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Dr Kevin O’Connor is an Assistant Professor of Neurology at Yale School of Medicine in Connecticut.
He earned a BS in Chemistry from the University of Massachusetts at Amherst and his PhD in Biochemistry at Tufts Medical School. He received his post-doctoral training and then established his own laboratory at Harvard Medical School.
His investigative interests are in human translational immunology and neurology. His laboratory is specifically interested in defining the mechanisms by which B cells, and the antibodies they produce, affect tissue damage in autoimmunity. To this end, his group is engaged in determining the specificity of autoantibodies and understanding how particular B-cell subsets initiate and sustain autoimmunity. Areas of special interest include the study of MS, inflammatory myopathy and myasthenia gravis.
Kevin O’Connor’s GMSI project
B-cell–mediated autoimmunity in multiple sclerosis: understanding autoantibody production and defects in B-cell tolerance mechanisms
The role of B cells in MS pathogenesis is not entirely understood. Among the fundamental steps that remain to be elucidated are those associated with autoantibody production. B cells that populate the central nervous system (CNS) of patients with MS are antigen experienced; however, their antigen targets have not been identified. Additionally, it is not understood whether MS involves an inherent tolerance defect that interferes with the removal of autoreactive B cells.
We hypothesize that patients with MS suffer from B-cell tolerance defects, causing B cells to produce autoantibodies and traffic to the CNS, where they contribute to inflammation and promote disease development. To test this model, we first propose to identify the antigen specificity/specificities of the B cells that populate the CNS of patients with MS. We have expressed a large series of recombinant immunoglobulin G (rIgG) antibodies from clonal B cells found throughout the CNS of patients with MS. We will test whether these rIgG antibodies bind candidate antigens, such as KIR4.1, and test for reactivity to other antigens with a novel, high-throughput screening strategy that uses a synthetic representation of the entire human genome.
Next, we will expand our studies indicating that MS displays specific peripheral B-cell tolerance defects. An altered phenotype of B cells, which can display increased homeostatic proliferation, is suspected to contribute to this dysfunction. To further define this mechanism, we will study MS-derived mature naïve B cells for evidence of an activated phenotype by examining their transcriptome and comparing it to that of normal controls. Markers of such activation that are identified through the transcriptome analysis will be validated with flow cytometry.