A New Classification of HLA-DRB1 Alleles Differentiates in RA
A New Classification of HLA-DRB1 Alleles Differentiates in RA
The HLA-DRB1 gene was reported to be associated with anticitrullinated protein/peptide autoantibody (ACPA) production in rheumatoid arthritis (RA) patients. A new classification of HLA-DRB1 alleles, reshaping the shared epitope (SE) hypothesis, was recently found relevant in terms of RA susceptibility and structural severity.
We investigated the relevance of this new classification of HLA-DRB1 SE alleles in terms of rheumatoid factor (RF) and ACPA production in a sample of French RA patients.
We studied 160 early RA patients included in a prospective longitudinal cohort of French Caucasian patients with recent-onset arthritis. RF, anticyclic citrullinated peptide 2 (anti-CCP2) and antideiminated human fibrinogen autoantibodies (AhFibA) were assessed in all patients at inclusion. The HLA-DRB1 gene was typed by PCR-sequence specific oligonucleotides probes (PCR-SSOP), and SE+ alleles were classified into four groups (S1, S2, S3P, S3D) according to the new classification.
The new classification of HLA-DRB1 SE+ alleles distinguishes predisposing and protective alleles for RF, anti-CCP2 or AhFibA production. The presence of S2 or S3P alleles is associated with both RF, anti-CCP2 or AhFibA positivity, whereas the presence of S3D or S1 alleles appears to be protective for RF, anti-CCP2 or AhFibA positivity.
The new classification of HLA-DRB1 SE alleles is relevant in terms of autoantibody production in early RA patients by differentiating predisposing and protective alleles for RF or ACPA production.
Since early rheumatoid arthritis (RA) is often indistinguishable from other inflammatory joint diseases, recent-onset inflammatory synovitis poses a diagnostic and prognostic challenge to rheumatologists. The identification and validation of immunologic and genetic markers with strong diagnostic and prognostic value in early RA may help rheumatologists to meet this challenge.
Among immunologic markers, anticitrullinated protein/peptide antibodies (ACPAs) constitute relevant tools in the diagnosis and prognosis of early RA. Citrulline is a nonstandard amino acid, generated by post-translational modifications of several proteins by deimination of arginine residues by peptidylarginine deiminases. The citrulline moiety is the true determinant in proteins recognized by antiperinuclear factor, antikeratin antibodies, antifilaggrin antibodies, anticyclic citrullinated peptide (anti-CCP) antibodies and anti-deiminated human fibrinogen autoantibodies (AhFibA). ACPAs may be detected in healthy individuals, years before the onset of symptoms of RA, and may predict progression to persistent erosive arthritis or to RA in patients with undifferentiated arthritis. ACPAs are as sensitive as, and more specific than, rheumatoid factor (RF) for early RA diagnosis. Furthermore, ACPAs represent a prognostic factor for erosive disease in early RA.
Among genetic markers, the HLA-DRB1 gene has been clearly involved in the pathogenesis of RA. The association between HLA-Dw4 and RA was first reported in 1976. The development of HLA-DRB1 genotyping led to the demonstration that different HLA-DR4 alleles were not equally associated with RA and that several non-DR4 HLA-DRB1 alleles were also associated with the disease. The shared epitope (SE) hypothesis, first proposed in 1987, represents an approach to understand the molecular genetics of susceptibility to RA. The SE hypothesis assumes that HLA-DRB1 alleles encoding a highly conserved amino acid sequence, known as the SE - which is characterized by the RAA pattern at positions 72-74 of the third hypervariable region of different HLA-DRĂŸ1 chains - are associated with susceptibility to RA. HLA-DRB1 alleles encoding the SE were then associated with structural severity of RA and have been more recently associated with production of ACPAs.
As was done in previous attempts, du Montcel and colleagues recently introduced a new classification of HLA-DRB1 alleles that reconsiders the SE hypothesis. In terms of susceptibility to RA, this new classification suggests that the risk of developing RA depends on whether the RAA sequence occupies positions 72-74 but the risk is modulated by the amino acids at position 71 (K confers the higher risk, R an intermediate risk, A and E a lower risk) and at position 70 (Q or R confers a higher risk than D) complexifying the classical SE epitope classification based on the presence of RAA in positions 72-74. In terms of structural severity of RA, this new classification allowed the differentiation of predisposing or protective alleles (two effects) - respectively characterized by the DRRAA or by the DERAA amino acid pattern at positions 70-74 - which was not possible using the classical SE epitope classification based on the only presence of RAA in positions 72-74.
In the present study, we investigated the relevance of this new classification of HLA-DRB1 alleles in terms of RF and ACPA production in a cohort of French Caucasian patients with early RA. Interestingly, the new classification of HLA-DRB1 alleles allows the differentiation between predisposing and protective alleles for autoantibody production.
