New Relationships for Old Autoantibodies in Rheumatoid Arthritis

Shelef, Miriam A.

doi:10.1002/art.40879

Cited by 11 publications

(12 citation statements)

References 26 publications

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“…Therefore, they are unlikely to denote any hierarchy of precedence or causality between the antibodies. Just recently, some of these examples of shared and overlapping immunological mechanisms have been characterized as the convergent pathways model of RA pathogenesis 54 .…”

Section: Discussionmentioning

confidence: 99%

“…This hypothesis has the appeal of the simplicity of considering a single protein as the link between the different RA antibodies. Accordingly, it has been characterized as the common antigen model 54 . However, only RF is known to recognize the IgGH fragment, in the form of IgGH/HLA class II complexes 60 , whereas the binding of the modified IgGH fragment by ACPA or ACarPA has not been reported.…”

Section: Discussionmentioning

confidence: 99%

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A predominant involvement of the triple seropositive patients and others with rheumatoid factor in the association of smoking with rheumatoid arthritis

Regueiro

Rodríguez‐Rodríguez

López‐Mejías

et al. 2020

Sci Rep

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the major environmental risk factor for rheumatoid arthritis (RA) is smoking, which according to a widely accepted model induces protein citrullination in the lungs, triggering the production of anticitrullinated protein antibodies (ACPA) and RA development. Nevertheless, some research findings do not fit this model. Therefore, we obtained six independent cohorts with 2253 RA patients for a detailed analysis of the association between smoking and RA autoantibodies. our results showed a predominant association of smoking with the concurrent presence of the three antibodies: rheumatoid factor (RF), ACPA and anti-carbamylated protein antibodies (ACarPA) (3 Ab vs. 0 Ab: OR = 1.99, p = 2.5 × 10-8). Meta-analysis with previous data (4491 patients) confirmed the predominant association with the concurrent presence of the three antibodies (3 Ab vs. 0 Ab: OR = 2.00, p = 4.4 ×10-16) and revealed that smoking was exclusively associated with the presence of RF in patients with one or two antibodies (Rf + 1+2 vs. Rf − 0+1+2 : oR = 1.32, p = 0.0002). In contrast, no specific association with ACPA or AcarpA was found. therefore, these results showed the need to understand how smoking favors the concordance of RA specific antibodies and RF triggering, perhaps involving smoking-induced epitope spreading and other hypothesized mechanisms. Rheumatoid arthritis (RA) is a systemic autoimmune disease that can be divided in two pathogenic subgroups 1,2. The largest subgroup comprises the patients presenting RA specific autoantibodies. These antibodies include the rheumatoid factor (RF), which is directed against the Fc of the IgG, and antibodies against some post-translational protein modifications. The best characterized are anti-citrullinated protein antibodies (ACPA), which in the clinic are assayed as anti-cyclic citrullinated peptides or anti-CCP, and the anti-carbamylated protein antibodies (ACarPA), which are not yet analyzed beyond research studies. The antibody positive patients are known as seropositive and they represent more than two thirds of the total, while the remaining are the seronegative patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A predominant involvement of the triple seropositive patients and others with rheumatoid factor in the association of smoking with rheumatoid arthritis

Regueiro

Rodríguez‐Rodríguez

López‐Mejías

et al. 2020

Sci Rep

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“…IgM did not preferentially target citrulline-containing peptides of IgG. IgM-RF, which also occurs in healthy individuals, may arise independently of citrulline due to smoking or pathogens, whereas the development of IgG-RF, which requires a break in tolerance and T cell help, may be driven by targeting citrulline, like other ACPAs (53). However, it is not known whether the IgG we detected originally developed against citrullinated IgG, or whether the observed targeting of citrulline-containing IgG peptides was due to cross-reactivity of ACPAs.…”

Section: Discussionmentioning

confidence: 90%

Disordered Antigens and Epitope Overlap Between Anti–Citrullinated Protein Antibodies and Rheumatoid Factor in Rheumatoid Arthritis

Zheng

Mergaert

Fahmy

et al. 2019

Arthritis & Rheumatology

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Objective. Anti-citrullinated protein antibodies (ACPAs) and rheumatoid factor (RF) are commonly present in rheumatoid arthritis (RA) without a clear rationale for their coexistence. Moreover, autoantibodies develop against proteins with different posttranslational modifications and native proteins without obvious unifying characteristics of the antigens. We undertook this study to broadly evaluate autoantibody binding in seronegative and seropositive RA to identify novel features of reactivity.Methods. An array was created using a total of 172,828 native peptides, citrulline-containing peptides, and homocitrulline-containing peptides derived primarily from proteins citrullinated in the rheumatoid joint. IgG and IgM binding to peptides were compared between cyclic citrullinated peptide (CCP)-positive RF+, CCP+RF−, CCP−RF+, and CCP−RF− serum from RA patients (n = 48) and controls (n = 12). IgG-bound and endogenously citrullinated peptides were analyzed for amino acid patterns and predictors of intrinsic disorder, i.e., unstable 3-dimensional structure. Binding to IgG-derived peptides was specifically evaluated. Enzyme-linked immunosorbent assay confirmed key results.Results. Broadly, CCP+RF+ patients had high citrulline-specific IgG binding to array peptides and CCP+RF− and CCP−RF+ patients had modest citrulline-specific IgG binding (median Z scores 3.02, 1.42, and 0.75, respectively; P < 0.0001). All RA groups had low homocitrulline-specific binding. CCP+RF+ patients had moderate IgG binding to native peptides (median Z score 2.38; P < 0.0001). The highest IgG binding was to citrulline-containing peptides, irrespective of protein identity, especially if citrulline was adjacent to glycine or serine, motifs also seen in endogenous citrullination in the rheumatoid joint. Highly bound peptides had multiple features predictive of disorder. IgG from CCP+RF+ patients targeted citrulline-containing IgG-derived peptides.Conclusion. Disordered antigens, which are frequently citrullinated, and common epitopes for ACPAs and RF are potentially unifying features for RA autoantibodies.

