those present on the cell
wall of bacteria or
mycoplasmas, the coat of
a virus, or on certain
pollens, dusts, or foods.
Every cell of a person has
surface proteins that would
be recognized as foreign
antigens by B or T
lymphocytes from another
person.
If an antigen causes either the B or T lymphocyte to
become activated and to multiply or differentiate further,
it is an immunogenic antigen.

12. Each individual possesses cell surface
antigens that are unique to that
individual. These antigens, the MHC
proteins, serve as a sort of cellular
fingerprint. (In humans, these proteins
are sometimes called histocompatibility
antigens.)
There are two main groups of MHC
proteins: MHC I and MHC II.
The MHC I proteins are found on nearly
all cells of the body except the red blood
cells.
The MHC II proteins are found only on the
surface of macrophages, B cells and DC.
MHC proteins have two functions:
1) they present self-antigens to T cells;
2) they bind foreign antigens and present
these to T cells.
The MHC I molecules bind and present
antigens only to cytotoxic T cells.
The MHC II molecules bind and present
antigens only to helper T cells (both Th1
and Th2 types).

13. 1. Known collectively as the human leukocyte
antigen (HLA) system
2. Located on short arm of chromosome 6 (6p)
3. Gene products are coded for on different loci.
4. Gene products are membrane-associated
glycoproteins.
• Located on all nucleated cells with the
exception of mature RBCs
5. HLA genes and their subtypes are transmitted
to children from their parents.
HLA association with disease
1. HLA-B27 with ankylosing spondylitis
2. HLA-DR2 with multiple sclerosis
3. HLA-DR3 and -DR4 with type 1 diabetes
mellitus
Class I antigens
Coded by HLA-A, -B and -C genes
Recognized by CD8 T cells & NK cells
• Altered class 1 antigens (e.g., virus-
infected cell) lead to destruction of the cell.
Class II antigens
Coded by HLA-DP, -DQ, and -DR genes
Present on antigen-presenting cells, APCs
• B cells, macrophages, dendritic cells
Recognized by CD4 T cells
Applications of HLA testing
1. Transplantation workup
• Close matches of HLA-A, -B, & -D loci in both the donor
and graft recipient increase the chance of graft survival.
2. Determining disease risk
Example: HLA-B27-positive
individuals have an Increased risk of
ankylosing spondylitis.

15. Th1 Effects
Reinforces early, local responses
Promotes inflammatory responses
and cell-mediated cytotoxicity
Mediates type IV (delayed-type)
hypersensitivity
Th2 Effects
 Activates later, systemic responses
 Promotes humoral and allergic
responses
 Limits inflammatory responses

19. IgG is the most common immunoglobulin and represents approximately 80% of all circulating
antibodies. IgG is the main antibody that crosses the placenta from the mother to the fetus during
pregnancy. Levels of IgG increase slowly during the primary (first) exposure to an antigen, but
increase immediately and to a much greater extent with a second exposure.
IgM antibody is produced first and in highest concentration during the primary exposure to an
antigen. IgM is the largest antibody in size.
IgA antibody is most concentrated in secretions such as saliva, vaginal mucus, breast milk,
gastrointestinal (GI) and lung secretions, and semen. IgA acts locally rather than through the
systemic circulation. Maternal IgA passes to an infant during breastfeeding (as do IgG and IgM to a
lesser extent).
IgE is responsible for allergic reactions. It is also the antibody most stimulated during a parasitic
infection. TH2 helper cells secrete cytokines that stimulate the production of IgE and activate
eosinophils, and thus the response to helminths is orchestrated by TH2 cells.
IgD exists in low concentration in the plasma. Its role in the immune response is not completely clear,
although it appears to be important for the maturation and differentiation of all B cells.

20. Human immunoglobulin contains four polypeptides:
two identical light chains and two identical heavy
chains linked by disulfide bonds to form a
monomeric unit. Heavy and light chains are aligned
such that the amino portion (NH terminus) of a single
heavy and a single light chain form an epitope-binding
site (more about this later in the chapter). Each heavy
and light chain may be subdivided into homologous
regions termed domains.
Light chains, termed K (kappa) or Λ
(lambda), are encoded on chromosomes
2 and 22, respectively. There are five
types of heavy chains, all encoded on
chromosome 14, termed mu (μ), delta (δ),
gamma (γ), ep-silon (ε), and alpha (α).
The genetically different forms of light
chains (K and X) and of heavy chains (μ, δ,
γ, ε, and α) are known as iso-types.
Immunoglobulin class or subclass is
determined by the heavy chain isotype.

22. is unresponsiveness to an antigen that is induced
by exposure of specific lymphocytes to that antigen. Self tolerance refers to a lack of immune
responsiveness to one’s own tissue antigens.
Central tolerance. The principal mechanism of central tolerance is the antigen-induced
deletion (death) of self-reactive T 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).
In the thymus, many autologous (self) protein antigens are processed and presented by
thymic APCs in association with self MHC. Any immature T cell that encounters such a self
antigen undergoes apoptosis (a process called deletion, or negative selection), and the T cells
that complete their maturation are thereby depleted of self-reactive cells.
Many autologous protein antigens,
including antigens thought to be restricted to
peripheral tissues, are processed and
presented by thymic antigen-presenting cells
in association with self-MHC molecules. A
protein called AIRE (autoimmune regulator)
is thought to stimulate expression of many
"peripheral" self-antigens in the thymus and
is thus critical for deletion of immature self-
reactive T cells. Mutations in the AIRE gene
(either spontaneous in humans or created in
knockout mice) are the cause of an
autoimmune polyendocrinopathy.
As with T cells, clonal deletion is also
operative in B cells. When developing B
cells encounter a membrane-bound antigen
within the bone marrow, they undergo
apoptosis.

23. Peripheral tolerance.
Self-reactive T cells that
escape negative
selection in the thymus
can potentially wreak
havoc unless they are
deleted or effectively
muzzled.
Several mechanisms in
the peripheral tissues
that silence such
potentially autoreactive
T cells have been
identified.

24. The barrier systems preserve an organism against the pathological factors of
the external environment. There are external and internal barriers.
• The external barriers are skin, mucous membranes, liver, spleen, lymphatic
nodes and other organs, which have the cells of the system of
mononuclear phagocytes.
• There are internal barriers in the organism, which are named histohematic
barriers. Wall of a capillary has the function of a barrier. The wall of a
capillary lets in only the nutritious substances and does not let in the
toxins, medicines.
• Examples of internal barriers:
1. hematoencephalic (blood-brain),
2. hematoophtalmic (blood-eye tissue),
3. hematolabirintic (blood-lymph of a labyrinth),
4. hematoovarial (blood-ovarium tissue),
5. hematotestical (blood-testicular tissue)
6. hematothyriod (blood-thyriod tissue),
7. placenta (mother’s blood-foetus blood).
• Connective tissue, which surrounds the vessels and penetrates into a
tissue, executes the protective function too.

