D R S H O AI B R AZ A

HYPERSENSITIVITY REACTIONS

HYPERSENSITIVITY REACTIONS

• Are exaggerated immune response upon antigenic

stimulation

• Individuals who have been previously exposed to

an antigen are said to be “Sensitized”

• Repeat exposure to same antigen may trigger a

pathologic reaction

• Implying an excessive response to an antigen

GENERAL CONSIDERATION

• Both exogenous and endogenous antigens may elicit

reaction

• Dust, pollen, foods, drugs, microbes, chemicals

• Autoimmune disorders against self antigens

• Reactions are often associated with inheritance of

particular susceptible gene(HLA-gene)

• Reflects an imbalance between the effector

mechanism and control mechanisms of immune

responses.

CLASSIFICATION

• Classification is based on

• Immunologic mechanism that mediate the disease

• Multiple mechanisms may be involved

• Classified into

• Type I (Immediate type)

• Type II (antibody mediated)

• Type III (Immune complex mediated)

• Type IV (cell mediated )

TYPE I HYPERSENSITIVITY REACTION

• Immediate type HR

• Rapid immunologic reaction occurring within minutes after

the combination of an antigen with antibody bound to

mast cells in individuals previously sensitized to the antigen

• Often called as ALLERGY

• Systemic disorder:

• Local reactions:

• Immediate or initial reaction

• Late phase reaction

• Most Type I HR are mediated by IgE dependent activation of the mast cells, and other leukocytes

• Mast cells:

• Bone marrow derived • Abundant near vessels, nerves • Cytoplasm has membrane bound

granules • Acid proteoglycans

• Histamine • Have high affinity for FcIgE • Activation may be through C5a

and C3a

Mast cell activation occur through

FcIgE C5a, C3a (anaphylatoxin) Chemokines e.g. IL-8

Drugs (e.g. codeine, morphine adenosine etc) Mellitin (present in venom) Physical stimuli heat, cold, sunlight

MECHANISM

• Immediate type hypersensitivity reaction

• Primary exposure:

• Exposure to antigen (allergen e.g. pollen)

• Activation of TH2 cells and IgE production by B-Cells

• Production of IgE

• IgE binds to allergen

• Immune complex binds through Fc to mast cells

• Mast cells become sensitized

• Secondary exposure:

• Allergen binds to IgE present on sensitized mast cells

• Activation of mast cells

• Release of mediators

MEDIATORS OF MAST CELLS

• Preformed Mediators:

• Vasoactive amines

• Histamine

• Enzymes (chymase, tryptase, acid hydrolase)

• Proteoglycan

• Lipid Mediators:

• Synthesized in mast cell membranes

• LT C4, D4

• LT B4

• PGD2

• PAF

• Cytokines: • TNF, IL-1

ACTIONS OF MAST CELL MEDIATORS

• Vasodilation, increased vascular permeability

• Histamine, PAF, Lt C4, D4, E4, Neutral proteases, PGD2

• Smooth muscle spasm

• LT C4, D4, E4, Histamine, Prostaglandins, PAF

• Cellular infiltration

• Cytokines (TNF, etc), LTB4, Eosinophil and neutrophil

chemotactic factors,

• It is a complex disorder resulting from an IgE-

mediated triggering of mast cells and subsequent accumulation of inflammatory cells at sites of antigen deposition.

• These events are regulated mainly by the induction of TH2 helper T-Cells that stimulate production of IgE, cause accumulation of inflammatory cells, and trigger secretion of mucus. The clinical features result from

release of mast cell mediators as well as the eosinophil rich inflammation.

CLINICAL EXAMPLES

• Systemic anaphylaxis:

• Vascular shock, generalized edema, dyspnea

• Antisera, hormone, enzyme administration

• Food allergens

• Skin erythema, itching, followed by bronchospasm occur within minutes after exposure

• Laryngeal edema may lead to death

• Local immediate Hypersensitivity Reaction:

• Pollen, animal dander, house dust, foods, etc

• Specific disease include urticaria, angioedema, allergic

rhinitis, bronchial asthma

TYPE II HYPERSENSITIVITY REACTION

• Antibody mediated hypersensitivity reaction

• Antibody react with antigens

• Present on the cell surface

• In the extracellular matrix

• The antigenic determinants may be

• Intrinsic

• Extrinsic or exogenous (drug metabolites)

