In this regard, laudable examples are the recent study by Lazaridis and coworkers which showed that a TNF gene variant amplifies a CTLA-4 genotype risk for PBC by examining the possible interaction between these two risk variants.37 The same authors also suggested an interaction between CTLA-4 and

programmed AZD1152-HQPA price cell-death 1 gene variants.35 In addition, because the genetic background may greatly vary among different ethnic groups, our group evaluated the association of other candidate genes in PBC by comparing multiple cohorts from different ethnic populations.38, 39 Finally, a recent French study reported that the progression rate of liver disease under ursodeoxycholic acid therapy was significantly linked to variants of TNF and AE2 genes.40 Clinical awareness of PBC has greatly increased over the past 50 years, laboratory diagnosis is far more precise, and therapy is more effective, yet the main reasons for the

female preponderance of PBC have remained unclear.41 We recently proposed that the presence of defects in sex chromosomes might explain both the disproportionate female affliction with PBC and the genetic predisposition to the disease. Indeed, we first reported an age-dependent enhanced monosomy X in the peripheral blood cells of women with PBC,5 later reported that one X chromosome is preferentially lost,6 and finally reported that epigenetic factors influencing PBC onset are more complex than selleck inhibitor Cyclic nucleotide phosphodiesterase methylation differences at X-linked promoters.26 The HLA is one of the most widely studied regions in the human genome and certainly contains valuable genetic information of many complex genetic diseases that have yet to be fully dissected.42-47 HLA genes are located on the short arm of chromosome 6 (6p21.31), with an extension of approximately 3.6 mega–base pairs, and consists of three subregions: the two telomeric class

I, class III, and the centromeric class II regions (Fig. 1). The true role of the various HLA alleles in inducing autoimmune reactions remains largely unclear, and the underlying mechanisms might be numerous.48 Among them, it has been suggested that certain HLA alleles are less efficient at presenting self peptides to developing T cells in the thymus, with failure of negative selection. In particular, it is possible that certain HLA molecules present peptide at an “intermediate level”, thus being recognized by T cells without inducing tolerance. Indeed, most self peptides are presented at levels below that which is needed to engage effector T cells, whereas others induce clonal deletion and anergy as presented at high levels. Alternatively, it is possible that specific HLA alleles enhance autoimmune activation by enhancing immunogenicity and influencing the expressed repertoire of T cells.