25. • Systemic autoimmune disease. Connective tissue disease that mainly affects the blood,
joints, skin, and kidneys
1. Antibodies against the host damage multiple tissues via type II (cytotoxic) and
type III (antigen-antibody complex) hypersensitivity.
2. More common in women of childbearing age, especially African American females (1 in
245). Female-to-male ratio of 9:1.
Etiology and Pathogenesis
Genetic
1) There is an increased risk for developing SLE in family members.
2) Genetic links appear to be located on chromosome 6.
Environmental factors are important in exacerbating SLE or triggering its initial onset.
Examples : Infectious agents (viruses, bacteria); Ultraviolet light; Estrogen
Medications; Extreme stress
Drug-induced lupus erythematosus
 Associated drug: Procainamide, Hydralazine and Isoniazid;
 Features that distinguish drug-induced lupus from SLE:
1) Antihistone antibodies
2) Low incidence of renal and CNS involvement
3) Disappearance of symptoms when the drug is discontinued

26. Hematologic
• Autoimmune
hemolytic anemia,
thrombocytopenia,
leukopenia (due to
autoAb against cell
surface proteins)
Lymphatic
1) Generalized
painful
lymphadenopathy
2) Splenomegaly
Musculoskeletal
• Small-joint
inflammation (e.g.,
hands) with absence
of joint deformity
Skin
1) Immunocomplex
deposition along basement
membrane
• Produces liquefactive
degeneration
2) Malar butterfly rash
Renal
• Diffuse prolifera-
tive glomeruloneph-
ritis (most common
glomerulonephritis)
Cardiovascular
1) Fibrinous pericarditis with or
without effusion
2) Libman-Sacks endocarditis
(sterile vegetations, small deposits
on both sides of the mitral valve;
18% of cases)
Respiratory
1) Interstitial
fibrosis of
lungs
2) Pleural
effusion with
friction rub
Pregnancy-related
1) Complete heart block
in newborns
• Caused by IgG anti-SS-
A (Ro) antibodies
crossing the placenta
2) Recurrent
spontaneous abortions
• Caused by
antiphospholipid
antibodies
Fever and
weight loss
Renal failure &
infection –
common causes of
death

27. CRITERION DEFINITION
1. Malar rash Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds
2. Discoid rash
Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may
occur in older lesions
3. Photosensitivity Rash occurring as an unusual reaction to sunlight, reported in patient history or as physician observation
4. Oral ulcers Oral or nasopharyngeal ulceration, usually painless, observed by a physician
5. Arthritis
Nonerosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling, or
effusion
6. Serositis
Pleuritis—convincing history of pleuritic pain or rub heard by a physician or evidence of pleural effusion or
Pericarditis—documented by electrocardiogram or rub or evidence of pericardial effusion
7. Renal disorder
Persistent proteinuria >0.5 g/dL or >3+ if quantitation not performed or Cellular casts—may be red blood
cell, hemoglobin, granular, tubular, or mixed
8. Neurologic
disorder
Seizures—in the absence of offending drugs or known metabolic derangements,
(e.g., uremia, ketoacidosis, or electrolyte imbalance) or
Psychosis—in the absence of offending drugs or known metabolic derangements,
(e.g., uremia, ketoacidosis, or electrolyte imbalance)
9. Hematologic
disorder
Hemolytic anemia—with reticulocytosis or
Leukopenia— <4.0 × 109/L (4000/mm3) total on two or more occasions or
Lymphopenia— <1.5 × 109/L (1500/mm3) on two or more occasions or
Thrombocytopenia— <100 × 109/L (100 × 103/mm3) in the absence of offending drugs
10. Immunologic
disorder
Anti-DNA antibody to native DNA in abnormal titer or
Anti-Sm—presence of antibody to Sm nuclear antigen or
Positive finding of antiphospholipid antibodies based on:
1) an abnormal serum level of IgG or IgM anticardiolipin antibodies,
2) a positive test for lupus anticoagulant using a standard test, or
3) a falsepositive serologic test for syphilis known to be positive for at least 6 months and confirmed
by negative
Treponema pallidum immobilization or fluorescent treponemal antibody absorption test
11. Antinuclear An abnormal titer of antinuclear antibody (ANA) by immunofluorescence or an equivalent assay at any

28. Laboratory- testing for SLE
a. Serum antinuclear antibody (ANA)
(1) Serum ANA is the best screening test for SLE (sensitivity 99%).
• False negative test results (have SLE but test is negative) are uncommon.
(2) Specificity of serum ANA is only 80%.
• False positive results due to other autoimmune diseases (e.g., systemic sclerosis)
b. Anti-dsDNA antibodies and anti-Sm (Smith) antibodies
(1) Tests used to confirm the diagnosis of SLE
• They have high specificity for diagnosing SLE (i.e.. few false positive results)
(2) Specificity for anti-dsDNA is 99% and 100% for anti-Sm.
c. Anti-Ro antibodies are positive in 25% to 50% of eases.
d. Antiphospholipid antibody syndrome is associated with SLE (30% of cases).
1. Characterized by autoantibody against proteins bound to phospholipids.
2. Anlicardiolipin and lupus anticoagulant are the most common antibodies,
i. Lead to false-positive syphilis test and falsely-elevated PTT lab studies,
respectively
3. Results in arterial and venous thrombosis including deep venous thrombosis,
hepatic vein thrombosis, placental thrombosis (recurrent pregnancy loss), & stroke
4. Requires lifelong anticoagulation
Prognosis
a. Improved survival due to advances in diagnosis and treatment
• Over 90% now survive for 10 years or more
b. Most common cause of death is infection due to immunosuppression.

29. Autoimmune destruction of lacrimal and salivary glands
Lymphocyte-mediated damage (type IV hypersensitivity)
with fibrosis
Classically presents as dry eyes (keratoconjunctivitis), dry
mouth (xerostomia), and recurrent dental carries in an
older woman (50-60 years)—"Can't chew a cracker, dirt
in my eyes"
Characterized by ANA and anti-ribonucleoprotein
antibodies (anti-SS-A/Ro & anti-SS-B/La)
Often associated with other autoimmune diseases,
especially rheumatoid arthritis
Increased risk for B-cell (marginal zone) lymphoma,
which presents as unilateral enlargement of the parotid
gland late in disease course
Salivary glands are often enlarged as a result of lympho-
cytic infiltrates. Extraglandular manifestations include
synovitis, pulmonary fibrosis, and peripheral neuropathy.

