Review
Smoking, citrullination and genetic variability in the immunopathogenesis of rheumatoid arthritis

https://doi.org/10.1016/j.smim.2011.01.014Get rights and content

Abstract

This review describes how studies on interactions between genetic variants, and environmental factors, mainly smoking, contribute to the understanding of how autoimmunity to post-translationally (citrullinated) proteins/peptides may occur and potentially contribute to certain subsets of rheumatoid arthritis. A main message is that studies on specific immune mechanisms in a complex and heterogeneous disease like RA should be undertaken with the help of results from genetic epidemiology. By those means, it may be possible to identify subsets of RA in a way that in the end allows development and testing of precise and subset-specific interventions against environment as well as genetically defined molecular pathways, in particular those that regulate specific immune responses.

Section snippets

Arthritis

Arthritis, or inflammation in joints, is a very common condition in humans as well as in many animals in our/their “natural states”, indicating that some sort of vulnerability for inflammation may exist in joints, perhaps due to functional demands and/or anatomical features. In experimental situations in animals, this is reflected by the fact that many different environmental stimuli and many genetic variants can contribute to the elicitation of experimental arthritis [1]. In most cases a

Rheumatoid arthritis

Rheumatoid arthritis (RA) is defined by a series of clinical criteria, where both the classical (1987 ACR criteria [11]) and the recent (2010 ACR/Eular criteria [12]) mainly rely on macroscopic symptoms such as patterns of swollen and tender joints. In order to also take into account the insights into possible etiologies and pathogenic pathways, that come from general/basic immunology and animal model studies, there is a need to subdivide arthritis into subsets, and to study these subsets

Genetics and RA

RA was one of the first inflammatory diseases where MHC class II genes, notably HLA-DRB1 01 and 04 variants (in Caucasians) were associated with disease risk, thus providing the best evidence so far for a contribution of MHC class II dependent T cell activation in the disease process [13], [14], [15]. Only decades later was it possible to define additional susceptibility genes, first PTPN22 [16] and shortly thereafter a multitude of genetic variants identified from large and globally

Genetics in subsets of RA

The subdivision of RA into subsets has traditionally, since the early 1940s, been by presence/absence of a certain titre of rheumatoid factors (RF) [21]. More recently, presence/absence of the more specific antibodies to citrullinated protein/peptide antigens (ACPAs) has proven to be an alternative and informative biomarker for subdivision of RA [22]. ACPA-positive and ACPA-negative disease exhibit different disease courses [23] and these antibodies may be a better marker for response to

Environment/life style, genetics and RA

The recognition of two distinct antibody-defined subsets of RA, and the refined knowledge of the genetic associations, enabled a renewed analysis also of the impact of environmental and life style factors in RA. The first and striking result of this analysis was the recognition that the best-known risk factor for RA, cigarette smoking, was a risk factor only for ACPA-positive and not for ACPA-negative RA [26], [34]. The second main finding was the pronounced gene-environment interaction between

Methodology for calculating gene-environment interactions

In the literature, gene–environment interactions are analyzed and described in two major ways. On the one hand, interaction refers to the biologic interaction of two or more causes of disease that together assert their influence on disease risk. On the other, interaction refers to statistical interaction which is the necessity for a product term in a mathematical model. Since mathematical models differ it is of importance to consider what model is the most suitable for identification of

Identifying targets of autoimmunity in RA with leads from gene-environment interactions and disease “sub-setting”

With the lead that smoking and other airway pollutants and irritants such as silica, coal dust, etc. might trigger citrullination in lungs and thereby provide a substrate for immune activation, we first identified an increased amount of citrullinated proteins/peptides in lungs using immunohistochemistry [26], and later also increased expression of the enzymes, peptidyl-arginase deiminases (PADs) [42], that catalyse the conversion from arginines to citrullines. This finding thus provided a link

Identification of citrullinated self-proteins in lungs, joints and elsewhere, with relationships to environmental exposures

Immunoprecipitation with sera from patients or other anti-citrulline antibodies, followed by protein identification by mass spectrometry or other means, has identified a number of different citrullinated proteins and protein fragments/peptides in inflamed tissues, until now primarily joints [47], [48], [49], [50]. Major proteins, including the immunodominant peptides, identified so far are vimentin [52], fibrinogen [47], alpha-enolase [51] and collagen type II [49], but it is likely that those

Genetic control of immunity to citrullinated antigens present in lungs and joints and further subdivisions of ACPA-positive RA

From the previous demonstration that ACPA-positive RA is associated with variants of HLA-DR, DQ as well as DP and, at least for HLA-DR, with several different alleles, indicate that different MHC class II molecules may function as restriction elements for different autoantigens/peptides (here tentatively citrullinated antigens). So far, however, we have little information of whether such control is exerted at the level of thymic control of the T cell repertoire or at the level of antigen

The evolution of autoimmunity into autoimmune disease – from “pre-RA” to RA

Immunity to citrullinated antigens can in many cases be identified many years before any signs of disease can be recognised [58], [59], [60]. Hence, it is of great interest to determine, on one hand which factors and mechanisms that determine the elicitation of autoimmunity, and on the other hand which factors and mechanisms that determine the transition from an autoimmune state without disease into the chronic inflammatory state we call RA. Of particular interest is also to determine which

