Faculty Summaries
Kyoko Hayakawa, MD, PhD
Kyoko Hayakawa, MD, PhD
Member
Kyoko.Hayakawa@fccc.edu
Office Phone: 215-728-5362
Fax: 215-728-3574
Lab: R388
Natural Autoreactive B cell Development and Cancer

B lymphocyte development progresses through several critical stages, initially establishing the antigen receptor repertoire and thereafter subject to selection influenced by the self-microenvironment. Strong self-reactivity results in deletion or inactivation of these cells during development, a process termed "negative selection" or "tolerance." However, not all autoreactive B cells are treated in this way. Rather, B cells with receptors specific for certain self-antigens persist for a long time without provoking autoimmune disease. Our research explores such natural autoreactive lymphocytes: the mechanisms whereby they develop, their functional significance, and their potential for dysregulation in relation to autoimmune disease and lymphoma development.

Natural autoreactive B cells bear unmutated B Cell antigen Receptors (BCRs) specific for certain self-antigens and such cells are found in healthy animals. A significant fraction of natural autoreactive IgM+ B cells are established early in ontogeny, as fetal B cells or "B-1", and are maintained as a self-renewing B cell population, capable of secreting autoantibody into serum. We have proposed that these natural autoreactive B cells and the autoantibody they produce constitute a part of the innate immune system, playing roles that complement and cooperate with adaptive immunity. Importantly, a characteristic feature of autoreactive B-1 cells is their expression of CD5. This CD5+ IgM+ phenotype resembles chronic B cell leukemia/lymphoma cells (B CLL) as well as B cells found in certain autoimmune diseases in mice and humans. This prompts us to consider that such long-maintained CD5+ B-1 cells, generated by self-antigen signaling, may constitute a pool of cells with a higher potential for malignant transformation. Our focus has been on understanding the mechanism of B cell development, in order to provide a comprehensive view on B subsets, and their potential for dysregulated growth.

Description of research projects
Selected Publications
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  1. Wen L, Brill-Dashoff J, Shinton SA et al. Evidence of marginal-zone B cell-positive selection in spleen. Immunity. 2005;23(3):297-308. PubMed
  2. Hayakawa K, Asano M, Shinton SA et al. Positive selection of anti-thy-1 autoreactive B-1 cells and natural serum autoantibody production independent from bone marrow B cell development. J Exp Med. 2003;197(1):87-99. PubMed
  3. Hardy RR, Hayakawa K. B cell development pathways. Annu Rev Immunol. 2001;19:595-621. PubMed
  4. Hayakawa K, Asano M, Shinton SA et al. Positive selection of natural autoreactive B cells. Science. 1999;285(5424):113-6. PubMed
  5. Hayakawa K, Hardy RR. Normal, autoimmune, and malignant CD5+ B cells: the Ly-1 B lineage? Annu Rev Immunol. 1988;6:197-218. PubMed
All publications