The Interplay Between Environmental and Genetic Factors in Autoimmune Disorders PDF Print E-mail
Saturday, 14 January 2012 10:23
Autoimmune disorders constitute a group of more than 80 different diseases characterized by immune attack of components of a person’s own body, mediated by autoantibodies and autoreactive T cells. Specifically, the common feature that defines autoimmune diseases is the breakdown of immune tolerance and the subsequent malfunction of the immune system, resulting in inflammation and tissue destruction (Cho and Gregersen, 2011).

Despite their heterogeneity, autoimmune diseases share epidemiological, etiopathogenic, and clinical features. Most autoimmune disorders affect more women, frequently of reproductive age, than men. This observation draws attention to the environmental etiology, especially the role of sex hormones and X-chromosome genes in autoimmune disorders. On the other hand, autoimmune diseases are treated with immunosuppressive strategies.

Finally, people frequently suffer from more than one autoimmune disorder at the same time or during different stages of their lives. Also, patients with chronic inflammatory diseases, such as systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA), are at higher risk than the general population of developing specific types of lymphoma (Hansen et al., 2007).

Autoimmune diseases can be classified into two canonical groups, depending on whether the effect is organ-specific or systemic. In the former case, the immune response specifically reacts against autoantigens located in a specific organ. Some examples of organ-specific autoimmune disorders are diabetes mellitus type 1, multiple sclerosis (MS), primary biliary cirrhosis, Hashimoto’s thyroiditis, and Grave’s disease, among others. On the other hand, systemic autoimmune disorders, such as RA, SLE, Sjögren’s syndrome, and psoriasis, are characterized by a multi-organ attack arising from the systemic distribution of the autoantigens (Javierre et al., 2008).

Autoimmune diseases affect around 5% of the world population, particularly people from developed countries. This biased distribution is explained by the existing differences in the genetic background and environmental agents. Autoimmune processes, like other complex diseases such as cancer, arise from a combination of genetic susceptibility and environmental factors. It is therefore critical not only to study them separately but also to understand their interactions in order to define risk levels and to develop therapeutic strategies.

Genetic susceptibility has a major role in autoimmunity development. In fact, polymorphisms in over 200 bona fide loci have been identified as contributors to autoimmune disorders and many of these are common to various autoimmune diseases (Cho and Gregersen, 2011). The combination of multiple polymorphisms of relatively small effect individually can generate a physiological context in which the threshold for attaining an autoimmune response is lower.

The majority of susceptibility loci affected by polymorphisms fall into one of three main groups: innate immune response, cytokine signaling, and lymphocyte activation. A clear example of a group of susceptibility genes related with lymphocyte activation is the major histocompatibility complex (MHC) family. Polymorphisms affecting these sequences significantly contribute to type 1 diabetes, MS, celiac disease, psoriasis, RA, and SLE. Another classic example of a susceptibility gene related with the innate immune response is Interferon regulatory factor 5 (IRF5). This gene is involved in the interferon-mediated signaling, featuring many polymorphisms that are associated with RA, SLE, systemic sclerosis, and primary biliary cirrhosis.

However, genetics cannot fully explain the hereditary patterns of autoimmune disorders. In fact, genome-wide association studies have shown that genetic polymorphisms account for only 20% of the phenotypic variance (Wallace, 2010). In addition, monozygotic (MZ) twins show moderate rates of concordance for autoimmune disorders (Ballestar, 2010). For example MZ twins are highly concordant for psoriasis or celiac disease.

In contrast, ulcerative colitis, RA, and type 1 diabetes have stronger environmental influences, as reflected by low concordance rates of around 10%. All of these data highlight the different contributions and interactions between genetic and environmental factors in various autoimmune diseases. Temporal associations between some environmental exposures and autoimmunity onset, and relationships between seasonality patterns in birth dates and autoimmunity development have been observed (Samuelsson and Carstensen, 2003; Sarkar et al., 2005).

Occurrence of geographic and occupational clustering of autoimmune patients provides further evidence of the environmental determinants of these diseases. Many environmental factors, including exposure to tobacco smoke, infectious agents, radiation, ultraviolet (UV) light, and chemical compounds, among other external conditions, are significantly associated with the development of autoimmune disorders. The majority of these environmental factors can directly or indirectly induce epigenetic changes, which modulate gene expression and therefore associate with changes in immune cell function. For this reason, epigenetics provides a source of molecular mechanisms that can explain the environmental effects on the development of autoimmune disorders.

The close relationship between environment and epigenetic status is exemplified by the ability to acquire DNA methylation alterations induced by a specific maternal diet in descendent mice (Cooney et al., 2002; Sandovici et al., 2011; Waterland et al., 2006; 2010). This relationship has not only been determined in mice; there is also a great deal of evidence of epigenetic changes induced by environment in humans (Heijmans et al., 2008; Katari et al., 2009; Waterland et al., 2010).

Other potential mechanisms underlying the induction of autoimmunity by environmental factors have been proposed. One model is the “hapten hypothesis” which proposes that certain chemical products may react with self components of the body to generate novel antigenic molecules (Mintzer et al., 2009). For example, tobacco smoke can convert arginine into citrulline. Interestingly, RA patients are frequently characterized by the presence of autoantibodies against citrullinated proteins (Klareskog et al., 2006). Environmental factors, such as UV radiation, can also alter the abundance and localization of some autoantigens (Casciola-Rosen et al., 1994; Kuhn and Beissert, 2005).

Another theory emphasizes the molecular mimicry based on the cross-reaction between environmental antigens with self antigens. This is highlighted by the detection of serum autoantibodies that also recognize pathogenic epitopes such as the anti-SM autoantibody obtained from SLE patients that also reacts against the Epstein-Barr virus antigen EBNA-1 (Harley and James, 2006). All these possibilities are compatible with the thesis that environmental factors induce epigenetic-mediated expression changes as discussed below in further detail.

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