Immunopathology lecture 2+3 ,final

Disorders of Immunity A- Mechanisms of immune- mediated injury (Hypersensitivity Reactions) B- Autoimmune Diseases C- Immunodeficiency Diseases D- Amyloidosis

Hypersensitivity (Allergy, immune mediated injury)
Hypersensitivity: A change in the tissue reaction following re-exposure to antigen
Antigen (first time)  No harmful effect + stimulation of formation of specific antibodies
(Second time)  Ag will react with the specific antibody fixed on the cells
Cellular damage with severe inflammatory reaction = hypersensitivity
OR Hypersensitivity is a state of altered immune responsiveness in which a severe and harmful immune reaction occurs on exposure to the antigen.

IMMUNE MECHANISMS OF TISSUE INJURY Hypersensitivity reactions/diseases
Classified into 4 types based on the immune mechanisms of tissue injury:
Type I , Type II , Type III and Type IV.

Type I Hypersensitivity Anaphylaxis; Anaphylactic Reaction
Mast cell proliferation and IgE production by plasma cells
IgE bound mast cells
Recurrent exposure:
-- Mast cell degranulation
-- Vasodilation
-- Bronchoconstriction, etc.
ECF = eosinophil chemotactic factor NCF = neutrophil chemotactic factor PAF = platelet-activating factor

Phases of Type I Hypersensitivity
Initial (rapid) response : within 5-30 min after re-exposure with resolution within 30 min, mediated by primary mast cell mediators
Second (delayed) phase: 2-8 hours later, lasts for days and characterized by an intense infiltration by inflammatory cells and tissue damage. It is mediated by secondary mast cell mediators.

Type I Hypersensitivity A sequence of Events Photo: Kumar, Cotran, Robbins. Robbins Basic pathology, 7 th ed., Saunders, Philadelphia, 2003.

Systemic anaphylaxis:
-- Acute asthma
-- Laryngeal edema
-- Diarrhea
-- Urticaria
-- Shock (Anaphylactic shock)
Typically follows oral administration pf allergen as:
E.g.: penicillin allergy
E.g.: bee sting allergy
Antisera, Drugs, Hormones
Type I Hypersensitivity Reaction Clinical Manifestations

Local anaphylaxis (Atopy):
- Food allergies
-- Urticaria or Hives
-- Asthma
-- Hay fever/ allergic rhinitis
(Ragweed pollen)
-Wheal reaction: Local area
Of erythema and edema due to Intradermal injection of antigen in sensitized individual.
Type I Hypersensitivity Reaction Clinical Manifestations Eosinophil

Type II Hypersensitivity
1- Complement Dependent Reaction:
Antibody is directed against a tissue antigen
-- e.g. RBC or basement membrane
Ag-Ab complexes activate complement leading to cell lysis or extracellular tissue damage
Two mechanisms:
A- Direct Lysis
B- Opsonization (Enhanced phagocytosis).
Ex:
Transfusion reactions
Hemolytic anemias
Goodpasture,s disease of the kidney

Type II Hypersensitivity 2- Antibody- Dependent Cell- Mediated Cytotoxicity (ADCC)
Targets are lysed by non- sensitized cells with Fc receptors.
NK (natural killer) cells, monocytes, and granulocytes then bind to the immunoglobulin Fc receptors and causes damage

Type II Hypersensitivity Reaction 3- Antibody- mediated cellular dysfunction
Myasthenia gravis : Antibodies against acetylcholine receptors in motor end plate of SM impair neuromuscular transmission & result in muscle weekness.
Grave's disease (thyrotoxicosis):
Anti-TSH receptor antibody stimulate thyroid and result in hyperthyroidism.
Antibodies directed against cell surface receptors impirs or dysregulate function without causing cell injury. Ex:

Type II Hypersensitivity Antibody-Mediated Injury
Myasthenia gravis
(Acetylcholine receptor antibody)
Photo: Kumar, Cotran, Robbins. Robbins Basic pathology, 7 th ed., Saunders, Philadelphia, 2003.

