Research Assistant Professor

Mirobiology and Immunology

Thomas Jefferson University (Philadelphia, PA)

Tim Manser

Working on B cell tolerance, autoimmune disease SLE (systemic lupus erythematosus) and immune mediated kidney disease in lupus

My lab focuses on (1) studying the basic mechanisms of peripheral tolerance notably germinal center (GC) and antibody-forming cell (AFC) pathways and how altered mechanisms might lead to the production of autoantibodies and the development of lupus nephritis under autoimmune conditions such as SLE and (2) mapping and identifying the gene(s) that might play critical role in immune-mediated end-organ damage such as kidney (nephritis).

(1) SLE (systemic lupus erythematosus) is a complex polygenic disease. Most of our understanding about the autoimmune disease such as SLE to date has come from the studies of animal models. The New Zealand Black (NZB)/NZ White (NZW)-derived NZM2410 strain develops a disease that resembles human SLE. Three major genomic intervals (Sle1, Sle2 and Sle3) were identified by the Wakeland group in the NZM2410 strain. B6 mice congenic for each of these loci exhibit different component phenotypes. For instance, B6.Sle1 mice spontaneously develop high titers of ANAs but these can mediate high penetrance of severe glomerulonephritis only in combination with other SLE susceptibility loci (Sle2, Sle3/Sle5, Yaa and lpr). Two of the most potent loci are Sle1 and Sle3. Sle3 in combination with Sle1 mediates severe lupus nephritis. B6.Sle3 has been shown to be associated with ANAs, T cell hyperactivity, elevated ratios of CD4/CD8 T cells and hyperstimulatory antigen-presenting cells (APCs). However, it is not clear whether this process is due to loss of central or peripheral tolerance. Using B cell antigen receptor transgenic mouse line (B6.HKIR) that produces autoreactive (DNA-reactive) B cells, we are investigating how Sle1 and Sle3 might be altering the peripheral B cell tolerance operative during GC and AFC pathways leading to the development of autoantibodies and autoimmune disease SLE.

(2) The development of immune-mediated kidney disease is a major hallmark of SLE. Recent studies in mice, using rabbit sera reactive to mouse kidney glomeruler basement membrane (GBM) to induce nephritis, have suggested that some laboratory strains (such as NZW, 129/svJ and C58/J) are more prone to immune-mediated kidney damage compared with C57BL/6 and BALB/c control strains. Currently, the studies are conducted in our lab to determine whether the kidney intrinsic events or the difference in infiltrating immune cells are responsible for a renal disease as a consequence of immunological insult. Also, the genetic basis of this immune-mediated kidney disease is poorly understood. Through genetic mapping studies and gene expression profile, our goal is to identify the genetic loci and candidate genes that specifically contribute to immune mediated kidney disease. Once the actual genes playing a pivotal role in immune mediated renal disease are identified in mice, we will continue to study these genes in lupus patients with kidney disease and develop therapeutic approaches by targeting these genes.