Anti-microbial Antibodies, Host Immunity, and Autoimmune Disease

Abstract

Autoimmune diseases are a spectrum of clinical inflammatory syndromes with circulating autoantibodies. Autoimmune diseases affect millions of patients worldwide with enormous costs to patients and society. The diagnosis of autoimmune diseases relies on the presence of autoantibodies and the treatment strategy is to suppress the immune system using specific or non-specific immunosuppressive agents. The discovery of anti-microbial antibodies in the blood of patients with Crohn's disease and Sjogren's syndrome and cross-reactivity of anti-microbial antibodies to human tissue suggests a new molecular mechanism of pathogenesis, raising the possibility of designing a new therapeutic strategy for these patients. The presence of anti-microbial antibodies indicates the failure of the innate immunity system to clear the microbial agents from the blood and activation of adaptive immunity through B-lymphocytes/plasma cells. More importantly, the specific antibodies against the microbial proteins are directed toward the commensal microbes commonly present on the surface of the human host, and these commensal microbes are important in shaping the development of the immune system and in maintaining the interaction between the human host and the environment. Persistence of these anti-microbial antibodies in patients but not in normal healthy individuals suggests abnormal interaction between the human host and the commensal microbes in the body. Elimination of the organism/organisms that elicits the antibody response would be a new avenue of therapy to investigate in patients with autoimmune diseases.

Autoantibodies and anti-microbial antibodies: Homology of the protein sequences of human autoantigens and the microbes with implication of microbial etiology in autoimmune diseases

“…The homologies between the microbial proteins EF-G, ATP5a from Staphylococcus aureus /pseudintermedius (10) , Hsp65 from mycobacterium avium subspecies hominissuis/Mycobacterium tuberculosis , and EF-Tu from Escherichia coli to the human proteins were significantly high, and the antibody against the microbes can cross react to the human tissues as shown previously (8). The clinical significance of these microbial proteins and their respective antibodies within the circulation in Crohn’s disease and Sjogren’s syndrome have been previously discussed (8, 9).…”

“…The presence of the microbial DNA in blood without culturable microbes raises two possibilities: the blood culture methods are insensitive to detect the microbes but the microbes are present within the circulation (7), or alternatively the intact microbes are destroyed by the host immune system but the microbial DNA and proteins are present in the circulation, eliciting the human immune response to these microbial DNA/proteins. The human immune responses to the microbial DNA and/or proteins may manifest as anti-microbial antibodies with potential cross-reactivity to human tissues through molecular mimicry (8, 9). In the process of identifying the infectious agents in Crohn’s disease and Sjogren’s syndrome, we have identified a group of microbial proteins from the commensal or pathogenic microbes reacting to patients’ plasma, and we showed that there were elevated antibodies within the circulation of patients reacting to the microbial proteins (8).…”

Serological Testing for Mycobacterial Heat Shock Protein Hsp65 Antibody in Health and Diseases

“…The Hsp65 protein from Mycobacterial avium ssp. hominissuis (MAH) was identified at PZM Diagnostics through a series of identification and mass spectrometry as described previously [14,18]. The genes encoding for Hsp65 proteins of mycobacterial species (MAH) were synthesized chemically at Genscript Corp., and cloned into pUC57 bacterial expression vectors with His-tag using proprietary technology at Genscript Corp.…”

“…We have collected plasma samples from 109 patients with Crohn's disease (CD) and from 28 patients with Sjogren's syndrome (Sjo). A portion of these samples were tested for the same anti-microbial antibodies using indirect ELISA assays with specific capturing antibodies and whole bacterial extracts as previously described [14,18]. Currently we re-tested these samples using the newly established direct ELISA assays and specific recombinant Hsp65 protein antigens.…”

“…Anti-hsp65 antibodies of likely mycobacterial antigenic origin are closely related to human anti-Hsp60 antibodies, and anti-Hsp60 antibodies of human antigens are considered "autoantibody"; thus, anti-Hsp60 antibody and the anti-Hsp65 antibody within the circulation of patients are likely identical, responding to the same or similar antigens through molecular mimicry [8,[14][15][16]. Whether the antigens of these two antibodies are identical remains largely controversial, as mycobacterial antigens are likely infectious from the environment, and the human antigens are likely autoimmune with unclear mechanisms [16].…”