1The odds ratio approximates values of increased risk of the disease associated with inheritance of particular HLA alleles. The data are from European-derived populations.

2Anti-CCP Ab, antibodies directed against cyclic citrullinated peptides. Data are from patients who test positive for these antibodies in the serum. 3SE refers to shared epitope, so called because the susceptibility alleles map to one region of the DRB1 protein (positions 70-74). (Courtesy Dr. Michelle Fernando, Imperial College, London.)

and adjacent non-HLA genes, that tend to be inherited together as a single unit.

• In many autoimmune diseases, the disease-associated nucleotide polymorphisms encode amino acids in the peptide-binding clefts of the MHC molecules. This finding is not surprising because polymorphic residues of MHC molecules are located within and adjacent to the clefts, and the structure of the clefts is the key determinant of both functions of MHC molecules, namely, antigen presentation and recognition by T cells (see Chapter 6). These results support the general concept that MHC molecules influence the development of autoimmunity by controlling T cell selection and activation.

• Disease-associated HLA sequences are found in healthy individuals. In fact, if all individuals bearing a particular disease-associated HLA allele are monitored pro-spectively, most will never acquire the disease. Therefore, expression of a particular HLA gene is not by itself the cause of any autoimmune disease, but it may be one of several factors that contribute to autoimmunity.

The mechanisms underlying the association of particular HLA alleles with various autoimmune diseases are still not clear. When positive associations of MHC alleles with disease are noted, the disease-associated MHC molecule may present a particular self peptide and activate pathogenic T cells, and this has been established in a few cases. When a particular allele is shown to be protective (a negative association with disease), it is surmised that this allele might induce negative selection of some developing and potentially pathogenic T cells, thus creating a "hole in the repertoire," or it might promote the development of regulatory T cells.

Polymorphisms in Non-HLA Genes Associated with Autoimmunity

Linkage analyses of autoimmune diseases identified a few disease-associated genes and many chromosomal regions in which the identity of the associated genes was suspected but not established. The technique of genome-wide association studies has greatly extended analysis of the genetic basis of complex diseases, and we now know several genes that are associated with autoimmune diseases (Table 14-4). Before the genes that are most clearly validated are discussed, it is important to summarize some of the general features of these genes.

• Many of the polymorphisms associated with various autoimmune diseases are in genes that influence the development and regulation of immune responses. Although this conclusion appears predictable, it has reinforced the utility of the approaches being used to identify disease-associated genes.

• Different polymorphisms may either protect against disease development or increase the incidence of the disease. The statistical methods used for genome-wide association studies have revealed both types of associations.

• Disease-associated polymorphisms are often located in noncoding regions of the genes. This unexpected result suggests that the polymorphisms may affect the expression of the encoded proteins.

Some of the genes associated with human autoimmune diseases, which have been defined by linkage analyses and genome-wide association studies, are described briefly next.

• PTPN22. A gain-of-function variant of the protein tyrosine phosphatase PTPN22, that replaces an argi-nine at position 620 with a tryptophan, is associated with rheumatoid arthritis, type 1 diabetes, autoimmune thyroiditis, and other autoimmune diseases. This activated phosphatase results in weaker T cell receptor and B cell receptor signaling and could thus contribute to defective central or peripheral tolerance in both B and T cells. A partial defect in tolerance in individuals with the tryptophan variant could predispose them to autoimmunity.

• NOD2. Polymorphisms in this gene are associated with Crohn's disease, one type of inflammatory bowel disease. NOD2 is a cytoplasmic sensor of bacterial wall peptidoglycans (see Chapter 4) and is expressed in

TABLE 14-4 Selected Non-HLA Genetic Associations with Autoimmune Diseases

Chromosomal Region

Gene of Interest



Genes Involved in Immune Regulation


Was this article helpful?

0 0
How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book

Post a comment