Goku Notes

Hypersensitivity Reactions LATE PHASE REACTION

Lecturer: Dra. Leila Ferrer
HYPERSENSITIVITY REACTIONS
Exaggerated or misdirected immune response
May be immediate or delayed
Occurs when an already sensitizied individual is re- SYSTEMIC ANAPHYLAXIS
exposed to the same foreign substance
Results in tissue injury or other pathophysiological
changes
Ensuing tissue injury may be caused by:
Release of vasoactive substances
Phagocytosis or lysis of cells
Activation of inflammatory and cytolytic
components of complement system
Release of cytokines (e.g. TNF), proteolytic enzymes
and other mediators of tissue injury or inflammation
Can happen 2-8 hours later without additional exposure to
antigen
More intense infiltration of tissues with eosinophils,
neutrophils, basophils, monocytes and CD4 T cells
With mucosal epithelial damage
Occur after administration of heterologous proteins (e.g.
Antisera, hormones, enzymes, polysaccharides and
drugs)
Exposure - itching, hives and skin erythema - contraction
of the respiratory bronchioles + respiratory distress
(+) laryngeal edema
Basis for skin test
CLINICAL EXAMPLES
1. Atopic disorders:

Allergic rhinitis
TYPE 1 HYPERSENSITIVITY Hay fever
Asthma
Immediate or anaphylactic type Atopic dermatitis
IgE mediated Urticaria
Occurs within minutes
Provoked by re exposure to the same antigen (by contact, 2. Anaphylaxis
inhalation, ingestion or injection)
Local or systemic
PRIMARY MEDIATORS
Local anaphylaxis
A. Biogenic amines
Atopy - genetically determined predisposition to develop
localized anaphylactic reactions to inhaled or ingested 1. Histamine
allergens 2. Adenosine - enhance mast cell mediator release
Positive family history - chr.5q31
With higher serum IgE levels compared to the general B. Chemotactic mediators
population
1. Enzymes - proteases, acid hydrolases (primary mediators)
2 phases:
2. Proteoglycans - heparin, chondroitin sulfate - package and
Initial Response store other mediators in the granules
Late Phase Reaction
SECONDARY MEDIATORS
INITIAL RESPONSE
1. Leukotrienes - LTC4, LTD4 - most potent vasoactive and
Vasodilation, vascular leakage, smooth muscle spasms or spasmogenic agents known; LTB4 (chemotaxis)
glandular secretions 2. Prostaglandin D2 - most abundant in mast cells
5-30 mins after exposure 3. PAF - release of histamine, bronchospasm, increased
Subside in 60 mins vascular permeability, vasodilation
4. Cytokines - e.g. TNF alpha, IL-1, IL-3, IL-4, IL-5, IL-6

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DIAGNOSIS CLINICAL EXAMPLES

History Myasthenia gravis - acetylcholine

Skin prick test - positive wheal and flare receptors
Blood eosinophilia Goodpasture’s syndrome - type IV
RAST (radioallergosorbent assay) collagen
Pernicious anemia - intrinsic factor
TREATMENT Acute rheumatic fever - antibodies vs
Streptococcal antigens cross react with
Anti-histamine - acts on first phase only the heart
Corticosteroids- late phase reaction
Desensitization - induce tolerance; no IgE production - TYPE III HYPERSENSITIVITY
deplete already bound IgE
Immune complex mediated
TYPE II HYPERSENSITIVITY Formation of immune complexes in circulation - deposit in
various tissues - trigger classical pathway of complement
Mediated by antibodies directed toward antigens present activation
on the surface of cells and other tissue components Produce damage as they localize within blood vessel walls
IgG and IgM or when trapped in filtering structures ( renal glomeruli)
Antigenic determinants - intrinsic or exogenous
CLINICAL EXAMPLES
MECHANISMS:
A. EXOGENOUS
1. Complement dependent reactions
INFECTIOUS AGENTS
Antibody-complement- mediated lysis
1. BACTERIA
Antibody (IgG and IgM) + antigen on cell surface -
activation of complement system - (+) MAC
Y. enterocolitica - arthritis
Results to MAC activation and later on tissue injury
Streptococci - GN, infective endocarditis
T. pallidum - glomerulonephritis
CLINICAL EXAMPLES
2. VIRUSES
Transfusion reactions
Erythroblastosis fetalis
Hep B, CMV - polyarteritis nodosa
Autoimmune hemolytic anemia,
agranulocytosis, thrombocytopenia - (+)
3. PARASITES
antibodies vs own blood cells
Pemphigus vulgaris - antibodies vs
Plasmodium, schistosoma -
desmosomes
glomerulonephritis
Drug reactions
4. FUNGI
2. Antibody dependent cell mediated cytotoxicity
Actinomycetes - farmer’s lung
Due to NK activity - non sensitized cells with Fc receptors
Ab + Ag - activation of NK cells - bind to Fc fragment of
IgG - cell lysis without phagocytosis B. ENDOGENOUS
Destruction of targets too large to be phagocytosed
(parasites, tumor cells) + graft rejection Nuclear antigens - SLE
Immunoglobulins - rheumatoid arthritis
ANTIBODY MEDIATED CELLULAR DYSFUNCTION Tumor antigens - glomerulonephritis

Antibodies directed against cell surface receptors - impair

or dysregulate function

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SERUM SICKNESS 2 MECHANISMS OF T CELL MEDIATED CYTOTOXICITY

Patient forms antibodies to xenogeneic Ig administered 1. Perforin granzyme dependent killing

during passive immune therapy regimens
Positive immunity cause perforation of plasma membrane

ARTHUS REACTION 2. Fas- FasL dependent killing

Higher levels of antibody with booster activation of apoptosis

Localized area of tissue necrosis due to acute immune
complex vasculitis
Complexes precipitate in the vessel wall - fibrinoid
necrosis

TYPE IV HYPERSENSITIVITY

Cell mediated hypersensitivity

Initiated by sensitized T lymphocytes
Principal pattern of immunologic response to intracellular
microbiologic agents particularly Mycobacterium
tuberculosis as well as viruses, fungi, protozoa and
parasites

2 forms:

1. Delayed type hypersensitivity

Mediated by CD4 T cells

1st exposure to Ag - CD4 T cells + class II MHC -
differentiation of naive CD4 T cells to TH1 cells - release
of IL-12, IFN- gamma, IL-2, TNF alpha and lymphotoxins

CLINICAL EXAMPLES

Tuberculin skin test

Contact dermatitis
Granulomatous
inflammation

2. T cell mediated cytotoxicity

Mediated by CD8 + T cells

Sensitized CD8 + t cells kill antigen bearing target cells

CLINICAL EXAMPLES

Graft rejection
Virus infection
Tumor immunity

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