30. • Excessive production of collagen that primarily targets the skin (scleroderma), GI tract, lungs, and kidneys
1. Occurs predominantly in women of childbearing age
2. Pathogenesis
a. Small-vessel endothelial cell damage produces blood vessel fibrosis and ischemic injury.
b. T-cell release of cytokines results in excessive collagen synthesis.
c. Stimulatory autoantibodies against platelet-derived growth factor
Laboratory findings in systemic sclerosis:
a. Serum ANA is positive in 70% to 90% of cases.
b. Anti-topoisomerase antibody is positive in 30%
of cases.
• Extractable nuclear antibody to Scl 70.
Respiratory
1) Interstitial fibrosis
2) Respiratory failure
(most common
cause of death)
CREST syndrome
• Limited sclerosis
1) C—calcification, anti-
centromere antibody
2) R—Raynaud's phenomenon
3) E—Esophageal dysmotility
4) S—sclerodactyly (i.e.,
tapered, claw-like fingers)
5) T—telangiectasias (i.e.,
multiple punctate blood vessel
dilations)
Renal
1) Vasculitis involving
arterioles (i.e., hyperplastic
arteriolosclerosis) & glomeruli
2) Infarctions, malignant
hypertension
Gastrointestinal
(1) Dysphagia for solids and liquids
(a) No peristalsis in the lower two
thirds of the esophagus (smooth
muscle replaced by collagen)
(b) Lower esophageal sphincter
relaxation with reflux
(2) Small bowel
(a) Loss of villi (malabsorption)
(b) Wide-mouthed diverticula
(bacterial overgrowth)
(c) Dysmotility (cramps and diarrhea)
Skin
(1) Skin atrophy and tissue swelling
beginning in the fingers and
extending proximally
(2) Parchment-like appearance
(3) Extensive dystrophic calcification
in subcutaneous tissue
(4) Tightened facial features (e.g.,
radial furrowing around the lips)
Raynaud's phenomenon
(1) Sequential color
changes (white to blue to
red) caused by digital
vessel vasculitis & fibrosis
• Most common initial
complaint (70% of cases)
(2) Tapered fingers often
with digital infarcts
Treatment: D-
Penicillamine;
recombinant
human relaxin
Laboratory
findings:
Anticentromere
antibodies in 50%
to 90% of cases

31. A. Raynaud phenomenon generally presents
as episodic modified blood flow of the digits,
usually in response to exposure to cold or stress.
The classic triphasic color change
progresses from white (ischemia) to blue
(deoxygenation) then red (reperfusion).
B. Common early symptoms of SSc include
swelling, skin tightening and contractures of the
fingers with polyarthralgia.
C. Gradual thickening of the skin of the face
and presence of teleangiectasias is characteristic
of advanced SSc.
D. Digital ulcers are one of the most frequent
clinical manifestations of microangiopathy in
patients with SSc. A decreased number of
capillary loops is associated with progressive
thickening of the skin and the development of
ulcers in the late stages of the disease.
Abbreviation: SSc, systemic sclerosis.
Systemic Sclerosis: Scleroderma, Hands and Face
This 55 year-old man with a 16-year history of diffuse systemic
sclerosis and positive Scl-70 antibody has characteristic
fibrotic, taut skin with atrophy over the bony prominences.
Note the calcification in the left hypothenar region, atrophy of
hypothenar muscles, digital pitting in pulp of left long finger,
and flexion contractures of proximal interphalangeal joints.
Terminal digit resorption allows nails to curve over fingertips
(upper left). Also note the temporal muscle atrophy, tight shiny
skin over forehead and cheeks, variations of pigment (nares,
forehead, ear, neck), loss of nasolabial folds, and retraction of
lips (right).

32. Defects in B
cells. T cells,
complement, or
phagocytic cells
Risk factors for
immune disorders
1. Prematurity
2. Autoimmune
diseases (e.g.. systemic
lupus erythematosus)
3. Lymphoproliferative
disorders (e.g.,
malignant lymphoma)
4. Infections (e.g..
human
immunodeficiency
virus, HIV)
5. Immunosuppressive
drugs (e.g..
corticosteroids)

33. DISEASE DEFECT(S) CLINICAL FEATURES
Bruton's
agammaglobulinemia
Failure of pre-B cells to
become mature B cells
Mutated tyrosine kinase
X-linked recessive disorder
Sinopulmonary infections
Maternal antibodies protective from birth to
age of  6 months
Immunoglobulins
IgA deficiency
Failure of IgA B cells to
mature into plasma cells
Sinopulmonary infections; giardiasis
Anaphylaxis if exposed to blood products
that contain IgA
 IgA and secretory IgA
Common variable
immunodeficiency
Defect in B-cell maturation
to plasma cells
Adult immunodeficiency
disorder
Sinopulmonary infections (90-100%), Gl
infections (e.g., Giardia), pneumonia,
autoimmune disease
(idiopathic thrombocytopenic purpura,
autoimmune hemolytic anemia),
malignancy (25%).
Common pathogens: Actinomyces israeli,
Streptococcus pneumoniae, Haemophilus
influenzae; chronic infections –
Staphylococcus aureus, Pseudomonas
aeruginosa.
 Immunoglobulins

34. - Ig G, not detectible Ig A & Ig M.
- T cells, normal function.
- diagnosed in male infants, 9-12 month.
Clinical manifestations:
- Pneumonia, otitis media, meningitis, sinusitis,
septicemia (Haemophilus influenzae type b,
Streptococcus pneumoniae, Neisseria
meningitidis);
-The recurrent infections can lead to tissue
destruction & injury;
- infants can grow normally if treated with
antibiotics & recurrent administration of human
immune globulin;
- passive immunotherapy isn’t always effective.
Many children die before the age 6.
- If the chield survives to adulthood, life
expectancy is decreased &large joint arthritis is
common.
Mutations in the gene for Bruton’s tyrosine kinase (Btk)
– an enzyme involved in intracellular signaling from
several B-cell receptors, including the IgM B-cell antigen
receptor, the IL-5 receptor, and the IL-6 receptor.
Ineffective signaling results in the arrest of the
development in the bone marrow of early cells in the B-
cell lineage into mature B cells.

35.  The most commonly diagnosed immune deficiency.
 Terminal differentiation of mature B cells to plasma cells is blocked.
 Characterized by hypogammaglobulinemia, but the particular class of
antibody that is  varies: most have low amounts of IgG, which may or may
not be accompanied by  levels of IgA or IgM, or both, with normal numbers
of B cells.
 Multiple genetic defects in terminal differentiation account for this condition,
although the specific defects have not been identified in most people.
 The age of onset of symptoms, such as recurrent bacterial respiratory
tract infections, is generally later than most primary immune deficiencies
(symptoms occurs much later, usually between the ages of 15 and 35 years,
and distribution of disease between the sexes is equal).
 Secondary complications include:
 - arthritis (infectious and noninfectious), chronic lung disease
-GIT symptoms
(malabsorption, chronic
diarrhea, hepatitis),
- autoimmune disease
(anemia, thrombocytopenia,
endocrine diseases),
- cancer (of the lymphoid
system, skin, and
gastrointestinal tract).
½ of persons with the disorder
have evidence of abnormal T-
cell immunity, suggesting that
this syndrome is a complex
immunodeficiency.

