Liver Autoimmunity Triggered by Microbial Activation of Natural Killer T Cells

Abstract

SummaryHumans with primary biliary cirrhosis (PBC), a disease characterized by the destruction of small bile ducts, exhibit signature autoantibodies against mitochondrial Pyruvate Dehydrogenase Complex E2 (PDC-E2) that crossreact onto the homologous enzyme of Novosphingobium aromaticivorans, an ubiquitous alphaproteobacterium. Here, we show that infection of mice with N. aromaticivorans induced signature antibodies against microbial PDC-E2 and its mitochondrial counterpart but also triggered chronic T cell-mediated autoimmunity against small bile ducts. Disease induction required NKT cells, which specifically respond to N. aromaticivorans cell wall α-glycuronosylceramides presented by CD1d molecules. Combined with the natural liver tropism of NKT cells, the accumulation of N. aromaticivorans in the liver likely explains the liver specificity of destructive responses. Once established, liver disease could be adoptively transferred by T cells independently of NKT cells and microbes, illustrating the importance of early microbial activation of NKT cells in the initiation of autonomous, organ-specific autoimmunity.

iNKT‐cell help to B cells: A cooperative job between innate and adaptive immune responses

“…These effects require the presence of iNKT cells, CD1d expression by B cells, and the provision of CD40-CD40L signaling, CD80-CD86 costimulation, and IFN-γ, but not of . Formulations involving proteins such as hen egg lysozyme in complex with αGalCer, or haptenated-αGalCer molecules, cannot generate MHC-II-restricted epitopes, and this observation confirms the fact that cognate iNKT-cell-mediated B-cell help can elicit Ab production and class switch independently of Th-cell recruitment [50,51].Cognate iNKT-cell-mediated B-cell help has also been described to occur spontaneously in a model of infection with the hepatotropic sphingomonas Novosphingobium aromaticivorans, which contains glycosphingolipid analogs (α-glycurunilceramides) that activate iNKT cells and the B-cell Ag enzyme pyruvate dehydrogenases complex E2 [52]. Infection of mice with this bacterium elicits rapid iNKT-cell-dependent production of high-affinity and classswitched Abs against bacterial pyruvate dehydrogenases complex E2, which also cross-react with the homologous mammalian mitochondrial enzyme that is expressed in small bile ducts, thereby initiating organ damage that resembles human primary biliary cirrhosis [52].…”

“…These studies used complex or particulated immunogens composed of proteins or hapten Ags that are either physically associated to αGalCer [50,51] or entrapped in bacterial fragments together with glycolipid analogs [52] (Fig. 1D and F).…”

Experimental evidence on the immunopathogenesis of primary biliary cirrhosis

“…42 Most recently, Mattner et al supported the pathogenic role of N. aromaticivorans being able to induce serum autoantibodies and PBC-like liver lesions in mice following immunization. 43 A novel human beta-retrovirus has been recently reported in perihepatic lymph nodes and other samples from patients with PBC, thus Experimental evidence on immunopathogenesis of PBC C Selmi et al 3…”

“…This is particularly intriguing considering the previously mentioned study by Mattner et al, who demonstrated that in a murine model of PBC, N. aromaticivorans was capable of inducing autoreactive AMAs and chronic T-cellmediated autoimmunity against small bile ducts in an NKT-dependent fashion. 43 Animal models Similar to all complex diseases, such as autoimmune disease, the development of an animal model is of obvious importance in elucidating the mechanism(s) responsible for the initiation and progression of disease.…”

Lights on MAIT cells, a new immune player in liver diseases

“…Previous studies by Mattner and colleagues have highlighted the role of bacterial infection in the pathophysiology of PBC [21]. Infection with Novosphinbium aromaticivorans promotes this autoimmune disease through invariant natural killer T cells …”