Hypersensitivity Reactions hematologic system

Hypersensitivity Reactions hematologic system

1. Hypersensitivity Reactions

2. Objectives

3. Mechanisms of Hypersensitivity Reactions Hypersensitivity reactions imply an excessive response to an antigenic stimulus. General concepts are: Both exogenous and endogenous antigens can elicit a hypersensitivity response. Diseases occurring as a result of hypersensitivity responses are often associated with particular susceptibility genes (e.g., histocompatibility molecules, also called human leukocyte antigens [HLA]). Hypersensivity reactions represent an imbalance between immune effector mechanisms and control mechanisms that normally limit immune responses.

4. Immediate (Type I) Hypersensitivity Immediate (type I) hypersensitivity is classically mediated by immunoglobulin E (IgE) antibodies directed against specific antigens (allergens). These can occur as local reactions or involve systemic responses. Susceptibility to immediate hypersensitivity reactions (atopy) is genetically determined, with linkage studies showing association with HLA and a number of cytokines that contribute to TH2 immune responses (mapping to 5q31).

5. Immediate (Type I) Hypersensitivity IgE synthesis requires TH2 CD4 + helper T cell responses; in particular, interleukin-4 (IL-4) and IL-13 induce and enhance B cell IgE synthesis. TH2 cells also produce other cytokines that contribute to the type I hypersensitivity response; thus, IL-4 promotes the development of additional TH2 cells, and IL-5 is involved in the development and activation of eosinophils— important effector cells in type I hypersensitivity responses.

6. Immediate (Type I) Hypersensitivity IgE antibodies synthesized after prior exposure to an allergen are bound to mast cells and basophils via specific surface Fc receptors (Fc E R1). On re-exposure, allergen binds to and cross-links the IgEFc E R1 and results in an immediate reaction (minutes), followed by late-phase reactions (hours) due to: Release (degranulation) of preformed vesicles containing primary mediators De novo synthesis and release of secondary mediators

7. Immediate (Type I) Hypersensitivity Mast cells can also be activated by other stimuli (yielding responses similar to those elicited by allergens): Complement fragments C3a and C5a (anaphylatoxins) binding to surface receptors Chemokines (chemotactic peptides, e.g., IL-8) and adenosine Drugs (e.g., codeine and morphine) Mellitin (in bee venom) Physical stimuli such as sunlight, trauma, and heat or cold

8. Immediate (Type I) Hypersensitivity The consequences of mast cell and basophil activation are schematized: An initial rapid response (i.e., 5 to 30 minutes) is characterized by vasodilation, increased vascular permeability, bronchial smooth muscle contraction, and glandular secretions. This is driven by pre-formed mediators stored in secretory vacuoles and typically resolves within 60 minutes: Biogenic amines (e.g., histamine): Bronchial smooth muscle contraction, increased vascular permeability and dilation, and increased mucus secretion Enzymes contained in granule matrix (e.g., chymase, tryptase): Generate kinins and activated complement by cleaving precursor proteins Proteoglycans (e.g., heparin)

9. Immediate (Type I) Hypersensitivity A second (delayed) phase, with onset 2 to 24 hours after initial allergen exposure, is characterized by inflammatory cell infiltrates and tissue damage (especially epithelium). It can persist for days and is driven by lipid mediators and cytokines produced by the activated mast cells: Lipid mediators: Produced from precursors released from mast cell membranes by phospholipase A2 Leukotriene B4 : Highly chemotactic for neutrophils, monocytes, and eosinophils Leukotrienes C4 , D4 , and E4 : Thousands-fold more potent than histamine for increasing vascular permeability and bronchial smooth muscle contraction

10. Immediate (Type I) Hypersensitivity Prostaglandin D2 : Intense bronchospasm and mucus secretion Platelet-activating factor (PAF): Platelet aggregation, histamine release, bronchoconstriction, vasodilation, and increased vascular permeability; chemotactic for neutrophils and eosinophils and can cause activation with degranulation Cytokine mediators: Recruit and activate inflammatory cells; include TNF- a , IL-1, and chemokines; IL-4 released from mast cells amplifies the TH2 response

11. SYSTEMIC ANAPHYLAXIS Systemic anaphylaxis typically follows parenteral or oral administration of foreign proteins, drugs (e.g., penicillin), food ( e.g.,peanuts ), or insect toxins (e.g., bee venom). The severity reflects the level of sensitization; even minuscule doses can induce anaphylactic shock in a sensitized host. Pruritus, urticaria, and erythema occur minutes after exposure, followed by bronchoconstriction and laryngeal edema ; this can escalate into laryngeal obstruction, hypotensive shock, and death within minutes to hours.