36.  Characterized by
elevated IgM
 Inability of T cells to induce B cell isotype switching (heavy chain) Due to
mutated CD40L (on helper T cells), located on X chromosome, or CD40 receptor
(on B cells); notably enzyme called activation-induced deaminase.
1. Second signal cannot be delivered to helper T cells during B-cell activation.
2. Consequently, cytokines necessary for immunoglobulin class switching are
not produced,
 Low IgA, IgG, and IgE result in recurrent pyogenic infections (due to poor
opsonization), especially at mucosal sites.
 Susceptible for intracellular pathogens, Pneumocystis jiroveci

37. DISEASE DEFECT(S) CLINICAL FEATURES
DiGeorge
syndrome
Failure of third and fourth
pharyngeal pouches to
develop
Thymus and parathyroid
glands fail to develop
Hypoparathyroidism (tetany); absent
thymic shadow on radiograph;
Pneumocystis jiroveci pneumonia
Danger of graft-versus-host reaction
Facial abnormalities, cardiac
malformations; depression of T-cell
number, & absence of T-cell responses
MHC class I
deficiency
Failure of TAP 1
molecules to transport
peptides to endoplasmic
reticulum
CD8+ T cells deficient,
CD4+ T cells normal,
Recurring viral infections, normal DTH,
normal Ab production
Bare
Lymphocyte
Syndrome/ MHC
class II
deficiency
Failure of MHC class II
expression, defects in
transcription factors
T cells present and responsive to
nonspecific mitogens, no GVHD,
deficient CD4+ T cells,
hypogammaglobulinemia. Clinically
observed as a severe combined
immunodeficiency.
Recurrent infections caused by intracellular pathogens
(fungi, viruses, protozoa)

38. Facial Anomalies Associated with
DiGeorge Syndrome
- Lack of thymus development,
- Partial or complete absence of the parathyroid gland (resulting in  blood calcium levels),
- Major structural defects in the heart and the aorta (resulting in inadequate blood flow and inadequate
oxygenation of the tissues),
- Abnormal facial characteristics (e.g., underdeveloped chin, low-set ears, shortened structure of the
upper lip). The facial disorders can include hypertelorism (i.e., increased distance between the eyes);
micrognathia (i.e., fish mouth); low-set, posteriorly angulated ears; split uvula; and high-arched palate.
- Urinary tract abnormalities also are common.
- The most common presenting sign is hypocalcemia and tetany that develops during the first 24 hours
of life. It is caused by the absence of the parathyroid gland and is resistant
to standard therapy.
The defect is attributed usually to deletions on chromosome 22, 22q11.2
(some deletions also have been identified on chromosome 10); about 25%
of which are inherited.
The deleted region encodes information for formation of organs
(structures that give rise to the thymus, parathyroid glands, and portions
of the face and aortic arch) that originate from the 3rd and 4th
pharyngeal pouches during the 12th week of gestation.

39. DISEASE DEFECT(S) CLINICAL FEATURES
Severe
combined
immunodefi-
ciency (SCID)
Adenosine deaminase deficiency
(15%); autosomal recessive disorder;
adenine toxic to B and T cells: 
deoxynucleoide triphosphate
precursors for DNA synthesis;
Other disorders: stem cell defect
Defective cell-mediated immunity;
 Immunoglobulins;
Treatment: gene therapy, bone marrow
transplant (patients with SCID do not reject
allografts).
Wiskott-Aldrich
syndrome
Progressive deletion of B and T cells
X-linked recessive disorder
Symptom triad: eczema, thrombocytopenia,
sinopulmonary infections; Associated risk of
malignant lymphoma; Defective cell-mediated
immunity. IgM, normal IgG,  IgA and IgE.
Ataxia-
telangiectasia
Mutation in DNA repair enzymes
Thymic hypoplasia
Autosomal recessive disorder
Cerebellar ataxia, telangiectasias of eyes and
skin;  Risk of lymphoma and/or leukemia;
adenocarcinoma;  Serum α-fetoprotein; IgA
50-80%,  IgE, IgM low molecular weight
variety,  IgG2 or total IgG;  T cell function
Defects in common γ chain of IL-2
receptor (present in receptor for IL-4, -
7, -9, -15)
Adenosine deaminase deficiency
(results in toxic metabolic products in
cell)
Chronic diarrhea; skin, mouth, & throat lesions;
opportunistic (fungal) infections; low levels of
circulating lymphocytes; cells unresponsive to
mitogens
Rag1 or rag2 gene nonsense
Total absence B + T cells

40. Deficiencies in
Complement
Components
Deficiency Signs/Diagnosis
Classic pathway C1q, C1r, C1s, C4, C2
Marked increase in
immune complex
diseases, increased
infections with
pyogenic bacteria
Both pathways C3
Recurrent bacterial
infections, immune
complex disease
C5, C6, C7, C8, or C9
Recurrent
meningococcal and
gonococcal infections
Deficiencies in
complement
regulatory proteins
C1-INH (hereditary
angioedema)
Overuse of C1, C4, or
C2, edema at mucosal
surfaces

41. a. Sexual transmission (75% of cases)
1) Most common cause is the man-to-man
transmission by anal intercourse;
2) Heterosexual transmission is the most
common cause in developing countries;
3) Virus enters blood vessels or dendritic cells
in areas of mucosal injury.
b. Intravenous drug abuse
• Rate of HIV infection is markedly  in female
sex partners of male intravenous drug
abusers.
c. Other modes of transmission
1) Vertical transmission (mother - baby):
 Transplacental route, blood contamination
during delivery, breast-feeding
 Most pediatric cases of AIDS are due to
transmission of virus from mother to child.
2) Accidental needlestick:
 Risk per accident is 0.3%.
 Most common mode of infection in health
care workers
3) Blood products

42.  Body fluids containing HIV
1) Blood, semen, breast milk
2) Virus can not enter intact skin or mucosa.
 Etiology
a. RNA retrovirus
b. HIV-1 is the most common cause in the USA, Europe, Central Arica.
c. HIV-2 is the most common cause in West Africa and India.
 Pathogenesis
a. HIV envelope protein (gp120) attaches to the CD4 molecule of T cells.
b. HIV infects CD4 T cells, causing direct cytotoxicity.
c. Infection of non-T cells:
1) Can infect monocytes and macrophages in tissue (e.g., lung, brain)
2) Can infect dendritic cells in mucosal tissue
Dendritic cells transfer virus to B-cell germinal follicles,
3) Macrophages and dendritic cells
are reservoirs for virus.
 Loss of cell-mediated immunity
d. Reverse transcriptase:
1) Converts viral RNA into pro-viral
double-stranded DNA
2) DNA is integrated into the bust DNA.

