The MHC confers the strongest genetic effect in SLE known to date; associations are well established for class I and class II MHC loci, particularly for HLA–DRB1*0301– and HLA–DRB1*1501–associated haplotypes. HLA loci may also influence SLE susceptibility through additional inherited or noninherited mechanisms. These hypotheses were tested using a large, well-characterized data set of SLE and control families.
The current study is the largest study to date to examine maternal–offspring HLA compatibility in SLE. Several biologically based hypotheses have been proposed, in which increased compatibility could result in a small number of nonhost cells that could 1) cause dysregulation among host cells, 2) lead to the presentation of nonhost peptides by host cells to other host cells, 3) inactivate T lymphocytes upon interaction, or 4) undergo differentiation and become targets of a later immune response (9
). Evidence for increased maternal–offspring HLA class II compatibility has been previously reported for both SLE and systemic sclerosis, suggesting that HLA class II loci may be involved through an undefined pathway dependent on maternal–offspring compatibility (10
). A recent study demonstrated that maternal–offspring HLA compatibility does not influence the risk of type 1 diabetes mellitus (12
Stevens et al reported evidence for increased bidirectional DRB1 compatibility for DRB1 allele groups in 30 pairs of mothers and their sons with SLE when compared with 76 independent, healthy mother–son pairs (OR 5.0, 95% CI 1.6–15.7, P
= 0.006) (10
). When the analyses were restricted to sons carrying DRB1*03 or DRB1*15/16, the results were stronger (OR 7.2, 95% CI 1.6–32.8, P
= 0.01) and remained significant when non–European Americans were excluded. In contrast, our results indicate that maternal–offspring DRB1 compatibility does not influence SLE susceptibility. We observed some weak evidence for decreased bidirectional compatibility in male and nulligravid female maternal–offspring pairs compared with paternal–offspring pairs; however, this result did not reach statistical significance (OR 0.56, 95% CI 0.29–1.04, P
= 0.06). Larger studies will be required to exclude the possibility of very modest DRB1 compatibility effects on the risk of SLE.
Several factors may have contributed to the disparity between the results of the current study and those reported by Stevens et al. The current study was larger and used both independent and family-based controls for all histocompatibility analyses. In addition, male and nulligravid (never pregnant at, or prior to, diagnosis) female patients were analyzed separately to account for the potential contribution of fetal microchimerism. In contrast, Stevens et al excluded a role for fetal microchimerism by including only mother–son pairs and used an independent control group for comparison. Whereas our study was limited to individuals of European ancestry, the previous study also included African American and Asian American individuals. Finally, SLE cases in our study were derived from trio families, whereas the study by Stevens et al included cases from families with multiple affected individuals. It is possible that 1 or more of these factors, or an undetermined difference in clinical phenotype represented by both groups, may help explain the observed differences. For example, disease differences attributed to familial SLE or subgroups defined by sex, race/ethnicity, or other clinical features such as the presence of particular autoantibodies and/or lupus nephritis may be relevant to studies of histocompatibility and SLE. Finally, to account for the potential contribution of sibling microchimerism, a future study could focus on analyzing male and nulligravid female patients conceived to mothers who had not previously been pregnant.
Parent-of-origin effects, potentially operating through imprinting, have been reported in multiple sclerosis with respect to the inheritance of HLA class II alleles (13
). The results of a similar HLA study in type 1 diabetes mellitus were negative (12
). Likewise, results from our study do not support a role for DRB1-associated parent-of-origin effects in SLE, even for the known risk alleles DRB1*1501, *0301, and *0801. Additional classic HLA loci were not the focus of the current study and should be included in future studies. Although strong linkage disequilibrium is present between DRB1, DQB1, and DQA1 loci, the association between particular alleles on haplotypes is not complete, and therefore, more may be learned by including additional HLA class II loci, as well as all HLA class I loci, in larger SLE studies.
There is evidence that HLA alleles may act as environmental risk factors. Exposure to HLA NIMAs may therefore shape the immune repertoire of the offspring and either predispose to or protect against future immune reactions. In addition to maternal–offspring cell trafficking and oral exposure through breast milk, NIMA effects may occur through maternal microchimerism. Both risk and protective NIMA effects have been reported for RA (8
). NIMA effects do not appear to play a strong role in type 1 diabetes mellitus, although some evidence for an association has been reported (12
). We tested the hypothesis that maternal histocompatibility antigens, specifically those for HLA–DRB1, may contribute to the risk of SLE. Our study did not reveal any evidence for NIMA effects in SLE at the DRB1 locus, even for established risk alleles. The current study had 80% power to detect a modest association (OR ≥1.5) for parent-of-origin or NIMA effects conferred by the SLE risk alleles DRB1*0301 and DRB1*1501. A role for other class I or class II NIMAs in the risk of SLE cannot be excluded.
In conclusion, the results of this large study of SLE families and healthy maternal–offspring pairs do not support a major role for DRB1 in disease susceptibility mediated through maternal–offspring compatibility, parent-of-origin effects, or NIMA effects. Future studies should examine additional classic HLA loci.