Proteins In Rheumatoid Arthritis Research Articles

Comprehensive Co-Inhibitory Receptor (Co-IR) Expression on T Cells and Soluble Proteins in Rheumatoid Arthritis.

Co-IRs T cells were immunophenotyped employing multicolor flow cytometry, and ELISA was utilized for measuring soluble PD-1, PDL-2, and TIM3. Correlations have been detected across the percentage of T cells expressing Co-IRs (MFI) and different indicators in the blood, including ESR, high-sensitivity CRP (hsCRP), 28 joint disease activity scores (DAS28), and soluble PD-1/PDL-2/TIM3. In RA patients, we recognized elevated levels of PD-1 (CD279), CTLA-4, and TIGIT in CD4+ T cells; TIGIT, HLA-DR, TIM3, and LAG3 in CD8+ T cells; and CD8+CD279+TIM3+, CD8+HLA-DR+CD38+ T cells. The following tests were revealed to be correlated with hsCRP: CD4/CD279 MFI, CD4/CD279%, CD4/TIM3%, CD8/TIM3%, CD8/TIM3 MFI, CD8/LAG3%, and CD8+HLA-DR+CD38+%. CD8/LAG3 and CD8/TIM3 MFIs are linked to ESR. DAS28-ESR and DAS28-CRP exhibited relationships with CD4/CD127 MFI, CD8/CD279%, and CD8/CD127 MFI, respectively. CD4+CD279+TIM3+% was correlated with DAS28-ESR (p = 0.0084, N = 46), DAS28-CRP (p = 0.007, N = 47), and hsCRP (p = 0.002, N = 56), respectively. In the serum of patients with RA, levels of soluble PD-1, PDL-2, and Tim3 were extremely elevated. CD4+ TIM3+% (p = 0.0089, N = 46) and CD8+ TIM3+% (p = 0.0305, N = 46) were correlated with sTIM3 levels; sPD1 levels were correlated with CD4+CD279+% (p < 0.0001, N = 31) and CD3+CD279+% (p = 0.0084, N = 30). Co-IR expressions on CD4+ and CD8+ T cells, as well as soluble PD-1, PDL-2, and TIM3 levels, could function as indicators of disease activity and potentially play crucial roles in the pathogenesis of RA.

Tofacitinib treatment modulates the levels of several inflammation-related plasma proteins in rheumatoid arthritis and baseline levels of soluble biomarkers associate with the treatment response.

The data on the effects of tofacitinib on soluble proteins in patients with rheumatoid arthritis (RA) is currently very limited. We analyzed how tofacitinib treatment and thus inhibition of the Janus kinase-signal transducer and activation of transcription pathway affects the in vivo levels of inflammation-related plasma proteins in RA patients. In this study, 16 patients with active RA [28-joint disease activity score (DAS28) >3.2] despite treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) started tofacitinib treatment 5 mg twice daily. Levels of 92 inflammation-related plasma proteins were determined by proximity extension assay at baseline and at 3 months. Tofacitinib treatment for 3 months, in csDMARD background, decreased the mean DAS28 from 4.4 to 2.6 (P < 0.001). Marked (>20%) and statistically significant (P < 0.05) changes were found in the levels of 21 proteins, 18 of which decreased and 3 increased. Of these proteins, 17 are directly involved in inflammatory responses or in the cellular response to cytokines. The highest (>50%) decrease was observed for interleukin-6 (IL-6), C-X-C motif chemokine ligand 1, matrix metalloproteinase-1, and AXIN1. Higher baseline levels of IL-6 and lower levels of C-C motif chemokine 11 and Delta and Notch-like epidermal growth factor-related receptors were associated with DAS28 improvement. Our results indicate that tofacitinib downregulates several proinflammatory plasma proteins that may contribute to the clinical efficacy of tofacitinib. In addition, soluble biomarkers may predict the treatment response to tofacitinib.

