Normal and Abnormal Immune Responses

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Normal and Abnormal Immune Responses

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

BOX 4-1 “Must-Knows” for the Nature of the Response: TICTOC

A 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

Acute phase (proinflammatory) cytokines are IL-1, IL-6, and TNF-α.

6. Early: DC maturation

• TLR stimulation promotes maturation and mobilization of DCs to lymph nodes

• IL-12 from DCs and macrophages activates NK cells and promotes helper T cell subset 1 (T_H1) responses.

IL-12 production signals need for local cellular and antibody protections (T_H1).

B 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).

TABLE 4-1

Cytokine Responses

IFN, interferon; IL, interleukin; PAMP, pathogen-associated molecular pattern; TGF, transforming growth factor; T_H, helper T cell; TNF, tumor necrosis factor; Treg/sup, regulatory or suppressive T cell.

^*IL-12 is not always part of an acute phase response.

4-1 Antigen-dependent lymphocyte activity in peripheral lymph node. Antigen carried in the lymph becomes associated with dendritic cells (DCs) to be presented to lymphocytes. The paracortex contains mainly T cells, many of which are associated with interdigitating antigen-presenting cells (DCs). After initial activation, T cells migrate to the cortex, where they interact with B cells in primary follicles, which develop into secondary follicles, with active B cell proliferation and differentiation occurring in the germinal centers. Lymphocytes leave the node through the efferent lymphatic vessel.

1. Initial activation of naive CD4 T_H 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 T_H cells

3. Proliferation of activated CD4 T_H cells and differentiation into cytokine-secreting T_H1 and T_H2 subsets

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

Primary antibody response: slow onset, initially IgM, low titer. Presence of IgM is good indication of a primary response.

Secondary antibody response: fast onset, primarily IgG, high titer

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

• Class switching (gene recombination) and affinity maturation (somatic mutation) occur.

• T_H1 cytokines stimulate B cells to make IgG1 (human).

• T_H2 cytokines stimulate production of other IgG subclasses, IgE, or IgA.

6. Swelling of lymph nodes because of lymphoid proliferation

Acute inflammation produces painful swelling of lymph nodes.

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; T_H1 cytokine), leading to enhancement of their antigen-presenting, antibacterial, antiviral, and antitumor activities

C 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).

4-2 Time course of primary and secondary humoral (antibody) immune responses. After initial challenge with a particular antigen, secreted antibody is detectable only after a lag period of several days and initially consists of IgM. The secondary immune response (anamnestic response) after rechallenge with the same antigen reaches a higher titer, lasts longer, and consists predominantly of IgG.

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

BOX 4-2 Original Antigenic Sin

Once generated during a primary response, antigen-specific memory B cells stop dividing (G₀ phase of cell cycle) and may have a life span of years. When these quiescent cells later encounter the same epitope on a closely related antigen X, they sometimes are preferentially activated, producing antibody that binds to antigen X and prevents activation of naive B cells specific for other epitopes on antigen X, thereby inhibiting a new primary antibody response to X. This phenomenon is often observed with strains of type A influenza virus and may contribute to influenza epidemics.

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).

TABLE 4-2

Hypersensitivity Reactions

T_H1, helper T cell subset 1.

^*Antibody (with complement)–initiated autoimmune diseases like rheumatoid arthritis, systemic lupus erythematosus, and possibly multiple sclerosis develop into T cell–mediated chronic diseases.

Type I: Soluble mediators, preformed actors—fast reactions of less than 30 minutes

Type II : soluble mediators, cellular actors—slower reactions of less than 8 hours

Type III: soluble mediators, cellular actors—slower reactions of less than 8 hours

Type IV: cellular mediators, cellular actors—slow reactions of more than 1 day

A Type I (immediate) hypersensitivity

• IgE-mediated atopic (allergic) and anaphylactic reactions in previously exposed (sensitized) individuals (Fig. 4-3)

4-3 Type I hypersensitivity. IgE produced in response to initial allergen exposure binds to Fc receptors on mast cells and basophils. Rechallenge with the same allergen leads to release of histamine and other mediators, which produce various symptoms of localized atopic reaction or generalized anaphylaxis. Ag, antigen; IL-4, interleukin-4.

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

• Acute generalized anaphylaxis: shock, vascular collapse, respiratory collapse

• Chronic, recurrent localized reactions: asthma, allergic rhinitis (hay fever), and wheal and flare (hives)

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 I hypersensitivity: IgE; mast cell degranulation; rapid local (allergic) or systemic (anaphylactic) effects

B Type II hypersensitivity

• Antibody-dependent cytotoxicity

1. Initiation: binding of antibody to cell surface antigens

2. Effector mechanisms

• Complement activated by cell surface antigen-antibody complex → cell lysis by membrane attack complex

• Antibody-dependent cellular cytotoxicity (ADCC) triggered by binding of antibody to Fc receptors on macrophages and NK cells → cell destruction

• C3a and C5a attract neutrophils and promote inflammation.

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)

BOX 4-3 Hemolytic Disease of the Newborn

An Rh-negative woman normally becomes sensitized to Rh antigens during birth of her first Rh-positive child. During a subsequent pregnancy with an Rh-positive infant, the sensitized mother produces anti-Rh IgG antibody, which crosses the placenta, leading to destruction of fetal RBCs by type II hypersensitivity reaction. Hemolysis causes hemoglobinemia, jaundice, and accumulation of indirect bilirubin, which can result in respiratory and brain damage to the fetus.

Anti-Rh antibody (RhoGAM) administered to the mother soon after delivery of her first Rh-positive child prevents sensitization by neutralizing fetal Rh antigens that enter the mother’s circulation during removal of the placenta. A Rhogam-treated mother will not mount an anti-Rh immune response in subsequent pregnancies.

Direct Coombs test

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