The genetics and epigenetics of autoimmune diseases

Abstract

Self tolerance loss is fundamental to autoimmunity. While understanding of immune regulation is expanding rapidly, the mechanisms causing loss of tolerance in most autoimmune diseases remain elusive. Autoimmunity is believed to develop when genetically predisposed individuals encounter environmental agents that trigger the disease. Recent advances in the genetic and environmental contributions to autoimmunity suggest that interactions between genetic elements and epigenetic changes caused by environmental agents may be responsible for inducing autoimmune disease. Genetic loci predisposing to autoimmunity are being identified through multi-center consortiums, and the number of validated genes is growing rapidly. Recent reports also indicate that the environment can contribute to autoimmunity by modifying gene expression through epigenetic mechanisms. This article will review current understanding of the genetics and epigenetics of lupus, rheumatoid arthritis, multiple sclerosis and type 1 diabetes, using systemic lupus erythematosus as the primary example. Other autoimmune diseases may have a similar foundation.

Fig. 1

Role of DNA methylation and histone modifications in gene regulation. A. Methylation of cytosines in CpG pairs recruits proteins containing a methyl-CpG-binding domain (MBD) such as MeCP2. Once bound, the MDB’s form a complex with histone deacetylases (HDAC) or directly block transcription factor binding. In addition, methylated histone tails may recruit DNMTs through chromodomain proteins, to methylate DNA for long term gene silencing. B. MBD cannot bind hypomethylated DNA. Thus the recruitment of HDAC is impaired. C. Acetylation of positively charged lysine amino groups in histones by histone acetyltransferases (HAT) neutralizes the charge and disrupts binding to the negatively charged phosphates in DNA. The “relaxed” DNA formed facilitates binding of transcription factors and RNA polymerase II promoting active transcription.

Fig. 2

Chromosomal location of genes predisposing to SLE. The number or letter beneath each chromosome identifies the chromosome, and the number below that shows the number of lupus associated sites on the chromosome. The locations of lupus predisposing genes are indicated by the lines.