Path: Immunology: Hypersensitivity

Your patient is a 77-year-old man with enterococcal endocarditis who was treated with penicillin G and gentamicin. Five days later, fever and a diffuse maculopapular rash developed. There is no urticaria, hypotension, or respiratory compromise. Urinalysis revealed proteinuria and granular casts. You suspect he may have serum sickness. Which one of the following immunopathogenic mechanisms is most likely to be the cause? (A) One of the drugs formed immune complexes with IgG. (B) One of the drugs activated CD4-positive T cells and macrophages. (C) One of the drugs activated the alternative pathway of complement. (D) One of the drugs cross-linked IgE on the mast cells and caused the release of histamine.

(A) One of the drugs formed immune complexes with IgG.

Your patient has episodes of eye tearing, "blood-shot" eyes, and runny nose, which you think may be due to an allergy to some plant pollen. You refer the patient to an allergist, who performs skin tests with various allergens. Within minutes, a wheal-and-flare reaction is seen on the patient's back at the site where several pollens were injected. What is the most likely sequence of events that produced the whealand-flare reaction? • (A) Allergen binds to IgE on the surface of B cells, and IL-4 is released. • (B) Allergen binds to IgE on the surface of mast cells, and histamine is released. • (C) Allergen binds to IgE in the plasma, which activates complement to produce C3b. • (D) Allergen binds to IgE in the plasma, and the allergen-IgE complex binds to the surface of macrophages and IL-1 is released.

(B) Allergen binds to IgE on the surface of mast cells, and hista- mine is released.

Of the following diseases, which one is most likely to be caused by a delayed hypersensitivity reaction? (A) Autoimmune hemolytic anemia (B) Contact dermatitis, such as poison oak (C) Hemolytic disease of the newborn (D) Poststreptococcal glomerulonephritis (E) Systemic lupus erythematosus

(B) Contact dermatitis, such as poison oak

One important test to determine whether your patient has been exposed to M. tuberculosis, the organism that causes tuberculosis, is to do a PPD skin test. In this test, PPD extracted from the organism is injected intradermally. Of the following, which one is most likely to occur at the site of a positive PPD? (A) Cytotoxic T cells kill target cells at the site. (B) Macrophages and CD4-positive T cells infiltrate the site. (C) Histamine and leukotrienes are liberated from mast cells at the site. (D) Immune complexes consisting of PPD and IgG are deposited at the site.

(B) Macrophages and CD4-positive T cells infiltrate the site.

Of the following four types of hypersensitivity reactions, which one causes the hemolysis that occurs in hemolytic disease of the newborn (erythroblastosis fetalis)? (A) Type I-immediate hypersensitivity (B) Type II-cytotoxic hypersensitivity (C) Type III-immune complex hypersensitivity (D) Type IV-delayed hypersensitivity

(B) Type II-cytotoxic hypersensitivity

Atopic individuals (i.e., those with a hereditary predisposition to immediate hypersensitivity reactions) produce an increased amount of IgE. Of the following, which one is the most likely explanation for the increased production of IgE? (A) Large amounts of IL-1 are produced by dendritic cells. (B) Large amounts of IL-2 are produced by macrophages. (C) Large amounts of IL-4 are produced by Th-2 cells. (D) Large amounts of gamma interferon are produced by Th-1 cells. (E) Large amounts of C3a are produced by the alternative pathway of complement.

(C) Large amounts of IL-4 are produced by Th-2 cells.

Type II

(Cytotoxic) IgG-, IgM-mediated (rarely, IgA) Sensitization: Antigens on a cell surface elicit Tfh and Bcell activation. Immunologic Reaction: Antibody binding to cell membrane antigens leads to complement-mediated lysis or ADCC (e.g., transfusion reaction, Rh reaction, or autoimmune hemolytic anemia).

