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

Abstract

Our findings suggest that the high level of cross reactivity amongst the RA autoreactive B cells is the result of different antigen encounters, possibly at different sites and at different time points. This is in line with the notion that RA is initiated in one context, such as in mucosal organs, and thereafter target other sites, such as joints. This article is protected by copyright. All rights reserved.

Complex Relationships of Smoking, HLA–DRB1 Genes, and Serologic Profiles in Patients With Early Rheumatoid Arthritis: Update From a Swedish Population‐Based Case–Control Study

“…The situation was substantially different in the RF−/anti-CCP2+ RA group, in whom there was a major and gene dose-dependent effect of HLA-DRB1 and a more limited, but still visible, effect of smoking, particularly in heavy smokers. This finding is compatible with prior reports of high numbers of T cell-dependent somatic mutations in genes coding for anticitrulline-reactive antibodies (15)(16)(17).…”

The importance of differences; On environment and its interactions with genes and immunity in the causation of rheumatoid arthritis

“…Whereas the anti-CCP assay captures most ACPAs, there is a notable heterogeneity in reactivity to distinct citrullinated peptides and proteins with a large number of overlapping subsets being formed [17][18][19][20] (see also Figure 1). Subsequent to the recognition of reactivity against epitopes modified by citrullination, RA autoantibodies have been shown to also react with proteins/peptides modified by additional post-translational modifications, including homocitrullination (or carbamylation) [21][22][23][24] as well as acetylation [25,26]. Although most of these antibodies are seen in ACPA-positive patients, there are also smaller subsets of RA with antibodies against these alternative modifications, while being negative for ACPA or RF [18,20].…”

“…A recently published report from our own group provided evidence that certain ACPAs may indeed activate synovial fibroblasts into a migratory behaviour after binding to citrullinated targets on their cell surface [193]; notably, only synoviocytes that had previously been activated by various stimuli, including pro-inflammatory cytokines and chemokines, were targeted by the ACPAs, thereby providing additional but still circumstantial support for a two-step model of the development of joint inflammation in ACPA-and RF-positive individuals [193]. Whether also other mechanisms involving ACPAs that cross-react with post-translationally modified cartilage molecules, including collagen II, CILP, tenascin and more [194][195][196][197], contribute to joint inflammation remains an additional possibility in need of exploration using polyclonal as well as monoclonal antibodies from RA patients. Importantly, however, we must recognize that multiple regulating events happen over time after initial triggering of potentially pathogenic immunity.…”

The Specificity of Monoclonal Anti–Citrullinated Protein Antibodies: Comment on the Article by Steen et al

“…I read with great interest the article by Steen et al , which reported that human plasma cell–derived monoclonal antibodies (mAb) to posttranslationally modified proteins recognize amino acid motifs rather than specific proteins. However, I believe some potentially misleading conclusions were drawn.…”

“…In fact, these 2 were the only antibodies that consistently showed those effects. Surprisingly, in the report by Steen et al , they maintain that ACPAs have in vitro and in vivo models shown to induce phenotypes consistent with symptoms associated with RA, such as bone loss and joint pain (citing refs. 4–6 below).…”