Autoimmune disease triggered by infection with alphaproteobacteria

Abstract

Despite having long been postulated, compelling evidence for the theory that microbial triggers drive autoimmunity has only recently been reported. A specific association between Novosphingobium aromaticivorans, an ubiquitous alphaproteobacterium, and primary biliary cirrhosis (PBC) has been uncovered in patients with PBC. Notably, the association between Novosphingobium infection and PBC has been confirmed in a mouse model in which infection leads to the development of liver lesions resembling PBC concomitant with the production of anti-PDC-E2 antibodies that cross-react with conserved PDC-E2 epitopes shared by Novosphingobium. The discovery of infectious triggers of autoimmunity is likely to change our current concepts about the etiology of various autoimmune syndromes and may suggest new and simpler ways to diagnose and treat these debilitating diseases. Keywords alphaproteobacteria; antibiotics; autoimmunity; E2 subunit of the pyruvate dehydrogenase complex; mitochondrial enzymes; molecular mimicry; Novosphingobium spp.; primary biliary cirrhosis Induction of autoimmunity by microbesThe underlying etiologies of autoimmune diseases have been difficult to elucidate, as they are driven by complex interactions between environmental factors and genetic traits [1][2][3]. Although autoimmunity often clusters together in individuals and families, indicating the potential for a broad-spectrum genetic defect in immunological tolerance mechanisms, the genetic factors leading to the development of immune responses against specific antigens in a tissue and/or organ-specific manner remain largely unknown. This compartmentalization of autoimmune responses is particularly surprising, as many autoantigens are ubiquitously expressed.

Innate and cytokine-driven signals, rather than microbial antigens, dominate in natural killer T cell activation during microbial infection

“…The diverse panel of bacteria was selected to include clinically important pathogens such as the Gram-positive bacteria S. pneumoniae , Listeria monocytogenes and Staphylococcus aureus , the Gram-negative bacteria Pseudomonas aeruginosa , S. typhimurium , and E. coli , the spirochete B. burgdorferi , the mycobacterium Mycobacterium tuberculosis , and the α-proteobacteria Sphingomonas capsulata , Novosphingobium aromaticivorans , and Sphingomonas yanoikuyae . Members of the class of α-proteobacteria are known to cause opportunistic infections in humans and have been associated with the induction of autoimmunity ( Mohammed and Mattner, 2009 ; Ryan and Adley, 2010 ). Furthermore, iNKT cells are critical in mice for protective immunity to infection with S. pneumoniae , B. burgdorferi , P. aeruginosa , S. capsulata , and L. monocytogenes , and iNKT cells have been implicated in the development of primary biliary cirrhosis in a mouse model after infection with N. aromaticivorans (see Table I for summary and references).…”

Distinct Roles of Cdc42 in Thymopoiesis and Effector and Memory T Cell Differentiation

“…Aberrant cytokine production is involved in the pathogenesis of a variety of autoimmune diseases. For example, IFN-γ contributes to the development of experimental autoimmune myasthenia gravis and liver damage in a liver-specific autoimmune disease model induced by alphaproteobacterium Novosphingobium aromaticivorans (N. aro) [7] , [8] , [9] . A small fraction of effector cells can further differentiate into memory cells, which are major players in recall immune responses [10] .…”

Ileal Mucosa-Associated Microbiota Overgrowth Associated with Diagnosis and Pathogenesis of Primary Biliary Cholangitis

“…and those belonging to the Alphaproteobacteria class is unusual as it contains glycosphingolipids (GSLs) instead of lipopolysaccharides [18,19]. The unique cell wall of these bacteria activates distinct innate immune pathways that may trigger the development of liver-speci c pathological conditions [17]. Mice infected with N. aromaticivorans, belonging to the genus Sphingomonadaceae, developed antibodies against PDC-E2 and had liver histology similar to patients with PBC [9].…”