Salivary citrullinated proteins in rheumatoid arthritis and associated periodontal disease

Periodontal disease (PD) can be an important precipitating factor in the production of citrullinated proteins. Its importance is emphasized, but it is not the only way to produce citrullinated proteins. The aim of the current study was to determine the periodontal conditions and the salivary citrullinated protein content in patients with rheumatoid arthritis (RA) compared to healthy controls. We also wished to correlate citrullinated protein levels in the saliva and serum biomarkers with the periodontal status and temporomandibular joint (TMJ) involvement of patients with RA. Twenty-three patients with RA and 17 healthy controls participated the study. Saliva samples were taken: citrulline content of saliva was measured. Blood test results for patients with RA were collected. TMJ disorders were described. Cariological and periodontal indices were registered. Periodontal conditions and periodontal staging were also registered. Comparison of measured values between groups was performed. Intragroup correlation of patients’ values was counted. The prevalence of TMJ complaints was significantly higher in the RA group (8/23) versus controls (1/17). The patients with RA had worse periodontal condition because more patients with RA had gingivitis with a significantly higher bleeding on probing (BOP) (RA: 22.4 ± 25.0%; controls: 6.36 ± 11.6%; p = 0.018). Gingival index (GI) was also significantly higher in the patients than in controls (RA: 0.68 ± 0.58; controls: 0.19 ± 0.38; p = 0.010). The citrullinated protein (relative) content of saliva did not differ significantly (p = 0.147) between patients with RA (1102.2 ± 530.8) and healthy controls (1873.1 ± 1594.9). In RA, the salivary anti-CCP levels positively correlated with PD staging (R = 0.464, p = 0.039). Control subjects more commonly had healthy gingiva than RA patients. Moreover, in the control group more individuals had intact and reduced height periodontium than periodontitis compared to the RA group. There was no significant difference in the levels of salivary citrulline between patients with RA and controls, despite the significant differences in their periodontal status. Thus, salivary citrulline levels are not associated with RA disease severity.

Redox-Mediated Carbamylation As a Hapten Model Applied to the Origin of Antibodies to Modified Proteins in Rheumatoid Arthritis.

Significance: The production of antibodies to posttranslationally modified antigens is a hallmark in rheumatoid arthritis (RA). In particular, the presence of citrullination-associated antibodies, targeting both citrullinating enzymes (the peptidylarginine deiminases [PADs]) and citrullinated antigens (anticitrullinated protein antibodies [ACPAs]), has suggested that dysregulated citrullination is relevant for disease pathogenesis. Antibodies to other protein modifications with physicochemical similarities to citrulline, such as carbamylated-lysine and acetylated-lysine, have also gained interest in RA, but their mechanistic relation to ACPAs remains unclear. Recent Advances: Recent studies using RA-derived monoclonal antibodies have found that ACPAs are cross-reactive to carbamylated and acetylated peptides, challenging our understanding of the implications of such cross-reactivity. Critical Issues: Analogous to the classic antibody response to chemically modified proteins, we examine the possibility that antibodies to modified proteins in RA are more likely to resemble antihapten antibodies rather than autoantibodies. This potential shift in the autoantibody paradigm in RA offers the opportunity to explore new mechanisms involved in the origin and cross-reactivity of pathogenic antibodies in RA. In contrast to citrullination, carbamylation is a chemical modification associated with oxidative stress, it is highly immunogenic, and is considered in the group of posttranslational modification-derived products. We discuss the possibility that carbamylated proteins are antigenic drivers of cross-reacting antihapten antibodies that further create the ACPA response, and that ACPAs may direct the production of antibodies to PAD enzymes. Future Directions: Understanding the complexity of autoantibodies in RA is critical to develop tools to clearly define their origin, identify drivers of disease propagation, and develop novel therapeutics. Antioxid. Redox Signal. 36, 389-409.