Type IV reaction

(Delayed) Several hours to 3 days Contact dermatitis, poison oak/ivy, tuberculin skin test reaction, drug rash, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis

Type IV

(Delayed) T-cell-mediated Sensitization: CD4 and/or CD8 T cells sensitized by protein antigens. Immunologic Reaction: Memory T cells release cytokines upon second contact with the same antigen. Cytokines induce inflammation and activate macrophages, which, in turn, release various inflammatory mediators.

Type I reaction

(Immediate, anaphylactic) Minutes Systemic anaphylaxis, urticaria (hives), asthma, hay fever, allergic rhinitis, allergic conjunctivitis, food allergies (e.g., nuts, shellfish, eggs), drug allergies especially penicillin, eczema (atopic dermatitis), bee venom, latex gloves, angioedema

Type I

(Immediate, anaphylactic, allergy) IgE-mediated Sensitization: Antigen (allergen) induces IgE antibody that binds to mast cells and basophils. Immunologic Reaction: When exposed to the allergen again, the allergen crosslinks the bound IgE on those cells. This causes degranulation and release of mediators (e.g., histamine).

Type III reaction

(Immune complex) 2-3 weeks Systemic lupus erythematosus, rheumatoid arthritis, poststreptococcal glomerulonephritis, IgA nephropathy, serum sickness, hypersensitivity pneumonitis (e.g., farmer's lung)

Type III

(Immune complex) Multiple types of antibodies Sensiitization: Soluble antigens elicit Tfh and B-cell activation. Immunologic Reaction: Antigen-antibody immune complexes are deposited in tissues, complement is activated, and polymorphonuclear cells are attracted to the site. They release lysosomal enzymes, causing tissue damage.

Desensitization

- Acute desensitization (temporary) is induced by repeated administration of small amounts of allergen at 15- min intervals. - Chronic desensitization (permanent) is induced by repeated administration of gradually increasing amounts of allergen over long period of time (years

Arthus reaction (localized)

- An inflammatory response following intradermal/subcutaneous injection of antigen mediated by high IgG levels - Hypersensitivity pneumonitis (allergic alveolitis or farmer's lung) caused by long-term inhalation of mold or other allergens

• Tissue damage is caused by multiple mechanisms:

- Complement fixation and complement-mediated lyses - ADCC - Cytotoxins produced by NK cells attracted by complement - Opsonization (Ig-mediated or complement-mediated)

Tuberculin-type hypersensitivity

- Exposure, acquiring the disease, or vaccination cause sensitization due to the formation of memory Th1 CD4+ T cells. - Purified protein derivative (PPD) is administered intradermally and results read 48-72 hours later.

• Prostaglandins

- Formed after degranulation - Vasodilation, increased permeability, and SM contraction

• Cytokines

- IL-4, IL-5, IL-9, IL-13, IL-21

Sources of antigen:

- Mismatched blood transfusion (ABO) and Rh hemolytic disease - Drugs (penicillin, quinidine, etc.) that bind surface molecules of RBCs and platelets creating new (foreign) epitopes - Antibodies directed against infectious agents that cross-react with self antigens, also known as "molecular mimicry" (Mycoplasma pneumoniae/hemolytic anemia and Streptococcus pyogenes/rheumatic fever)

• Important notes

- Non-allergic individuals mount an IgG response to the same allergens that cause an IgE response in allergic individuals. - Mast cells and basophils don't have receptors for IgG. - Complement is not involved in type I hypersensitivity since IgE does not fix complement. - Eosinophils play different roles that are not completely understood. - They play a role in the pathogenesis of asthma and other type I response conditions. - They also produce histaminase, which implicates them in modulation of the type I response. - In anaphylactoid reactions, mast cells and basophils degranulate without IgE involvement.

