Research Interests
My laboratory is directed to two main areas of research. The major and longest funded
area has been to understand the molecular and cellular bases for autoimmunity to DNA
in mouse models for human systemic lupus erythematosus (SLE). This research employs
anti-DNA antibody transgenic, genetically autoimmune-prone (NZB x NZW)F1 mice to analyze
DNA-specific B cell tolerance and activation in an autoimmune background. The development
of autoimmunity to DNA and lupus-like autoimmune disease in the normally autoimmune,
lupus-prone (NZB x NZW)F1 mice depends upon whether the mice inherit the 3H9 anti-DNA
heavy chain as a conventional IgM heavy-chain transgene (3H9-m) or as a VH3H9 heavy-chain
variable region gene “knock-in” into the JH locus. 3H9-m transgenic (NZB x NZW)F1
do not produce anti-DNA autoantibodies and do not develop lupus nephritis. The VH3H9
knock-in transgenic (3H9R) (NZB x NZW)F1 mice develop autoimmune anti-DNA antibody
and lupus nephritis similar to non transgenic (NZB x NZW)F1 mice. Tolerance to DNA
in the conventional VH3H9 transgenic (NZB x NZW)F1 mice is a function of both B cells
and T cells. B cell receptor-dependent stimulation is less effective in the conventional
transgenic (NZB x NZW)F1 mice, and helper T cell activation is also less effective
in the conventional transgenic (NZB x NZW)F1 mice. The latter deficiency may be the
consequence of the anergic B cell environment in which CD4 T cells develop. Present
and future research will take advantage of difference in autoimmune response between
the two different transgenic (NZB x NZW)F1 to understand the cellular and molecular
bases for autoimmune B cell activation in this important model for human SLE. A second
project in this area of research involves analyses of pathogenic function of anti-DNA
antibodies in lupus nephritis in mice and humans. The potential for monoclonal anti-DNA
antibodies to passively induce glomerulonephritis appears to be independent of specificity
for or binding to DNA or chromatin. The structural basis for pathogenic anti-DNA antibody
function is being determined by proteomic analysis of mouse kidneys with passive experimentally
induced disease.
The other main area of research in my laboratory is immunity to hepatitis C virus
in individuals chronically infected with hepatitis C. This project is part of the
Center for Hepatitis C Research at UTHSC. The major focus of the Center’s research
has been to understand the basis for racial differences in response to combination
pegylated interferon-alpha and Ribavarin therapy for chronic hepatitis C. African
Americans have only a 26% response rate, determined as sustained clearance of circulating
virus, compared to 56% for Caucasians. Recent results from our clinical research also
indicate a much higher frequency of a particular HLA DR allele among chronically infected
African Americans at our Center. Present and future studies are directed toward understanding
the relevance of the increased frequency of HLA DR among chronically infected Afrcrican
Americans. Ongoing research will also seek to determine how differences in immune
responses may or may not be related to differences in response to therapy between
chronically infected African American and Caucasian individuals.
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