Effect of Rheumatoid Arthritis (RA) Susceptibility Genes on the Immune Response to Viral Citrullinated Peptides in RA

Pratesi, Federico; Petit-Teixeira, Élisabeth; Sidney, John; Teixeira, Vítor Hugo; Puxeddu, Ilaria; Sette, Alessandro; Cornélis, François; Migliorini, Paola

doi:10.3899/jrheum.111548

Cited by 8 publications

(8 citation statements)

References 13 publications

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“…Examining the influence of genes conferring susceptibility to RA, all four antibodies were found to be associated with HLA-SE after disease onset; on the contrary, only anti-VCP2 antibodies were associated with HLA-SE, even before symptom onset, as was already observed with other ACPA specificities [ 30 ]. When analysing the contribution of individual SE alleles in pre-symptomatic individuals, the *0401 allele was associated with both anti-VCP2 and anti-HCP2 antibody positivity, in line with previous findings in a French Caucasian population [ 31 , 32 ]. Among the other genetic factors analysed, we found no association between anti-VCP or anti-HCP and PTPN22 .…”

Section: Discussionsupporting

confidence: 88%

Antibodies directed against endogenous and exogenous citrullinated antigens pre-date the onset of rheumatoid arthritis

et al. 2016

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BackgroundAnti-citrullinated-peptide antibodies (ACPA) have been detected in individuals with developing rheumatoid arthritis (RA) before the onset of symptom, with an initially limited spectrum of reactivities that gradually broadens. The aim was to analyze the evolution of ACPA response pre-dating symptom onset, using four selected citrullinated exogenous and endogenous antigens.MethodsA cohort of 521 individuals sampled before symptoms of RA appeared and 272 population controls were identified from the Biobank of Northern Sweden; 241 samples from patients with early RA were also collected. ACPA were detected by ELISA on viral citrullinated peptides (VCP) derived from Epstein-Barr-virus nuclear antigen (EBNA)1 and EBNA2 (VCP1 and VCP2) and histone-4-derived citrullinated peptides (HCP1 and HCP2).ResultsIn pre-symptomatic individuals vs. patients with early RA, anti-VCP1 antibodies were detected in 10.4 % vs. 36.1 %, anti-VCP2 in 17.1 % vs. 52.3 %, anti-HCP1 in 10.2 % vs. 37.3 %, and anti-HCP2 in 16.3 % vs. 48.5 %, respectively. Anti-VCP and anti-HCP concentrations were significantly increased in pre-symptomatic individuals vs. controls (p < 0.001) and were increased approaching symptom onset. Anti-VCP and anti-HCP appeared simultaneously (median (IQR) 5.3 (6) years before symptom onset) and in combination yielded a high-risk ratio for disease development (OR = 8.0–18.9). Anti-VCP2 and anti-HCP2 antibodies were associated with HLA-DRB1*0401 in pre-symptomatic individuals. Three peptidylarginine deiminase (PAD)I3/PADI4 single nucleotide polymorphisms (SNPs) were significantly associated with anti-HCP1.ConclusionsAnti-VCP and anti-HCP antibodies pre-date symptom onset and predict disease development, but no hierarchy of citrullinated epitopes can be identified. These results suggest that no inciting citrullinated antigen so far described is common to all patients with RA. The association between PADI3/PADI4 polymorphism and anti-HCP1 antibodies suggests a novel link between deimination and production of ACPA.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1031-0) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 88%

Antibodies directed against endogenous and exogenous citrullinated antigens pre-date the onset of rheumatoid arthritis

et al. 2016

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“…Indeed, the article that was supposed to have demonstrated the point studied the binding of one unique citrullinated vimentin peptide to three shared epitope-positive and five shared epitope-negative HLA-DRB1 alleles ( 11 ). Conversely, thorough studies of the binding of hundreds of peptides to shared epitope-positive or -negative HLA-DRB1 alleles did not show preferential binding of citrullinated peptides to shared epitope-positive alleles, compared with their native counterparts ( 12 – 14 ).…”

Section: Discussionmentioning

confidence: 88%

“…Furthermore, this explanation implies that RA-associated HLA-DR alleles bind citrullinated peptides to allow their presentation to T cells. This “citrullinated peptide binding” hypothesis is controversial, supported by very limited binding data ( 11 ) and contradicted by extensive binding data on fibrinogen, vimentin, collagen, and Epstein–Barr virus peptides under native and citrullinated forms ( 12 – 14 ).…”

mentioning

confidence: 99%

Peptidyl arginine deiminase immunization induces anticitrullinated protein antibodies in mice with particular MHC types

Arnoux

Mariot

Peen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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SignificanceThe presence and development of autoantibodies to citrullinated proteins (ACPAs) are highly associated with rheumatoid arthritis (RA). The mechanisms leading to the production of ACPAs are unknown. Here, we propose a model to explain the emergence of anticitrullinated protein autoantibodies in RA. Indeed, we could trigger the development of anticitrullinated fibrinogen autoantibodies in normal mice by immunization with peptidyl arginine deiminase (PAD), most likely through a hapten/carrier mechanism in which the carrier is the PAD enzyme that performs citrullination and the hapten is any protein being citrullinated (hence bound) by PAD. Our results allow us to understand the birth of anticitrullin autoimmunity.

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“…Even if the immune response to VCPs is under the genetic control of the *0401 and *0404 alleles, biologically relevant binding was not detected with either peptide for any of the HLA class II molecules tested [44].…”

Section: Hla Se and Peptide Bindingmentioning

confidence: 99%

“…As far as the effect of individual alleles is concerned, the *0401 allele confers an increased risk to produce anti-VCP2 and anti-CCP antibodies, while *0404 is associated with the production of anti-VCP1 and anti-VCP2 antibodies [44].…”

Section: Hla Se and Acpa+mentioning

confidence: 99%

HLA shared epitope and ACPA: Just a marker or an active player?

Pratesi¹,

Teixeira²,

Sidney³

et al. 2013

Autoimmunity Reviews

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Effect of Rheumatoid Arthritis (RA) Susceptibility Genes on the Immune Response to Viral Citrullinated Peptides in RA

Cited by 8 publications

References 13 publications

Antibodies directed against endogenous and exogenous citrullinated antigens pre-date the onset of rheumatoid arthritis

Antibodies directed against endogenous and exogenous citrullinated antigens pre-date the onset of rheumatoid arthritis

Peptidyl arginine deiminase immunization induces anticitrullinated protein antibodies in mice with particular MHC types

HLA shared epitope and ACPA: Just a marker or an active player?

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