Histamine

- Preformed in mast cells and basophils - Vasodilation, increased permeability, and SM contraction

Platelet-activating factor (PAF)

- Produced by multiple cell types (basophil, mast cell, neutrophil, eosinophil, monocyte, macrophages, and endothelial cells) - Vasodilation, increased permeability, and SM contraction

Type IV hypersensitivity Contact hypersensitivity

- Triggered by simple chemicals (metals), plant oils (poison ivy, poison oak), drugs applied to the skin (neomycin), and cosmetics, which come in contact with the skin. - Allergens act as haptens that bind to, and alter self proteins. - Patients are sensitized when their DCs take up altered proteins, present them to naïve CD4+ T cells, resulting in their differentiation into Th1 memory cells. - CD8 CTLs may be involved depending on the nature of the trigger. - Symptoms include erythema, pruritic rash, vesicles, eczema, and necrosis.

Serum sickness (systemic)

- Widespread immune complex deposition due to coexistence of large quantities of antigen and antibody - Animal serum, mouse monoclonal antibodies, and penicillin are common examples.

Skin

1. Eczema Pruritic, vesicular lesions Uncertain Uncertain 2. Urticaria Pruritic, bullous lesions 1. Various foods Ingestion 2. Drugs Various

Type I hypersensitivity diagram

1. Sensitization by allergen induces production of specific IgE. 2. IgE (Fc region) binds FcεRI on mast cells and basophils. 3. Allergen cross-links bound IgE causing degranulation.

Basophils and mast cells

A basophil showing intensely blue-purple cytoplasmic granules that partially obscure nucleus, which is typically bi-lobed. A mast cell showing large dark blue to purple granules that mostly obscure the centrally placed nucleus.

Eosinophils

An eosinophil with characteristic bi-lobed nucleus, present in virtually all normal eosinophils, and a cytoplasm filled with eosinophilic granules. The granules do not obscure the nucleus as is characteristic in basophils.

Lung

Asthma Wheezing, dyspnea, tachypnea Pollens, house dust (feces of dust mite), animal danders, many occupational airborne allergens Inhalation

GIT

Eosinophilic esophagitis Vomiting, dysphagia, esophageal "rings" Various foods Ingestion

1. Tuberculosis, coccidioidomycosis

Granuloma Constituents of bacterium or fungus

Tuberculin or coccidioidin (spherulin) skin tests

Induration PPD (purified protein derivative) or coccidioidin

1. Allergic contact dermatitis

Pruritic, vesicular rash Oil of poison oak or poison ivy, topical drugs, soaps, heavy metals (in jewelry)

Nose & eyes

Rhinitis, conjunctivitis , hay fever Runny nose, redness and itching of eyes Pollens Contact with mucous membranes

2. Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis

Target lesion (EM) Epidermal necrosis & detachment (SJS, TEN) Herpes simplex virus-1, Mycoplasma pneumoniae, sulfonamides, & penicillin

Delayed (cell-mediated) hypersensitivity

The macrophage ingests the antigen, processes it, and presents an epitope on its surface in association with class II major histocompatibility complex (MHC) protein. The helper T (Th-1) cell is activated and produces gamma interferon, which activates macrophages. These two types of cells mediate delayed hypersensitivity.

Type II reaction

cytotoxic Hours to days Hemolytic anemia, neutropenia, thrombocytopenia, ABO transfusion reactions, Rh incompatibility (erythroblastosis fetalis, hemolytic disease of the newborn), rheumatic fever, Goodpasture's syndrome

Examples

hay fever (allergic rhinitis/conjunctivitis), asthma, eczema (atopic dermatitis), and urticaria (hives)

• Autoimmune diseases are the result of

inappropriate responses to endogenous (self) antigens.

In hypersensitivity, first exposure to antigen

sensitizes the host, but does not cause symptoms.

Hypersensitivity is

the result of overly aggressive immune responses to exogenous antigens.

Exposure of a sensitized host to recall antigen results in

the symptoms associated with hypersensitivity reactions.

