Normal and Abnormal Immune Responses

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Chapter 4

Normal and Abnormal Immune Responses

Cascade of Events in Typical Immune Responses (Box 4-1)

Localized antigen-nonspecific responses at site of antigen exposure

1. Fast: activation of alternate or lectin complement pathway leading to inflammatory response, opsonization, and bacterial killing

2. Fast: interferon-mediated protection against viral infection and natural killer (NK) cell killing of virus-infected cells

3. Soon after: migration of phagocytes (neutrophils, macrophages, dendritic cells [DCs]) to site of antigen and phagocytosis

4. Early: pathogen-associated molecular patterns (PAMPs) on microbial structures (e.g., lipopolysaccharide and peptidoglycan) stimulate toll-like receptors (TLRs) and other receptors on DCs and macrophages that make cytokines

5. Early: acute phase response induced by interleukin-1 (IL-1), IL-6, and tumor necrosis factor (TNF) secreted from macrophages and DCs

6. Early: DC maturation

Primary antigen-specific responses

• Lymphocytes interact with antigen-presenting cells (APCs) in lymph nodes (Fig. 4-1), the spleen, and mucosal-associated lymphoid tissue, which includes tonsils, adenoids, appendix, and Peyer patches; cytokines define the nature of the response (Table 4-1).

1. Initial activation of naive CD4 TH cells triggered by binding to antigenic peptides associated with class II major histocompatibility complex (MHC) molecules on DCs, but not other APCs

2. Activation of naive B cells (T dependent) expressing membrane immunoglobulin M (IgM) triggered by binding of antigen and interaction with TH cells

3. Proliferation of activated CD4 TH cells and differentiation into cytokine-secreting TH1 and TH2 subsets

4. Initial activation and proliferation of naive CD8 cytotoxic T (TC) cells triggered by binding of antigenic peptides associated with class I MHC molecules on DCs for recognition of infected cells, tumor cells, and grafts

5. Cytokine-induced proliferation of activated B cells and differentiation into memory cells and antibody-secreting plasma cells

6. Swelling of lymph nodes because of lymphoid proliferation

7. Exit of activated lymphocytes from lymph node or other peripheral lymphoid tissue and mobilization to site of infection

8. Activation of macrophages and DCs by interferon-γ (IFN-γ; TH1 cytokine), leading to enhancement of their antigen-presenting, antibacterial, antiviral, and antitumor activities

Secondary immune response

1. Rechallenge with an antigen produces a secondary specific response that is faster and stronger (anamnestic response) than primary response to the same antigen because DCs and any APCs can present antigen to T cells and because of the presence of memory B and T cells (Fig. 4-2).

2. Persistence of memory B cells accounts for the phenomenon called “original antigenic sin” (Box 4-2).

II Hypersensitivity Reactions

• Hypersensitivity reactions are important in the immune response to certain antigens, but they also cause pathologic changes associated with many autoimmune diseases and infections, especially viral infections (Table 4-2).

Type I (immediate) hypersensitivity

1. Initiation: cross-linkage by antigen (allergen) of IgE bound to Fc receptors on mast cells and basophils after reexposure of sensitized host to allergen

2. Effector mechanism: degranulation of mast cells and basophils releasing numerous vasoactive and other mediators, such as histamine and SRS-A (slow-reacting substance of anaphylaxis)

3. Clinical manifestations

4. Desensitization therapy: repeated injections of increasing doses of allergen induce production of IgG, which binds the allergen and prevents its binding to IgE on sensitized cells.

Type II hypersensitivity

1. Initiation: binding of antibody to cell surface antigens

2. Effector mechanisms

3. Clinical manifestations

• Hemolytic transfusion reactions: antibodies to red blood cell (RBC) antigens

• Drug-induced thrombocytopenia and hemolytic anemia: antibodies to drugs absorbed on platelets and RBCs

• Hemolytic disease of the newborn (erythroblastosis fetalis): maternal antibody to antigens on fetal RBCs, especially Rh antigens (Box 4-3)