The pathologies of many infectious, autoimmune and malignant diseases are influenced by the profiles of cytokine production in pro-inflammatory (TH1) and anti-inflammatory (TH2) T cells. Interindividual differences in cytokine profiles appear to be due, at least in part, to allelic polymorphism within regulatory regions of cytokine gene. Many studies have examined the relationship between cytokine gene polymorphism, cytokine gene expression in vitro, and the susceptibility to and clinical severity of diseases. A review of the findings of these studies is presented. An on-line version featuring appropriate updates is accessible from the World Wide Web site, http://www.pam.bris.ac.uk/services/GAI/cytokine4.htm.

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Cytokine gene polymorphism in human disease: on-line databases.

The major histocompatibility complex (MHC) is one of the most extensively studied regions in the human genome because of the association of variants at this locus with autoimmune, infectious, and inflammatory diseases. However, identification of causal variants within the MHC for the majority of these diseases has remained difficult due to the great variability and extensive linkage disequilibrium (LD) that exists among alleles throughout this locus, coupled with inadequate study design whereby only a limited subset of about 20 from a total of approximately 250 genes have been studied in small cohorts of predominantly European origin. We have performed a review and pooled analysis of the past 30 years of research on the role of the MHC in six genetically complex disease traits - multiple sclerosis (MS), type 1 diabetes (T1D), systemic lupus erythematosus (SLE), ulcerative colitis (UC), Crohn's disease (CD), and rheumatoid arthritis (RA) - in order to consolidate and evaluate the current literature regarding MHC genetics in these common autoimmune and inflammatory diseases. We corroborate established MHC disease associations and identify predisposing variants that previously have not been appreciated. Furthermore, we find a number of interesting commonalities and differences across diseases that implicate both general and disease-specific patho- genetic mechanisms in autoimmunity.

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Defining the Role of the MHC in Autoimmunity: A Review and Pooled Analysis

The receptor for advanced glycation end products (RAGE) and its proinflammatory S100/calgranulin ligands are enriched in joints of subjects with rheumatoid arthritis (RA) and amplify the immune/inflammatory response. In a model of inflammatory arthritis, blockade of RAGE in mice immunized and challenged with bovine type II collagen suppressed clinical and histologic evidence of arthritis, in parallel with diminished levels of TNF-alpha, IL-6, and matrix metalloproteinases (MMP) 3, 9 and 13 in affected tissues. Allelic variation within key domains of RAGE may influence these proinflammatory mechanisms, thereby predisposing individuals to heightened inflammatory responses. A polymorphism of the RAGE gene within the ligand-binding domain of the receptor has been identified, consisting of a glycine to serine change at position 82. Cells bearing the RAGE 82S allele displayed enhanced binding and cytokine/MMP generation following ligation by a prototypic S100/calgranulin compared with cells expressing the RAGE 82G allele. In human subjects, a case-control study demonstrated an increased prevalence of the 82S allele in patients with RA compared with control subjects. These data suggest that RAGE 82S upregulates the inflammatory response upon engagement of S100/calgranulins, and, thereby, may contribute to enhanced proinflammatory mechanisms in immune/inflammatory diseases.

RAGE and arthritis: the G82S polymorphism amplifies the inflammatory response.

Reading the daily headlines proclaiming the current revolution in human genetics and the imminent completion of the Human Genome Project (1), it is often difficult to restrain one’s excitement, and also easy to overlook the formidable challenges that remain for understanding the role of genes in human disease. This challenge is particularly germane to multifactorial diseases in which multiple genes contribute to disease risk, along with other factors, and in which heterogeneity of disease etiology and phenotype complicate the analysis. Both of these conditions hold for rheumatoid arthritis (RA), the most common, and still poorly understood, form of inflammatory arthritis. When thinking about the causes of biologic phenotypes, the simple dichotomy of nature versus nurture has been replaced by a more subtle view, in which both genes and environment interact over time and contribute to disease. It is also important to recognize that nongenetic factors do not simply consist of exposure to environmental influences such as infection or diet, but also include stochastic processes that may occur quite early in development as well as close in time to the onset of disease. This is probably a significant reason for the relatively low concordance of autoimmunity in monozygotic (MZ) twins (2–6). In addition, disease must be viewed as a phenomenon that occurs in populations as well as individuals, and thus the historical and evolutionary factors that have shaped populations need to be taken into account for us to achieve full understanding. This interactive approach to appreciating the role of genetics in complex human disease is illustrated in Figure 1. The main practical result of this more complex model is the realization that genetic associations with disease are very unlikely to yield simple one-to-one correlations between genes and phenotypes. Rather, there will be considerable noise obscuring these relationships which can only be resolved by obtaining large numbers of observations. The need for large collaborative studies in RA is clear. The purpose of this discussion is to review the current status of RA genetics and the approaches being used to increase our knowledge of this genetically complex disorder.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/1529-0131%28199906%2942%3A6%3C1071%3A%3AAID-ANR1%3E3.0.CO%3B2-8

The genetics revolution and the assault on rheumatoid arthritis.

The role of TNF and its receptors in Alzheimer’s disease

The major histocompatibility complex class III tumor necrosis factor-lymphotoxin (TNF-LT) region (6p21.3) was investigated as a possible susceptibility locus for rheumatoid arthritis (RA). Inheritance of five TNF microsatellite markers was determined in 50 multiplex families. Overall, 47 different haplotypes were observed. One of these, the TNF a6, b5, c1, d3, e3 (H1) haplotype, was present in 35.3% of affected, but in only 20.5% of unaffected, individuals (P < .005). This haplotype accounted for 21.5% of the parental haplotypes transmitted to affected offspring and only 7.3% not transmitted to affected offspring (P = .0003). The TNF a6 and TNF c1 alleles were individually associated with RA (P = .0005 and .0008, respectively), as were the HLA-DRB1 "shared epitope" (SE) (P = .0001) and HLA-DRB1*0401 (P = .0018). Both univariate and bivariate conditional logistic regression analysis showed significant effects of TNF c1 and SE in increasing risk to RA (P < .001). Stratification by the presence of SE indicated an independent effect of the TNFc1 allele (P = .0003) and the HLA A1, B8, DR3 extended haplotype (always TNFa2, b3, c1, d1, e3) (P = .0027) in SE heterozygotes, while the H1 haplotype was associated with RA in SE homozygotes (P = .0018). The TNF-LT region appears to influence susceptibility to RA, distinct from HLA-DR.

F. Waldron-Lynch

Papers

Genetic variability in the tumor necrosis factor-lymphotoxin region influences susceptibility to rheumatoid arthritis.