Host-microbial interactions in Wegener’s Granulomatosis: The role of ANCA and S. aureus persistence

Investigator: Robert D. Inman, M.D.
Location: University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada
Timeline: September 1, 2002 – August 31, 2003 (extended to Spring 2004)

Abstract:  There is compelling circumstantial evidence to implicate a role for infection in the pathogenesis of Wegener’s Granulomatosis (WG). Recently there has been confirmation of a higher nasal carriage of Staphylococcus aureus in WG patients. Yet it is not known whether this finding is a cause or an effect of the disease process. Secondly, there continues to be mounting evidence of the efficacy of antibiotic therapy for WG. It is unresolved however whether agents such as ulfonamide or trimethoprim function as antibiotics or by an alternative mechanism. Third, neutrophils represent the first line of defense against bacterial pathogens. The ANCA antibody response that is the hallmark of WG may influence host defenses against such infections in a fundamental way.

Specific Aims:  The aims of the proposed project are to analyze the relationship between ANCA and clearance of pathogens. This will shed new light on the relationship between infection and autoantibody formation. This is one of the fundamental problems in all autoimmune disease, and the insights from this study will have important implications for other chronic inflammatory conditions, which may have an infectious trigger.

1. To define the impact of ANCA on the internalization and intracellular killing of S. aureus by neutrophils and by endothelial cells.
2. To examine the impact of ANCA on the parameters of innate immunity, particularly TLR2 and TLR4 signaling and activation of NFkB, as marker of gene transcription and cytokine production.

What this means for patients:  There is compelling reason to resolve the possible role of infection in WG:
1. As has just been confirmed, WG patients have a higher prevalence of nasal carriage in S. aureus. The reason for this microbial persistence has not been resolved.
2. Antibiotics form an important part of the treatment regimen of WG, and it has been assumed that the primary mode of action of these agents is their antimicrobial effect.
3. Since the neutrophil functions as a first line of defense against pathogens such as S. aureus, it is important to resolve whether ANCA may be significantly impairing host defenses against infection by altering neutrophil function.