Although it is widely accepted that B cells with self-reactivity are deleted or rendered functionally inactive, self-reactive antibodies, referred to as """"""""natural autoantibodies"""""""" can be found in the serum of healthy animals. Such natural autoantibodies are produced by a small fraction of B cells with distinctive expression of the cell surface glycoprotein CD5. These CD5+ autoreactive B cells are more frequently generated from fetal B cell precursors as a part of """"""""B-1"""""""" B cell development than those in the adult bone marrow. The importance of fetal/neonatal natural autoantibodies in protective immunity is exemplified by T15 idiotype positive anti-phosphorylcholine antibody, the most protective antibody to virulent pnuemococcal infection, rapidly produced after infection. Our research explores why such autoreactive B cells exist naturally, the mechanism whereby they develop, and their potential for dysregulation. By establishing and investigating mouse natural autoreactive B cell models expressing natural anti-Thy-1 autoantibody (ATA), we found that self-antigen is important for CD5+ ATA autoreactive B-1 B cell accumulation with relatively higher B cell receptor (BCR) signal intensity mediating a positive selection process. In contrast, negative selection occurs for cells expressing the identical BCR during conventional B cell (""""""""B-2"""""""") development in spleen from bone marrow precursors. In this renewal, we will obtain a comprehensive understanding of the mechanism for development of this B cell subset . We will first investigate the mechanism of follicular B cell maturation and maintenance in B-2 B cell development. The significance of non-BCR signaling, provided by other lymphocytes, T cells and B-1 B cells, for the maturation of B cells that lack a BCR crosslinking signal, and a role for bacterial products in B cell survival will be examined (Aim 1). To understand why autoreactive B-1 positive selection occurs from fetal B cell development, we will identify a """"""""fetal B-1 signature"""""""" that we hypothesize reflects distinctive cellular machinery determining a difference in the BCR signaling threshold, relative to bone marrow B-2 development. The fate of such earlygenerated B-1 cells will be examined in Lysmd2-GFP reporter mice, based on our recent identification of this gene as a component of the fetal B-1 signature (Aim 2). Accomplishing these aims will significantly advance our understanding of B cell development, and the importance of self-antigen and microenvironment in establishing a fully competent immune system. In humans, CD5 expression is a hallmark of late developing chronic B cell leukemia ( B CLL). Arriving at a comprehensive understanding of B cell development and the mechanism of their maintenance will be critically important for designing rational therapies of such dysregulated CD5+ B cells in the future. PUBLIC HEALTH RELLEVANCE: The immune system plays a crucial role in the acute response to infectious agents and natural autoreactive B-1 B cells play a key role in this system, rapidly producing antibodies to eradicate microorganisms. However, abnormal expansions of B-1 B cells can occur with age in certain autoimmune mouse strains, sometimes progressing to CD5+ B leukemia/lymphoma. Arriving at a comprehensive understanding of the mechanism(s) of B cell development, and establishing how natural autoreactive B-1 B cell are normally regulated and function, as proposed in this application, will be critically important both for designing rational therapies of infectious disease and for treating dysregulated B cell expansions that may lead to cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049335-08
Application #
7877950
Study Section
Special Emphasis Panel (ZRG1-HAI-G (09))
Program Officer
Nasseri, M Faraz
Project Start
2001-09-30
Project End
2013-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
8
Fiscal Year
2010
Total Cost
$431,888
Indirect Cost
Name
Research Institute of Fox Chase Cancer Center
Department
Type
DUNS #
064367329
City
Philadelphia
State
PA
Country
United States
Zip Code
19111
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Hayakawa, Kyoko; Formica, Anthony M; Brill-Dashoff, Joni et al. (2016) Early generated B1 B cells with restricted BCRs become chronic lymphocytic leukemia with continued c-Myc and low Bmf expression. J Exp Med 213:3007-3024
Hayakawa, K; Formica, A M; Colombo, M J et al. (2016) Loss of a chromosomal region with synteny to human 13q14 occurs in mouse chronic lymphocytic leukemia that originates from early-generated B-1 B cells. Leukemia 30:1510-9
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