hypersensitivity reactions - rawal college of...
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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????