12. LOCAL IMMEDIATE HYPERSENSITIVITY REACTIONS About 10% to 20% of the U.S. population suffers from localized allergic symptoms (e.g., urticaria, angioedema, rhinitis, and asthma) to common inhaled or ingested allergens (pollens, house dust, animal dander, etc ).

13. Antibody-Mediated (Type II) Hypersensitivity Antibody-mediated (type II) hypersensitivity is mediated by antibodies against extrinsic or endogenous antigens present on cell surfaces or in the extracellular matrix; complement activation also plays a significant role. Opsonization and phagocytosis : Cells can be directly lysed by the C5-C9 complement membrane attack complex (MAC) or can be opsonized (enhanced phagocytosis) as a result of fixation of antibody or C3b fragments. Bound antibody can also cause cell lysis (without phagocytosis) by cells bearing Fc receptors (e.g., natural killer [NK] cells), so-called antibody-dependent cell-mediated cytotoxicity (ADCC).

14. Antibody-Mediated (Type II) Hypersensitivity Inflammation: Antibodies (and subsequent complement activation) lead to recruitment and activation of antigen non-specific inflammatory cells (neutrophils and macrophages). These release injurious proteases and reactive oxygen species that lead to tissue pathology. Cellular dysfunction : Certain antibodies can inappropriately activate or block normal cellular or hormonal function without causing tissue damage.

15. Immune Complex–Mediated (Type III) Hypersensitivity Immune complex–mediated (type III) hypersensitivity is mediated by antigen-antibody complexes—immune complexes—forming either in the circulation or at sites of antigen deposition. Antigens can be exogenous (e.g., infectious agents) or endogenous; immune complex–mediated disease can be either systemic or local

16. Immune Complex–Mediated (Type III) Hypersensitivity Systemic disease results from the deposition of circulating immune complexes; it can occur as a response to inoculation of a large volume of exogenous antigen (acute serum sickness) or can result from antibody responses to endogenous antigens (lupus erythematosus) or infectious agents (polyarteritis nodosa).

17. Immune Complex–Mediated (Type III) Hypersensitivity The process is divided into three phases: Formation of immune complexes: Newly synthesized antibodies typically arise about a week after antigen inoculation; the antibodies then bind to the foreign molecules to form circulating immune complexes. Deposition of immune complexes: Propensity for deposition depends on the physicochemical nature of the complexes (e.g., charge, size) and local vascular characteristics (e.g., fenestration, permeability). Deposition is greatest with mediumsized complexes (e.g., slight antigen excess) and in vascular beds that filter (e.g., glomerulus and synovium). Injury caused by immune complexes : Immune complex deposition activates the complement cascade; subsequent tissue injury derives from complement-mediated inflammation and cells bearing Fc receptors.

18. LOCAL IMMUNE COMPLEX DISEASE (ARTHUS REACTION)

19. Cell–Mediated (Type IV) Hypersensitivity

20. T Cell–Mediated (Type IV) Hypersensitivity T cell–mediated (type IV) hypersensitivity is mediated by antigen specific T lymphocytes and includes delayed-type hypersensitivity (CD4 + T) cells and T cell–mediated cytotoxicity (CD8 + T) cells

21. REACTIONS OF CD4 + T CELLS: DELAYED-TYPE HYPERSENSITIVITY AND IMMUNE INFLAMMATION This response is largely mediated by helper CD4+ T cells and can be of two major types; responses associated with TH1 CD4+ T cells are predominated by macrophages, while those driven by TH17 cells are characterized by a greater neutrophil infiltration.

