Submitted to: Microbes and Infection
Publication Type: Peer reviewed journal
Publication Acceptance Date: 3/29/2007
Publication Date: 7/9/2007
Citation: Berger, S., Bannantine, J.P., Griffin, J.F. 2007. Autoreactive Antibodies are Present in Sheep with Johne's Disease and Cross-react with Mycobacterium avium subsp. paratuberculosis Antigens. Microbes and Infection. 9(2007):963-970. Interpretive Summary: The findings in this study provide first-time evidence that some of the pathology that is a hallmark of Johne’s disease, such as the inflamed, corrugated intestine in cattle, might be due to an autoimmune component. The main point of the article is the discovery of the presence of antibodies in Johne’s disease sheep that react with BOTH ovine proteins and a Mycobacterium avium subsp. paratuberculosis protein. This communication extensively describes and characterizes this dual reactivity. Results include the isolation of a specific antibody, termed AutoH1, and identification of a peptide sequence that can block the effects of AutoH1. These findings also have implications for Crohn’s disease, which is thought to be an autoimmune disorder of humans, but may have an infectious disease component as well.
Technical Abstract: Mycobacterial infection has been linked to the generation of autoantibodies, including antineutrophil cytoplasmic autoantibodies (ANCA), in clinical studies and small animal models. In an attempt to identify antibodies that react with both self and mycobacterial antigens in naturally-infected ruminants, we generated a phage display library comprising single chain antibody fragments (scFv) derived from sheep with Johne's disease (JD). The library was screened simultaneously against ovine small intestinal tissue and Mycobacterium avium subsp. paratuberculosis (MAP). A clone (termed AutoH1) was identified that reacted strongly with both host tissue and MAP, recognizing a proteinase-susceptible 32 kDa determinant in ovine gut tissues and lymphatics, and in blood granulocytes not mononuclear cells. In granulocytes, binding was to cytoplasmic granules and cell membranes; in MAP, AutoH1 bound bacterial cell wall determinants. We further identified a synthetic peptide sequence recognized by AutoH1, using this to generate a carrier:peptide fusion protein (paH1). Sera of normal and JD sheep were screened for AutoH1-like autoantibody activity; 7/11 JD animals showed autoreactivity that could be blocked by paH1, while 0/21 normal animals showed no such serological reactivity. This study raises the possibility that the severe pathology observed in ruminant JD may have an autoimmune component, possibly due to ANCA-type binding.