Anti–Citrullinated Protein Antibodies With Multiple Specificities Ameliorate Collagen Antibody–Induced Arthritis in a <scp>Time‐Dependent</scp> Manner

Gomez, Alejandro M.; Brewer, R. Camille; Moon, Jae‐Seung; Acharya, Suman; Kongpachith, Sarah; Wang, Qian; Jahanbani, Shaghayegh; Wong, Heidi H.; Lanz, Tobias V.; Love, Zelda Z.; Min‐Oo, Gundula; Niedziela‐Majka, Anita; Robinson, William H.

doi:10.1002/art.42679

Cited by 10 publications

(2 citation statements)

References 49 publications

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“…Recently, it was reported that ACPA might protect against arthritis progression in mice [43]. These findings were subsequently replicated by three other groups [44 ▪▪ ,45,46], each using other ACPA MoAbs. Likewise, injection of purified ACPA from patients were also reported to have anti-inflammatory effects in the murine arthritis model used.…”

Section: Recent Antimodified Protein Antibody Developmentsmentioning

confidence: 82%

Autoantibodies in rheumatoid arthritis – rheumatoid factor, anticitrullinated protein antibodies and beyond

Steiner,

Toes

2024

Current Opinion in Rheumatology

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Purpose of review RA is characterized by the presence of autoantibodies among which rheumatoid factors (RFs) and antimodified protein antibodies (AMPA) are serological hallmarks of the disease. In recent years, several novel insights into the biology, immunogenetics and clinical relevance of these autoantibodies have been obtained, which deserve to be discussed in more detail. Recent findings RFs from RA patients seem to target distinct epitopes which appear to be quite specific for RA. Determination of immunoglobulin A (IgA) isotypes of RF and anticitrullinated protein antibodies (ACPA) may provide prognostic information because their presence is associated with reduced therapeutic responses to TNF inhibitors. Furthermore, IgA levels are increased in RA patients and IgA immune complexes are more potent than immunoglobulin G (IgG) complexes in inducing NET formation. Concerning AMPAs, investigations on variable domain glycosylation (VDG) revealed effects on antigen binding and activation of autoreactive B cells. Studies on pathogenetic involvement of ACPA suggest Janus-faced roles: on the one hand, ACPA may be involved in joint destruction and pain perception while on the other hand protective anti-inflammatory effects may be attributed to a subset of ACPAs. Summary The autoimmune response in RA is extremely complex and still far from being fully understood. Antibodies are not only valuable diagnostic biomarkers but also seem to play pivotal roles in the pathophysiology of RA.

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Section: Recent Antimodified Protein Antibody Developmentsmentioning

confidence: 82%

Autoantibodies in rheumatoid arthritis – rheumatoid factor, anticitrullinated protein antibodies and beyond

Steiner,

Toes

2024

Current Opinion in Rheumatology

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“…It remains to be investigated whether immunisation with acetylated bacterial proteins leads to the onset of symptoms in mice prone to develop arthritis, although it is also conceivable that no arthritis will develop given the recent anti-inflammatory effects of ACPA in murine arthritis models. 17 19 …”

Section: Discussionmentioning

confidence: 99%

Acetylated bacterial proteins as potent antigens inducing an anti-modified protein antibody response

Volkov,

Kampstra,

van Schie

et al. 2024

RMD Open

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ObjectiveGut-residing bacteria, such asEscherichia coli, can acetylate their proteome under conditions of amine starvation. It is postulated that the (gut) microbiome is involved in the breach of immune tolerance to modified self-proteins leading to the anti-modified protein antibodies (AMPAs), hallmarking seropositive rheumatoid arthritis (RA). Our aim was to determine whether acetylated bacterial proteins can induce AMPA responses cross-reactive to modified self-proteins and be recognised by human AMPA (hAMPA).MethodsE. colibacteria were grown under amine starvation to generate endogenously acetylated bacterial proteins. Furthermore,E. coliproteins were acetylated chemically. Recognition of these proteins by hAMPA was analysed by western blotting and ELISA; recognition by B cells carrying a modified protein-reactive B cell receptor (BCR) was analysed by pSyk (Syk phosphorylation) activation assay. C57BL/6 mice were immunised with (modified) bacterial protein fractions, and sera were analysed by ELISA.ResultsChemically modified bacterial protein fractions contained high levels of acetylated proteins and were readily recognised by hAMPA and able to activate B cells carrying modified protein-reactive BCRs. Likely due to substantially lower levels of acetylation, endogenously acetylated protein fractions were not recognised by hAMPA or hAMPA-expressing B cells. Immunising mice with chemically modified protein fractions induced a strong cross-reactive AMPA response, targeting various modified antigens including citrullinated proteins.ConclusionsAcetylated bacterial proteins are recognisable by hAMPA and are capable of inducing cross-reactive AMPA in mice. These observations provide the first conceptual evidence for a novel mechanism involving the (endogenous) acetylation of the bacterial proteome, allowing a breach of tolerance to modified proteins and the formation of cross-reactive AMPA.

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The Changing Paradigm of Anti–Citrullinated Protein Antibodies in Rheumatoid Arthritis

Demoruelle

2023

Arthritis & Rheumatology

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Anti-citrullinated protein antibodies (ACPAs) have long been associated with more severe rheumatoid arthritis (RA), with ACPA inherent to more erosive and difficult-to-treat disease. This relationship, along with studies demonstrating that certain ACPAs can induce or enhance osteoclastogenesis, joint pain, and joint inflammation, has supported the notion that ACPAs are directly pathogenic in RA. [1][2][3][4] However, more recent studies have begun to support a contrasting concept that certain ACPAs may be therapeutic and reduce symptoms of arthritis and inflammation. [5][6][7] Although these studies are limited to in vitro experiments and mouse models, the concept that some ACPAs are "protective" in humans has been a core component of the mucosal origins hypothesis, 8 which outlines how different mucosal sites can be involved in RA pathogenesis through inflammation and autoantibody generation during the preclinical phase of RA development. It also hypothesizes that some ACPAs present before arthritis, particularly immunoglobin (Ig) A-ACPAs that are localized to a mucosal site, may be beneficial or protective in the setting of inflammation. It is evident that further investigation is needed to better understand distinct functions of different ACPA subsets as they relate to RA pathogenesis.In this issue, Gomez and colleagues reported a set of human-derived recombinant ACPAs that ameliorate and prevent arthritis in the collagen antibody-induced arthritis (CAIA) mouse model. 9 The ACPAs used in this study were derived from plasmablast antibody repertoires sequenced from a patient with RA. The authors used multiple antigen arrays to characterize a selected set of nine recombinantly expressed ACPAs and demonstrate that these ACPAs are polyspecific but preferentially bind citrullinated (cit) antigens with high affinity. The primary antigen targets of these nine selected ACPAs included cit-fibrinogen, cit-peptidylarginine deiminase (PAD) 4, cit-histone H3, cit-histone H4, and some binding to native histone H3 and native histone H4.

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Anti–Citrullinated Protein Antibodies With Multiple Specificities Ameliorate Collagen Antibody–Induced Arthritis in a Time‐Dependent Manner

Cited by 10 publications

References 49 publications

Autoantibodies in rheumatoid arthritis – rheumatoid factor, anticitrullinated protein antibodies and beyond

Autoantibodies in rheumatoid arthritis – rheumatoid factor, anticitrullinated protein antibodies and beyond

Acetylated bacterial proteins as potent antigens inducing an anti-modified protein antibody response

The Changing Paradigm of Anti–Citrullinated Protein Antibodies in Rheumatoid Arthritis

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