Protective effect of noninherited maternal HLA-DR antigens on rheumatoid arthritis development

Abstract

Rheumatoid arthritis (RA) is a complex genetic disorder in which the HLA-region contributes most to the genetic risk. HLA-DRB1-molecules containing the amino acid sequence DERAA (i.e., HLA-DRB1*0103, *0402, *1102, *1103, *1301, *1302, and *1304) are associated with protection from RA. It has been proposed that not only inherited but also noninherited HLA-antigens from the mother (NIMA) can influence RA-susceptibility. Up to now, no protective NIMAs were described. Here, we studied whether DERAA-containing HLA-DRB1-alleles as NIMA are associated with a protective effect. One hundred seventy-nine families were studied, 88 from the Netherlands and 91 from the United Kingdom. The frequency of DERAA-containing HLA-DRB1-alleles of the Dutch mothers (16.1%), but not of the fathers (26.2%), was lower compared with the general Dutch population (29.3%; P ‫؍‬ 0.02). This was replicated in the English set of patients and controls (P ‫؍‬ 0.01). Further, of all families, 45 contained at least one DERAAnegative child with RA and at least one DERAA-positive parent. The odds for the DERAA-negative RA patients of having a DERAApositive mother was significantly lower compared with having a DERAA-positive father (OR 0.25; P ‫؍‬ 0.003). These data show a protective NIMA-effect in a human autoimmune disease and indicate that a DERAA-positive mother can transfer protection against RA to her DERAA-negative child.autoimmunity ͉ DERAA ͉ NIMA

Tic‐tac‐toe does not provide lessons for appreciating the HLA–rheumatoid arthritis relationship: Comment on the editorial by Bridges et al

“…As such, the comparison of subgroups allowed differentiation of the effects of protection and non-predisposition. These observations were confirmed in an analysis of the influence of DERAA-encoding HLA alleles on RA susceptibility in a family-based study (4).…”

Indirect evidence that maternal microchimerism in cord blood mediates a graft-versus-leukemia effect in cord blood transplantation

“…We suggest future investigations take this question into account. Similarly, both anti-IPA and anti-NIMA immunity might play a role in known associations between pregnancy and autoimmune disease (32,33).…”

Crossreactivity to vinculin and microbes provides a molecular basis for HLA-based protection against rheumatoid arthritis

“…These protective HLA alleles, mainly HLA-DRB1*13, carry the five amino-acid sequence DERAA at positions 70-74 of the beta chain and protect also in the presence of predisposing alleles 16,17 . Intriguingly, protection by these alleles is transferred from mother to child, supporting an active protective role of these alleles, possibly via microchimeric cells influencing thymic selection of CD4 þ T cells, and indicating a dominant role of HLA-DRB1*13 in disease protection 18 .…”