New insights on the role of human leukocyte antigen complex in primary biliary cholangitis

Abstract

Primary Biliary Cholangitis (PBC) is a rare autoimmune cholangiopathy. Genetic studies have shown that the strongest statistical association with PBC has been mapped in the human leukocyte antigen (HLA) locus, a highly polymorphic area that mostly contribute to the genetic variance of the disease. Furthermore, PBC presents high variability throughout different population groups, which may explain the different geoepidemiology of the disease. A major role in defining HLA genetic contribution has been given by genome-wide association studies (GWAS) studies; more recently, new technologies have been developed to allow a deeper understanding. The study of the altered peptides transcribed by genetic alterations also allowed the development of novel therapeutic strategies in the context of immunotolerance. This review summarizes what is known about the immunogenetics of PBC with a focus on the HLA locus, the different distribution of HLA alleles worldwide, and how HLA modifications are associated with the pathogenesis of PBC. Novel therapeutic strategies are also outlined.

Keywords: HLA haplotypes; genetics; human leukocyte antigens complex; immunotolerance; primary biliary cholangitis.

Figure 1

The complex milieux of HLA alleles and its association with PBC (increased vs protective risk).

Figure 2

Imperfect HLA interactions and autoimmunity: (A) Molecular mimicry: Foreign antigens (i.e. either from infecious or chemical agents) with similarities to self-antigens are primed by T and B cells, that autoreactive and trigger autoimmunity. (B) Immunological synapse and autoimmunity: several mechanisms of the complex interplay between APC, B- and T- cells might lead to the activation of autoimmune B and T cells. Among them, mechanical binding alterations (atypical binding orientation, altered docking) and TCR stabilization of weak peptide. Weak HLA binding of self-peptides might contribute to autoimmunity by allowing the escape of autoreactive T-cellsfrom the thymus. (C) Post translational modifications (PTM): they are spontaneous or enzymatically induced modifications of one or more amino acids occuring after protein biosynthesis. After PTM, these proteins become modified self-antigens, and they do not “tolerize” developing thymocytes. Consequently, modified self-antigens can be taken and processed by APC, that will present them to autoreacitve T and B cells. (D): Generation of hybrid peptides: proteasomal-mediated degradation and splicing of intracellular self-peptides can promote the generation of non-self-hybrid peptides. This mechanism occurs with high protein concentrations in a confined environment, that favours protease-mediated peptide fusion.

Figure 3

Tolerogenic vaccine platforms: The goal of NPs-, peptides-, and DNA/RNA-based platformes is to stimulate tolerogenic DCs to suppress CD4⁺ T cell-mediated autoimmunity. NPS, nanoparticles; DC, dendritic cells.