The Central Role of Acute Phase Proteins in Rheumatoid Arthritis: Involvement in Disease Autoimmunity, Inflammatory Responses, and the Heightened Risk of Cardiovascular Disease.

Rheumatoid arthritis (RA) is an autoimmune disease of complex etiopathogenic origin and traditionally characterized by chronic synovitis and articular erosions. Furthermore, there is strong evidence that infectious agents, including those that become dormant within the host, play a major role in much of the etiology of RA and its hallmark of inflammation. A combination of genetic predisposition, environmental exposure, and presence of infectious agents may therefore lead to a loss of immune tolerance to citrullinated proteins, which present as self-antigens to the human immune system. This results in generation of highly RA-specific autoantibodies, known as anti-citrullinated protein antibodies (ACPAs). Protein citrullination occurs via posttranslational deamination of arginine residues by peptidylarginine deiminase enzymes, which have confirmed sources of both endogenous and infectious origins. A recognized plasma protein target of citrullination and RA autoantibody generation is fibrin and its soluble precursor fibrinogen, both key components of hemostasis and acute phase reaction. Increased titers of ACPAs that accompany rapid progression to clinical RA disease have been shown to drive a variety of proinflammatory processes, and therefore results in aberrant fibrin clot formation and increased cardiovascular risk. However, the full extent to which hemostasis is affected in RA remains controversial, owing to the differential impact that citrullinated fibrin(ogen) and concurrent systemic inflammation may have on resulting hemostatic outcome. This review highlights key events in initiation of autoimmune-driven inflammatory events, including the role of bacterial infectious agents, which subsequently result in clinical RA disease and associated secondary cardiovascular disease risk, with specific focus on plasma proteins that are heavily involved throughout the immunopathological progression process.

Recognition of Amino Acid Motifs, Rather Than Specific Proteins, by Human Plasma Cell-Derived Monoclonal Antibodies to Posttranslationally Modified Proteins in Rheumatoid Arthritis.

ObjectiveAntibodies against posttranslationally modified proteins are a hallmark of rheumatoid arthritis (RA), but the emergence and pathogenicity of these autoantibodies are still incompletely understood. The aim of this study was to analyze the antigen specificities and mutation patterns of monoclonal antibodies (mAb) derived from RA synovial plasma cells and address the question of antigen cross‐reactivity.MethodsIgG‐secreting cells were isolated from RA synovial fluid, and the variable regions of the immunoglobulins were sequenced (n = 182) and expressed in full‐length mAb (n = 93) and also as germline‐reverted versions. The patterns of reactivity with 53,019 citrullinated peptides and 49,211 carbamylated peptides and the potential of the mAb to promote osteoclastogenesis were investigated.ResultsFour unrelated anti–citrullinated protein autoantibodies (ACPAs), of which one was clonally expanded, were identified and found to be highly somatically mutated in the synovial fluid of a patient with RA. The ACPAs recognized >3,000 unique peptides modified by either citrullination or carbamylation. This highly multireactive autoantibody feature was replicated for Ig sequences derived from B cells from the peripheral blood of other RA patients. The plasma cell–derived mAb were found to target distinct amino acid motifs and partially overlapping protein targets. They also conveyed different effector functions as revealed in an osteoclast activation assay.ConclusionThese findings suggest that the high level of cross‐reactivity among RA autoreactive B cells is the result of different antigen encounters, possibly at different sites and at different time points. This is consistent with the notion that RA is initiated in one context, such as in the mucosal organs, and thereafter targets other sites, such as the joints.

