Objective Recognition of a new type of rheumatoid arthritis (RA)–specific autoantibody, the anti–carbamylated protein antibodies (anti‐CarP), has provided an opportunity to improve the management and understanding of RA. The current study was undertaken to assess the relationship between anti‐CarP antibodies and HLA–DRB1 alleles in RA. Methods Serum samples were obtained from 3 different collections, comprising a total of 1,126 RA patients. Serum reactivity against in vitro carbamylated fetal calf serum proteins was determined by enzyme‐linked immunosorbent assay. HLA–DRB1 alleles were determined using either hybridization techniques or imputation from HLA‐dense genotypes. Results of these analyses were combined in a meta‐analysis with data from 3 previously reported cohorts. The carrier frequencies of the common HLA–DRB1 alleles were compared between the antibody‐positive RA subgroups and the double‐negative subgroup of RA patients stratified by anti–citrullinated protein antibody (ACPA)/anti‐CarP antibody status, and also between the 4 RA patient strata and healthy controls. Results Meta‐analysis was conducted with 3,709 RA patients and 2,305 healthy control subjects. Results revealed a significant increase in frequency of HLA–DRB1*03 carriers in the ACPA−/anti‐CarP+ subgroup as compared to ACPA−/anti‐CarP− RA patients and healthy controls; this was consistently found across the 6 sample collections. This association of HLA–DRB1*03 with ACPA−/anti‐CarP+ RA was independent of the presence of the shared allele (SE) and any other confounders analyzed. No other allele was specifically associated with the ACPA−/anti‐CarP+ RA patient subgroup. In contrast, frequency of the SE was significantly increased in the ACPA+/anti‐CarP− and ACPA+/anti‐CarP+ RA patient subgroups, without a significant distinction between them. Furthermore, some alleles (including HLA–DRB1*03) were associated with protection from ACPA+ RA. Conclusion These findings indicate a specific association of HLA–DRB1*03 with ACPA−/anti‐CarP+ RA, suggesting that preferential presentation of carbamylated peptides could be a new mechanism underlying the contribution of HLA alleles to RA susceptibility.

Behçet's disease (BD) is an immune-mediated vasculitis related to imbalances between the innate and adaptive immune response. Infectious agents or environmental factors may trigger the disease in genetically predisposed individuals. HLA-B51 is the genetic factor stronger associated with the disease, although the bases of this association remain elusive. NK cells have also been implicated in the etiopathogenesis of BD. A family of NK receptors, Killer-cell Immunoglobulin-like Receptor (KIR), with a very complex organization, is very important in the education and control of the NK cells by the union to their ligands, most of them, HLA class I molecules. This study aimed to investigate the contribution of certain KIR functional polymorphisms to the susceptibility to BD. A total of 466 BD patients and 444 healthy individuals were genotyped in HLA class I (A, B, and C). The set of KIR genes and the functional variants of KIR3DL1/DS1 and KIR2DS4 were also determined. Frequency of KIR3DL1*004 was lower in patients than in controls (0.15 vs. 0.20, P = 0.005, Pc = 0.015; OR = 0.70; 95% CI 0.54–0.90) in both B51 positive and negative individuals. KIR3DL1*004, which encodes a misfolded protein, is included in a common telomeric haplotype with only one functional KIR gene, KIR3DL2. Both, KIR3DL1 and KIR3DL2 sense pathogen-associated molecular patterns but they have different capacities to eliminate them. The education of the NK cells depending on the HLA, the balance of KIR3DL1/KIR3DL2 licensed NK cells and the different capacities of these receptors to eliminate pathogens could be involved in the etiopathogenesis of BD.