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“…In this study, both smoking and the presence of the SE conferred independent disease risk for RA with the two antibodies, ACPA and RF, whereas the ACPA − /RF + patients showed an increased risk of disease among smokers, which was only marginally affected by the presence of the SE, and the ACPA + /RF − patients were predominantly associated with the SE. These results have been interpreted as meaning the smoking may be a critical driver of RF production whereas the SE could be the main driver of ACPA development 3. In this inquiry on the specific factors contributing to the RA subsets, we think the additional information regarding the Japanese population studied by Ishikawa et al will be very welcomed.…”

mentioning

confidence: 91%

“…Perhaps, it is possible to obtain more information about these differences from the Ishikawa et al data. This would be very useful because there is currently a lot of interest in the relationship between smoking and the autoantibody-defined subgroups of RA patients 2–6. Specifically, we think it will be informative to know if smoking introduced a differential association between the two subsets of patients with SE and high ACPA described in figure 3B in the Ishikawa et al article.…”

mentioning

confidence: 99%

Correspondence on ‘Shared epitope defines distinct associations of cigarette smoking with levels of anticitrullinated protein antibody and rheumatoid factor’ by Ishikawa et al

Regueiro

González

2019

Ann Rheum Dis

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We read with great interest the paper of Ishikawa et al, 1 which addressed the link between smoking and the levels of anti-citrullinated protein antibodies(ACPA) and rheumatoid factor (RF) in a total of 6239 Japanese rheumatoid arthritis (RA) patients. We particularly appreciate the detailed smoking history collected that allowed a very detailed analysis. The authors collected information about the number of cigarette packs smoked per day, the years smoking and the time of smoke cessation when it was present. They also distinguished the ever smoker patients in three categories: smokers at disease onset, ex-smokers before onset and smokers after onset, which looks like a very pertinent stratification for exploring the pathogenic role of cigarette smoking. The study found a significant and dosedependent association between smoking and antibody positivity for ACPA or RF antibodies, as well as, an association with high titres of ACPA or RF antibodies, which was only dose-dependent regarding RF. In both cases, the association was stronger with RF than ACPA. Moreover, the association of smokers with ACPA levels only was significant in the subgroup of patients with shared epitope (SE) alleles in the HLA-DRB1. In contrast, the association of smoking with RF was significant independently of the SE alleles. The authors conclude that these results suggest that the development of RF and ACPA is driven by different mechanisms without further detailing the implications. Perhaps, it is possible to obtain more information about these differences from the Ishikawa et al data. This would be very useful because there is currently a lot of interest in the relationship between smoking and the autoantibody-defined subgroups of RA patients. [2][3][4][5][6] Specifically, we think it will be informative to know if smoking introduced a differential association between the two subsets of patients with SE and high ACPA described in figure 3B in the Ishikawa et al article. Also, we think that a conditional analysis of one antibody on the other autoantibody, or stratified analyses on the serologically defined subgroups, could clarify the interpretation of the results regarding specific autoantibodies given the common concurrent presence of RF and ACPA. An analysis of this type has been recently reported in a large Swedish study that also counted with high-quality information on cigarette smoking. 2 In this study, both smoking and the presence of the SE conferred independent disease risk for RA with the two antibodies, ACPA and RF, whereas the ACPA − /RF + patients showed an increased risk of disease among smokers, which was only marginally affected by the presence of the SE, and the ACPA + /RF − patients were predominantly associated with the SE. These results have been interpreted as meaning the smoking may be a critical driver of RF production whereas the SE could be the main driver of ACPA development. 3 In this inquiry on the specific factors contributing to the RA subsets, we think the additional information regarding the Japanese popula...

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New Relationships for Old Autoantibodies in Rheumatoid Arthritis

Cited by 11 publications

References 26 publications

A predominant involvement of the triple seropositive patients and others with rheumatoid factor in the association of smoking with rheumatoid arthritis

A predominant involvement of the triple seropositive patients and others with rheumatoid factor in the association of smoking with rheumatoid arthritis

Disordered Antigens and Epitope Overlap Between Anti–Citrullinated Protein Antibodies and Rheumatoid Factor in Rheumatoid Arthritis

Correspondence on ‘Shared epitope defines distinct associations of cigarette smoking with levels of anticitrullinated protein antibody and rheumatoid factor’ by Ishikawa et al

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