Mechanisms of human autoimmunity - PubMed (original) (raw)

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Mechanisms of human autoimmunity

Michael D Rosenblum et al. J Clin Invest. 2015 Jun.

Abstract

Autoimmune reactions reflect an imbalance between effector and regulatory immune responses, typically develop through stages of initiation and propagation, and often show phases of resolution (indicated by clinical remissions) and exacerbations (indicated by symptomatic flares). The fundamental underlying mechanism of autoimmunity is defective elimination and/or control of self-reactive lymphocytes. Studies in humans and experimental animal models are revealing the genetic and environmental factors that contribute to autoimmunity. A major goal of research in this area is to exploit this knowledge to better understand the pathogenesis of autoimmune diseases and to develop strategies for reestablishing the normal balance between effector and regulatory immune responses.

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Figure 2

Figure 2. Genetic susceptibility, environmental stimuli, and defective regulation are responsible for initiating autoimmunity.

Genetic polymorphisms in immune-related genes (including HLA, cytokines/receptors, and those involved in central tolerance) may lower the threshold for the activation of autoreactive T cells. Environmental triggers such as infection, the microbiome, and tissue injury generate a proinflammatory environment that supports the activation of autoreactive lymphocytes. Tregs normally function to suppress autoreactive T cells, but defects in development, stability, or function may render these cells dysfunctional and unable to control autoreactive T cell responses. Alone or in combination, these factors can contribute to the escape, activation, and proliferation of autoreactive lymphocytes that result in tissue injury and clinical disease.

Figure 1

Figure 1. Three major phases of autoimmune disease.

Autoimmunity is initiated by a combination of genetic predisposition and environmental triggers. Patients in the initiation phase of disease are typically unaware of clinical symptoms (subclinical). Patients present with clinical disease during the propagation phase, which is characterized by self-perpetuating inflammation and tissue damage due to cytokine production, epitope spreading, and a disrupted effector T cell/Treg (Teff/Treg) balance. Autoimmune reactions resolve with the activation of cell-intrinsic (inhibitory pathways) and cell-extrinsic (Tregs) mechanisms to limit effector responses and restore the Teff/Treg balance. Patients in this phase often suffer from relapsing and remitting disease as a result of a persistent struggle between pathogenic effector responses and regulation.

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