Stevens T R, Winrow V R, Blake D R, Rampton D S. pathogens can potentiate antimicrobial immunity. However, long-term confrontation of the immune system with hsp antigens which are similar in the host and invaders may convert the immune response against these host antigens and promote autoimmune disease. This review provides an overview of the role of hsp in immunity with a focus on infectious and autoimmune diseases. Heat shock proteins (hsp) are widely distributed in nature and are among the most highly conserved molecules of the biosphere. hsp perform important functions in the folding and unfolding or translocation of proteins, as well as in the assembly and disassembly of protein complexes. Because of these helper functions, hsp have been termed molecular chaperones. The molecules involved in antigen recognition, i.e., immunoglobulins (Ig), T-cell receptors (TCR), and gene products of the major histocompatibility complex (MHC), are all multimeric complexes, and their assembly is promoted by distinct chaperones. Several lines of evidence also favor an important role for members of the hsp family in intracellular antigen-processing pathways. The first part of this review PEG6-(CH2CO2H)2 describes the biological roles of hsp as they relate to the assembly of protein complexes and participation in different processing and presentation steps of antigens. hsp synthesis is increased to protect prokaryotic or eukaryotic cells from various insults during periods of stress caused by infection, inflammation, or similar events. Consistent with this abundance, in several infections and autoimmune diseases, hsp represent prominent antigens in the humoral and cellular immune response mediated by antibodies and T cells, respectively. The second part of this review summarizes the diseases, in both experimental-animal models and humans, where evidence has been obtained for a unique role of hsp as antigens. Although hsp play an important role in several infectious and autoimmune diseases, evidence arguing against the direct involvement of hsp in protection or autoaggression has been gathered. At present, initiation of protective immunity against infectious agents or autoimmune disorders by hsp alone appears unlikely. Rather, it seems more likely that they become important antigens during infection and inflammation and in this way influence and sustain anti-infectious and autoimmune responses. Thus, hsp act as chaperones, not only during the biogenesis of other proteins but also during PEG6-(CH2CO2H)2 the immune response to other antigens. ACQUIRED IMMUNE RESPONSE TO INFECTIOUS AGENTS The vertebrate immune system encounters an enormous variety of pathogens. Specific identification and elimination of such a multitude of potentially infectious agents depends on a broad array of detection and execution systems. The specific recognition of foreign invaders is effected by clonally distributed receptors expressed on lymphocytes, such as antibodies produced by B lymphocytes and TCR Rabbit Polyclonal to HER2 (phospho-Tyr1112) expressed on the surface of T lymphocytes. These receptors specifically recognize structures termed antigens that encompass subunits named epitopes. While antibodies directly recognize peptide or carbohydrate epitopes, T cells interact only with antigens presented by products of the MHC complex expressed on the surface of target cells. In the extracellular space, antibodies specifically recognize pathogens and neutralize microbial products, for example bacterial toxins. In contrast to the humoral response, the cellular immune responsemediated by T lymphocytespossesses the capacity to recognize antigens of intracellular microbes, which are hidden from antibody detection (127). Whenever T or B cells are confronted with an antigen, a lymphocyte clone expressing unique receptor specificity is expanded. Frequent encounters with PEG6-(CH2CO2H)2 the same antigen result in immunological memory, which enables the immune system to respond to repeated microbial confrontation more potently both in qualitative and in quantitative terms. B cells produce antibodies which further segregate into five different Ig classes (208). T cells can be subdivided into at least three major classes according to the expression of specific surface molecules (127). In humans and mice the majority of T cells ( 90%) express a TCR composed of an -chain and a -chain. In addition to the highly variable TCR, these T cells express a diverse set of accessory CD4 or CD8 molecules. Most mature T cells express either the CD4 or the CD8 molecule in a mutually exclusive way, and the expression of these molecules correlates with a characteristic recognition pattern. CD4 T cells recognize peptides presented by MHC class II molecules, which consist of an -chain and a -chain with a peptide binding groove composed of polymorphic domains of both chains (35). The expression of MHC class II molecules is restricted to a few antigen-presenting cells (APC), such as mononuclear phagocytes, dendritic cells, and B cells. Epitopes which are recognized by CD4 T cells are generally of extracellular origin and are derived from the endosomal compartment (147). Thus, antigens of intracellular microbes which are localized in the endosome are processed primarily through the.