Serum proteomic-based analysis by iTRAQ of damp-heat impeding syndrome of rheumatoid arthritis

IntroductionIn this study we aim to investigate the characteristic proteins in rheumatoid arthritis (RA) by using iTRAQ-based proteomics approach to explore the possible inherent molecular mechanisms, disease monitoring and therapeutic targets of damp-heat impeding syndrome. MethodsThe iTRAQ analyses combined with liquid chromatography–tandem mass spectrometry (LC–MS/MS) was performed to compare serum protein expression patterns of damp-heat impeding syndrome of RA with that of cold-damp impeding syndrome of RA, and healthy volunteers. Gene-ontology (GO) analysis of these differentially expressed proteins were performed using WEB based bioinformatics tools (DAVID v6.7, UniProtKB/Swiss-Prot, and Ingenuity Pathway Analysis). Ingenuity Pathways Analysis (IPA) was also used to interpret the interaction network and predominant canonical pathways involved in these differentially expressed proteins. ResultsBy iTRAQ analyses and mass spectroscopic identification, 6 proteins including FLJ00382, Ig lambda chain V-I region WAH, Myosin-reactive immunoglobulin light chain variable region, C-reactive protein, S100A9, and Cathepsin G were found significantly overexpressed in damp-heat impeding syndrome. Bioinformatics analyses showed that these proteins were involved in inflammatory response, suggesting that RA patients with damp-heat impeding syndrome have severe inflammatory responses and high RA inflammatory activity. ConclusionThis preliminary work provides a better understanding of the proteomic alterations of serum from RA patients with damp-heat impeding syndrome and may provide us insights into the pathophysiology and potential diagnostic biomarkers for early detection, disease monitoring and therapeutic targets for damp-heat impeding syndrome.

Update on autoantibodies to modified proteins.

This article provides an update on the recent findings on autoantibodies to modified proteins in rheumatoid arthritis (RA). In the past few years, the knowledge on the autoantibodies to citrullinated antigens has expanded considerably. More specifically, it is now clear that many different citrullinated protein antigens present in the synovial compartment can be recognized by anticitrullinated protein antibody (ACPA). This is most likely a consequence of the cross-reactivity the ACPA response displays to citrullinated proteins. It is now also clear that the isotype usage and the citrullinated epitope repertoire recognized by ACPA expands before the manifestation of full-blown RA and that this goes hand in hand with a rise in ACPA level. Next to ACPA, several other autoantibody systems directed against other posttranslationally modified proteins, such as proteins containing a homocitrulline residue resulting from protein carbamylation, have been identified. On the whole, the evolution of these autoantibody systems in time mimics the evolution of the ACPA response, indicating that the break of tolerance underlying different autoimmune responses present in RA occurs before disease onset, with a further maturation of these responses shortly before or concurrent with the manifestation of clinical symptoms. Since the discovery of rheumatoid factor over 65 years ago, our knowledge on autoantibodies and their relevance for rheumatic disease has expanded enormously. Especially, the realization that next to rheumatoid factor, also other autoantibodies recognizing posttranslationally modified proteins are present in RA patients has contributed significantly to the understanding of disease. In the past few years, several new autoantibody systems to differentially modified proteins have been identified and their relation to clinical outcome has been scrutinized. Here, we provide an update on the recent developments in our knowledge on the presence and consequences of autoantibodies to modified proteins in RA.

Lungs, joints and immunity against citrullinated proteins in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a prototype for a criterion-defined inflammatory disease, for which the aetiology and initial molecular pathogenesis has been elusive for a long time. We describe in this Review how studies on the interplay between specific immunity, alongside genetic and environmental predisposing factors, provide new tools to understand the molecular basis of distinct subsets of the disease. A particular emphasis is on the possibility that pathogenic immune reactions might be initiated at other sites than the joints, and that the lungs could harbour such sites. New data strengthen this concept, showing that local immunity towards citrullinated proteins and accompanying inflammation might be present in the lungs early during disease development. This progress makes RA an interesting case for the future development of therapies that might be directed against disease-inducing immunity even before inflammation and destruction of joints has begun.