43. Clinical findings
a. Acute phase
• Mononucleosis-like syndrome 3 to 6 weeks after infection
b. Latent (chronic) phase
1) Asymptomatic period 2 to 10 years after infection
2) CD4 T-cell count greater than 500 cells/mm3
3) Viral replication occurs in dendritic cells (reservoir cells)
in germinal follicles of lymph nodes.
• Cytotoxic T cells control but do not clear HIV reservoirs.
c. Early symptomatic phase
1) CD4 T-cell count 200 to 500 cells/mm3
2) Generalized lymphadenopathy
3) Non-AlDS-defining infections, including hairy leukoplakia,
or Epstein-Barr virus (EBV)-caused glossitis, oral candidiasis.
4) Fever, weight loss, diarrhea.
• Most common CNS fungal infection in AIDS: cryptococcosis
d. AIDS:
Criteria - HIV-positive with CD4 T-cell count of 200 cells/mm3 or less or an AIDS defining
condition
Most common AIDS-defining infections: Pneumocystis Jiraveci pneumonia, systemic candidiasis
AIDS-defining malignancies: Kaposi's sarcoma, Burkitt's lymphoma (EBV), primary CNS
lymphoma (EBV)
Causes of death: Disseminated infections (cytomegalovirus, Mycobacterium avium complex)
HIV Rash

44. HUMAN
IMMUNODEFICIENCY
VIRUS (HIV) -
ASSOCIATED APHTHOUS
ULCER.
A, This large ulcer
extends from the uvula
to the soft palate. These
lesions are frequent in
patients with acquired
immunodeficiency
syndrome (AIDS) and
may occur on the
tongue or buccal
mucosa or in the
hypopharynx. They may
become large,
simulating an infectious
or neoplastic process.
B, Deep ulcer on the
lateral aspect of the
tongue. Note in the
distance a well-
circumscribed,
similarappearing ulcer is
present on the hard
palate.
C, Well-circumscribed,
clean-based ulcer on the
tongue.
D, Multiple ulcerations on the lower lip. This patient with severe odynophagia
also had a large idiopathic esophageal ulceration.

45. Immunologic abnormalities
1) Lymphopenia (low CD4 T-cell count)
2) Cutaneous anergy (defect in cell-mediated
immunity)
3) Hypergammaglobulinemia (due to polyclonal B-
cell stimulation by EBV)
4) CD4:CD8 ratio < 1
 CD4 count and risk for certain diseases
1) 700 to 1500: normal
2) 200 to 500; oral thrush, herpes zoster (shingles),
hairy leukoplakia
3) 100 to 200: Pneumocystis pneumonia, dementia
4) Below 100: toxoplasmosis, cryptococcosis,
cryptosporidiosis
5) Below 50: CMV retinitis. Mycobacterium avium
complex, progressive multifocal
leukoencephalopathy, primary central nervous
system lymphoma
Pregnant women with AIDS
• Treatment with a reverse transcriptase inhibitor
reduces transmission to newborns to
less than 8%.

46. Allergy (from Greek “allos” – “other”, “ergon” –
“action”) is the state of the increasing sensitiveness of
the organism to the repeated penetrating of allergen
which is characterized by immunological mechanisms
and self injury.
Allergy is an immune response, which is
followed by damage of own tissues.
Allergic diseases – is a group of diseases, in development base of
which damage lies, caused by an immune reaction on allergens.
Allergic diseases are widely spread among people. It is considered that
they cover about 10 % of earth population. In different countries these
sizes vacillate from 1 to 50 % and more.

47. General etiology of allergic diseases
The cause of allergic diseases is the allergen, the conditions of their
appearing are the specific peculiarities of the environment and state of organism
reactivity.
Allergen – is a substance that causes
development of an allergic reaction.
Allergens have all properties of antigens (macromolecularity, mainly protein
nature, foreign for a particular organism). However allergic reactions can be
caused by substances of not only antigen nature, but also substances, not
possessing these properties. To this group belong many officinal preparations,
bacterial products, polysaccharides, simple chemical substances (bromine, iodine,
chrome, nickel). These substances are called
haptens.
While entering the organism they become
antigens (allergens) only after binding with
tissues proteins. Here with complex antigens,
which sensitize the organism are formed.

49. 49
HYPERSENSITIVITY
IMMEDIATE
TYPE I
Ig E - mediated
TYPE II
Cytotoxic
TYPE III
Immune Complex
DELAYED
TYPE IV
Cellular
The classification by
P.Gell, R.Coombs is
widely spread in the world. It is
based on pathogenic principle.
By Rought (in 1980)
V type - stimulating.
I – IgE,
II, III – IgM, G,
IV – T-effectors,
V - IgM, G
Soluble mediators, performed
actors-fast reactions of less than
30 min
Soluble mediators, performed
actors-slower reactions of less
than 8 hours
Soluble mediators, performed
actors-slower reactions of less
than 8 hours
Cellular mediators, performed
actors-slow reactions of more
than 1 day

50. THE PATHOGENESIS OF
ALLERGIC REACTIONS
STAGE I: IMMUNOLOGICAL
STAGE II: PATHOCHEMICAL CHANGES
STAGE III: PATHOPHYSIOLOGICAL CHANGES

51. In the development of
allergic reaction there are
three stages:
• 1. Immunological stage. It covers all
the changes in immune system during
the penetration of an allergen into the organism, formation of
antibodies or sensitized lymphocytes and their binding with the
repeatedly entering allergen.
• 2. Pathochemical stage. Its sense is in formation of biological
active substances. The stimulus to their formation is the binding of
allergen to antibodies or sensitized lymphocytes at the end of
immunological stage.
• 3. Pathophysiological stage. It is described by pathogenic action of
formed mediators onto cells, organs and tissues of the organism
with a clinical display.

52. • Sensibilization is the
immunologically mediated
increasing sensitiveness of
the organism to the allergens.
• Sensibilization
(sensitizing) are:
– active (independent
production of immunoglobulin
by the organism)
– passive (introduction of the ready antibodies from
actively sensitized animals). The synthesis of the
antibodies begins on the 3rd - 4th day after the first
penetrating of the allergen and achieves the maximum
in 2 weeks.

53. • IgE and IgG4 are formed as an answer to
penetrating of allergen into the
organism. They get fixed on the mast
cells and basophiles of blood.
• These cells have on their surface
Fc-receptors for immunoglobulin. The
state of sensitization of the organism
appears. If the same allergen again gets
into the organism or it still stays in the
organism after the first penetration,
connection of antigen with IgE-
antibodies occurs.
The same thing is observed with IgG4.
They bind with their receptors on
basophiles, macrophages, eosinophiles,
trombocytes.
Depending on the quantity of
molecules of IgE-antibodies connected
to antigen, quantity of antigen we can
observe either inhibition of activity of
the cell or its activation and transfer of
the process to the next, pathochemical
stage.
1. Initial antigen contact

54. Stage II (pathochemical)
• At the repeated
penetrating the allergen
associates with the
Fc-fragment of IgE
activating of basophiles activation
of arachidonic acid cascade is
liberation of prostaglandins and
leukotrienes degranulation of mast cells
(the freeing of biologically active substances
(BAS).

