hypersensitivities, autoimmune diseases, and immune deficiencies

P.G.H. Gell and R.R.A Coombs CLASSIFICATION

Proposed a classification scheme in which hypersensitivity reactions are divided into 4 types

Type I, II,III, IV

four types of hypersensitivity reactions

type I

immediate hypersensitivity

type II

cytotoxic hypersensitivity

type III

immune- complex mediated hypersensitivity

type IV

delayed hypersensitivity

type I

cause: IgE sensitized cells membranes binds antigen, causing degranulation

type II

cause: antibodies and complement lyse target cells

type III

nonphagocytized immune complexes trigger mast cell degranulation

type IV

Tc cells attack the body’s cells

type I

time course: seconds to minutes

type II

time course: minutes to hours

type III

time course: several hours

type IV

time course: several days

type I

mast cells, basophils, and eosinophils

type II

characteristics cells involved : red blood cells

type III

characteristics cells involved : neutrophils

type IV

characteristics cells involved: activated T cells

type I

IgE mediated hypersensitivity

type I

Ag induces crosslinking of IgE bound to mast cells and basophils with release of vasoactive mediators

type I

typical manifestations include systemic anaphylaxis such as hay fever, asthma, hives, food allergies, and eczema

type II

IgG mediated cytotoxic hypersensitivity

type II

AB directed against cell surface antigens mediates cell destruction via complement activation of ADCC

type II

typical manifestations include blood transfusion reactions, erythroblastosis fetal is, and immune hemolytic anemia

type III

immune complex mediated hypersensitivity

type III

Ag Ab complexes deposited in various tissues induce complement activation and ensuring inflammatory response mediated by massive infiltration of neutrophils

type III

typical manifestations include localized Arthur’s reaction generalized reactions such as serum sickness, necrotizing vascukities, glomlnephritis, rheumatoid arthritis, and systemic lupus erythematosus

type IV

cell mediated hypersensitivity

type IV

sensitized TH1 cells release cytokines that activate macrophages or Tc cells which mediate direct cellular damage

type IV

typical manifestation include contact dermatitis, tubercular lesions and graft rejection

type I

anaphylactic

type II

cytotoxic

type III

immune complex

type IV

cell- mediated or delayed- type

<30 mins

time before clinical signs: type I

5-12 hours

time before clinical signs: type II

3-8 hours

time before clinical signs: III

24-48 hours

time before clinical signs: type IV

type I

IgE binds to mast cell or basophils; causes degranulation of mast cell or basophil and release of reactive substances such as histamine

type I

example: Anaphylactic shock from drug injections and insect venom; common allergic conditions, such as hay fever, asthma

type II

Antigen causes formation of gM and IgG antibodies that bind to target cell; when combined with action of complement, destroys target cell

type II

Transfusion reactions, Rh incompatibility

type III

Antibodies and antigens form complexes that cause damaging inflammation

type III

example: Arthus reactions, serum sickness

type IV

Antigens cause formation of Tc that kill target cells

type IV

example: Rejection of transplanted tissues; contact dermatitis, such as poison ivy; certain chronic diseases, such as tuberculosis

Type 1 (Immediate) Hypersensitivity

are localized or systemic reactions that result from the release of inflammatory molecules such as histamine in response to an antigen.

Type 1 (Immediate) Hypersensitivity

also commonly called ALLERGIES, and the antigens that stimulate them are called allergens

allergens

antigens that stimulate type I are called

1. Sensitization upon an initial exposure to an allergen and

2. Degranulation of sensitized cells

2 Part Mechanisms of type 1

Type 1 (Immediate) Hypersensitivity

example: allergic rhinitis or hay fever (mold spores, pollens, feces and dead bodies of house dust mites)

Type 1 (Immediate) Hypersensitivity

example: asthma

Type 1 (Immediate) Hypersensitivity

example: Food Allergies (eggs, soy, dairy products, shellfish, peanuts) (Hives or Urticaria)

Type 1 (Immediate) Hypersensitivity

example: Atopic Dermatitis (allergic eczema)

ANTIHISTAMINES, corticosteroid, bronchodilator, epinephrine (low-level exposure overtime)