The HLA-DRB1 gene was reported to be associated with anticitrullinated protein/peptide autoantibody (ACPA) production in rheumatoid arthritis (RA) patients. A new classification of HLA-DRB1 alleles, reshaping the shared epitope (SE) hypothesis, was recently found relevant in terms of RA susceptibility and structural severity.
We investigated the relevance of this new classification of HLA-DRB1 SE alleles in terms of rheumatoid factor (RF) and ACPA production in a sample of French RA patients.
We studied 160 early RA patients included in a prospective longitudinal cohort of French Caucasian patients with recent-onset arthritis. RF, anticyclic citrullinated peptide 2 (anti-CCP2) and antideiminated human fibrinogen autoantibodies (AhFibA) were assessed in all patients at inclusion. The HLA-DRB1 gene was typed by PCR-sequence specific oligonucleotides probes (PCR-SSOP), and SE+ alleles were classified into four groups (S1, S2, S3P, S3D) according to the new classification.
The new classification of HLA-DRB1 SE+ alleles distinguishes predisposing and protective alleles for RF, anti-CCP2 or AhFibA production. The presence of S2 or S3P alleles is associated with both RF, anti-CCP2 or AhFibA positivity, whereas the presence of S3D or S1 alleles appears to be protective for RF, anti-CCP2 or AhFibA positivity.
The new classification of HLA-DRB1 SE alleles is relevant in terms of autoantibody production in early RA patients by differentiating predisposing and protective alleles for RF or ACPA production.
Since early rheumatoid arthritis (RA) is often indistinguishable from other inflammatory joint diseases, recent-onset inflammatory synovitis poses a diagnostic and prognostic challenge to rheumatologists. The identification and validation of immunologic and genetic markers with strong diagnostic and prognostic value in early RA may help rheumatologists to meet this challenge.
Among immunologic markers, anticitrullinated protein/peptide antibodies (ACPAs) constitute relevant tools in the diagnosis and prognosis of early RA. Citrulline is a nonstandard amino acid, generated by post-translational modifications of several proteins by deimination of arginine residues by peptidylarginine deiminases. The citrulline moiety is the true determinant in proteins recognized by antiperinuclear factor, antikeratin antibodies, antifilaggrin antibodies, anticyclic citrullinated peptide (anti-CCP) antibodies and anti-deiminated human fibrinogen autoantibodies (AhFibA). ACPAs may be detected in healthy individuals, years before the onset of symptoms of RA, and may predict progression to persistent erosive arthritis or to RA in patients with undifferentiated arthritis. ACPAs are as sensitive as, and more specific than, rheumatoid factor (RF) for early RA diagnosis. Furthermore, ACPAs represent a prognostic factor for erosive disease in early RA.
Among genetic markers, the HLA-DRB1 gene has been clearly involved in the pathogenesis of RA. The association between HLA-Dw4 and RA was first reported in 1976. The development of HLA-DRB1 genotyping led to the demonstration that different HLA-DR4 alleles were not equally associated with RA and that several non-DR4 HLA-DRB1 alleles were also associated with the disease. The shared epitope (SE) hypothesis, first proposed in 1987, represents an approach to understand the molecular genetics of susceptibility to RA. The SE hypothesis assumes that HLA-DRB1 alleles encoding a highly conserved amino acid sequence, known as the SE - which is characterized by the RAA pattern at positions 72-74 of the third hypervariable region of different HLA-DRĂŸ1 chains - are associated with susceptibility to RA. HLA-DRB1 alleles encoding the SE were then associated with structural severity of RA and have been more recently associated with production of ACPAs.
As was done in previous attempts, du Montcel and colleagues recently introduced a new classification of HLA-DRB1 alleles that reconsiders the SE hypothesis. In terms of susceptibility to RA, this new classification suggests that the risk of developing RA depends on whether the RAA sequence occupies positions 72-74 but the risk is modulated by the amino acids at position 71 (K confers the higher risk, R an intermediate risk, A and E a lower risk) and at position 70 (Q or R confers a higher risk than D) complexifying the classical SE epitope classification based on the presence of RAA in positions 72-74. In terms of structural severity of RA, this new classification allowed the differentiation of predisposing or protective alleles (two effects) - respectively characterized by the DRRAA or by the DERAA amino acid pattern at positions 70-74 - which was not possible using the classical SE epitope classification based on the only presence of RAA in positions 72-74.
In the present study, we investigated the relevance of this new classification of HLA-DRB1 alleles in terms of RF and ACPA production in a cohort of French Caucasian patients with early RA. Interestingly, the new classification of HLA-DRB1 alleles allows the differentiation between predisposing and protective alleles for autoantibody production.
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