Identification of Cd101 as a Susceptibility Gene for Novosphingobium aromaticivorans-Induced Liver Autoimmunity

Abstract

Environmental and genetic factors define the susceptibility of an individual to autoimmune disease. Although common genetic pathways affect general immunological tolerance mechanisms in autoimmunity, the effects of such genes could vary under distinct immune challenges within different tissues. Here we demonstrate this by observing that autoimmune type 1 diabetes (T1D) protective haplotypes at the susceptibility region 10 (Idd10) introgressed from chromosome 3 of B6 and A/J mice onto the NOD background increase the severity of autoimmune primary biliary cirrhosis (PBC) induced by infection with Novosphingobium aromaticivorans (N. aro), an ubiquitous alphaproteobacterium, when compared to mice having the NOD and NOD.CAST Idd10 T1D susceptible haplotypes. Substantially increased liver pathology in mice having the B6 and A/J Idd10 haplotypes correlates with reduced expression of CD101 on dendritic cells (DCs), macrophages and granulocytes following infection, delayed clearance of N. aro and the promotion of overzealous, IFN-γ- and IL-17-dominated T cell responses essential for the adoptive transfer of liver lesions. CD101-knockout mice generated on the B6 background also exhibit substantially more severe N.aro-induced liver disease correlating with increased IFN-γ and IL-17 responses compared to wild type mice. These data strongly support the hypothesis that allelic variation of the Cd101 gene, located in the Idd10 region, alters the severity of liver autoimmunity induced by N. aro.

Evidence thatCd101Is an Autoimmune Diabetes Gene in Nonobese Diabetic Mice

“…Although the biological functions of CD101 remain unclear and there are no known ligands for CD101, this transmembrane molecule having seven Ig-like domains is expressed by multiple subsets of immune cells including FoxP3 + regulatory T cells, effector CD4 and CD8 T cells, granulocytes, dendritic cells, and monocytes in humans and mice (2–6). There are multiple lines of evidence using human cells suggesting that CD101 modulates T cell activation either directly or indirectly via dendritic cells that express CD101 (5–8).…”

Impact of Microbes on the Pathogenesis of Primary Biliary Cirrhosis (PBC) and Primary Sclerosing Cholangitis (PSC)

“…These include the ATP (adenosine triphosphate)-dependent Clp protease of Escherichia coli , the β-galactosidase of Lactobacillus delbrueckii (a constituent of the vaginal flora), and two yet-undefined lipoylated proteins of Novosphingobium aromaticivorans , a ubiquitous α-proteobacterium also found at mucosal surfaces and in the feces of humans [66,67,68,69,70,71,74,75,76]. Furthermore, the infection of genetically susceptible mouse strains with Novosphingobium aromaticivorans induced anti-PDC E2 responses and liver lesions resembling PBC in humans [77,78,79]. Novosphingobium spp.…”

Impact of Microbes on Autoimmune Diseases

“…The pathogenicity of T cells that promote or inhibit disease is strongly influenced by the cytokines they secrete and requires antigen presentation by activated antigen-presenting cells (APC) and costimulatory interactions. From the three polarized disease-promoting CD4-positive T cell subsets, T helper (Th)1 and Th17 cells have been implicated in the pathogenesis of PBC (Lan et al 2009; Mohammed et al 2011). Thus, the interaction of the APC with the respective T cell needs to be tightly controlled.…”

“…Although our animal studies provided evidence that Sphingomonas/ Novosphingobium spp. have the potential to initiate liver damage and to promote severe biliary inflammation dependent on the genetic background of the mice, none of the infected mouse strains progressed to liver fibrosis or cirrhosis (Mattner et al 2008; Mohammed et al 2011). Despite the technical difficulties to induce liver fibrosis/ cirrhosis in mouse models, a second signal might be required to initiate the progression from inflammation to fibrosis/cirrhosis.…”