Fingerprinting of anti-citrullinated protein antibodies (ACPA): specificity, isotypes and subclasses

Pratesi, Federico; Panza, Filomena; Paolini, Ilaria; Petrelli, Fiorella; Puxeddu, Ilaria; Casigliani-Rabl, S; Ancillotti, D.; Alcaro, C; Rovero, Paolo; Migliorini, Paola

doi:10.1177/0961203314560005

Cited by 12 publications

(11 citation statements)

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“…ACPA IgG may trigger inflammation by Fc-gamma receptor ligation and/or classical complement activation, which may be enhanced by altered glycosylation patterns of ACPA IgG [7]. The half-life of circulating IgM is short, and the fact that ACPA IgM has been detected in patients with long-standing RA suggests continuous recruitment of naive B cells [9]. The half-life of circulating IgM is short, and the fact that ACPA IgM has been detected in patients with long-standing RA suggests continuous recruitment of naive B cells [9].…”

Section: Introductionmentioning

confidence: 99%

“…ACPA IgM has been reported to induce cell-activating properties following complement activation [8]. The half-life of circulating IgM is short, and the fact that ACPA IgM has been detected in patients with long-standing RA suggests continuous recruitment of naive B cells [9]. ACPA IgA does not activate the classical complement pathway, but may exert dual effects after ligation to Fc-alpha receptors expressed on cell-surfaces [10,11].…”

Section: Introductionmentioning

confidence: 99%

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Changes in anti-citrullinated protein antibody isotype levels in relation to disease activity and response to treatment in early rheumatoid arthritis

Kastbom

Ljungberg

Ziegelasch

et al. 2018

Clinical and Experimental Immunology

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Rheumatoid arthritis (RA) is a chronic inflammatory disease where serum analysis of anti-citrullinated peptide/protein antibodies (ACPA) is an important diagnostic/prognostic tool. Levels and changes of ACPA in RA patients have been studied previously in relation to disease course and therapy response, but less is known regarding ACPA isotype changes in early RA. Hence, recent-onset RA patients (n = 231) were subjected to a 3-year clinical and radiological follow-up. Serum samples were serially collected and ACPA isotypes were analysed using the second-generation cyclic citrullinated peptide (CCP) as capture antigen. Changes in ACPA isotype levels and status were related to disease course and pharmacotherapy. At inclusion, 74% of the patients tested positive for ACPA IgG; 55% for immunoglobulin (Ig)A, 37% for secretory IgA (SIgA) and 35% for IgM. The proportion of positive patients decreased significantly at follow-up regarding ACPA SIgA, IgM and IgA. During the initial 3 months, reduction of the 28-joint disease activity score (DAS28) correlated with reduced levels of ACPA IgG (Rho = 0·242, P = 0·003), IgA (Rho = 0·260, P = 0·008), IgM (Rho = 0·457, P < 0·001) and SIgA (Rho = 0·402, P < 0·001). Levels of ACPA SIgA (P = 0·008) and IgM (P = 0·021) decreased significantly among patients with good response to treatment, which was not seen regarding ACPA IgA or IgG. Changes in ACPA isotype levels were not associated with radiographic damage. In conclusion, ACPA SIgA and IgM declined rapidly upon anti-rheumatic therapy and correlated with decreased disease activity in recent-onset RA. This may indicate that down-regulation of mucosal immunity to citrullinated proteins/peptides and recruitment of new B cells are key features of therapy responses in early RA.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Changes in anti-citrullinated protein antibody isotype levels in relation to disease activity and response to treatment in early rheumatoid arthritis

Kastbom

Ljungberg

Ziegelasch

et al. 2018

Clinical and Experimental Immunology

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“…Cross-reactivity of ACPA was reported by several groups, and the concept that Cit-Gly motif has importance in the recognition was also studied earlier [ 26 , 29 , 30 , 36 , 41 , 42 ]. Several combinations of Cit-peptides and ACPAs have been tested for cross-reactivity: antibodies to Cit-EBNA (35–58) strongly cross-reacted with the immunodominant epitope of citrullinated fibrin [ 43 ] and vice versa; and two proteins encoded by Epstein-Barr virus (EBV), EBNA-1 and EBNA-2 were specifically recognized by antibodies of the ACPA family [ 44 ]. Additionally, monoclonal antibodies obtained from an RA patient and specifically directed against a citrullinated fibrin peptide also recognized Cit-peptides derived from enolase and vimentin [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Affinity Purification and Comparative Biosensor Analysis of Citrulline-Peptide-Specific Antibodies in Rheumatoid Arthritis