Potential arthritogenic effects of immunity to citrullinated antigens

Several different experiments have been performed that indicate that at least certain immune reactions towards citrullinated antigens can cause arthritis in experimental animals. The first indication was from an experiment where citrullinated collagen II was shown to be more arhritogenic than native collagen II [65]. Subsequently immunisation with citrullinated fibrinogen has been shown to induce arthritis in HLA-DR0101 transgenic mice [66], and also that citrullinated collagen type II and

Concluding remarks on potentials to understand and modulate specific and potentially arthritogenic immunity in distinct subpopulations of RA

The now emerging picture of the longitudinal course of the variants of RA associated with anti-citrulline immunity has revealed a number of features that make this disease a very interesting prototype for understanding of how environment, such as smoking but also other environmental (silica [43], coal dust [69], air pollution [70]) or internal agents (bacteria such as Porphyromonas gingivalis [51], [71], [72]), may interact with genes, in particular MHC class II genes, in triggering specific

Acknowledgments

The data from our own units that provide part of the basis of this review, were supported by grants from the Swedish Research Council, The Söderberg Foundations, The AFA Insurance company, the Swedish Rheumatism Foundation and the Combine program. We also want to acknowledge the significant contributions from funding as well as networking with colleagues in the EU-supported AutoCure and Masterswitch programs.

References (72)

  • T.T. Glant et al.

    Proteoglycan-induced arthritis in BALB/c mice. Clinical features and histopathology

    Arthritis Rheum

    (1987)
  • C.M. Pearson

    Development of arthritis, periarthritis and periostitis in rats given adjuvants

    Proc Soc Exp Biol Med

    (1956)
  • J. Keffer et al.

    Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis

    EMBO J

    (1991)
  • R. Horai et al.

    Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in interleukin 1 receptor antagonist-deficient mice

    J Exp Med

    (2000)
  • D. Plows et al.

    Mice lacking mature T and B lymphocytes develop arthritic lesions after immunization with type II collagen

    J Immunol

    (1999)
  • F.C. Arnett et al.

    The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis

    Arthritis Rheum

    (1988)
  • D. Aletaha et al.

    Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative

    Arthritis Rheum

    (2010)
  • P. Stastny

    Association of the B-cell alloantigen DRw4 with rheumatoid arthritis

    N Engl J Med

    (1978)
  • P.K. Gregersen et al.

    The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis

    Arthritis Rheum

    (1987)
  • L. Klareskog et al.

    Evidence in support of a self-perpetuating HLA-DR-dependent delayed-type cell reaction in rheumatoid arthritis

    Proc Natl Acad Sci USA

    (1982)
  • The Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and...
  • R.M. Plenge et al.

    TRAF1-C5 as a risk locus for rheumatoid arthritis—a genomewide study

    N Engl J Med

    (2007)
  • E.F. Remmers et al.

    STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus

    N Engl J Med

    (2007)
  • E.A. Stahl et al.

    Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci

    Nat Genet

    (2010)
  • E. Waaler

    On the occurrence of a factor in human serum activating the specific agglutintion of sheep blood corpuscles

    Acta Path Microbiol Scand

    (1940)
  • G.A. Schellekens et al.

    Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies

    J Clin Invest

    (1998)
  • J.K. de Vries-Bouwstra et al.

    Progression of joint damage in early rheumatoid arthritis: association with HLA-DRB1, rheumatoid factor, and anti-citrullinated protein antibodies in relation to different treatment strategies

    Arthritis Rheum

    (2008)
  • H. van Dongen et al.

    Efficacy of methotrexate treatment in patients with probable rheumatoid arthritis: a double-blind, randomized, placebo-controlled trial

    Arthritis Rheum

    (2007)
  • R.M. Thurlings et al.

    Synovial tissue response to rituximab: mechanism of action and identification of biomarkers of response

    Ann Rheum Dis

    (2008)
  • L. Klareskog et al.

    A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination

    Arthritis Rheum

    (2006)
  • A.H. van der Helm-van Mil et al.

    Emerging patterns of risk factor make-up enable subclassification of rheumatoid arthritis

    Arthritis Rheum

    (2007)
  • B. Ding et al.

    Different patterns of associations with anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative rheumatoid arthritis in the extended major histocompatibility complex region

    Arthritis Rheum

    (2009)
  • H.S. Lee et al.

    Several regions in the major histocompatibility complex confer risk for anti-CCP-antibody positive rheumatoid arthritis, independent of the DRB1 locus

    Mol Med

    (2008)
  • S. Sigurdsson et al.

    Association of a haplotype in the promoter region of the interferon regulatory factor 5 gene with rheumatoid arthritis

    Arthritis Rheum

    (2007)
  • L. Padyukov et al.

    A genome-wide association study suggests contrasting associations in ACPA positive vs. ACPA negative rheumatoid arthritis

    Ann Rheum Dis

    (2011)
  • M. Pedersen et al.

    Strong combined gene-environment effects in anti-cyclic citrullinated peptide-positive rheumatoid arthritis: a nationwide case-control study in Denmark

    Arthritis Rheum

    (2007)
  • Cited by (181)

    View all citing articles on Scopus
    View full text