Chapter Three - Autoimmunity in Rheumatoid Arthritis: Citrulline Immunity and Beyond

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Abstract

Rheumatoid arthritis (RA) represents a disease where we have recently acquired new knowledge on etiology and molecular pathogenesis, by combining data from studies on genetic end environmental determinants of disease with molecular and cellular immunology. This combined approach has provided insights into the heterogeneous nature of the clinical syndrome we call RA, and the subdivisions into different functional disease subsets now permit a better use of molecular immunology in contexts where genotypes and environmental triggers are defined.

In this chapter, we discuss a series of different autoimmunities described in RA, with an initial emphasis on immunity to autoantigens that have been posttranslationally modified by citrullination. We then discuss a series of unresolved issues and challenges related both to the citrulline immunity and to other immune events in RA. Our perspective is that current studies on genes, environment, and immunity in this disease provides us with a great outlook to investigate interesting general aspects of autoimmunity and development of human autoimmune disease—in addition to the opportunity to better understand, prevent, and ultimately treat RA.

Introduction

The understanding of possible etiologies of the clinical syndrome we call rheumatoid arthritis (RA) (Aletaha et al., 2010, Arnett et al., 1988, van der Linden et al., 2011) has grown considerably during recent years, and this progress has been summarized in several recent reviews, most of them focusing on the etiology and molecular pathogenesis of the subset of RA that is characterized by the presence of antibodies to posttranslationally citrullinated autoantigens (Arend and Firestein, 2012, Bax et al., 2011, Klareskog et al., 2011, Klareskog et al., 2008; McInnes & Schett, 2011; Willemze, Trouw, Toes, & Huizinga, 2012). Thus, research on the interplay between environmental triggers, susceptibility genes, and anticitrullinated protein/peptide antibodies (ACPAs) has provided a more comprehensive picture than in almost any other human autoimmune disease, possibly with the exception of celiac disease (Qiao, Iversen, Ráki, & Sollid, 2012), of how specific triggers in a defined genetic contact can trigger potentially disease-inducing immunity.

This review gives an update on the most recent advances on anticitrulline immunity in RA and then mainly focuses on unresolved questions, with relevance also to other autoimmune conditions, using this interesting case of human autoimmune arthritis as a basis.

Section snippets

Present State of the Art Concerning Genes, Environment, and Anticitrulline Immunity in RA

The concept that specific and MHC class II-dependent immune reactions have an important role in the pathogenesis of RA has been a pillar of pathogenetic research in RA ever since the recognition of the association between certain HLA-D/DR alleles and risk for RA (Stastny, 1976) and the recognition of the high expression of MHC class II molecules on antigen-presenting cells in the RA joints (Janossy et al., 1981, Klareskog et al., 1981). This concept was further developed into a functional

Unresolved Issues Concerning the Specificity and Genetic Basis of Autoimmune Reactions in RA: Focus on the Heterogeneity of the RA Syndrome

A basis for our current understanding of RA is that this disease represents a clinical syndrome and that many different pathogenetic pathways may result in the clinical symptoms that fulfill the current (and past) diagnostic criteria for RA (Aletaha et al., 2010, Arnett et al., 1988, van der Linden et al., 2011) (Fig. 3.3). In this respect, the human disease resembles the experimental mouse and rat models, where a number of different mechanisms exist for the development of arthritis (which by

Unresolved Issues Concerning the Triggering of Various Autoimmune Reactions in RA: Focus on Events Outside the Joints

The fact that antibodies toward several investigated autoimmune targets in RA, including multiple citrullinated antigens, BiP, and RFs, are present long before the first signs of inflammation in joints strongly suggests that the initiation of production of these antibodies occurs somewhere else than in the joints. The findings, described earlier, that smoking induces protein citrullination as well as activation of antigen-presenting cells in the lungs suggest one possible way whereby loss of

Unresolved Issues Concerning the Contributions of Various Autoimmune Reactions to Symptoms of RA: Focus on Events in Joints and in Sites of Extra-Articular Manifestations of RA

The main focus of inflammation in RA is diarthrodial joints, but also several other tissues, including bone (osteopenia and bone marrow edema), blood vessels (increased atherosclerosis and, more rarely, vasculitis), subcutaneous nodules, surfaces of the lungs and heart, and not least the nervous system including the brain (pain and fatigue), may be involved. We have to consider whether and how anticitrulline immunity may contribute to some or all of these symptoms of RA (Fig. 3.5).

A major

Conclusions Concerning Research Strategies and Efforts to Turn the Emerging Insights of Adaptive Immunity in RA into Personalized Prevention and Therapy

In this review, we have described the multifaceted appearance of citrulline immunity and its dependency on a complex interaction between genes and environment. Furthermore, we have scrutinized the emerging evidence that citrulline immunity is involved in RA pathogenesis. A major question now is how to proceed to be able to demonstrate which of the different fine specificities may contribute to the various symptoms of the disease, and which are the causal relationships between the different

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