Investigator: Patrick H. Nachman, M.D.

Location: University of North Carolina at Chapel Hill, North Carolina

Timeline: January 1, 2007 - December 31, 2007

Abstract

Anti-neutrophil cytoplasmic autoantibodies (ANCA), directed against myeloperoxidase and proteinase 3 are found in patients with small vessel vasculitis, and play an important role in their pathogenesis. However, the mechanisms of loss of tolerance that allow production of these autoantibodies are poorly understood.  Imbalances in positive and negative regulation of B cells, and changes in their phenotypic distribution have been implicated in autoimmunity. 

The objective of this proposal is to investigate perturbations of B cells phenotypes in patients with ANCA vasculitis and their clinical impact on the course of disease.  Based on our preliminary findings, we hypothesize that patients with ANCA vasculitis have subsets of autoreactive B cells characterized by an increased likelihood of activation by antigen, and are associated with more severe manifestations of disease and/or a higher frequency of relapse.  Specifically, we will test the hypotheses that, compared to healthy controls, patients with ANCA vasculitis: (1) demonstrate the presence of B cell subsets that are activated, or are “poised for activation” based on their increased expression of the activation-related markers CD19, CD 86, CD40 and HLA-II, and decreased expression of down-regulatory molecules CD5 and CD21; and (2) have alterations in memory B cells (based on the expression of IgD and CD27) that are associated with a higher state of disease activity. 

We will further evaluate the impact of these alterations in B cell phenotypes on the clinical course of patients with vasculitis. We suggest that the observed B cell changes affect the response to treatment and the severity of subsequent disease activity.  We will examine B cell phenotypes in patients presenting with active vasculitis, and prospectively thereafter.  We will specifically evaluate whether the observed B cell alterations: (1) correlate with the response to initial therapy; (2) “normalize” with response to therapy and (3) predict the subsequent severity of disease.

LAY PERSON SUMMARY

Anti-neutrophil cytoplasmic autoantibodies (ANCA), are found in patients with small vessel vasculitis, and play an important role in causing the disease. However, the mechanisms that allow for the production by B lymphocytes of these antibodies directed against “self” are poorly understood.  B lymphocytes undergo an elaborate maturation process which commits them to various sub-types, such as “antibody producing cells” or “memory” cells.  Under normal circumstances, self-reacting B cells are either deleted or neutralized.  Conversely, breakdown in regulation allows self-reacting B cells to remain active.  Changes in the distribution of B cells among their various sub-types have been found in some autoimmune diseases.

The objective of this proposal is to investigate alterations of B cells sub-types in patients with ANCA vasculitis and their clinical impact on the course of disease.  Based on our preliminary findings, we hypothesize that patients with ANCA vasculitis have subsets of self-reactive B cells that are more easily activated, and are associated with more severe disease or a higher frequency of relapse.  Specifically, we will test the hypotheses that, compared to healthy controls, patients with ANCA vasculitis: (1) have B cell subsets that are activated or are “poised for activation” based on their expression of cell-surface markers; and (2) have alterations in memory B cells that are associated with increased disease activity. 

We will further evaluate whether these alterations in B cell sub-types affect the response to treatment and the severity of the subsequent course of disease.  We will specifically assess whether the observed B cell changes: (1) show a relationship with the response to initial treatment; (2) “normalize” with therapy and (3) predict the subsequent severity of disease.  We believe that understanding these B cell perturbations can lead to better monitoring of disease activity and tailoring treatment to each patient’s individual needs.

RESEARCH ACTIVITIES (of the PI for the past 3 years)

Over the last three years Dr. Nachman has continued his clinical and laboratory research endeavors in the field of anti-neutrophil cytoplasmic autoantibodies (ANCA). 

Clinical research activities were based upon, and contributed to the large cohort of patients with anti-neutrophil cytoplasmic autoantibodies-associated vasculitis followed in the University of North Carolina Vasculitis and Glomerular Disease clinic in collaboration with Doctors Ronald J. Falk, Susan L. Hogan and Mary Ann Dooley (rheumatology). 

1- Study of clinical and serologic predictors of disease resistance and relapse based on the analysis of a prospective cohort of 350 patients.  This work has published in November 2005 in the Annals of Internal Medicine (Hogan SL, Falk RJ, Chin H, Cai J, Jennette CE, Jennette JC, Nachman PH.  Predictors of Relapse and Treatment Resistance in ANCA Small Vessel Vasculitis.  Annals Internal Med. 2005;143(9):621-31.  See attached copy of the manuscript).  Research aimed at improving our understanding of predictors of clinical course and outcomes of patients with ANCA vasculitis bears direct clinical impact as it can help tailoring the long-term immunosuppressive therapy to the needs of each individual patient based on his or her risk profile for relapse.  This research is currently ongoing with a validation study in collaboration with Doctors Loic Guillevin and Christian Pagnoux in Paris, France, with an abstract submitted for the upcoming meeting of the American Society of Nephrology and a manuscript in preparation.  This work was supported in part by a grant from the NIDDK (P01-DK58335).     

2- Efforts to expand collaboration with other North American centers with expertise in vasculitis have led to the formation of the Glomerular Disease Trials Consortium under the leadership of Dr. Ronald J. Falk.  This Consortium aims to design and implement multicentric, collaborative trials in vasculitis and glomerulonephritis, and has led to several NIH grant submissions in these fields.  These efforts have led to the establishment of an electronic, secure, web-based registry of patients with ANCA vasculitis which is currently operational.  This expanded registry is aimed at facilitating epidemiologic studies of patients with vasculitis, and serve as a necessary infrastructure for the implementation of future clinical trials.  The web-based registry is funded by a granted from Aspreva Pharmaceuticals. 

3- Pilot study on the use of mycophenolate mofetil in the treatment of resistant or relapsing ANCA vasculitis. (Joy MS, Hogan SL, Jennette JC, Falk RJ, Nachman PH.  A Pilot Study Using Mycophenolate Mofetil in Relapsing ANCA Small Vessel Vasculitis.  Nephrol Dial Transplantation. 2005;20(12):2725-32.).  This study was funded by a grant from Roche. 

Dr Nachman clinical research also includes participation in a number of multicentric trials notably in lupus nephritis, and focal segmental glomerulosclerosis.

Laboratory research activities have likewise focused on ANCA vasculitis, and specifically the study of the regulation of the B cell response in this autoimmune disease.  Dr. Nachman is the PI for the following 3 projects:

1-            Study of the immunodominant epitopes of anti-myeloperoxidase autoantibodies (MPO-ANCA) using a model of mouse-human chimeric molecules.  This work was recently published in Kidney International (Erdbrugger U, Hellmark T, Bunch DO, Alcorta DA, Jennette JC, Falk RJ, Nachman PH.  Mapping of myeloperoxidase epitopes recognized by MPO-ANCA using human-mouse MPO chimers. Kidney Int. 2006 May;69(10):1799-805.). 

2-            The study of B cell regulation in ANCA vasculitis was started based on an animal model of transgenic mice that express an anti-MPO immunoglobulin light chain (manuscript in preparation). 

This work is now fully focused on studying the dysregulation of B cells in patients with ANCA vasculitis as is reflected in this grant proposal.        

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