Revisiting B cell tolerance and autoantibodies in seropositive and seronegative autoimmune rheumatic disease (AIRD)

Abstract

Summary Autoimmune rheumatic diseases (AIRD) are categorized seropositive or seronegative, dependent upon the presence or absence of specific autoreactive antibodies, including rheumatoid factor and anti-citrullinated protein antibodies. Autoantibody-based diagnostics have proved helpful in patient care, not only for diagnosis but also for monitoring of disease activity and prediction of therapy responsiveness. Recent work demonstrates that AIRD patients develop autoantibodies beyond those contained in the original categorization. In this study we discuss key mechanisms that underlie autoantibody development in AIRD: defects in early B cell development, genetic variants involved in regulating B cell and T cell tolerance, environmental triggers and antigen modification. We describe how autoantibodies can directly contribute to AIRD pathogenesis through innate and adaptive immune mechanisms, eventually culminating in systemic inflammation and localized tissue damage. We conclude by discussing recent insights that suggest distinct AIRD have incorrectly been denominated seronegative.

Seronegative Autoimmune Hepatitis

“…Some reports indicate that plasma cell frequencies may be increased in snAIH cases with increased frequencies of plasma cells producing IgM, IgG, and IgA, suggesting the lack of autoantibodies in snAIH, and seronegativity is a matter of timing. 9,[17][18][19] It has been proposed that early intense antigen-antibody complex formation can confound assays. Wang et al 14 found that upon further review of subjects with snAIH during a 5 to 26 months follow-up, four of 17 (23%) became ANA positive.…”

Low Serum BAFF Concentration Is Associated with Response to TNF Inhibitors in Seropositive Patients with Rheumatoid Arthritis

“…The development of autoantibodies is hypothesised to be explained by a failure of the immune system which renders it incapable of eliminating or controlling autoreactive B cells. This failure contributes to a break of B-cell tolerance, promoting the persistence of autoreactive B cells through defective central and peripheral B-cell development checkpoints [ 8 ]. In this regard, an excessive production of BAFF has been suggested to be a potential contributor to the breach of B-cell tolerance and the consequent development of autoantibodies [ 18 , 19 ].…”

“…Several investigations have pointed out the role of BAFF in the development of autoantibodies, such as rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs) [ 7 , 8 , 9 , 10 ]. The presence of these autoantibodies in RA patients would imply a higher degree of inflammation during disease, which results in a more aggressive and joint-erosive condition for the patients showing higher disease activity, as well as worse prognosis owing to accelerated progression of the disease [ 11 , 12 , 13 ].…”

The Genetic, Environmental, and Immunopathological Complexity of Autoantibody-Negative Rheumatoid Arthritis

“…The progressive improvement in autoantibody laboratory assays, together with the recognition of other possible autoantibody specificities beyond RF and ACPA, have led some authors to hypothesize that at least a proportion of autoantibody-negative RA is in fact incorrectly denominated seronegative [9]. Apart from non-canonical ACPAs, which can be detected in as many as 16% of ACPA-negative patients by multiplex citrullinated peptide arrays [101], the occurrence of autoantibody responses to other post-translational modified proteins is a well-known phenomenon in RA (Table 1).…”

“…Intensive research into the etiopathogenesis of ACPA-positive RA over the last years has substantially clarified the complex interplay between genetic risk factors and environmental susceptibility resulting in dysregulated adaptive immunity with the generation of pathogenic autoantibodies [6,7]. In contrast, the genetic architecture and the predisposing factors of autoantibody-negative RA remain an area of uncertainty, and the relative contribution of innate over adaptive immune pathways has been hypothesized but not formally proven [8,9]. Although RA is currently managed the same way irrespective of the autoantibody profile, a better understanding of the pathophysiological heterogeneity of the disease would definitively improve personalized approaches more focused on specific risk factors and immune pathways.…”