Vitamin D receptor (VDR) gene SNPs influence VDR expression and modulate protection from multiple sclerosis in HLA-DRB1*15-positive individuals.

Multiple sclerosis (MS) is an autoimmune disease with a multifactorial etiology. The HLA-DRB1*15 allele, is the main genetic risk factor for MS in Caucasians; recent findings showed that the transcription of this molecule is regulated by the vitamin D/vitamin D receptor (VDR) complex. We analyzed SNPs within the VDR gene in association with the HLA-DRB1 locus in 641 MS patients diagnosed according to McDonald criteria and 558 age- and sex-matched healthy controls, to verify possible correlations between the vitamin D/VDR complex, HLA-DRB1, and susceptibility to MS. Results confirmed that HLA-DRB1*15 is a strong predisposing allele (p<1×10(-7); OR: 3.04; 95% CI: 2.02-4.60) for MS. Cosegregation analyses of VDR SNPs with HLA-DRB1*15 indicated a reduction of risk for MS given by the presence of the -DRB1*15-rs731236 T VDR haplotype (p=9.5×10(-5); OR: 2.52; 95% CI: 1.56-4.06) and, conversely, an augmented risk for disease associated with the -DRB1*15-rs731236 C VDR haplotype. Analyses performed on HLA-DRB1*15-positive MS patients and HC alone confirmed the protective role of rs731236 TT VDR genotype (p(y)=0.004; OR: 0.53; 95% CI: 0.33-0.83); notably, FACS, PCR, and confocal microscopy analyses showed that rs731236 TT genotype is associated with an augmented VDR expression in MBP-stimulated PBMC from patients. In conclusion, rs731236 TT VDR genotype modulates VDR expression and confers protection against MS in HLA-DRB1*15-positive individuals. Results herein offer a model justifying the interaction between the major genetic (HLA-DRB*15) and environmental (vitamin D) factors associated with MS onset.

Phenotype frequencies of autosomal minor histocompatibility antigens display significant differences among populations.

Minor histocompatibility (H) antigens are allogeneic target molecules having significant roles in alloimmune responses after human leukocyte antigen-matched solid organ and stem cell transplantation (SCT). Minor H antigens are instrumental in the processes of transplant rejection, graft-versus-host disease, and in the curative graft-versus-tumor effect of SCT. The latter characteristic enabled the current application of selected minor H antigens in clinical immunotherapeutic SCT protocols. No information exists on the global phenotypic distribution of the currently identified minor H antigens. Therefore, an estimation of their overall impact in human leukocyte antigen-matched solid organ and SCT in the major ethnic populations is still lacking. For the first time, a worldwide phenotype frequency analysis of ten autosomal minor H antigens was executed by 31 laboratories and comprised 2,685 randomly selected individuals from six major ethnic populations. Significant differences in minor H antigen frequencies were observed between the ethnic populations, some of which appeared to be geographically correlated.

Cytokines and chronic rejection: a study in kidney transplant long-term survivors.

BACKGROUND: In part, the long-term survival of kidney transplants depends on the efforts to perform grafts with good human leukocyte antigen (HLA) compatibility, but there are other mechanisms that must induce some sort of tolerance and impair the anti-graft immune reaction. Because cytokines are one of the main components of immune response, we evaluated single nucleotide polymorphisms (SNPs) of several cytokine genes that may influence the production of a given cytokine and therefore the features of immune reactions. METHODS: A total of 416 first cadaveric kidney transplants were monitored for HLA matching. After 10 years, the graft was still functional in 171 of 416 patients; 102 of 171 patients were also typed for cytokine polymorphisms. RESULTS: The mismatch distributions in patients who underwent transplantation were not statistically different from the entire group of patients who underwent transplantation during the same time period. Moreover, it seems that almost all of the HLA class I incompatible long-term survivors are homozygous for GG at the -1082 interleukin (IL)-10 or CC at the -33IL4. CONCLUSIONS: We observed that a match for class I and class II HLA antigens apparently does not favor the long-term survival of transplanted kidneys. In fact, matched grafts are lost before 10 years in the same proportion as the mismatched grafts. We also demonstrated (1) that patients who are homozygous for GG at the SNP -1082IL10 (high IL-10 producers) and HLA class I mismatched (but matched for class II) are protected from chronic rejection, and (2) that patients who are homozygous for CC at the SNP -33IL4 (low IL-4 producers) and HLA class I mismatched (regardless of matching for class II) are protected from chronic rejection.