Type II Hypersensitivity Reaction Clinical Manifestations
Transfusion and transplant reactions
Rhesus incompatibility between Rh-negative mother and Rh-positive fetus ( erythroblastosis fetalis )
Erythroblastosis fetalis
Elevated Rh antibody titers
Many immature RBCs in blood
Excess bilirubin from RBC breakdown
-- Hyperbilirubinemia (yellow tissues)
First baby = OK, because IgM cannot cross
placenta, after that, IgG takes over
Progressive anemia, ischemia, death
Brain damage from bilirubin: kernicterus
Prevention: Rh- mother gets anti-D
immunoglobulin after birth (covers antigenic
sites on baby’s RBCs in mother’s blood
Rx: phototherapy of baby (breaks bilirubin)
Immune hydrops from Rh hemolysis

Type II Hypersensitivity Reaction Clinical Manifestations
Autoimmune hemolytic anemia
Agranulocytosis
Thrombocytopenia
Pemphigus vulgaris
Pemphigoid
(Cicatricial pemphigoid)
Pemphigoid Pemphigoid

Type III Hypersensitivity Immune Complex Mediated
Ag-Ab complexes is formed either in circulation or extravascular.
Tissue damage primarily through complement activation
Exogenous antigen: i.e. bacterial, viral
Endogenous antigen: i.e. DNA antigens
C3b acts as an opsonin
C5a acts as a chemoattractant for neutrophils
-- Acute Necrotizing Vasculitis

Type III Hypersensitivity Immune Complex Mediated
Immune complexes can be deposited:
I- Systemically (Serum sickness type) due to administration of large amount of foreign serum.
II- Locally (Arthus reaction type)
Common clinical findings: Fever Urticaria Arthralgia Lymphadenopathy Proteinuria

I- Systemic Immune Complex Disease

Immune Complex Mediated (Type III) Damage Systemic
Acute (single large dose of Ag exposure):
Acute serum sickness
Poststreptococcal glomerulonephritis
Chronic (persistent/repeated Ag exposure):
Systemic lupus erythematosus
Rheumatoid arthritis
Membranous glomerulonephritis
-- Inciting antigens = unknown

Immune Complex Deposition in Glomerulus Type III Hypersensitivity

II- Local Immune Complex Disease (Arthus Reaction)
It is defined as a localized area of tissue necrosis resulting from acute immune complex vasculitis.
local formation and deposition of immune complexes
Planting of antigen within a particular tissue (e.g., renal glomeruli) with subsequent formation of immune complexes
Produced experimentally by intracutaneous antigen injection in a sensitized host carrying antibody= Ab in excess
Large immune complexes deposition  complement and coagulation cascades activation and platelets aggregation lead to fibrinoid necrosis
Superimposed thrombosis may cause tissue necrosis.

Type IV Hypersensitivity (Cell- Mediated)
Initiated by specifically sensitized T lymphocytes rather than antibodies.
Includes Delayed-type hypersensitivity and T-cell mediated cytotoxicity .
1) Delayed-Type Hypersensitivity (DTH):
Principle pattern of response in T.B., fungi, protozoa & parasites, & graft rejection and tumor immunity.
Mediated by CD4 cells of the Th1 that secrete specific cytokines after encounter the processed antigen in association with class II major histocompatibility complex.
The induction of CD4 response is facilitated by IL-12 that secreted by macrophages that have engulfed microbes or other antigen
cytokines mediate injury by recruiting and activating antigen-nonspecific monocytes and macrophages.
with persistence of non-degradable antigens, the initial non-specific infiltrate of T cells and macrophages is replaced by collections of macrophages that transform into epitheliod cells forming local granuloma. So a granuloma is a special form of DTH.

Type IV Hypersensitivity Delayed Hypersensitivity Reaction
CD4+ T lymphocytes + class II HLA molecules
Numerous cytokines
Macrophages
Anti-CD4 Antibodies

Granuloma Formation Multinucleated giant cell

2) T cell-Mediated Cytotoxicity
Sensitized CD8+ cytotoxic T lymphocytes (CTLs) is the principle pattern of response in this type of response.
e.g. a- Viral infection b- Tumor cells c- Transplant rejection
Class I MHC molecules bind to intracellular viral peptides and present them to CD8+ T lymphocytes.
Mechanism of of CTL Killing:
1- Perforin- granzyme- dependent killing:
Perforin and granzyme are soluble mediators of the CTLs that induce apoptosis of the target cells.
2- Fas- Fas ligand- dependent killing :
Activated CTLs express Fas ligand (a molecule with homology to TNF) which binds to Fas on target cells that leads to apoptosis.

Immunopathology lecture 2+3 ,final

by دكتور مريض on Dec 26, 2011

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