Rethinking mechanisms of autoimmune pathogenesis

Abstract

Why exactly some individuals develop autoimmune disorders remains unclear. The broadly accepted paradigm is that genetic susceptibility results in some break in immunological tolerance, may enhance the availability of autoantigens, and may enhance inflammatory responses. Some environmental insults that occur on this background of susceptibility may then contribute to autoimmunity. In this review we discuss some aspects related to inhibitory signaling and rare genetic variants, as well as additional factors that might contribute to autoimmunity including the possible role of clonal somatic mutations, the role of epigenetic events and the contribution of the intestinal microbiome. Genetic susceptibility alleles generally contribute to the loss of immunological tolerance, the increased availability of autoantigens, or an increase in inflammation. Apart from common genetic variants, rare loss-of-function genetic variants may also contribute to the pathogenesis of autoimmunity. Studies of an inhibitory signaling pathway in B cells helped identify a negative regulatory enzyme called sialic acid acetyl esterase. The study of rare genetic variants of this enzyme provides an illustrative example showing the importance of detailed functional analyses of variant alleles and the need to exclude functionally normal common or rare genetic variants from analysis. It has also become clear that pathways that are functionally impacted by either common or rare defective variants can also be more significantly compromised by gene expression changes that may result from epigenetic alterations. Another important and evolving area that has been discussed relates to the role of the intestinal microbiome in influencing helper T cell polarization and the development of autoimmunity.

Keywords: Autoimmunity; Epigenetics; Genetic variants; Microbiome; SIAE.

Fig 1

The SIAE/Siglec pathway. This pathway regulates peripheral B cell tolerance as described in the text. Glycoproteins including membrane immunoglobulins can be acetylated on the 9-OH position of sialic acid in the late Golgi by a sialic acid acetyl transferase (SIAT) and subsequently de-acetylated by a sialic acid acetyl esterase (SIAE). Loss of function mutations in SIAE and more commonly epigenetic inhibition of expression of this enzyme may contribute to the loss of B cell tolerance and the induction of autoimmunity.

Fig 2

A model integrating genetics, microbiota and epigenetics in the pathogenesis of autoimmunity. Common genetic variants and rare genetic variants may cause alterations in the functions of certain genes that contribute to changes in the internal or external milieu of immune cells. Alteration of cytokine levels for instance could change the external milieu while changes in levels of intracellular metabolites may change the internal milieu. Similarly changes in the microbiome or in exposure chemical toxins or drugs could result either in altered stimulation of immune cells, or the production of unique metabolites that potentially alter the intracellular milieu in immune cells. These changes in the milieu of immune cells could contribute to the altered levels of expression of certain immune cell genes, either by inducing or inhibit certain microRNAs or by regulating the expression of chromatin modifying enzymes. These "epigenetic" changes in gene expression in immune cells caused by the microbiome or by genetic alterations or both could alter immune cell function causing these cells to change the expression of proteins in a way that results in a break in tolerance, or the increased availability of a self-antigen, or an increased ability to induce inflammation. Such changes could contribute to the development of autoimmunity.