22. REACTIONS OF CD4 + T CELLS: DELAYED-TYPE HYPERSENSITIVITY AND IMMUNE INFLAMMATION Stimulation and differentiation : Recognition of processed peptide antigens on antigen presenting cells leads to production of IL-2, an autocrine proliferation factor. Whether proliferating CD4 + T cells differentiate into TH1 or TH17 lineages depends on the cytokine environment at the time of initial T cell activation. IL-12 production by antigen presenting cells induces TH1 cells, which—in turn—produce interferon- g (IFN- g ) that promotes further TH1 development and thus amplifies the reaction. Conversely, IL-1, IL-6, IL-23, and transforming growth factor- b (TGF- b ) will stimulate differentiation to TH17 cells.

23. REACTIONS OF CD4 + T CELLS: DELAYED-TYPE HYPERSENSITIVITY AND IMMUNE INFLAMMATION Responses of differentiated effector T cells: The major effector cytokine of activated TH1 cells is IFN- g ; it activates macrophages, increases class II histocompatibility molecule expression (improving antigen presentation capacity), induces TNF- a and IL-1 production (promoting inflammation), and increases IL-12 secretion (amplifying the TH1 process). Activated macrophages then clear the offending agent; sustained activation (or the inability to clear the stimulus) can result in greater inflammation and tissue injury. Stimulated TH17 cells secrete IL-17, IL-22, and other cytokines that recruit and activate neutrophils and monocytes—and IL-21, which amplifies the TH17 response.

24. REACTIONS OF CD4 + T CELLS: DELAYED-TYPE HYPERSENSITIVITY AND IMMUNE INFLAMMATION The classic delayed-type hypersensitivity (DTH) response is the tuberculin reaction to intracutaneous injection of purified protein derivative (PPD) derived from the tubercle bacillus. Prior tuberculosis infection results in circulating PPD-responsive memory CD4 + T cells; subsequent PPD injection into such an individual leads to the recruitment and activation of these cells beginning at 6 to 8 hours and peaking at 24 to 72 hours (the delayed in DTH). Histologically, there is a perivascular mononuclear cell infiltrate (CD4+ T cells and macrophages) with evidence of endothelial activation.

25. REACTIONS OF CD4 + T CELLS: DELAYED-TYPE HYPERSENSITIVITY AND IMMUNE INFLAMMATION Granulomatous inflammation occurs when persistent or nondegradable antigens (e.g., foreign bodies) lead to chronic macrophage activation manifesting as large epithelioid cells; nodules of these activated cells are called granulomas .

26. REACTIONS OF CD4 + T CELLS: DELAYED-TYPE HYPERSENSITIVITY AND IMMUNE INFLAMMATION Contact dermatitis is another example of a DTH response, in this case to modified self. An example is poison ivy; its active constituent, urushiol, binds to host proteins and alters their antigenicity.

27. Summary Immune responses that cause tissue injury are called hypersensitivity reactions, and the diseases caused by these reactions are called hypersensitivity diseases or immune-mediated inflammatory diseases Immediate hypersensitivity (type I, commonly called allergy) is caused by the production of IgE antibody against environmental antigens or drugs (allergens), sensitization of mast cells by the IgE, and degranulation of these mast cells on subsequent encounter with the allergen. Antibodies against cell and tissue antigens may cause tissue injury and disease (type II hypersensitivity). IgM and IgG antibodies promote the phagocytosis of cells to which they bind, induce infl ammation by complement- and Fc receptor–mediated leukocyte recruitment, and may interfere with the functions of cells by binding to essential molecules and receptors.

28. Summary Antibodies may bind to circulating antigens to form immune complexes, which deposit in vessels and cause tissue injury (type III hypersensitivity). Injury is due mainly to leukocyte recruitment and inflammation. T cell–mediated diseases (type IV hypersensitivity) are caused by TH1-mediated delayed-type hypersensitivity reactions or TH17-mediated infl ammatory reactions, or by killing of host cells by CD8 + CTLs.