Human leukocyte antigen in primary biliary cirrhosis: An old story now reviving

Abstract

Primary biliary cirrhosis (PBC) is an autoimmune biliary disease characterized by injury of small and medium size bile ducts eventually leading to liver cirrhosis and death. While the causes remain enigmatic, recent evidence has strengthened the importance of genetic factors in determining the susceptibility to the disease. Besides the strong heritability suggested by familial occurrence and monozygotic twins concordance, for decades there has not been a clear association with specific genes, with the only exception of a low risk conferred by a class II human leukocyte antigen (HLA) variant, the DRB1*08 allele, at least in some populations. Only recently the story began to change when a strong protective associations between PBC and the HLA DRB1*11 and DRB1*13 alleles were found in Italian and UK series. But HLA genes fully returned to attract interest thanks to recent genome-wide association studies (GWAS) which clearly demonstrated that the major component of the genetic architecture of PBC are within the HLA region. As expected in a genetically complex disease, GWAS also identified several novel non-HLA variants, but it is to note that all of them are in immuno-related genes. In this review, the paradigmatic tale of what, and how, we learned about HLA genes in PBC will be retraced with particular focus on how GWAS are enabling us to rewrite the story of PBC pathogenesis. These recent discoveries will not only driving functional studies but will also held the promise of developing novel disease-specific treatments.

Geoepidemiology, Genetic and Environmental Risk Factors for PBC

“…HLA allele determines the structure of the antigenbinding site and the specific characteristics of each expressed HLA molecule (HLA class I, A, B, Cw; HLA class II, DR, DQ and DP), thereby acting as a determinant of both susceptibility and resistance of autoimmunity [26][27][28][29] . Similar to many other autoimmune diseases, HLA has been extensively studied in PBC.…”

Relationship between HLA-DRB1 Allele Polymorphisms and Familial Aggregations of Hepatocellular Carcinoma

“…Given the high polymorphism of the hla complex, finding the same phenotype in multiple individuals is very rare, and thus hla has become an important target in the investigation of many diseases, including autoimmune, infectious, and malignant diseases, among others [25][26][27][28] . High expression of hla-dr is a marker of T-cell activation.…”

HLA-B27 and Ankylosing Spondylitis

“…In addition to those different clinical characteristics, such as bone proliferation in enthesis site and sacroiliitis, in AS patients from those of patients with rheumatoid arthritis, AS is also known for its high association with HLA-B27. It has been known for more than 30 years since this association was discovered at 1973 (Schlosstein, 1973;Brewerton et al, 1973), although afterward, researchers found several HLA antigens were associated with other diseases (Invernizzi, 2011;McElroy, 2011;Piga, 2011), the strongest of any HLA antigens associated with human disease is HLA-B27 molecule. Hence, the roles of HLA-B27 in the pathogenesis and clinical manifestation of ankylosing spondylitis were among most frequent discussed topics in the past three decades.…”