AB0284 The Diagnostic Utility of Anti-Mutated Citrullinated Vimentin Antibodies, Anti-Cyclic Citrullinated Peptide Antibodies and Rheumatoid Factor in Rheumatoid Arthritis

BackgroundAntibodies against citrullinated peptides have gained special importance in the diagnosis of rheumatoid arthritis (RA) (1,2).ObjectivesThis study aims to investigate the diagnostic sensitivity and specificity of anti-mutated citrullinated vimentin (anti-MCV)...

The autoantibody repertoire in periodontitis: a role in the induction of autoimmunity to citrullinated proteins in rheumatoid arthritis?

BackgroundStudies suggest that periodontitis may be a risk factor for rheumatoid arthritis (RA). The purpose of this study was to determine whether periodontitis is associated with autoantibodies characteristic of RA.MethodsSerum...

Identification of Novel Autoantigen in the Synovial Fluid of Rheumatoid Arthritis Patients Using an Immunoproteomics Approach

Rheumatoid arthritis (RA) is a chronic, autoimmune and inflammatory joint disease with a poorly understood etiology. Despite widespread diagnostic use of anti-citrullinated protein antibodies and rheumatoid factor proteins there is a strong demand for novel serological biomarkers to improve the diagnosis this disease. The present study was aimed to identify novel autoantigens involved in rheumatoid arthritis (RA) pathogenesis through immune-proteomic strategy. Synovial fluid samples from clinically diagnosed RA patients were separated on two-dimensional gel electrophoresis (2-DE). Samples from patients with non-RA rheumatisms (osteoarthritis and trauma) were used as controls. Immunoreactive proteins were spotted by Western blotting followed by identification through Q-TOF mass spectrometer analysis. Forty Western blots were generated using plasma from ten individual RA patients and 33 reactive spots were identified, 20 from the high molecular weight (HMW) gel and 13 from the low molecular weight (LMW) gel. Among the 33 common immunogenic spots, 18 distinct autoantigens were identified, out of which 14 are novel proteins in this context. Expression analysis of five important proteins, vimentin, gelsolin, alpha 2 HS glycoprotein (AHSG), glial fibrillary acidic protein (GFAP), and α1B-glycoprotein (A1BG) by Western blot analysis using their specific antibodies revealed their higher expression in RA synovial fluid as compared to non-RA samples. Recombinantly expressed GFAP and A1BG protein were used to develop an in-house ELISA to quantify the amount of autoantibodies in the RA patients. RA patients revealed an increase in the expression of GFAP and A1BG in the plasma as compared to osteoarthritis patients. Therefore, GFAP and A1BG can be proposed as potential new autoantigens of diagnostic importance for RA subjects. Further characterization of these proteins in rheumatoid arthritis will be helpful in understanding the role of these proteins in the disease pathogenesis providing new diagnostic tool with better specificity and accurate detection of the disease.

Altered glycosylation and expression of plasma alpha-1-acid glycoprotein and haptoglobin in rheumatoid arthritis

Altered glycosylation patterns in plasma proteins are found to be associated with the pathogenesis of various malignancies and autoimmune disorders. Our previous studies demonstrated the occurrence of some differentially glycosylated plasma proteins in rheumatoid arthritis (RA) patients. The current study was conducted to evaluate the alterations in expression and glycosylation of major acute phase proteins from wheat germ agglutinin enriched RA patients’ plasma. Immunoblotting studies revealed a significant enhancement in the plasma levels of alpha-1 acid glycoprotein (AGP) and haptoglobin (Hp) in RA patients with respect to healthy controls. Monosaccharide analysis by high performance anion exchange-chromatography with pulse amperometric detection showed significant variations in the relative percentage of galactose, glucosamine and mannose in AGP and of mannose in Hp in RA patients. Altered patterns of mannosylation in AGP and Hp were also established by enzyme linked immunosorbent assay and Western blotting using Concanavalin-A lectin. These results could give information for understanding the disease pathogenesis and may provide an insight into the development and progression of the disease.