Atopy is

the tendency to develop IgE antibodies to commonly encountered environmental allergens by natural exposure in which the route of entry of allergen is across intact mucosal surfaces.*

• Erythema Multiforme, Stevens-Johnson Syndrome, & Toxic Epidermal Necrolysis

• Caused primarily by a CD8+ CTL response against skin cells • Triggers include infections (HSV-1 and Mycoplasma pneumoniae) and drugs (penicillin and sulfonamides). • 3-10% of body surface in SJS • > 30% of body surface in TEN

Type I hypersensitivity

• Common triggers include pollen, animal dander, food (peanut, shellfish, fruits), insect venom, drugs (penicillin). • Sensitization results in the formation of IgE antibodies. - Th2 and Tfh CD4+ T cells and class-switched B cells - T-cell cytokines include IL-4 (CS to IgE), IL-5 (eosinophils), IL-21 (B-cell differentiation) • Antibodies bind to mast cells, basophils, and eosinophils via their FcεRI receptors. • Subsequent exposure to allergens results in degranulation of mast cells, basophils, and eosinophils. • Inflammatory mediators and chemokines are released.

Type II hypersensitivity

• Cytotoxic hypersensitivity is caused by antibodies (IgM & IgG, rarely IgA) directed against membrane components of target cells, which activate the complement system or ADCC

Type I hypersensitivity chemicals

• Degranulation of mast cells and basophils releases preformed inflammatory mediators causing symptoms ranging from urticaria (hives) to anaphylaxis within minutes. • These mediators are short-lived due to being inactivated by enzymatic degradation within minutes

Type I hypersensitivity phases

• Immediate phase (5-30 minutes) - Vasodilation, SM contraction, increased vascular permeability - Mainly due to immediate mediators (histamine) • Late phase (2-24 hours) - Infiltration by neutrophils, eosinophils, basophils, and monocytes - Tissue damage - Due to late mediators (leukotrienes) and action of infiltrating cells

Type III hypersensitivity

• Immune-complex hypersensitivity is the result of an inflammatory response incited by antigen-antibody complexes deposited in various organs, such as kidneys (nephritis), joints (arthritis), or blood vessels (vasculitis). • Complement is activated resulting in tissue damage.

Type III hypersensitivity comparison

• Note: Type II is induced by cell-bound antigen, while type III is induced by soluble antigen.

Type I hypersensitivity mediators

• The mediators released are either preformed or de novo synthesized. • These mediators collectively induce vasodilation, increased vascular permeability, smooth-muscle contraction (bronchospasm), increased mucus production, and chemotaxis. • Clinical presentation differs in nature and severity depending on 1) anatomical site affected, 2) the type of allergen, and 3) magnitude and nature of host responses. • Functional categories of mast-cell/basophil mediators: - Vascular permeability & SM contraction: histamine, platelet-activating factor, and slow-reacting substance of anaphylaxis (SRS-A) - Chemotaxis and activation of inflammatory cells: leukotrienes - Modulation of the release of other mediators: platelet-activating factor

Slow-reacting substance of anaphylaxis (SRS-A)

- Several leukotrienes formed after degranulation - Increased permeability and SM contraction

Type I hypersensitivity diagnostic testing

- Skin test - Quantitation of specific IgE antibodies against suspected allergen

• Eosinophil chemotactic factor of anaphylaxis (ECF-A)

- Preformed in mast cells and basophils - Attracts eosinophils

Systemic

Anaphylaxis Shock, hypotension, wheezing, pruritis, urticaria, asphyxia, cardiac arrest 1. Insect venom Sting 2. Drugs Various 3. Foods Ingestion

Stevens-Johnson syndrome

erythema multiforme

Type IV (cell-mediated or delayed) hypersensitivity

• Type IV hypersensitivity is the result of T-cell responses. • It's called "delayed" because it takes hours to days for a response to appear. • The responding lymphocytes could be CD4+ Th1 cells, which orchestrate the response along with macrophages, or both CD4+ Th1 cells and CD8+ cytotoxic T lymphocytes. • Involvement of CD8+ CTLs is associated with significant tissue damage.