Selftolerance

Microbe DC expresses Self-

costimulatory reactive Activation molecules {T cell of DC

Self antigen

B7 CD28 Presentation of antigen by APC

Self tissue

Microbe DC expresses Self-

costimulatory reactive Activation molecules {T cell of DC

Self tissue

Autoimmunity

Microbe

Microbial antigen

Molecular mimicry

Microbial antigen

Microbe

Self-reactive T cell that recognizes microbial peptide

Microbial protein

Self-reactive T cell that recognizes microbial peptide

Activation of T cells

Microbial protein

Activation of T cells

Self antigen

Self tissue

Self protein

FIGURE 14-12 Role of infections in the development of autoimmunity. A, Normally, encounter of a mature self-reactive T cell with a self antigen presented by a costimulator-deficient resting tissue antigen-presenting cell (APC) results in peripheral tolerance by anergy. (Other possible mechanisms of self-tolerance are not shown.) B, Microbes may activate the APCs to express costimulators, and when these APCs present self antigens, the self-reactive T cells are activated rather than rendered tolerant. C, Some microbial antigens may cross-react with self antigens (molecular mimicry). Therefore, immune responses initiated by the microbes may activate T cells specific for self antigens.

Self antigen

Self tissue

Self protein

FIGURE 14-12 Role of infections in the development of autoimmunity. A, Normally, encounter of a mature self-reactive T cell with a self antigen presented by a costimulator-deficient resting tissue antigen-presenting cell (APC) results in peripheral tolerance by anergy. (Other possible mechanisms of self-tolerance are not shown.) B, Microbes may activate the APCs to express costimulators, and when these APCs present self antigens, the self-reactive T cells are activated rather than rendered tolerant. C, Some microbial antigens may cross-react with self antigens (molecular mimicry). Therefore, immune responses initiated by the microbes may activate T cells specific for self antigens.

• Infections of particular tissues may induce local innate immune responses that recruit leukocytes into the tissues and result in the activation of tissue APCs. These APCs begin to express costimulators and secrete T cell-activating cytokines, resulting in the breakdown of T cell tolerance. Thus, the infection results in the activation of T cells that are not specific for the infectious pathogen; this type of response is called bystander activation. The importance of aberrant expression of costimulators is suggested by experimental evidence that immunization of mice with self antigens together with strong adjuvants (which mimic microbes) results in the breakdown of self-tolerance and the development of autoimmune disease. In other experimental models, viral antigens expressed in tissues such as islet P cells induce T cell tolerance, but systemic infection of the mice with the virus results in the failure of tolerance and autoimmune destruction of the insulin-producing cells.

Microbes may also engage Toll-like receptors (TLRs) on dendritic cells, leading to the production of lymphocyte-activating cytokines, and on autoreactive B cells, leading to autoantibody production. A role of TLR signaling in autoimmunity has been demonstrated in mouse modes of SLE.

• Infectious microbes may contain antigens that cross-react with self antigens, so immune responses to the microbes may result in reactions against self antigens. This phenomenon is called molecular mimicry because the antigens of the microbe cross-react with, or mimic, self antigens. One example of an immuno-logic cross-reaction between microbial and self antigens is rheumatic fever, which develops after streptococcal infections and is caused by antistrepto-coccal antibodies that cross-react with myocardial proteins. These antibodies are deposited in the heart and cause myocarditis. Molecular sequencing has revealed numerous short stretches of homologies between myocardial proteins and streptococcal protein.

The significance of limited homologies between microbial and self antigens in common autoimmune diseases remains to be established, and it has been difficult to prove that a microbial protein can actually cause a disease that resembles a spontaneous autoimmune disease. On the basis of transgenic mouse models, it has been suggested that molecular mimicry is involved in triggering autoimmunity when the frequency of autoreactive lymphocytes is low; in this situation, the microbial mimic of the self antigen serves to expand the number of self-reactive lymphocytes above some pathogenic threshold. When the frequency of self-reactive lymphocytes is high, the role of microbes may be to induce tissue inflammation, to recruit self-reactive lymphocytes into the tissue, and to provide second signals for the activation of these bystander lymphocytes.

Some infections may protect against the development of autoimmunity. Epidemiologic studies suggest that reducing infections increases the incidence of type 1 diabetes and multiple sclerosis, and experimental studies show that diabetes in NOD mice is greatly retarded if the mice are infected. It seems paradoxical that infections can be triggers of autoimmunity and also inhibit autoimmune diseases. How they may reduce the incidence of autoimmune diseases is unknown.

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