The immunogenetics of primary biliary cirrhosis: A comprehensive review

Abstract

Primary biliary cirrhosis (PBC), a classic autoimmune liver disease, is characterised by a progressive T cell predominant lymphocytic cholangitis, and a serologic pattern of reactivity in the form of specific anti-mitochondrial antibodies (AMA). CD4+ T cells are particularly implicated by PBC's cytokine signature, the presence of CD4+ T cells specific to mitochondrial auto-antigens, the expression of MHC II on injured biliary epithelial cells, and PBC's coincidence with other similar T cell mediated autoimmune conditions. CD4+ T cells are also central to current animal models of PBC, and their transfer typically also transfers disease. The importance of genetic risk to developing PBC is evidenced by a much higher concordance rate in monozygotic than dizygotic twins, increased AMA rates in asymptomatic relatives, and disproportionate rates of disease in siblings of PBC patients, PBC family members and certain genetically defined populations. Recently, high-throughput genetic studies have greatly expanded our understanding of the gene variants underpinning risk for PBC development, so linking genetics and immunology. Here we summarize genetic association data that has emerged from large scale genome-wide association studies and discuss the evidence for the potential functional significance of the individual genes and pathways identified; we particularly highlight associations in the IL-12-STAT4-Th1 pathway. HLA associations and epigenetic effects are specifically considered and individual variants are linked to clinical phenotypes where data exist. We also consider why there is a gap between calculated genetic risk and clinical data: so-called missing heritability, and how immunogenetic observations are being translated to novel therapies. Ultimately whilst genetic risk factors will only account for a proportion of disease risk, ongoing efforts to refine associations and understand biologic links to disease pathways are hoped to drive more rational therapy for patients.

Keywords: Animal models; CD4+ T cell; Genome-wide association study; HLA; Immunochip; Regulatory T cell.

Fig. 1

CD4+ T cells dominate the inflammatory infiltrate of PBC. Explanted PBC liver specimen stained with rabbit anti-CD4 (clone ab133616, Abcam, UK) and revealed with alkaline phosphatase red kit (Vector laboratories, UK); hematoxylin counterstain; ×20 magnification.

Fig. 2

PBC shares risk loci with multiple other autoimmune diseases. Circos plot of gene variants associated with PBC and other selected autoimmune conditions in high-throughput genetics studies and their meta-analyses. Note that significant pleiotropy exists with some loci implicated in multiple conditions and variable HLA associations a universal feature. PBC = primary biliary cirrhosis; AA = alopecia areata; AIH = autoimmune hepatitis; AS = ankylosing spondylitis; ATD = autoimmune thyroid disease; JIA = juvenile idiopathic arthritis; MG = myasthenia gravis; MS = multiple sclerosis; Narc = narcolepsy; PSC = primary sclerosing cholangitis; Pso = psoriasis; RA = rheumatoid arthritis; Scl = scleroderma; Sjö = Sjögren's syndrome; SLE = systemic lupus erythematosus; T1DM = type 1 diabetes mellitus; UC = ulcerative colitis; Vit = vitiligo. Only validated associations at p < 5 × 10⁻⁸ are included; supporting citations available at request.

Fig. 3

Schematic representation of CD4+ T cell activation by antigen presenting cells and the IL-12/STAT4 pathway. Antigen activates APC through TLR, which in turn produce IL-12 after phosphorylation of IRF5. Antigen is presented to CD4+ T cells by HLA II with co-stimulation via CD80 and 86 to CD28. There is competitive inhibition of this co-stimulation by CTLA4. IL-12 activates a cascade of signaling factors including NFKB and STAT4 to promote the production of Th1-type cytokines including TNFα and IFNγ; the transcription factor IRF8 is involved. IL7R supports lymphocyte development. There is positive feedback from Th1 cytokines to APCs. Red text denotes confirmed risk associations with PBC; blue text putative associations. Arrows denote positive effects; barred lines denote negative effects. APC = antigen-presenting cell; CD = cluster of differentiation; CTLA4 = Cytotoxic T lymphocyte antigen 4; HLA II = human leucocyte antigen class II; IFN-γ = interferon-γ; IFNγR = interferon-γ receptor; IL-12 = interleukin-12; IL-12Rβ1/2 and IL-12 receptor β subunits 1 and 2; IL7R = interleukin-7 receptor; IRF5 and IRF8 = interferon response factors 5 and 8; JAK2 = Janus kinase 2; Lck = lymphocyte-specific protein tyrosine kinase; NFKB = nuclear factor kappa-light-chain-enchancer of activated B cells; PKC = protein kinase C; SOCS1 = suppressor of cytokine signaling 1; STAT4 = signal transducer and activator of transcription 4; TCR = T-cell receptor; TLR = Toll-like receptor; TNFAIP3 = tumor necrosis factor alpha-induced protein 3; TNFRSF1a = Tumor necrosis factor receptor superfamily 1a; TNFα = tumour necrosis factor alpha; TYK2 = Tyrosine kinase 2. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

Schematic representation of T-cell:B-cell interaction demonstrating genes with variants associated with PBC Antigen binds B-cell receptor triggering multiple events including the suppression of apoptosis by BCL-xL in a mechanism involving the phosphorylation of IKZF3. B-cell receptor signaling is also partly mediated by the transcription factor SPIB and PLCL2; the former is involved with differentiation and the latter controls subsequent proliferation. B cells present antigen to T cells on MHC class II. Multiple co-stimulatory molecules promote both B cell activation and continued T cell activation: ICOS-ICOSL, CD28-CD80/CD86, CD40L-CD40. IL7R is involved in the development of both T and B cells. A number of other factors key to B cell development and survival are associated with PBC risk (IRF5, IRF8, NFKB and POU2AF1). CXCR5 guides both B and T cell positioning along CXCL13 chemokine gradients and facilitates migration to germinal centres. Red text denotes confirmed risk associations with PBC; blue text putative associations. Arrows denote positive effects; barred lines denote negative effects. BCR = B-cell receptor; IL-4 = interleukin-4; IL7R = Interleukin-7 receptor; ICOS(L) = inducible co-stimulator (ligand); PLCL2 = phospholipase C-like 2 protein; TCR = T-cell receptor; IRF5 & 8 = interferon regulatory factors 5 & 8; SPIB = Spi-B; NFKB = nuclear factor kappa-light-chain-enhancer of activated B cells; POU2AF1 = POU class 2 associating factor 1; IKZF3 = Ikaros family zinc finger protein 3; CXCR5 = chemokine (C-X-C motif) receptor 5.