SECTION 2

HYPERSENSITIVITY DISEASES

CONTACT INFORMATION

Anthony DeFranco, PhD (Email)

READING

• Basic Immunology: Functions and Disorders of the Immune System. Abbas, Abul K., and Andrew H. Lichtman. -- Chapter 11

OBJECTIVES

• To understand the types of diseases caused by abnormal immune responses, and the meaning of the term “hypersensitivity”

• To describe the nature of the immune response and the mechanisms of tissue damage in the four major types of hypersensitivity reactions

• To understand the sequence of reactions in different types of hypersensitivity, with particular emphasis on the roles of the following:

• TH2 cells, IgE and eosinophils in immediate hypersensitivity

• Antibodies, complement and Fc receptors in antibody- and immune complex-mediated diseases

• T cells and cytokines in T cell-mediated diseases.

• To list selected examples of diseases in which these mechanisms of tissue injury have been defined and established.

• To understand the principles underlying rational, targeted therapies for immune-mediated diseases

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KEY WORDS:

• HYPERSENSITIVITY

• IMMEDIATE HYPERSENSITIVITY

• ALLERGY

• ANTIGEN-ANTIBODY COMPLEXES

• DELAYED TYPE HYPERSENSITIVITY (DTH)• AUTOIMMUNITY

MAIN IDEAS:

• Abnormal immune responses are causes of many important diseases. Hypersensitivity refers to pathologic immune responses (responses capable of causing tissue injury and disease).

• The underlying mechanism of many of these diseases is failure of tolerance and other control mechanisms.

• Abnormal immune responses may be directed against self antigens (autoimmune diseases), normally harmless environmental antigens

(allergies and some types of contact sensitivity), or microbial antigens.

• Tissue injury may be caused by antibodies: IgE antibodies that bind to mast cells, IgM or IgG antibodies against tissue antigens, or antibodies that form immune complexes and deposit in vessels. In the latter two cases, tissue injury is the result of antibodies binding to Fc receptors on phagocytes and activating complement proteins, leading to phagocytosis and inflammation. IgM and IgG antibodies against cell surface antigens cause depletion of these red cells and platelets.

• Tissue injury may also be caused by T cells – CD4+ T cells secrete cytokines that induce inflammation, and CD8+ CTLs kill host cells.

HYPERSENSITIVITY DISEASES: DISORDERS CAUSED BY IMMUNE RESPONSES

These diseases are classified on the basis of pathogenic mechanisms and clinico-pathologic manifestations. The four types of hypersensitivity are well recognized and useful for understanding immunological mecha-

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nisms, but in any disease, more than one of these mechanisms may be operative.

In general, the mechanisms of tissue injury are the same as the mechanisms used by normal immune re-sponses to combat microbes. The reason why immune responses are injurious is that the responses are inap-propriately directed against normally harmless anti-gens (self antigens in autoimmune diseases, environ-mental antigens in allergies), or the responses are against microbes that are difficult to eradicate, or the tissue injury is because of an immune response that is not appropriately regulated. We will discuss examples illustrating each of these in the lecture.

Details about specific disorders will be covered in later lectures; here we will emphasize general principles.

Immediate hypersensitivity (allergy): the “classi-cal” TH2 diseases

IgE- and mast cell-mediated rapid (“immediate”) vas-cular and smooth muscle reaction, usually in re-sponse to environmental antigens; may be followed by late-phase reaction (inflammation); develops in geneti-cally susceptible individuals. Genetic susceptibility is multigenic, involving many allelic variants each with

small individual effects. Some of these allelic variants are in immune components related to TH2 immunity.

Sequence of events: antigens induce TH2 responses production of IgE antibody IgE “sensitizes” mast

cells (IgE binds to FcεRI on mast cells) mast cell de-granulation upon antigen encounter mast cell me-diators are released and act on target tissues.

Mast cell mediators: histamine and other vasoactive amines; prostaglandins and leukotrienes (two classes of lipid mediators generated from the fatty acid arachi-donic acid, as described in the Pharmacology lecture on anti-inflammatory drugs, later in I-3); proteases; cy-tokines.

Clinico-pathologic manifestations vary according to site of reaction. Some allergic diseases are domi-nated by the acute vascular and smooth muscle reac-tions (anaphylaxis, acute asthmatic attacks), and oth-ers by inflammation and tissue destruction (chronic asthma, allergic rhinitis).

Treatments: antidotes against mediators (anti-histamines, epinephrine, theophylline); steroids (anti-inflammatory); desensitization (“immunotherapy”).

Immune complex-mediated diseases

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Antigen-antibody complexes form in the circulation and deposit in vessels, joints, kidney glomeruli or are formed locally activate complement and engage Fc receptors on leukocytes recruitment and activation of inflammatory cells tissue injury.

Antigens may be self-antigens (e.g. in lupus) or foreign antigens (post-streptococcal glomerulonephritis, HBV-associated polyarteritis).

Diseases caused by antibodies against cell or tis-sue antigens (“fixed” antigens)

Antibodies bind to cells or tissues and cause disease by any of several mechanisms: phagocytic destruction of cells (autoimmune hemolytic anemia, thrombocy-topenic purpura); inflammation (anti-glomerular base-ment membrane antibody-mediated nephritis); inter-ference with normal function (antibodies against hor-mone and other receptors, e.g. in Graves' disease and myasthenia gravis).

Antibodies are usually autoantibodies; less commonly, they may be antibodies against microbes that cross-react with self antigens. One clearly established exam-ple of the latter are antibodies against a type of food poisoning bacteria called Campylobacter, which cross-

react with glycolipids found on peripheral myelinated nerves, resulting in a peripheral neuropathy called Guillain-Barre syndrome.

T cell-mediated diseases

Tissue injury caused by immune inflammation (CD4+ TH17 cells secrete cytokines that recruit leuko-cytes, CD4+ TH1 cells secrete cytokines that activate macrophages) and/or CTL-mediated killing of tar-get cells.

Delayed type hypersensitivity (DTH) is an inflamma-tory reaction of a previously immunized (“sensitized”) individual to challenge with the immunizing antigen. The reaction is mediated mainly by CD4+ T cells and their cytokines (particularly TH1 and TH17 cells), takes 24-48 hours to develop (time for migration of T cells to site of antigen challenge, synthesis and secretion of cy-tokines, recruitment and activation of other leuko-cytes). Note that DTH is fundamentally different from immediate hypersensitivity in terms of kinetics, mecha-nisms and manifestations.

T cell-mediated diseases may be caused by T cell reac-tions against self-antigens (type 1 diabetes, MS), or

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against normally harmless microbes (probably Crohn’s disease).

Protective T cell reactions against microbial antigens may also cause tissue injury and disease (granuloma-tous inflammation in TB, since the bacteria are difficult to eradicate and elicit strong, persistent immune reac-tions; killing of infected hepatocytes in viral hepatitis – even though the virus is not cytopathic). This type of hypersensitivity is often referred to as “immunopathol-ogy”.

Hypersensitivity diseases tend to be chronic and self-perpetuating, because the eliciting agents are difficult to get rid of and the immune response contains many positive feedback loops that tend to amplify the reac-tion and keep it going in some individuals. Since inflam-mation is a common and fundamental feature of most of these diseases, they are now sometimes grouped un-der immune-mediated inflammatory diseases. Therapies are often directed towards disrupting the cel-lular communications that underlie the immune reac-tions and inflammation (e.g. drugs that block cytokines such as TNF).

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