Atypical p-ANCA in PSC and AIH: A Hint Toward a “leaky gut”?

Abstract

Primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) are enigmatic chronic inflammatory diseases of the liver, which are frequently associated with chronic inflammatory bowel diseases. Both types of liver disease share various distinct autoantibodies such as atypical perinuclear antineutrophil cytoplasmic antibodies (p-ANCA), and thus are considered autoimmune disorders with atypical features. The discovery that atypical p-ANCA recognize both tubulin beta isoform 5 in human neutrophils and the bacterial cell division protein FtsZ has renewed the discussion on the potential role of microorganisms in the pathogenesis of both diseases. In this paper, we review the evidence for microbial infection in PSC and AIH and discuss new concepts how cross-recognition between microbial antigens in the gut and host components by the immune system along with stimulation of pattern recognition receptors might give rise to chronic hepatic inflammatory disorders with features of autoimmunity.

Association between chronic liver and colon inflammation during the development of murine syngeneic graft-versus-host disease

“…4F) or CD11b ϩ GR-1 Ϫ myeloid/macrophage cells were observed in LAM from SGVHD vs. control animals. As activation of innate effector cells via signaling through TLR may play a significant role in the generation of adaptive immunity and more pointedly in the initial stages of PSC pathology (53), increases in macrophages may be significant in the development in SGVHD-associated liver inflammation.…”

Extraintestinal Manifestations of Ulcerative Colitis

“…PSC is believed to be the result of a combination of genetic and immunological factors, resulting in immune dysfunction and improper targeting of the biliary system by lymphocytes and autoantibodies (Bergquist et al, 2008;Karlsen et al, 2007;Saarinen et al, 2000). Multiple autoantibodies including ANA, RF and atypical p-ANCA have been described in UC and PSC patients (Chapman et al, 2010;Terjung & Spengler, 2009). Atypical p-ANCA is detected by indirect immunofluorescence staining on ethanol fixed neutrophils in a perinuclear or nuclear pattern whereas classical ANCA targets myeloperoxidase and proteinase 3 in a perinuclear pattern (Terjung et al, 1998).…”

“…Atypical p-ANCA is detected by indirect immunofluorescence staining on ethanol fixed neutrophils in a perinuclear or nuclear pattern whereas classical ANCA targets myeloperoxidase and proteinase 3 in a perinuclear pattern (Terjung et al, 1998). Atypical p-ANCA is detectable in approximately 70% of PSC patients with or without UC and is also described in autoimmune hepatitis in patients with IBD (Duerr et al, 1991;Saxon et al, 1990;Terjung & Spengler, 2009). Atypical p-ANCA recognizes both beta isoform 5 in human neutrophils and bacterial cell division protein FtsZ, which is highly conserved across bacterial microflora in the gut (Terjung et al, 2010).…”

“…It is proposed that an altered immune response to bacterial antigen in the gut lumen results in a "leaky gut" and stimulation of pattern recognition receptors (cross-recognition between bacterial antigen in the gut and host components, such as beta isoform 5 in neutrophils) which gives rise to autoimmunity phenomenon. (Terjung & Spengler, 2009). PSC typically affects young to middle aged males (male to female ratio of 2:1) and while only 5% of patients with UC will develop PSC, about 70% to 80% of cases of PSC occur in patients with UC (Charatcharoenwitthaya & Lindor, 2006;Lundqvist & Broome, 1997).…”

Primary Sclerosing Cholangitis

“…However, unlike in primary biliary cirrhosis (PBC) where ubiquitous, xenobiotic-metabolising bacteria, Novosphingobium aromaticivorans has been suggested as a source of molecular mimicry (Selmi et al 2003), there is no conclusive evidence which bacterial antigens might cross-react with human autoantigens and thereby play the trigger's role of autoimmunity phenomena in PSC. Recently, the bacterial cell division protein FtsZ has been proposed as a potential antigen for p-ANCA in patients with PSC and AIH (Terjung and Spengler 2009).…”