Genes, environment and immunity in the development of rheumatoid arthritis

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The combined role of genes, environment and immunity in the development of rheumatoid arthritis (RA) has been the subject of recent investigations. New data support a gene–environment interaction between smoking and the MHC class II HLA-DRB1 shared epitope (SE) genes in anti-citrulline antibody (anti-CP+) RA but not in anti-CP disease. These data from genetic epidemiology, together with information on citrullination in the lungs of smokers, have prompted the formulation of a new etiological hypothesis for anti-CP+ RA, suggesting that smoking in the context of HLA-DR SE might trigger immunity to citrulline-modified proteins and that this immunity, after several years, might cause arthritis.

Introduction

Rheumatoid arthritis (RA) is a disease that is mainly defined by its clinical features, notably chronic inflammation in several joints associated with a characteristic destruction of bone and cartilage. Several different diagnostic criteria have been used to define the disease; the most recent ones were described by a group appointed by the American College of Rheumatology in 1988 [1]. However, no common etiological or pathogenetic features exist that a priori characterize rheumatoid arthritis, and any effort to define putative etiologies and pathogenic pathways has to consider the likelihood that several etiologies and several pathogenic pathways are in action in different subsets of RA.

In this review, we will use data on environmental triggers, genetics and specific immunity as major determinants in our efforts to define subsets of RA that might involve different etiological pathways. By applying such a subset-oriented approach to RA pathogenesis, we might begin to understand how triggers, genes and immunity interact, as has been possible for various well-defined animal models of arthritis.

Section snippets

Genes

To date, genes important for the onset or course of RA have been described mainly by the association of variations in genes coding for proteins that participate in known immune and/or inflammatory events of putative importance for joint inflammation. The genes for the MHC class II transplantation antigens were described as susceptibility genes in the 1970s [2], and subsequent studies have detailed which genes and which structures within these genes, in particular the so-called shared epitope

Environment

Information on environmental factors important for the development or course of RA is surprisingly scarce. Smoking is the only conventional environmental factor that has reproducibly been linked to an increased risk of developing RA [9, 10, 11], whereas other exposures such as silica dust and mineral oil exposures have been reported in a few studies [12, 13, 14, 15]. Frequently hypothesized stimuli such as microbial infections have not been possible to verify with the methods used to date.

Immunity

Studies on specific immune reactions in RA have been almost entirely confined to those involving autoantibodies; the knowledge of T-cell reactivates of importance for disease is very limited. The rheumatoid factor (RF) described in the late-1930s was, until recently, the most significant reactivity associated with RA and this reactivity was used in the RA classification criteria [1]. The formation of RF is, however, a feature of many immune reactions involving immune complex formation [18, 19].

Genes, environment and immunity considered together

Until now, the roles of genes, environment and immunity as etiological factors for RA have mainly been studied separately. Developing a greater understanding of RA etiologies requires, however, knowledge on how different risk factors, including genes and environment, interact in different subsets of RA. To contribute to such knowledge, we started, ten years ago, a Swedish population-based case control study on incident cases of RA and controls (matched for sex, age and location). We collected

Interactions between smoking, HLA-DRB1 SE alleles and anti-CP immunity

To investigate gene–environment interactions in major subsets of RA, we first considered smoking as the best-known environmental risk factor along with the presence of HLA-DRB1 SE alleles as the best-known genetic risk factor. Our aim was to correlate these factors with the occurrence of the two major serologically defined dichotomous subsets of RA that affect disease course, the RF+/RF and anti-CP+/anti-CP subsets.

The first experiment using this approach for RF, published in 2004 [33],

Biological interpretations of data from studying gene–environment–immunity interactions in different subsets of RA

The most interesting consequence of the new studies on the interactions between genes, environment and immunity in RA relates to the possible biological basis of the findings, and whether the findings from genetic epidemiology can help to develop a better molecular understanding of the chain of events that ultimately leads to arthritis in discrete subsets of RA patients.

The finding of smoking–HLA-DRB1 SE interactions in the anti-CP+ subset of disease led to the question of whether smoking can

Conclusions

The data summarised in this review indicate that detailed studies on interactions between genes, environment and immunity in large prospective studies of a disease — here RA — might provide us with new hypotheses on molecular pathways leading to the disease. The obvious aim of this research is to investigate these hypotheses via functional studies in subgroups of RA patients defined by their genes, their antibody profiles and their background environmental exposures. Only by using this

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We primarily acknowledge the Epidemiological Investigation of Risk Factors for RA (EIRA) study group, without which the Swedish case-control study would not have been possible. The members of the EIRA group are listed in [37••]. Studies from our own group that have been referred to here were financially supported by the Swedish Research Council, Söderbergs Foundations, the EU (the AUTOCURE consortium), King Gustaf V:s 80-year Foundation, the Swedish Rheumatism Foundation, the Swedish Council

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