Mechanisms of immunological tolerance and their dysregulation in rheumatic diseases

Abstract

The major tasks of the immune system are protection against infectious agents, maintaining homeostasis by recognizing and neutralizing noxious substances from the environment, and monitoring pathological, e.g. neoplastic tissue changes. It accomplishes these tasks through complex interactions of cellular and humoral components of the innate and adaptive immune system. This review article focuses on acentral problem of self versus non-self discrimination in the development of B and Tlymphocytes as carriers of adaptive immunity. During maturation of the lymphocytes in the bone marrow, large repertoires of lymphocyte receptors are randomly generated by somatic recombination, which as awhole have the capability of recognizing any foreign antigen. In order to reduce the implicit risk of autoaggressive immunity that might arise from evolutionary conserved structural motifs in self and foreign antigens, the adaptive immune system must provide redundant mechanisms (clonal deletion, anergy, quiescence and suppression) to eliminate or inactivate lymphocytes expressing highly avid receptors for autoantigens. Thus, the provision of costimulatory signals resulting in areduced activation threshold of potentially autoreactive anergic Tcells through infection, molecular mimicry, disrupted apoptosis regulation, altered "self" by post-translational modification, genetic changes in transcription factors with critical importance for thymic tolerance induction or signaling components of apoptosis can lead to adisruption of self-tolerance and the induction of pathogenic autoimmunity.