• Either of three mechanisms:

• Opsonization and phagocytosis (ADCC)

• Complement and Fc receptor mediated inflammation

• Cellular dysfunction

OPSONIZATION & PHAGOCYTOSIS

• Responsible for depletion of cells coated with antibodies

• Cells opsonized by IgG are recognized by phagocyte Fc receptor

• When IgG or IgM deposited on cell surface, complement may be

activated forming C3b

• Phagocytosis of the opsonized cell and their destruction

• Complement activation may lead to formation of membrane

attack complex

• Antibody dependent cellular toxicity

• Clinically characterized by

• Transfusion reaction

• HDN (erythroblastosis fetalis)

• Autoimmune hemolytic anemia

INFLAMMATION

• Antibodies deposit in fixed tissues (BM, ECM)

• Deposited antibodies activate complement

• C5a Chemotaxis of neutrophil

• C3a & C5a Increase vascular permeability

• Leukocyte activation results in protease release

• Clinically characterized by

• Glomerulonephritis

• Graft Rejection

CELLULAR DYSFUNCTION

• Antibodies directed against cell surface receptor

(anti-receptor antibody)

• Impair or dysregulate functions

• Clinically characterized by

• Myasthenia gravis

• Anti-acetylcholine receptor antibody blocks neuromuscular

transmission and causes muscle weakness

• Grave’s Disease

• Anti TSH receptor antibody stimulate the cell, resulting in

hyperthyroidism

TYPE III HYPERSENSITIVITY REACTIONS

• Immune-complex mediated hypersensitivity reaction

• Antigen antibody complexes produce tissue damage

mainly by eliciting inflammation

• Circulating immune complex

• In-situ immune complexes (planted antigen)

• Antigen may be

• Endogenous

• Exogenous

• Disease can be

• Systemic (SLE)

• Localized (RA, GN)

SYSTEMIC IMMUNE COMPLEX DISEASES

• Acute serum sickness is the prototype

• Disease develops in three phases

• Immune complex formation

• Circulating immune complexes are formed

• Deposition of immune complexes

• Tissue injury by immune complexes

• Initiation of acute inflammatory reaction

• Characterized by:

• Vasculitis

• Glomerulonephritis

• Arthritis

LOCAL IMMUNE COMPLEX DISEASE

• Prototype is Arthus Reaction

• Localized area of tissue necrosis resulting from

• Acute immune complex vasculitis

TYPE IV HYPERSENSITIVITY REACTION

• Delayed type or T-cell mediated type

hypersensitivity reaction

• Initiated by antigen activated (sensitized) T-Cells

• CD4+ or CD8+ T-Cells

• CD4+ T-Cells mediated hypersensitivity can be a

cause of chronic inflammatory diseases

• CD8+ T-Cells may also be involved

• In certain viral infections CD8+ T Cells may be the

predominant cells

EXAMPLES

Disease Specificity of pathogenic T-

Cells

Clinicopathologic

manifestations

Type I diabetes Antigens of pancreatic β

cells

Insulinitis; diabetes

Multiple sclerosis Protein in CNS myelin Demyelination in CNS;

paralysis, ocular lesions

Rheumatoid

arthritis

Unknown antigen in joint

synovium

Chronic arthritis

Crohn disease Unknown antigen Chronic intestinal

inflammation

(granuloma)

Contact

dermatitis

Environmental antigens Skin inflammation with

blisters

Tuberculin test PPD of M. tuberculosis Indurated swelling

REACTION OF CD4+ T-CELLS

• Delayed type hypersensitivity and immune

inflammation

• Chronic inflammatory reactions against self

antigens

• Proliferation & differentiation of CD4+ T Cells

• IL-2, TH1 or TH17, IFN-γ, TGF-β

• Response of differentiated effector T-Cells

• IFN-γ secreted by TH1 responsible for

• Activated macrophages are altered

• Increased expression of class II MHC

• Morphologically characterized by

• Accumulation of mononuclear cells (Granuloma formation)

REACTION OF CD8+ T-CELLS

• CD8+ T-Cells (CTL)kill antigen bearing target cells

• CTL directed against cell surface histocompatibility

antigens important in graft rejection

• Killing of virally infected cells presenting MHC I

• Perforins facilitates release of granzyme

• Granzyme activate caspases

• Produce IFN-γ, and involve in inflammatory reactions

ANY QUESTIONS????