Clinical Applications of Autoimmunity to Citrullinated Proteins in Rheumatoid Arthritis, from Improving Diagnostics to Future Therapies

Rheumatoid arthritis (RA), although widely considered to be the most commonly occurring autoimmune disease, has only truly been substantiated as a distinct autoimmune disease very recently. The lack of understanding of the specific autoimmune system/s at work in rheumatoid patients resulted in an absence of robust diagnostic tools and had meant that the rational choice for use and design of therapy was based on broad-spectrum immunosuppression. The revelation that the autoimmune response specific for patients with RA is to particular protein antigens bearing the post-translational modification 'citrulline' has therefore revolutionized diagnostics and has helped explain why patients carrying particular MHC alleles are predisposed to the disease. The last two decades have seen the characterization of citrullinated antigens targeted by both antibodies and T cells in rheumatoid patients. In more recent years, we have also witnessed the success of biological therapies in the treatment of RA that specifically target T cells and B cells. Ongoing mapping of antibody targets is increasing the percentage of patients who can be definitively diagnosed with, and prognosed to develop, RA. These advances have led to a great number of patents for citrullinated peptides that have been and may be, in the coming years, used in diagnostic test kits. More recently, characterization of T cell targets (citrullinated peptides) has resulted in the patenting of peptides that could be used in antigen specific therapy. This review focuses on the characterization of the autoimmune response to citrullinated protein targets in RA and how the community is translating this knowledge to improve diagnostics, prognostics and therapy.

Citrullinated proteins in Rheumatoid Arthritis

Rheumatoid arthritis is an autoimmune disease of multifactorial etiology characterized by inflammation of the joints and presence of autoantibodies directed against multiple autoantigens. Recently the study of the anti-citrullinated protein antibodies (ACP) has acquired great interest due to its high specificity and sensitivity for diagnosis, in addition to which it has shown to be a predictor of severity in patients with rheumatoid arthritis, suggesting an important participation in the pathogenesis of the disease.

Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and α‐enolase: Implications for autoimmunity in rheumatoid arthritis

To investigate protein citrullination by the periodontal pathogen Porphyromonas gingivalis as a potential mechanism for breaking tolerance to citrullinated proteins in rheumatoid arthritis (RA). The expression of endogenous citrullinated proteins was analyzed by immunoblotting of cell extracts from P gingivalis and 10 other oral bacteria. P gingivalis-knockout strains lacking the bacterial peptidylarginine deiminases (PADs) or gingipains were created to assess the role of these enzymes in citrullination. Citrullination of human fibrinogen and α-enolase by P gingivalis was studied by incubating live wild-type and knockout strains with the proteins and analyzing the products by immunoblotting and mass spectrometry. Endogenous protein citrullination was abundant in P gingivalis but lacking in the other oral bacteria. Deletion of the bacterial PAD gene resulted in complete abrogation of protein citrullination. Inactivation of arginine gingipains, but not lysine gingipains, led to decreased citrullination. Incubation of wild-type P gingivalis with fibrinogen or α-enolase caused degradation of the proteins and citrullination of the resulting peptides at carboxy-terminal arginine residues, which were identified by mass spectrometry. Our findings demonstrate that among the oral bacterial pathogens tested, P gingivalis is unique in its ability to citrullinate proteins. We further show that P gingivalis rapidly generates citrullinated host peptides by proteolytic cleavage at Arg-X peptide bonds by arginine gingipains, followed by citrullination of carboxy-terminal arginines by bacterial PAD. Our results suggest a novel model where P gingivalis-mediated citrullination of bacterial and host proteins provides a molecular mechanism for generating antigens that drive the autoimmune response in RA.

