Journal Article

Genetics of autoimmune diseases — disorders of immune homeostasis

Behrens, Timothy W., Gregersen, Peter K.

2006

Overview

Key Points Complex and diverse mechanisms have evolved to regulate the immune system and prevent it from inappropriately turning against the self. Overall, autoimmunity can be viewed as an alteration in the normal homeostatic mechanisms that regulate self–non-self discrimination. The immune system comprises two interacting systems that are based on innate and adaptive immune responses. Innate responses are immediate and generally use pre-formed recognition structures, whereas adaptive immunity involves the production and selection of specific recognition structures that develop following exposure and persist as a memory response. A number of genes involved in adaptive immunity have been implicated in autoimmune diseases. Several of these genes regulate T-cell tolerance to self, and give rise to rare and highly penetrant Mendelian disorders. Other genes are common and have more subtle 'threshold' effects on T-cell reactivity. In general, T-cell tolerance is effected 'centrally' in the thymus, or peripherally through the action of regulatory T cells or other mechanisms. The genetic variants involved in regulating T-cell and B-cell tolerance predispose to multiple autoimmune disorders. This demonstrates that there are common underlying mechanisms for many of these diseases, such as type 1 diabetes, systemic lupus erythematosus and rheumatoid arthritis, among others. Recent studies have also demonstrated the involvement of the innate immune system in autoimmunity. In particular, Toll-like receptors have been implicated in the development of B-cell autoimmunity, and genetic associations in Toll-receptor signalling pathways have been found in systemic lupus erythematosus. New gene-identification strategies, such as whole-genome association studies, are likely to reveal many additional genes that predispose to autoimmunity. A consideration of gene–gene and gene–environment interactions will be essential for the proper interpretation of these new genetic findings. Combined with advances in immunology, genetic studies in human populations are revealing the diverse alterations in adaptive immunity that underlie autoimmune diseases. Recent studies have also highlighted an unexpected contribution of the innate immune system to these complex diseases. In the past few years, our extensive knowledge of the mammalian immune system and our increasing ability to understand the genetic causes of complex human disease have opened a window onto the pathways that lead to autoimmune disorders. In addition to the well-established role of genetic variation that affects the major histocompatibility complex, a number of rare and common variants that affect a range of immunological pathways are now known to have important influences on the phenotypic diversity that is seen among autoimmune diseases. Recent studies have also highlighted a previously unanticipated interplay between the innate and adaptive immune system, providing a new direction for research in this field.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Adaptive immunity / Agriculture / Animal Genetics and Genomics / Animals / Antibodies / Antigens / Autoimmune diseases / Autoimmune Diseases - genetics / Autoimmunity / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Cancer Research / Defense / Disease / Fundamental and applied biological sciences. Psychology / Gene Function / Genetics / Genetics of eukaryotes. Biological and molecular evolution / Homeostasis - immunology / Human Genetics / Humans / Immune System / Immunology / Microorganisms / Proteins / review-article / Tumor necrosis factor-TNF