Research Program:

Historically, a major goal of my research program has been to reveal the cellular and molecular basis of antibody formation and the development of memory B cells. Somatic hypermutation plays a critical role in these processes by altering the sequences of antibody variable (V) genes, and thus receptor antibody molecules, while B cells respond to foreign immunogen. In the context of a physiological immune response, selection pressures normally favor the continued participation of rare B cell clones expressing mutant receptor antibodies that bind immunogen with improved affinity without also binding to any of the plethora of available self-antigens expressed by the animal. As such, the memory B cell repertoire is normally established.

More recently, my laboratory has taken an interest in elucidating the etiology of autoantibody formation in systemic autoimmune diseases such as lupus (SLE). Although it plays a decisive role in acquired immunity, somatic hypermutation is a potentially dangerous process and one that we suspect is critical for the generation of such pathological autoantibodies. Conventional wisdom holds that newly minted B cells emerging from the bone marrow with an autoreactive receptor sometimes escape the self-tolerance mechanisms that normally censor the repertoire and that following activation by self-antigen, such B cells acquire somatic mutations that may improve the affinity with which their receptor antibodies bind self-antigen. Alternatively, somatic hypermutation may be playing a much more decisive role by creating autoreactive B cell clones de novo from nonautoreactive antecedents. In a nutshell, the question we are addressing is: are the pathological autoreactive B cells observed in lupus “born” with an autoreactive receptor or do they acquire it via somatic hypermutation during the course of a normal immune response? This is one of the most basic unresolved issues regarding the etiology of systemic autoimmune disease.

In order to participate in autoimmune response, B cells must receive help from  T cells. But the origin and antigenic specificity of this help are unknown. One possibility we are exploring is that somatic hypermutation creates new T cell epitopes within the B cell receptor that enable the autoreactive B cell to obtain T cell help. This is plausible because B cells not only process and present peptides from foreign immunogen in the context of class II MHC, they also process and present peptides derived from their receptor antibody. We refer to this idea as the receptor presentation hypothesis. We are looking at this from two perspectives. On the one hand, we are testing the idea that receptor presentation ultimately provides the major avenue of help to pathological autoreactive B cells. On the other, we are determining how receptor presentation is normally precluded under physiological circumstances. We assume that specialized tolerance mechanisms must normally regulate this avenue of help, otherwise autoimmunity would be the rule not the exception. To test our ideas, we have developed transgenic lines of mice that carry B cells expressing mutant antibody molecules with defined T cell epitopes and corresponding transgenic lines that carry corresponding  T cells that react to these epitopes.

In a final project, we are exploring mechanisms by which B cells attain a state of tolerance with respect to self-antigens. To this end, we have developed a unique transgenic model in which B cells express a receptor that is both autoreactive (ssDNA) and reactive to a defined hapten called p-azophenylarsonate (Ars). The dual specificity of this receptor enables us to control the binding interaction between the receptor and the self-antigen by selectively blocking this interaction with a monovalent form of Ars under controlled circumstances. Using this model, we are exploring how engagement of a self-antigen influences the biological capabilities of B cells.

Selected Publications:

• Guo W, DS Smith, A Guth, K Aviszuz and LJ Wysocki, T cell tolerance to germline-encoded antibody sequences in a lupus-prone mouse. J. Immunol. 175:2184-90, 2005.
• Snyder CM, K Aviszus, RA Heiser, DR Tonkin, AM Guth and LJ Wysocki, Activation and tolerance in CD4+ T cells reactive to an immunoglobulin variable region. J Exp Med 200:1-11, 2004.
• Guth AM, X Zhang, D Smith, T Detanico and LJ Wysocki. Chromatin specificity of anti-double-stranded DNA antibodies and a role for arginine residues in the third complementarity-determining region of the heavy chain. J Immunol 171:6260-6, 2003.
• Shapiro GS, MC Ellison and LJ Wysocki. Sequence-specific targeting of two bases on both DNA strands by the somatic hypermutation mechanism. Mol Immunol 40:287-95, 2003
• Benschop RJ, Aviszus K, Zhang X, Manser T, Cambier JC and Wysocki LJ. Activation and anergy in a novel immunoglobulin transgenic mouse that is both hapten-specific and autoreactive. Immunity 14:33-43, 2001

View of Recent Publications in PubMed