Effects of tobacco smoke on immunity, inflammation and autoimmunity

Smoking is a central factor in many pathological conditions. Its role in neoplasm, lung and cardiovascular diseases has been well established for years. However it is less acknowledged the cigarette smoking affects both the innate and adoptive immune arms. Cigarette smoke was shown to augment the production of numerous pro-inflammatory cytokines such as TNF-α, IL-1, IL-6, IL-8 GM-CSF and to decrease the levels of anti-inflammatory cytokines such as IL-10. Tobacco smoke via multiple mechanisms leads to elevated IgE concentrations and to the subsequent development of atopic diseases and asthma. Cigarette smoke has also been shown activate in many ways macrophage and dendritic cell activity. While it is better evident how cigarette smoke evokes airway diseases more mechanisms are being revealed linking this social hazard to autoimmune disorders, for instance via the production of antibodies recognizing citrullinated proteins in rheumatoid arthritis or by the elevation of anti-dsDNA titers in systemic lupus erythematosus. The current review underlines the importance of smoking prevention and eradication not only in respiratory disorders but also in autoimmune conditions as well.

BH3-only proteins in rheumatoid arthritis: potential targets for therapeutic intervention

Rheumatoid arthritis (RA) is a debilitating disease, resulting in the destruction of bone and cartilage, and in the permanent disfigurement of joints. Although the precise cause of RA is currently unresolved, it has become clear that the damaging effects are a result of the toxic milieu caused by an influx of inflammatory cells and the resulting heightened proinflammatory state within the joint. As the amount of literature suggesting that this preponderance of cells is a result of decreased local apoptosis in the joint continues to increase, in this review, we describe how Bcl-2 family pro-apoptotic BH3-only proteins, particularly Bim and Bid, could act to protect against the development of the disease. We also suggest a role for BH3-mimetic drugs as potential therapeutics in the treatment of RA.

Immunity to Citrullinated Proteins in Rheumatoid Arthritis

Antibodies to citrullinated proteins (ACPA), i.e., to peptides posttranslationally modified by the conversion of arginine to citrulline, are specific serological markers for rheumatoid arthritis (RA). Studies on anticitrulline immunity, summarized in this review, demonstrate that the criterion-based syndrome RA should be subdivided into at least two distinct subsets (ACPA-positive and ACPA-negative disease). A new etiological model is proposed for ACPA-positive RA, built on MHC class II-dependent activation of adaptive immunity. Fundamentals of this model include the following: (a) ACPA antedate onset of arthritis; (b) ACPA may aggravate arthritis in rodents; (c) ACPA are triggered in the context of genes that confer susceptibility to RA (HLA-DRB1 SE) and by environmental agents triggering RA (smoking or bacterial stimuli); (d) ACPA may complex with citrullinated proteins present in target tissue as part of a multistep process for arthritis development. The model provides a new basis for molecular studies on the pathogenesis of ACPA-positive arthritis.

Smoking as a trigger for inflammatory rheumatic diseases

This review has two purposes: to describe the known effects of cigarette smoking on the development of inflammatory rheumatic diseases, in particular rheumatoid arthritis and systemic lupus erythematosus, and to review recent research aimed at understanding the mechanisms by which smoking may interact with genes and immunity in triggering these diseases. Large case-control studies as well as cohort studies have demonstrated that cigarette smoking is a risk factor for RF positive and anti-citrulline antibody with rheumatoid arthritis and that the risk diminishes only several years after cessation of smoking. Evidence exists that smoking is a risk factor also for systemic lupus erythematosus, and that the risk may be related to the presence of anti-dsDNA antibodies. Mechanistic studies are reviewed that suggest that smoking can trigger specific and potentially disease-inducing immune reactions against citrullinated proteins in rheumatoid arthritis, and dsDNA in systemic lupus erythematosus, and it is suggested that the genetic context determines which immune reactions may be triggered by smoking. Counselling against smoking should be mandatory in rheumatological practice both to patients and to their relatives. Studies on the mechanisms whereby smoking triggers rheumatoid arthritis and systemic lupus erythematosus may provide fundamental new knowledge about the cause and molecular pathogenesis of these diseases.