55.  Stimulation of H1 promotes to contraction of smooth
muscles, endothelial cells and postcapillary part of
microcirculation. This leads to increasing of permeability of
vessels, development of edema and inflammation.
 Stimulation of H2 causes the opposite effects.
 Besides this releasing of histamine from basophile leucocytes
and from the lungs is diminished through them, the function of the
lymphocytes modulates, formation of migration ingibitory factor
(MIF) by T-lymphocytes gets
oppressed, releasing of lysosome
enzymes by neutrophile leucocytes
diminishes as well. In many cases
the increasing of quantity of
histamine in blood is observed in
the intensive stage of bronchial
asthma, nettle-rash, officinal
allergy.

56. • Stage III.
• Under the influence of mediators the permeability of vessels and chemotaxis of
neutrophiles and eosinophiles increase, which leads to development of
inflammatory reaction.
• The increasing of permeability of vessels promotes the exit of fluid,
immunoglobulins and complement into tissues. With the help of mediators and
also through the IgE-antibodies, the cytotoxic effect of macrophages is activated,
secretion of enzymes, prostaglandins and leukotriens, trombocyte activating factor
is stimulated.
• The released mediators cause also a damaging action onto cells and connective
tissue structures.
• Bronchospasm develops in respiratory organs. These effects are clinically
manifested by attacks of bronchial asthma, rhinitis, conjunctivitis, nettle-rash, skin
itch, diarrhea.
• They distinguish the local reactions of the anaphylactic type. E.g.: bronchial
asthma, pollinosis (or pollen disease, grass pollen allergy, hay fever), nettle-rash (or
hives) and general ones (anaphylactic shock).

57. IgE antibody-mediated activation of mast cells (effector cells) produces an inflammatory reaction.
1. IgE antibody production (sensitization)
 a. Allergens (e.g., pollen, drugs) are first processed by APCs (macrophages or dendritic cells).
 b. APCs interact with CD4 Th2 cells, causing interleukins (ILs) to stimulate B-cell maturation.
 c. IL-4 causes plasma cells to switch from IgM to IgE synthesis.
 d. IL-5 stimulates the production and activation of eosinophils.
2. Mast cell activation (re-exposure)
 a. Allergen-specific IgE antibodies are bound to mast cells.
 b. Allergens cross-link IgE antibodies specific for the allergen on mast cell membranes.
 c. lgE triggering causes mast cell release of preformed mediators.
1) Early phase reaction with release of histamine, chemotactic factors for eosinophils, proteases
2) Produces tissue swelling and bronchoconstriction
 d. Late phase reaction
1) Mast cells synthesize and release prostaglandins and leukotrienes,
2) Enhances and prolongs acute inflammatory reaction
3. Tests used to evaluate type I hypersensitivity
 a. Scratch test (best overall sensitivity)
• Positive response is a histamine-mediated wheal-and-flare reaction after introduction of an allergen
into the skin.
 b. Radioimmunosorbent test
• Detects specific IgE antibodies in serum that are against specific allergens.
4. Clinical examples: Atopic disorders: hay fever, eczema, hives, asthma, reaction to bee sting
Drug hypersensitivity: penicillin rash or anaphylaxis.

58. Anaphylactic shock develops in severe complication. Spasm of
smooth muscles of internal organs with clinical manifestation
of bronchospasm (cough, expiratory breathlessness),
 spasm of gastro-intestinal tract muscles (spastic pain in the
whole abdomen, nausea, vomiting, diarrhea),
 spasm of uterus in women (pain below abdomen) are
observed.
Spastic phenomena are worsened by edemas of mucous covers
of internal organs, during the edema of larynx the picture of
asphyxia may develop.
The arterial pressure is sharply decreased, the heart
insufficiency, ischemia of brain, seizes, paralysis develop,
danger for the life of the patient appears.

61. • Antigens:
a) components of membranes of own cells (unchanged and changed under the action of
different factors);
b) antigens are fixed (adsorbed) on cellular membranes (for example, medicinal preparations);
c) non-cellular components of tissues (collagen, myelin).
• Antibodies: IgG1, IgG2, IgG3, rare Ig M and Ig A.
• Mechanisms of tissue injury: opsonization and phagocytosis of cells;
complement- and Fc receptor-mediated recruitment and activation of neutrophils and
macrophages; abnormalities in cellular functions (hormone/receptor signaling)

62. THE PATHOGENESIS OF THE CYTOTOXIC TYPE ALLERGIC REACTIONS
► Stage II:
Mediators of the cytotoxic type allergic reactions:
► Complement components; Lysosomal enzymes;
► Oxygen’s radicals; TNF;
► Perforine (channel-forming protein).
The damage of the cell with the antigen properties
may be caused by three reasons:
► the 1st variant – complement-mediated cytotoxicity.
► the 2nd variant – antibody-mediated immune clearance
(phagocytosis).
► the 3rd variant – antibody-dependent [cell-mediated]
cytotoxicity
Stage III:
► Remedies [medicamentous] allergy;
► Hemolytic anemia (illness) of newborns;
► Post transfusion reactions (shock) in incompatible
blood transfusion after the groups of АВО or Rhesus factor;
► Auto allergic diseases.
Cytotoxic type of the
allergy can be a
manifestation of
officinal allergy with
the development of
leucocytopenia,
trombocytopenia,
hemolytic anemia etc.
This may also happen
in blood transfusion
and also in rhesus
incompatibility of
mother and fetus.

64. Antibody-dependent cytotoxic reactions
1. Complement-dependent reactions
a. Lysis (IgM-mediated)
1) Antibody (IgM) directed against antigen on the cell membrane activates the complement
system, leading to lysis of the cell by the membrane attack complex.
2) Example: IgM types of cold immune hemolytic anemias;
Transfusion of group A blood (contains anti-B-lgM antibodies) into a group B
individual
b. Lysis (IgG-mediated)
1) IgG attaches to basement membrane/matrix → activates complement system → C5a is
produced (chemotactic factor) → recruitment of neutrophils/monocytes to the activation site →
release of enzymes, reactive oxygen species → damage to tissue
2) Example: Coodpasture’s syndrome with lgG antibodies directed against pulmonary and
glomerular capillary basement membranes;
Acute rheumatic fever with IgG antibodies directed against antigens in heart, skin,
brain, subcutaneous tissue, joints.
c. Phagocytosis
1) Fixed macrophages (e.g., in spleen) phagocytose hematopoietic cells (e.g., RBCs)
coated by IgG antibodies or complement (C3b).
2) Example: Warm (IgG) immune hemolytic anemia;
ABO hemolytic disease of the newborn.
• Croup O mother has anti-A,B-IgG antibodies that cross the placenta and attach to fetal blood
group A or B red blood cells.

