Senior Scientist Division of Genetics & Development Toronto Western Research Institute (TWRI)
Keywords: tolerance, B cells, autoimmunity, Systemic Lupus Erythematosus, immunogenetics
The focus of my laboratory is the immune mechanisms that lead to the development of systemic autoimmune rheumatic diseases, such as Systemic Lupus Erythematosus (SLE). The approach that we have taken is to rigorously investigate the immune defects leading to these diseases in mouse strains that spontaneously develop a lupus-like illness and then to apply the insights obtained to a focused investigation of the human disease. Using genetically manipulated lupus-prone mice with various transgenes and gene-deletions, we have shown that lupus-prone mice have a disturbance in the immune processes that remove self-reactive B cells from the peripheral B cell repertoire, permitting their differentiation into autoantibody producing cells. We have generated a series of congenic mice in which chromosomal intervals from lupus-prone mice, containing a single lupus susceptibility gene or small cluster of these genes, have been backcrossed onto a normal mouse genetic background. This has enabled us to determine how these genes promote the development of lupus and work towards identification of specific lupus-susceptibility genes. Our investigations on human SLE have provided evidence that B cell tolerance defects, similar to those observed in our lupus-prone mice, are present in humans and that some of the lupus-susceptibility alleles identified in mouse strains also contribute to development of the disease in humans.
Ongoing experiments in the laboratory focus upon the following areas:
Characterization of lupus-susceptibility genes in lupus-prone mice and investigation of the immune mechanisms through which they promote lupus.
Identification of B cell functional and tolerance defects in humans with lupus.
Elucidation of lupus-susceptibility genes in humans with lupus.
Identification and validation of novel-biomarkers of disease activity in lupus.