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Research Interests
Our laboratory studies the structure of immunoglobulins, the chemical
and genetic basis of their diversity and specificity as antibodies and
of their
allelically controlled antigenic determinants (allotypes). We have isolated
and characterized structural genes for rabbit immunoglobulin heavy and
light
chains and related T-cell receptor genes, characterized heavy chain locus
recombinants and the molecular basis for mutant phenotypes that result
in
altered expression of the genes encoding antibody heavy and light chains.
We demonstrated an important role of the young rabbit appendix and other
gut
associated lymphoid tissue in primary diversification of the antibody
repertoire and positive and negative selection of B-lymphocytes. We are
now
investigating whether human appendix may play a comparable role in early
development of the human immune repertoire. Our studies demonstrated that
in rabbit B-lymphocytes, hypermutation and gene-conversion-like diversification
mechanisms generate somatic variants of germline-encoded sequences of
antibody heavy and light chains. We recently showed that this occurs not
only in gut-associated lymphoid tissues but in sites such as splenic
germinal centers where immune responses occur after exposure to foreign
antigens. Current studies aim to characterize further the mechanisms that
lead to altered variable region sequences and accompanying maturation
of
antibody affinities.
Selected Publications Top
High RAD51 mRNA levels in young rabbit appendix. A role in B-cell gene conversion? . E. Schiaffella, P. Fuschiotti, S.J. Bensinger, R.G. Mage. Immunogenetics 48:108-115(1998).
Gene conversion and hypermutation during diversification of VH sequences in developing splenic germinal centers of immunized rabbits. E. Schiaffella, D. Sehgal, A.O. Anderson, R.G. Mage. Journal of Immunology 162:3984-3995(1999).
Generation of heterogeneous rabbit anti-DNP antibodies by gene conversion and hypermutation of rearranged VL and VH gene during clonal expansion of B cells in splenic germinal centers. D. Sehgal, E. Schiaffella, A.O. Anderson, R.G. Mage. European Journal of Immunology 30:3634-3644(2000).
Generation of the primary antibody repertoire in rabbits: Expression of a diverse set of Igk-V genes may compensate for limited combinatorial diversity at the heavy chain locus. D Sehgal, G Johnson, TT Wu, RG Mage. Immunogenetics 50:31-42(1999).
CD5 and other superantigens may select and maintain rabbit self-renewing
B-lymphocytes and human B-CLL cells. RG Mage, R Pospisil. Current Topics
in Microbiology and Immunology 252:87-96(2000).
Contact
Information Top
National Institutes of Health
10 Center Drive
Building 10 / Room 11N311
Bethesda, Maryland 20892
Phone Number: 301-496-6113
Fax Number: 301-496-0222
Email Address: rmage@niaid.nih.gov
Web Site: http://www.niaid.nih.gov/dir/labs/li/mage.htm
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