Eric Meffre, PhD

Research Description

B cell tolerance: from healthy individuals to patients with autoimmune diseases

Antibodies are generated during early B cell development by random joining of immunoglobulin (Ig) gene segments. Ig gene recombination can result in the assembly of self reactive antibodies or B cell receptors (BCR). B cells that develop self-reactive receptors can be silenced by several mechanisms such as clonal deletion, anergy, ignorance, and "receptor editing" that replaces autoreactive BCRs by continued V(D)J recombination. Despite the central role of BCRs in regulated B cell development, little is known about the effect of antibody specificity in regulating the balance between deletion, anergy, ignorance, and "receptor editing". To analyze how B cell tolerance is established in humans, we analyzed the evolution of antibody specificity during B cell development by amplifying, cloning and expressing recombinant antibodies from single bone marrow B cell precursors and peripheral mature B cells in healthy donors. We found that human autoantibody producing B cells were removed from the population at two discrete checkpoints during B cell development. The first checkpoint occurs in the bone marrow between the early immature and immature B cell stage. The second counterselection step of autoreactive antibody expressing B cells takes place in the periphery at the transition between new emigrant to mature naïve B cells. However, the mechanisms that prevail in silencing these autoreactive B cells remain to be characterized.

The long range goal of our current research is to elucidate the mechanisms and molecules that regulate B cell tolerance in humans by studying patients with primary immunodeficiencies and autoimmune diseases such as rheumatoid arthritis. These studies have significant implications for understanding how B cells may produce autoantibodies with or without maintaining tolerance.

Appointments

Assistant Scientist, Hospital for Special Surgery

Assistant Professor, Weill Medical College of Cornell University

Selected Publications

Eric Meffre, Eric Davis, Claudine Schiff, Charlotte Cunningham-Rundles, Lionel B. Ivashkiv, Louis M. Staudt, James W. Young, and Michel C. Nussenzweig. Circulating human B cells that express surrogate light chains and edited receptors. Nature Immunology 2000. 1:207-213.

Eric Meffre, Rafael Casellas, and Michel C. Nussenzweig. Antibody regulation of B cell development. Nature Immunol. 2000. 1:379-385.

Eric Meffre, Michèle Milili, Carla Blanco-Betancourt, Henedina Antunes, Michel C. Nussenzweig, and Claudine Schiff. Immunoglobulin heavy chain expression shapes the B cell receptor repertoire in human B cell development. J. Clin. Invest. 2001. 108:879-886.

Eric Meffre and Michel C. Nussenzweig. Deletion of Immunoglobulin b in developing B cells leads to cell death. Proc. Natl. Acad. Sci. USA. 2002. 99:11334-39.

Hedda Wardemann, Sergey Yurasov, Anne Schaefer, James W. Young, Eric Meffre and Michel C. Nussenzweig. Predominant autoantibody production by early human B cell precursors. Science. 2003. 301:1374-77. These authors contributed equally.

Y.-S. Ng, H. Wardemann, J. Chelnis, C. Cunningham-Rundles and E. Meffre. Bruton’s Tyrosine Kinase (Btk) is Essential for Human B Cell Tolerance. J. Exp. Med. 2004. 200:927-934.

M. Herve, K. Xu, Y.-S. Ng, H. Wardemann, E. Albesiano, B. T. Messmer, N. Chiorazzi, and E. Meffre. Unmutated and mutated chronic lymphocytic leukemia derive from self-reactive B cell precursors despite expressing different antibody reactivity. J. Clin. Invest. 2005. 115:1636-1643.

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

For more publications, please see the PubMed listing.