Immunology of IgE-Mediated and Other Hypersensitivity States

8/9/2019 Immunology of IgE-Mediated and Other Hypersensitivity States

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Immunology of IgE-mediated and

Other Hypersensitivity States

Dr Paul T Antony


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When an individual has been immunologically

primed, further contact with antigen leads to

secondaryboosting of the immune response.

However,the reaction may be excessive and

lead to gross tissue changes (hypersensitivity)

if the antigen is present in relatively large

amounts or if the humoral and cellular

immune state is at a heightened level.


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HISTORICAL REVIEW OF IgE-MEDIATED

HYPERSENSITIVITY

1902, Richet and Portier anaphylaxis in dogs

given sea anemone toxin

1906, Clemons von Pirquet immunity andhypersensitivity would have similar underlying

immunologic mechanisms

1921, Prausnitz and Kstner described thetransfer of immediate hypersensitivity

Johansson and Bennich


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Allergen

nonparasitic antigens capable of stimulating

type I hypersensitive responses in allergic

individuals.

Genetic predisposition

5q (IL-3, IL-4, IL-5, IL-9, IL-13, and GM-CSF)

11q(chain of the high-affinity IgE receptor)


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Der p 1: cleave CD25, the 55-kDa a subunit of

the IL-2 receptor, cleaving CD23 on murine B

cells that would normally serve to inhibit IgE

synthesis


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IgE

190,000

Additional constant-region domain

Glycoprotein receptors on the surface ofbasophils and mast cells


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Sites of IgE Production, Turnover, and

Tissue Localization

Lymphoid tissue of the tonsils, adenoids, and

the bronchial and peritoneal areas &

respiratory and intestinal mucosa

The mean total circulating IgE pool was found

to be 3.3 g/kg of body weight,

half-life of only 2.3 days.

The rate of IgE production was found to be 2.3

g/kg/day.


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FceR1 receptor

Mast cells, basophils, eosinophils,Langerhans

cells

Cross-linking of high-affinity receptor-boundIgE by allergen results in the release of

mediators from mast cells and basophils.


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FcRI & FcRII


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FcRII ( CD23)

CH3/ CH3 domain of IgE

Lower affinity for IgE

Up regulated on all cell types by interleukin-4(IL-4) and IL-13

Allergen cross linkage activate B cells, alveolar

macrophages, and eosinophils


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HIGH-AFFINITY RECEPTOR (FCRI)

40,000 -90,000 on basophils

4 chains of polypeptides

, and two identical disulfide-linked

- 2 90 aa domains ext which binds CH3/ CH3

& CH4/ CH4 of IgE

- 4 chains span cell membrane & links

- ITAM


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Basophils

0.5%1.0% of the circulatingWBC

Granulated cytoplasm stains with basic dyes

Multilobed nucleus,

Few mitochondria,

Numerous glycogen granules, and

Electron-dense membrane-bound granules


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Mast cells

BM

Vascularized peripheral tissues attain maturity

Near blood and lymphatic vessels

Skin and mucous membrane surfaces of the

resp and gastrointestinal tracts plenty

membrane-bounded granules distributedthroughout the

cytoplasm


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IgE Crosslinkage Initiates

Degranulation


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Pharmacologic Agents Mediate

Type I Reactions Local tissues

Secondary effector cells are recruited

Amplifying terminal effector mechanism


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HISTAMINE

Decarboxylation of the amino acid histidine

10% of granule weight

Quick onset

H1

contraction of intestinal and bronchial smooth

muscles, increased permeability of venules,and increased mucus secretion by goblet cells

H2 increases vasopermeability

Dilation and stimulates exocrine glands


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LEUKOTRIENES AND PROSTAGLANDINS

Slow onset

pronounced and longer lasting

bronchoconstriction, increased vascularpermeability, and mucus production.

Prostaglandin D2 causes bronchoconstriction


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II HS REACN

Antibody mediated

Complement or ADCC or opsonin action


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ADCC

Cells with low concentrations of IgG

'nonspecifically' through an extracellular

nonphagocytic mechanism involvingnonsensitized leukocytes

Cy2 and Cy3 domains of IgG Fc

Phagocytic and non phagocytic myeloid cells

Large granular lymphocytes with Fc receptors

dubbed 'K-cells


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IMMUNE COMPLEX-MEDIATED

HYPERSENSITIVITY (TYPE Ill)

Ag & Ab to form a complex within the body

Absolute amt and proportions of Ag and Ab

Antibody excess and mild antigen excess :-rapidly precipitated & localized

Moderate to gross antigen excess:-soluble

complexes are formed


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Covalent attachment of C3b prevents the Fc-Fc

interactions required to form large insoluble

aggregates, and these small complexes bind to

CR1 complement receptors on the human

erythrocyte and are transported to fixed

macrophages in the liver where they are safely

inactivated


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The Arthus reaction

Hyperimmunized

soluble antigen

Erythematous and edematous reaction

Intense infiltration with neutrophils

Depletion of neutrophils by nitrogen mustard or of

complement by anti-C5a Complement regulatory proteins CD46 (membrane

cofactor protein) and CD55 (DAF)


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Reactions to inhaled antigens

farmer's lung:-thermophilic actinomycetes

pigeon-fancier's disease


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Reactions to internal antigens

Release of antigen from infectious organisms

Chemotherapy may cause an abrupt release of

microbial antigens in individuals with high

antibody levels :- Jarisch-Herxheimer reaction,

ENL


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Immune complex glomerulonephritis


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Diffuse immune complexes

Persistent Ag

Low affinity Ab or Ab to restricted epitopes

Choroid plexus BM of the dermal-epidermal junction


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CELL-MEDIATED (DELAYED-TYPE)

HYPERSENSlTlVlTY (TYPE IV)

Allergic reactions to bacteria, viruses and fungi

Contact dermatitis resulting from sensitization

to certain simple chemicals

Rejection of transplanted tissues


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'Jones-Mote

Primed with antigen alone or in incomplete

Freund's adjuvant

Delayed hypersensitivity state shorter

Dermal response more transient.

Cutaneous basophil hypersensitivity


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Cannot be transferred with serum antibody

ViableWBC and, interestingly, by a LMW

material extracted from them

Factors which appear capable of stimulating

pre committed T-cells mediating delayed

hypersensitivity

Exaggerated interaction between Ag and the

normal CMI


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Memory T-cells recognize the antigen together

with class II (MHC) on APC and are stimulated

into blast cell transformation and proliferation

Stimulated T-cells release cytokines

Macrophages Thl subset

Eosinophils if they are Th2

Tc precursors to become killer cells


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Infections

TB, leprosy

Granulomas can also arise from the

persistence of indigestible antigen-antibody

complexes or inorganic materials, such as talc,

within macrophages

Absence of lymphocytes


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IBD

Herpes, measles and hep B

Contact dermatitis


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Th2-mediated hypersensitivity


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STIMULATORY HYPERSENSlTlVlTY

(TYPE V)

Many cells are signaled by agents such as

hormones through surface receptors to which

they specifically bind the external agent,

presumably through complementarity of

structure

TSH

Cimetidine resisitant DU


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INNATE' HYPERSENSlTlVlTY REACTIONS

toxic shock syndrome

TNF, IL-1 and IL-6 by macrophages & endoth

cells

GNB-LPS

Staphylococcus aureus to macrophages

induces TNFa synthesis, andpeptidoglycan-

mediated aggregation of platelets

staphylococcal and streptococcal enterotoxins


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THANK YOU

Immunology of IgE-Mediated and Other Hypersensitivity States

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