Identification and Characterization of Human Auto-Reactive B cells in Normal Donors and in Autoimmune Diseases

Eric Meffre, Ph.D.

Rockefeller University

Funded in June, 2002: $300000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY . FINDINGS . SELECTED PUBLICATIONS .

LAY SUMMARY

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Exploring the Role of B cells in Autoimmune Disease, Using a Rheumatoid Arthritis Model

Antibodies that misidentify the body's own cells as "foreign" (called "self-reactive antibodies" or "auto antibodies") are a hallmark of autoimmune disease. Certain B cells produce these autoantibodies. Scientists have found that antibodies are generated by random immunoglobulin (Ig) gene recombination, a process that can produce self-reactive antibodies.

Normally, certain biological processes such as deletion or "editing" of receptors silence the B cells that produce these autoantibodies. In mice, for instance, receptor editing is highly efficient in B cells that carry pre-recombined autoantibody genes. In humans, however, scientists have had difficulty identifying B cells that have edited receptors. But Rockefeller University scientists have identified a small population of human peripheral B cells that may represent edited B cells. These B cells display an unusual immunoglobulin heavy and light chain antibody repertoire that may be consistent with reactivity against the body's own cells. These cells also accumulate in the joints of patients with rheumatoid arthritis, an autoimmune disease.

The researchers plan to determine the function of these B cells in healthy individuals and in those with autoimmune disease. They hypothesize that these B cells carry low affinity self-reactive receptors that may play a role in autoimmunity. They will compare the actions of antibodies cloned from single B cells taken from healthy individuals to those taken from the joints of patients with rheumatoid arthritis. They also will analyze the contribution of these B cells to other autoimmune diseases, such as systemic lupus erythematosis.

In aggregate, these studies may provide important new insight into understanding how B cells may produce autoantibodies implicated in autoimmune disease.

ABSTRACT

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Identification and Characterization of Human Auto-Reactive B cells in Normal Donors and in Autoimmune Diseases

Immunoglobulin (Ig) gene recombination can result in the assembly of self-reactive antibodies. Deletion, anergy, or receptor editing normally silences B cells that produce these autoantibodies. Receptor editing is highly efficient in mouse B cells that carry pre-recombined autoantibody transgenes or gene "knock ins." Although it has been difficult to identify cells that have edited receptors in humans, we identified a small population of human peripheral B cells that may represent edited B cells. These B cells co-express surrogate and conventional light chains and we refer to them as V-preB+L+ B cells. V-preB+L+ B cells display an unusual heavy and light chain antibody repertoire consistent with anti-self reactivity and show evidence of receptor editing. These cells also accumulate in the joints of patients with rheumatoid arthritis (RA).

The long range goal of the proposed research is to elucidate physiological function of V-preB+L+ B cells in normal individuals and patients with autoimmune disease. The working hypothesis is that V-preB+L+ B cells carry low affinity self-reactive receptors that may be the human counterpart of mouse B1 cells and may play a role in autoimmunity. The first part of the project will consist of cloning antibodies from single V-preB+L+ B cells from normal individuals and determining whether antibodies are indeed self-reactive or polyreactive. The second part of the project will be to clone and characterize the antibodies from single V-preB+L+ B cells from the joints of patients with RA. The third part of this research proposal will analyze the contribution of V-preB+L+ B cells in the development of other autoimmune diseases such as systemic lupus erythematosis.

These studies have significant implications for understanding how B cells may produce autoantibodies with or without maintaining tolerance.

INVESTIGATOR BIOGRAPHIES

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Eric Meffre, Ph.D.

Born in Marseille, France, Eric Meffre, Ph.D. ,was educated at the Ecole Normale Superieure de Cachan/University of Paris, the Pasteur Institute, and the University of Aix-Marseille II, where he received his Ph.D. in Immunology in 1996. Pursuing his interest in B cell research, he continued his postdoctoral training at Rockefeller University, where he made important contributions to the study of B cells and the antibodies they produce. He recently joined the Hospital for Special Surgery/ Cornell University as an Assistant Professor. His laboratory is dedicated to studying the basic mechanisms responsible for the etiology and pathogenesis of autoimmune diseases, with a particular emphasis on lupus and rheumatoid arthritis.

FINDINGS

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Scientific Results:
We reported that, in healthy humans, the autoreactive B cells that arise spontaneously during early B cell development are removed at two discrete checkpoints, first in the bone marrow and then in the periphery.  To determine whether these checkpoints were effective at removing developing autoreactive B cells in RA patients, we analyzed six untreated, active RA patients.  We found that in fact both of these checkpoints were defective in RA patients, thereby favoring the break in B cell tolerance that is characteristic of patients with autoimmune diseases.  Our study subjects now include 22 RA patients, who show that B cells from RA patients suffer from one of three distinct defective mechanisms of B cell tolerance.  Hence, we can now immunologically classify RA patients in at least three distinct groups of patients who are clinically indistinguishable.  This may contribute to a better understanding of how patients develop autoimmune diseases like RA and why some patients respond to some treatments, whereas others do not, thereby increasing the probability that those affected can receive targeted treatments that will help them maintain mobility throughout their life.

SELECTED PUBLICATIONS

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Samuels J., Ng Y.S., Coupillaud C., Paget D., and Meffre E.  Human B cell tolerance and its failure in rheumatoid arthritis.  Ann N Y Acad Sci. 2005 Dec;1062:116-26.

Samuels J., Ng Y.S., Coupillaud C., Paget D., and Meffre E. Impaired early B cell tolerance in patients with rheumatoid arthritis. J. Exp. Med. 2005. 201:1659-1667.

Hervé M., Xu K., Ng Y.S., Wardemann H., Albesiano E., Messmer B.T., Chiorazzi N., and Meffre E.  Unmutated and mutated chronic lymphocytic leukemia derive from self-reactive B cell precursors despite expressing different antibody reactivity.  J Clin Invest. 2005 Jun;115(6):1636-43.

Ng Y.S., Wardemann H., Chelnis J., Cunningham-Rundles C., Meffre E.   Bruton's tyrosine kinase is essential for human B cell tolerance.  J Exp Med. 2004 Oct 4;200(7):927-34.

Meffre E., Schaefer A., Wardemann H., Wilson P., Davis E., and Nussenzweig M.C.  Surrogate light chain expressing human peripheral B cells produce self-reactive antibodies. J Exp Med. 2004 Jan 5;199(1):145-50.

Wardemann H., Yurasov S., Schaefer A., Young J.W., Meffre E, and Nussenzweig M.C.  Predominant autoantibody production by early human B cell precursors. Science. 2003 Sep 5;301(5638):1374-7.