TX for Type 1 (Immediate) Hypersensitivity

IgE secreting plasma cells

exposure to an allergen activated B cells to form

Fc receptors

the secreted IgE molecules bind to IgE specific___in mast cells and blood basophils

mediators, vasoactive amines

Second exposure to the allergen leads to crosslinking of the bound IgE, triggering the release of pharmacologically active ___, from mast cells and basophils

mediators

cause smooth muscle contraction, increased vascular permeability and vasodil

antigen

antigen presenting cells (APC) phagocytizes and processes __

TH2 cell

APC presents antigenic determinant to __

B cell

IL-4 from TH2 cell stimulates__

IgE

B cell becomes plasma cell which secretes

foreign serum

vaccines

common allergies with type I from proteins

nuts, seafoods, eggs, peas, bean, milk

common allergies with type I from foods

rye grass, ragweed, Timothy grass, birch trees

common allergies with type I from plant pollens

bee venom, wasp venom, ant venom, cockroach calyx, dust mites

common allergies with type I from insect products

penicillin, sulfonamides, local anesthetics, salicylates

common allergies with type I from drugs

animal hair and dander

common allergies with type I from mold spores

allergic rhinitis or hay fever

Symptoms: water exudations of the conjunctiva, nasal mucosa, and URT, sneezing and coughing

asthma

Symptoms: airway edema, mucus secretion, inflammation (bronchoconstriction, airway obstruction)

primary response

(occurs within minutes from allergen exposure)

Broncho-constriction

Vasodilation

Some mucus buildup

late response

occurs hours later after allergen exposure

late response

Occlusion of the bronchial lumen with mucus, proteins, and cellular debris, sloughing of the epithelium, thickening of the basement membrane, fluid buildup (edema), hypertrophy of the bronchial smooth muscle, mucus plug, spirals of bronchial tissue (Cursch-mann’s spirals

Cursch-mann’s spirals

spirals of bronchial tissue

histamine, heparin

serotonin

primary: increased vascular permeability; smooth muscle contraction

eosinophils chemotactic factor (ECF-A)

primary: eosinophil chemotaxis

neutrophilchemotactic factor (NCF-A)

primary: neutrophils chemotaxis

protease

primary: bronchial mucus secretion; degradation of blood vessel basement membrane; generation of complement split products

platelet activating factor

secondary: platelet aggregation and degranulation: contraction of pulmonary smooth muscles

leukotrienes (slow reactive substance of anaphylaxis, SRS-A)

secondary: increased vascular permeability: contraction of pulmonary smooth muscles

prostaglandins

secondary: Vasodilation; contraction of pulmonary smooth muscles; platelet aggregation

bradykini, cytokines

secondary: Increased vascular permeability, smooth- muscle contraction

IL-1 and TNF-a

secondary: Systemic anaphylaxis; increased expression of CAMs on venular endothelial cells

IL-2, IL-3, IL-4, IL-5, IL-6, TGF-B and GMF CSF

various effects

urticaria

Others develop atopic ___ known as hives, when food allergen is carried to sensitized mast cells in the skin, causing swollen (edematous) red (erythematous) eruptions, this is the wheal and flare response or P-K reaction

angioedema

food allergies that occurs in mouth swollen

atopic dermatitis (allergic eczema)

an inflammatory disease of the skin that is frequently associated with a family atopy; observed most frequently in young children, often developing during infancy.

atopic dermatitis (allergic eczema)

serum IgE levels are often elevated; have TH2 cells and increased number of unlike in DTH reaction which involves TH1

akin testing by intradermal injectionmof allergens into the forearm

methods to detect type I hypersensitivity reactions

antigen dose

mode of antigen presentation

genetic constitution

Type 1 Responses Are Regulated by Many Factors

antigen dose

repeated low doses induces a persistent IgE response; higher antigen result in transient IgE production and a shift toward IgG. doses

adjuvant

Mode of Antigen Presentation: an __ induces a strong IgE response

50%

Genetic Constitution: if both parents are allergic, there is a __chance that a child will also allergic

30%

genetic constitution: if one parent is allergic, there is a __% chance.

1) Avoid Contact with Known Allergens

2) Immunotherapy with repeated injections of increasing doses of allergens

(3) Use of homonized monoclonal anti-IgE

Type 1 Hypersensitivities Can be Controlled Medically

hyposensitization

Immunotherapy with repeated injections of increasing doses of allergens

IgG production

such repeated introduction of allergen by subcutaneous injections appears to cause a shift toward ___ or to induce T-cell- mediated suppression (possibly by a shift to the TH1 subset and IFN gamma production) that turns off the IgE response

blocking antibodies

in this situation, the IgG antibody is referred to as ___ because it competes with the allergen, binds to it, and forms a complex that can be removed by phagocytosis, as a result, the allergen is not available to crosslink the fixed IgE on the mast cell membrane, and allergic symptoms decrease

Ab’s

these ___ bind to IgE, but only if IgE is not already bound to FC€RI; would lead to histamine release