65. DISEASE TARGET ANTIGEN
MECHANISM OF
PATHOGENESIS
CLENICAL
MANIFESTATTIONS
Cytotoxic
Autoimmune
hemolytic anemia
(HDNB)
RBC membrane proteins
(Rh, I Ags)
Opsonization, phagocytosis, &
complement-mediated
destruction of RBCs
Hemolysis, anemia
Acute rheumatic
fever
Streptococcal cell-wall Ag-Ab
cross-reacts with myocardial Ag
Inflammation, macrophage
activation
Myocarditis, artritis
Goodpasture
syndrome
Type IV collagen in basement
membranes of kidney
glomeruli & lung alveoli
Complement- & Fc-receptor-
mediated inflammation
Nephritis, lung
hemorrhage, linear
Ab deposits
Transfusion
reaction
ABO blood glycoproteins Ig M isohemagglutinins
formed naturally in response
to normal bacterial flora cause
opsonization + complement
activation
Hemolysis
Autoimmune
thrombocytopenic
purpura
Platelet membrane proteins Ab-mediated platelet
destruction through
opsonization &complement
activation
Bleeding

66. 2. Complement-independent reactions:
a. Antibody IgG-dependent cell-mediated cytotoxicity
 Cells are coated by IgG → leukocytes (neutrophils, monocyte, NK cells) bind to IgG
→ activated cells release inflammatory mediators causing Iysis of the cells.
 Example: killing virus-infected cells or tumor cells.
b. Antibody IgE-dependent cell-mediated cytotoxicity
• Helminth in tissue is coated by IgE antibodies → eosinophil IgE receptors attach
to the IgE → eosinophils release major basic protein, which kills the helminth.
c. IgG autoantibodies directed against cell surface receptors → impair function of the
receptor (e.g.. anti-acetylcholine receptor antibodies in myasthenia gravis) or
stimulate function (e.g., anti-thyroid-stimulating hormone receptor antibodies in
Graves' disease)
Tests used to evaluate type II hypersensitivity:
a. Direct Coombs’ test detects IgG and C3b attached to RBCs.
b. Indirect Coombs’ test detects antibodies (e.g., anti-D) in serum.

67. DISEASE TARGET ANTIGEN
MECHANISM OF
PATHOGENESIS
CLENICAL
MANIFESTATTIONS
Non-cytotoxic
Myasthenia gravis Acetylcholine receptor Ab inhibits acetylcholine
binding, down-
modulates receptors.
Muscle weakness,
paralysis
Graves disease TSH receptor Ab-mediated
stimulation of TSH
receptors
Hyperthyroidism
followed by
hypothyroidism
Type II (non-insulin-
dependent) diabetes
Insulin receptor Ab inhibits binding of
insulin
Hyperglycemia
Pernicious anemia Intrinsic factor of
gastric parietal cells
Neutralization of
intrinsic factor,
decreased absorption
of vitamin B12
Abnormal
erythropoiesis,
anemia

69. Activation of the complement system by
circulating antigen-antibody complexes (e.g.,
DNA - anti-DNA complexes)
First exposure to antigen → synthesis of
antibodies;
Second exposure to antigen:
a. Deposition of antigen-antibody complexes
b. Complement activation, producing C5a, which
attracts neutrophils that damage tissue
Arthus reaction
a. Localized immunocoinplex reaction
b. Example: farmer's lung from exposure to
thermophilic actinomycetes, or antigens, in air
Test used to evaluate type III hypersensitivity
a. Immimofluorescent staining of tissue biopsies
b. Example: glomeruli in glomerulonephritis
TYPE III (IMMUNOCOMPLEX)
HYPERSENSITIVITY

70. The inflammation may lead to formation of ulcers, hemorrhages,
thrombosis is possible in the vessels. This type of allergic reactions is
the prominent one in development of serum, some cases of officinal
and food allergy, some autoallergic diseases (rheumatoid arthritis,
systemic red lupus erythematosus). In case of massive activation of
complement anaphylactic shock, bronchial asthma may develop.
Pathophysiological
stage. Usually immune
complexes are placed on
vessels of cannalicular
apparatus of kidneys,
inflammation with alteration,
exudation and proliferation
(glomerulonephritis)
develops, in case if the
complexes are placed in the
lungs alveolitis appears, in
skin – dermatitis.

71. 71
In systemic lupus
erythematosus (a.k.a. SLE,
lupus), nuclear components
of disintegrating white blood
cells elicit IgG production
Immune complexes aggregate
in the skin and organs, causing
rash and lesions
Rheumatoid arthritis (RA) is
an inflammatory condition
resulting in accumulation of
immune complexes in joints

72. Disease Antigen Involved
Clinical
Manifestations
Systemic
lupus erythe-
matosus
dsDNA, Sm, other
nucleoproteins
Nephritis, arthritis,
vasculitis, butterfly
facial rush
Rheumatoid
arthritis
Ig M versus IgG Fc
region
Joint pain, erosions
Poststrepto-
coccal
glome-
rulonephritis
Streptococcal cell wall
Ags (may be “planted”
in glomerular
basement membrane
Nephritis, “lumpy-
bumpy” deposits
Serum
sickness
Various proteins Arthritis, vasculitis,
neprhritis
Arthus
reaction
Any injected protein Local pain and
edema

73. 1. Initial contact with antigen
Cell-mediated hypersensitivity reactionImmunological stage.
☻ The foreign antigen is
phagocyted by macrophages
and get to T-helpers.
☻ At the same time
macrophages secrete IL-1,
which stimulates T-helpers.
The latest excrete the growth
factor pro-T-lymphocytes –
IL-2, which activates and
supports proliferation of
antigen stimulated T-cells.
☻ This process leads to
formation of sensitized
lymphocytes.
☻ They belong to T-
lymphocytes and in the cell
membrane they have
receptors of the antibody
type, which are able to
connect with the antigen.
☻ In case of repeated
penetration of the allergen
into the organism it binds
with the sensitized
lymphocytes.

74. Pathochemical stage. This leads to morphological, biochemical and
functional change in lymphocytes.
They are presented by blast transformation and proliferation,
increasing of synthesis of DNA, RNA and proteins and
excretion of different mediators, which are called
lymphokines. With the help of lymphokines (MIF,
interleukines, chemotaxic factors, factor of transfer)
mobilization of different cells (macrophages, polymorph-
nuclear), increasing of chemotaxic activity and placing in
the site of allergen occur.
• MIF promotes accumulation of macrophages in the site
of allergic damage, increases their activity and phagocytosis.
It takes part in formation of granulems during infectious-
allergic diseases, increase the ability of macrophages
to destroy certain kinds of bacteria.
• There are several kinds of chemotaxic factors, each
of which is called chemotaxis of leukocytes –
macrophages, neutrophiles, eosinophiles and basophiles.
Lymphotoxins cause damage and destroying of all
different target-cells.
• Interferon is secreted by lymphocytes and under the
influence of α-interferon and nonspecific mitogens. It
acts a modulating influence on cellular and
humoral mechanisms of immune reaction.
• Besides lymphokines, lizosome enzymes also provide
a damaging activity. They are released during
phagocytosis and destroying of cells. Kallikreine-kinine
system is also activated. Histamine doesn’t play a big role
in this type of allergic reactions.

