Chief, Experimental Medicine Section
Oral Infection and Immunity Branch
NATIONAL INSTITUTES OF HEALTH/NIDCR
BUILDING 30 ROOM 106
30 CONVENT DR, MSC 4352
BETHESDA MD 20892-4352
Phone: (301) 496-4535
Fax: (301) 402-4163
E-mail: anotkins@mail.nih.gov
Education
B.A. Yale University
M.D. New York University
House Staff (internal medicine) Johns Hopkins Hospital
Research Interests
Autoimmune Diabetes and Immunology
The laboratory is focusing on three related areas. The first is concerned with the identification of new autoantigens, the autoantibodies with which these autoantigens react and the value of autoantibodies in predicting the development of autoimmune diseases. The long term goal is to define the human “autoantigenome” --- that is the identification and characterization of the major autoantigens in the most common human autoimmune diseases --- by high throughput procedures and extensive screening of the proteome.
The second area concerns the properties and function of IA-2 and IA-2ß which are major autoantigens in type 1 diabetes and transmembrane proteins of dense core secretory vesicles. These proteins are present in most of the neuroendocrine cells in the body. Knockout and knock down technology has shown that these proteins affect the secretion of hormones (e.g., insulin). Current studies are concerned with the effect of IA-2 and IA-2ß on the secretion of neurotransmitters and how this, in turn, alters behavior, learning and life-span.
The third area involves polyreactive antibodies. Hybridoma technology has shown that many antibody molecules are polyreactive — that is, they can bind to a variety of different and structurally unrelated self and non-self foreign antigens. These antibodies generally have low binding affinity and are encoded by germ-line or near germ-line sequences. Further studies revealed that much of the natural antibody repertoire is made up of polyreactive antibody. The function of the natural antibody repertoire has remained an enigma. Current studies are focusing on the role of polyreactive antibodies in: defense against foreign organisms (i.e., bacteria/viruses); the clearance of damaged proteins and cells; and the possible role of these antibodies in the induction and/or maintenance of immunological tolerance. The cells that make polyreactive antibodies also are under investigation.
Recent publications
Cai, T., Fukushige, T., Notkins, A.L. and Krause, M. 2004. Insulinoma-Associated Protein IA-2, a Vesicle Transmembrane Protein, Genetically Interacts with UNC-31/CAPS and Affects Neurosection in Caenorhabditis elegans. J Neuroscience 24:3115-3124.
Notkins, A.L. 2004. Polyreactivity of Antibody Molecules. Trends in Immunol 25:174-179.
Kubosaki, A., Nakamura, S., Clark, A., Morris, J.F., Notkins, A.L. 2005. Disruption of the Transmembrane Dense Core Protein Vesicle Proteins IA-2 and IA-2ß Causes Female Infertility. Endocrinology 147, 811-815.
Harashima, S., Clark, A., Christie, M.R., Notkins, A.L.: 2005. The Dense Core Transmembrane Vesicle Protein IA-2 is a Positive Regulator of Vesicle Number and Insulin Secretion. Proc. Natl. Acad. Sci. USA 102, 8704-9709.
Zhou, Zhao-Hua, Zhang, Y, Hu, Y, Wahl, L.M., Cisar, J.O., Notkins, A.L.: 2007. The Broad Antibacterial Activity of the Natural Antibody Repertoire is Due to Polyreactive Antibodies. Cell Host & Microbe, 1, 51-61.
Notkins, A.L.: 2007. New Predictors of Disease. Scientific American 296, 72-9 (Cover Story).
Short CV