Szarka

Aradi

Huber

et al. 2018

IJMS

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Background: In rheumatoid arthritis (RA), anti-citrullinated protein/peptide antibodies (ACPAs) are responsible for disease onset and progression, however, our knowledge is limited on ligand binding affinities of autoantibodies with different citrulline-peptide specificity. Methods: Citrulline-peptide-specific ACPA IgGs were affinity purified and tested by ELISA. Binding affinities of ACPA IgGs and serum antibodies were compared by surface plasmon resonance (SPR) analysis. Bifunctional nanoparticles harboring a multi-epitope citrulline-peptide and a complement-activating peptide were used to induce selective depletion of ACPA-producing B cells. Results: KD values of affinity-purified ACPA IgGs varied between 10−6 and 10−8 M and inversely correlated with disease activity. Based on their cross-reaction with citrulline-peptides, we designed a novel multi-epitope peptide, containing Cit-Gly and Ala-Cit motifs in two–two copies, separated with a short, neutral spacer. This peptide detected antibodies in RA sera with 66% sensitivity and 98% specificity in ELISA and was recognized by 90% of RA sera, while none of the healthy samples in SPR. When coupled to nanoparticles, the multi-epitope peptide specifically targeted and depleted ACPA-producing B cells ex vivo. Conclusions: The unique multi-epitope peptide designed based on ACPA cross-reactivity might be suitable to develop better diagnostics and novel therapies for RA.

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“…Likewise, the various IgG subclasses have different affinities to interact with activating or inhibitory Fc receptors [ 17 ]. The isotype usage of the ACPA response has been well studied, showing a broad usage of different isotypes by ACPA in RA patients [ 18 – 20 ]. ACPA-IgM and ACPA-IgA are mainly confined to ACPA-IgG-positive patients [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

The isotype and IgG subclass distribution of anti-carbamylated protein antibodies in rheumatoid arthritis patients

et al. 2017

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BackgroundAnti-carbamylated protein (anti-CarP) antibodies have recently been reported to occur in around 45% of rheumatoid arthritis (RA) patients and to have prognostic and diagnostic properties. At present, the breadth and molecular make-up of the anti-CarP antibody response is ill defined. To understand the anti-CarP antibody immune response and potential immune effector mechanisms it can recruit, we determined the anti-CarP antibody isotype and IgG-subclass usage in RA patients.MethodsAnti-CarP antibody IgM, IgA, and IgG or IgG subclasses were detected by enzyme-linked immunosorbent assay (ELISA) in sera from 373 unselected RA patients and 196 healthy controls. An additional 114 anti-citrullinated protein antibody (ACPA) and anti-CarP IgG double-positive patients were selected to study the concomitant presence of both antibody systems.ResultsAnti-CarP IgG was present in around 45% of the patients and comprised all anti-CarP IgG subclasses. The presence of anti-CarP IgG1 particularly associates with radiological damage. Anti-CarP IgM was detected in 16% of RA patients, even in anti-CarP IgG-positive individuals, and is indicative of an actively ongoing immune response. Around 45% of the patients were positive for IgA which included ACPA-positive cases but also 24% of the ACPA-negative cases. In ACPA and anti-CarP double-positive patients, the distribution and number of isotypes and IgG subclasses was similar for both autoantibodies at the group level, but substantial variation was observed within individual patient samples.ConclusionsIn RA, the anti-CarP antibody response uses a broad spectrum of isotypes and seems to be an actively ongoing immune reaction. Furthermore, the anti-CarP and ACPA autoantibody responses seems to be differentially regulated.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1392-z) contains supplementary material, which is available to authorized users.

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Fingerprinting of anti-citrullinated protein antibodies (ACPA): specificity, isotypes and subclasses

Cited by 12 publications

References 77 publications

Changes in anti-citrullinated protein antibody isotype levels in relation to disease activity and response to treatment in early rheumatoid arthritis

Changes in anti-citrullinated protein antibody isotype levels in relation to disease activity and response to treatment in early rheumatoid arthritis

Affinity Purification and Comparative Biosensor Analysis of Citrulline-Peptide-Specific Antibodies in Rheumatoid Arthritis

The isotype and IgG subclass distribution of anti-carbamylated protein antibodies in rheumatoid arthritis patients

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