75. Pathophysiological stage. A particular form of lymphokines
(lymphotoxin, interferon) shows a cytotoxic action and
decreases activity of cell. In allergic reaction of delayed type
damaging action may develop in several ways:
• 1) direct cytotoxic action of sensitized T-lymphocytes on target-
cells, which acquired autoallergen properties;
• 2) cytotoxic activity of T-lymphocytes, mediated by
lymphotoxin;
• 3) releasing of lysosome enzyme, which damage tissue
structures during phagocytosis.
• Inflammation that is associated to immune reaction by action of
mediators is a component of allergic reaction of delayed-type.
Nevertheless inflammation is at the same time a factor of
damage of function of the organs.
• Allergic reactions of delayed type make the base of development
of infectious-allergic diseases (tuberculosis, lepra, brucellosis,
syphilis), rejection of transplant, and autoallergic diseases
(disturbance of nervous system, endocrine glands etc.).

76. A, In delayed type hypersensitivity reactions, CD4+ T cells (and sometimes CD8+ cells) respond
to tissue antigens by secreting cytokines that stimulate inflammation and activate phagocytes,
leading to tissue injury. B, In some diseases, CD8+ cytolytic T lymphocytes (CTLs) directly kill
tissue cells. APC, antigenpresenting cell.

77. Type IV hypersensitivity
 Antibody-independent T cell-mediated reactions (cellular-mediated immunity, CMI)
Functions of CMI
a. Control of infections caused by viruses, fungi, helminths, mycobacteria, intracellular bacterial
pathogens
b. Graft rejection
c. Tumor surveillance
Types of reactions:
a. Delayed reaction hypersensitivity (DRH)
• CD4 cells interact with macrophages (APCs with MHC class II antigens), resulting in cytokine
injury to tissue.
b. Cell-mediated cytotoxicity
1) CD8 T cells interact with altered MHC class I antigens on neoplastic, virus-infected, or donor
graft cells, causing cell lysis.
2) Contact dermatitis → CD8 T cells attack antigens in skin (e.g.. poison ivy, nickel).
Test used to evaluate type IV hypersensitivity:
a. Patch test to confirm contact dermatitis.
• Example: suspected allergen (e.g.. nickel) placed on an adhesive patch is applied to the skin to
see if a skin reaction occurs.
b. Skin reaction to Candida.
c. Quantitative count of T cells.
d. Various mitogenic assays.

80. Factors enhancing graft viability
1. ABO blood group compatibility between recipients and donors
2. Absence of preformed anti-HLA cytotoxic antibodies in recipients
• People must have previous exposure to blood products to develop anti-HLA cytotoxic
antibodies.
3. Close matches of HLA-A, -B, and -D loci between recipients and donors
4. Chance of a sibling in a family having another sibling with a 0, 1, or 2 haplotype match.
Types of grafts
1. Autograft (i.e., self to self), associated with the best survival rate
2. Syngeneic graft (isograft),
Between identical twins
3. Allograft - between genetically
different individuals of the same species
4. Xenograft - between two species,
Example—transplant of heart valve from
pig to human

81. • Transplantation rejection involves a humoral or cell-mediated host response against
MHC antigens in the donor graft.
1. Hyperacute rejection - irreversible reaction occurs within minutes.
Pathogenesis
1) ABO incompatibility or action of preformed anti-HLA antibodies in the recipient directed
against donor antigens in vascular endothelium
2) Type II hypersensitivity reaction (pathologic finding: vessel thrombosis)
Example—blood group A person receives a blood group B heart.
2. Acute rejection, most common transplant rejection; reversible reaction that occurs
within days to weeks
1) Type IV cell-mediated hypersensitivity:
(a) Host CD4 T cells release cytokines, resulting in activation of host macrophages,
proliferation of CD8 T cells, and destruction of donor graft cells.
(b) Extensive interstitial round cell lymphocytic infiltrate in the graft, edema, and
endothelial cell injury
2) Antibody-mediated type II hypersensitivity reaction:
(a) Cytokines from CD4 T cells promote B-cell differentiation into plasma cells,
producing anti-HLA antibodies that attack vessels in the donor graft.
(b) Vasculitis with intravascular thrombosis in recent grafts
(c) Intimal thickening with obliteration of vessel lumens in older grafts
3. Chronic rejection, irreversible reaction that occurs over months to years
Pathogenesis: not well characterized, involves continued vascular injury with ischemia to
tissue; blood vessel damage with intimal thickening and fibrosis.

82. In the direct pathway,
donor class I and class II
antigens on antigen-
presenting cells in the graft
(along with B7 molecules,
not shown) are recognized
by CD8+ cytotoxic T cells
and CD4+ helper T cells,
respectively, of the host.
CD4+ cells proliferate and
produce cytokines that
induce tissue damage by a
local delayed
hypersensitivity reaction
and stimulate B cells and
CD8+ T cells. CD8+ T cells
responding to graft antigens
differentiate into cytotoxic T
lymphocytes that kill graft
cells.
In the indirect pathway,
graft antigens are displayed
by host APCs and activate
CD4+ cells, which damage
the graft by a local delayed
hypersensitivity reaction.
The example shown is of a
kidney allograft.

84. 1. Causes
a. Potential complication in bone marrow (85% of Cases) and liver transplants
b. Potential complication in blood transfusions given to patients with a T-cell
• immunodeficiency and newborns
2. Pathogenesis
a. Donor cytotoxic T cells recognize host tissue as foreign
b. Proliferate in host tissue and produce severe organ damage
3. Clinical findings
a. Bile duct necrosis (jaundice)
b. Gastrointesitnal mucosa ulceration (bloody diarrhea)
c. Dermatitis
4. Treatment
 Treat with anti-thymocyte globulin or monoclonal antibodies before grafting
 Cyclosporine reduces the severity of the reaction.
TYPES OF SOME TRANSPLANTS
TYPE OF TRANSPLANT COMMENTS
Cornea
Best allograft survival rate
Danger of transmission of Creulzfeldt-Jakob disease
Kidney Belter survival with kidney from living donor than from cadaver
Bone marrow
Craft contains pluripotential cells that repopulate host stem cells
Host assumes donor ABO group
Danger of graft-versus-host reaction and cytomegalovirus infection

86.  Robbins and Cotran Pathologic Basis of Disease 9th edition./ Kumar, Abbas, Fauto.
– 2013. – Chapter 4.
 Robbins and Cotran Pathologic Basis of Disease 8th edition./ Kumar, Abbas, Fauto.
– 2007. – Chapter 7.
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2011.
 Essentials of Pathophysiology: Concepts of Altered Health States (Lippincott
Williams & Wilkins), Trade paperback (2003) / Carol Mattson Porth, Kathryn J.
Gaspard. Chapter 10.
 Pathophysiology, N.K. Symeonova. Kyiv, AUS medicine Publishing. – 2010.
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 Pathophysiology, Concepts of Altered Health States, Carol Mattson Porth, Glenn
Matfin.– New York, Milwaukee. – 2009.
 Silbernagl S. Color Atlas of Pathophysiology / S. Silbernagl, F. Lang // Thieme.
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