R01AI194467

SPECIFIC AFFINITY REQUIREMENTS FOR ANTIBODY SOMATIC HYPERMUTATION - PROJECT SUMMARY ANTIBODIES DIVERSIFY THROUGH TWO DISTINCT PATHWAYS. THE FIRST INVOLVES THE COMBINATORIAL ASSEMBLY OF IMMUNOGLOBULIN (IG) HEAVY AND LIGHT CHAIN VARIABLE REGION (V) EXONS, FORMING THE ANTIGEN RECOGNITION DOMAINS OF THE B CELL RECEPTOR (BCR), WHICH IS INITIALLY EXPRESSED AS IGM ON IMMATURE B CELLS. THE SECOND DIVERSIFICATION PATHWAY IS SOMATIC HYPERMUTATION (SHM) OF V EXONS IN GERMINAL CENTERS (GCS). IN THIS SETTING, B CELLS THAT ACQUIRE MUTATIONS ENHANCING AFFINITY FOR ANTIGEN RECEIVE LIMITED COGNATE T CELL HELP AND ARE SELECTED FOR CLONAL EXPANSION, LEADING TO AFFINITY MATURATION. THESE PRIMARY AND SECONDARY DIVERSIFICATION SYSTEMS WORK TOGETHER TO GENERATE PROTECTIVE ANTIBODY RESPONSES. THE PRIMARY, OR PRE-IMMUNE, REPERTOIRE PROVIDES THE FOUNDATION FOR INITIAL ANTIGEN RECOGNITION. SHM AND AFFINITY MATURATION REFINE THESE BASELINE SPECIFICITIES. WHILE IT IS WELL ESTABLISHED THAT SHM IMPROVES AFFINITIES ALREADY PRESENT IN THE PRIMARY REPERTOIRE, THIS PROJECT EXPLORES THE HYPOTHESIS THAT SHM CAN ALSO GENERATE NEW SPECIFICITIES IN B CELLS THAT INITIALLY LACK MEASURABLE ANTIGEN RECOGNITION. THIS PROCESS, TERMED AFFINITY BIRTH, MAY ENABLE ACCESS TO OTHERWISE EXCLUDED V GENE SEGMENTS AND EXPAND THE LANDSCAPE OF ANTIBODY EVOLUTION. THIS HYPOTHESIS WILL BE TESTED THROUGH TWO SPECIFIC AIMS: (I) TO ELUCIDATE THE EXTENT OF SHM-MEDIATED IG DIVERSIFICATION IN NON-SPECIFIC OR BYSTANDER B CELLS. AND, (II) TO DEFINE PARAMETERS THAT INFLUENCE SHM-MEDIATED ANTIBODY AFFINITY BIRTH. THE SIGNIFICANCE OF THIS WORK LIES IN ITS POTENTIAL TO REVEAL PREVIOUSLY UNAPPRECIATED FLEXIBILITY IN THE ANTIBODY DIVERSIFICATION PROCESS AND TO UNCOVER MODIFIABLE FACTORS THAT INFLUENCE THE EMERGENCE OF NEW SPECIFICITIES. THE PROPOSED STUDIES ARE INNOVATIVE IN SUGGESTING THAT B CELLS POSSESS INTRINSIC CAPACITY TO UNDERGO SHM AND SELECTION REGARDLESS OF THEIR INITIAL ANTIGEN SPECIFICITY. THIS RESEARCH MAY ADVANCE UNDERSTANDING OF HOW GERMINAL CENTERS SUPPORT ANTIBODY EVOLUTION AND INFORM STRATEGIES TO DESIGN VACCINES THAT ANTICIPATE EMERGING PATHOGENS.

Brigham & Womens Hospital

<P>THE GOALS ARE:</P><UL><LI>TO FOSTER FUNDAMENTAL CREATIVE DISCOVERIES, INNOVATIVE RESEARCH STRATEGIES, AND THEIR APPLICATIONS AS A BASIS FOR ULTIMATELY PROTECTING AND IMPROVING HEALTH;</LI><LI>TO DEVELOP, MAINTAIN, AND RENEW SCIENTIFIC HUMAN AND PHYSICAL RESOURCES THAT WILL ENSURE THE NATION'S CAPABILITY TO PREVENT DISEASE;</LI><LI>TO EXPAND THE KNOWLEDGE BASE IN MEDICAL AND ASSOCIATED SCIENCES IN ORDER TO ENHANCE THE NATION'S ECONOMIC WELL-BEING AND ENSURE A CONTINUED HIGH RETURN ON THE PUBLIC INVESTMENT IN RESEARCH; AND</LI><LI>TO EXEMPLIFY AND PROMOTE THE HIGHEST LEVEL OF SCIENTIFIC INTEGRITY, PUBLIC ACCOUNTABILITY, AND SOCIAL RESPONSIBILITY IN THE CONDUCT OF SCIENCE.</LI></UL><P>IN REALIZING THESE GOALS, THE NIH PROVIDES LEADERSHIP AND DIRECTION TO PROGRAMS DESIGNED TO IMPROVE THE HEALTH OF THE NATION BY CONDUCTING AND SUPPORTING RESEARCH:</P><UL><LI>IN THE CAUSES, DIAGNOSIS, PREVENTION, AND CURE OF HUMAN DISEASES;</LI><LI>IN THE PROCESSES OF HUMAN GROWTH AND DEVELOPMENT;</LI><LI>IN THE BIOLOGICAL EFFECTS OF ENVIRONMENTAL CONTAMINANTS;</LI><LI>IN THE UNDERSTANDING OF MENTAL, ADDICTIVE AND PHYSICAL DISORDERS; AND</LI><LI>IN DIRECTING PROGRAMS FOR THE COLLECTION, DISSEMINATION, AND EXCHANGE OF INFORMATION IN MEDICINE AND HEALTH, INCLUDING THE DEVELOPMENT AND SUPPORT OF MEDICAL LIBRARIES AND THE TRAINING OF MEDICAL LIBRARIANS AND OTHER HEALTH INFORMATION SPECIALISTS.</LI></UL>

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Boston, Massachusetts 021156110 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-25-301)