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Larry Wysocki, Ph.D.

Professor of Immunology & Microbiology

1400 Jackson St., Rm K902a
Denver, CO 80206
Phone: 303-398-1385 Office, 303-398-1718 Lab
Dr. Wysocki's National Jewish Health webpage

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 while B cells respond to foreign immunogen in germinal centers.  Selection pressures normally favor the continued participation of rare B cell clones expressing mutant receptor antibodies that bind immunogen with improved affinity.  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, SHM 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, SHM may be playing a much more decisive role by actually creating autoreactive B cell clones de novo from nonautoreactive antecedents.  Our studies to date support the latter of these two alternatives.  As such, we are building a new model to examine self-tolerance in B cells and their escape from self-tolerance at the post-mutational, germinal center stage of activation. We are also investigating the possibility that spontaneous somatic mutagenesis in genes that regulate the immune system is the ultimate cause of autoimmunity.

In order to participate in autoimmune response, B cells must receive help from αβ 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 αβ T cells that react to these epitopes.

Click here for a list of Dr. Wysocki's recent publications.
  • Detanico T, Phillips M and LJ Wysocki. Functional versatility of AGY serine codons in Immunoglobulin variable region genes.  Front. Immunol. in Press (2016).

  • Detanico T, Guo W, and LJ Wysocki. Predominant role for activation-induced cytidine deaminase in generating IgG anti-nucleosomal antibodies of murine SLE.  J. Autoimmun. 58:67-77, 2015.

  • Kirchenbaum GA, St. Clair JB, Detanico T, Aviszus K and LJ Wysocki.  Functionally responsive self-reactive B cells of low affinity express reduced levels of sIgM.  Eur. J. Immunol. 44:970, 2014. PMCID: [PMC3984621].

  • Detanico T, St. Clair JB, Aviszus K, Kirchenbaum G, Guo W and LJ Wysocki.  Somatic mutagenesis in autoimmunity. J. Autoimmunity 46:102. 2013. [PMCID:3743419].

  • Aviszus K, MacLeod MK,  Kirchenbaum G, Detanico T, Heiser RA, St. Clair JB, Guo W and Wysocki LJ.  Antigen specific suppression of humoral immunity by anergic Ars/A1 B cells.  J. Immunol. 189:4275, 2012.    [PMCID: 3478495].

  • Detanico T, Heiser R, Aviszus A, Bonorino CB and LJ Wysocki.  Self-Tolerance Checkpoints in CD4+ T Cells Specific for a Peptide Derived from the B Cell Antigen Receptor.  J. Immunol. 187:82.  2011. [PMCID:3124280].

  • Heiser RA, Snyder C, St. Clair J and LJ Wysocki.  Aborted Germinal Center Reactions and Memory B Cell Responses Mediated by CD4+ B Cells Specific for a BCR V Region Peptide. J. Immunol. 187:212. 2011. [PMCID:3133611].

  • Guo W, Smith D, Aviszus K, Detanico T, Heiser R and LJ Wysocki.  Somatic hypermutation as a generator of anti nuclear antibodies in a murine model of systemic autoimmunity. J. Exp. Med. 207:2225, 2010.

  • Guth A, Detanico T, Smith D, Tung SK, Bonorino, C. and LJ Wysocki. Spontaneous autoimmunity in mice that carry an Igh V  partial transgene: A Required Arginine in VHCDR3. Lupus 18:299-308, 2009.

  • Aviszus K, Zhang X, and LJ Wysocki.  Silent development of memory progenitor B cells. J Immunol 179:5181-90, 2007.

  • 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.

Click here for a list of Dr. Wysocki's recent publications.