Assistant Professor of Neurology

Center for Neurologic Diseases
Brigham and Women's Hospital
Harvard Medical School, NRB641E
77 Avenue Louis Pasteur
Boston, MA 02115

Tel: (617) 525-5348
Fax: (617) 525-5333
Email:koconnor@rics.bwh.harvard.edu
www: O'Connor Laboratory Site

__________________________________________________________________________

Education

• 1995-1999, Ph.D., Biochemistry, Tufts University School of Medicine,
• 1984-1988, B.Sc., Chemistry, University of Massachusetts, Amherst

Postdoctoral Training:

• 1999-2003, Postdoctoral fellow, Neuroimmunology, Harvard Medical School

Professional experience:

• 2007-present Assistant Professor of Neurology, Harvard Medical School
• 2003-2006 Instructor in Neurology, Harvard Medical School
• 2003-present Associate Immunochemist, Brigham and Women's Hospital
• 1995-present Adjunct Lecturer, Tufts University School of Medicine,
• 1992-1994 Associate Scientist, Ares-Serono Pharmaceuticals
• 1988-1991 Applications Chemist, Waters Chromatography-Millipore

Research interests: Characterization of B cells in MS brain lesions.

My research program centers on elucidating an elementary unknown in many autoimmune diseases, the antigen specificity of B cells. The program focuses particularly on multiple sclerosis (MS), although it has been extended to include the inflammatory myopathies and brain tumors.

A question fundamental to the understanding the pathology of MS concerns the characteristics of antibodies that recognize myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG). Through the application of novel technologies, I demonstrated that MBP and MOG antibodies are uncommon in the serum and CSF of patients with MS. In contrast, immunoglobulin isolated directly from CNS plaques in patients with MS include high-affinity MOG-specific autoantibodies. Collectively, these studies demonstrate that resident B cells in the brain parenchyma rather than those in the periphery are the source of these MS autoantibodies.

The work has generated several important collaborations:

• Kai Wucherpfennig (Harvard Medical School) and I developed self-assembling MOG tetramers to identify an autoantibody-associated form of acute disseminated encephalomyelitis.
• Nancy Monson (University of Texas-Southwestern) and I are examining the reactivity of B cells derived from MS CSF.
• Amit Bar-Or (Montreal Neurological Institute) and I are examining myelin-reactive autoantibodies in pediatric MS.
• Bill Robinson (Stanford University) and I are studying the broad reactivity of MS autoantibodies using protein chips.

Currently, I am leading a group that studies the antigen specificity of B cells derived directly from the plaque tissue. We are isolating single cells from plaques by laser microdissection and then cloning and sequencing the immunoglobulin variable domains. We have begun generating the recombinant antibodies that will be used for identification of antigens. This investigation affords the following:

1. Detailed analysis of both the B-cell clonal expansion and the characteristics of antigen-driven responses.
2. Assessment of the B-cell expansion within the microenvironment of the plaque and among plaques. The assignment of individual sequences to individual cells allows us to determine if the expansion and selection is compartmentalized. Evaluation of accessory cells through histology will also be performed.
3. Production of large amounts of recombinant immunoglobulin from B cells. Isolation of single cells will preserve the natural VH and VL pairings, allowing authentic reconstruction of these rare antibodies.

These recombinant antibodies will be used for antigen identification by sensitive biochemical strategies capable of identifying antigens comprising protein, lipid, carbohydrate, or nucleic acid. First, we will evaluate whether these antibodies stain tissue sections of brain and/or cells infected with various pathogens. To isolate target antigens, we will probe western blots of whole myelin and cell lysates and screen expression libraries. To capture the antigen(s) we will then fabricate affinity columns. Precise molecular definition of the target(s) will subsequently be aided by mass spectrometry.

Our future work with identified antigens will include detailed characterization of 1) animal models; 2) a large set of patients with MS; 3) role of antigen(s) in immunopathology or in myelin repair or as a biomarker; 4) role of T-cell recognition; 5) molecular characteristics of the antibody:antigen recognition; 6) B-cell dysregulation.

Publications:

Original Research Articles

1. Dion, D. M., K. O'Connor, D. Phillips, G. J. Vella, and W. Warren. 1990. New family of high-resolution ion exchangers for protein and nucleic acid purifications from laboratory to process scales. J Chromatogr 535:127.

2. Hines, R. N., K. C. O'Connor, G. Vella, and W. Warren. 1992. Large-scale purification of plasmid DNA by anion-exchange high-performance liquid chromatography. Biotechniques 12:430.

3. O'Connor, K. C., S. Ghatak, and B. D. Stollar. 2000. Use of hydrophobic interaction chromatography to separate recombinant antibody fragments from associated bacterial chaperone protein GroEL. Anal Biochem 278:239.

4. Bar-Or, A., E. M. Oliveira, D. E. Anderson, J. I. Krieger, M. Duddy, K. C. O'Connor, and D. A. Hafler. 2001. Immunological memory: contribution of memory B cells expressing costimulatory molecules in the resting state. J Immunol 167:5669.

5. Li, J., L. Fernandez, K. C. O'Connor, T. Imanishi-Kari, and B. D. Stollar. 2001. The rearranged V(H) domain of a physiologically selected anti-single-stranded DNA antibody as a precursor for formation of IgM and IgG antibodies to diverse antigens. J Immunol 167:3746.

6. O'Connor, K. C., K. Nguyen, and B. D. Stollar. 2001. Recognition of DNA by VH and Fv domains of an IgG anti-poly(dC) antibody with a singly mutated VH domain. J Mol Recognit 14:18.

7. Hirano, N., M. O. Butler, M. S. Von Bergwelt-Baildon, B. Maecker, J. L. Schultze, K. C. O'Connor, P. H. Schur, S. Kojima, E. C. Guinan, and L. M. Nadler. 2003. Autoantibodies frequently detected in patients with aplastic anemia. Blood 102:4567.

8. O'Connor, K. C., T. Chitnis, D. E. Griffin, S. Piyasirisilp, A. Bar-Or, S. Khoury, K. W. Wucherpfennig, and D. A. Hafler. 2003. Myelin basic protein-reactive autoantibodies in the serum and cerebrospinal fluid of multiple sclerosis patients are characterized by low-affinity interactions. J Neuroimmunol 136:140.

9. Ausubel, L. J., K. C. O'Connor, C. Baecher-Allen, C. Trollmo, B. Kessler, B. Hekking, D. Merritt, A. L. Meyer, B. Kwok, H. Ploegh, B. T. Huber, and D. A. Hafler. 2005. Characterization of in vivo expanded OspA-specific human T-cell clones. Clin Immunol 115:313.

10. Greenberg, S. A., E. M. Bradshaw, J. L. Pinkus, G. S. Pinkus, T. Burleson, B. Due, L. S. Bregoli, K. C. O'Connor, and A. A. Amato. 2005. Plasma cells in muscle in inclusion body myositis and polymyositis. Neurology 65:1782.

11. O'Connor, K. C., H. Appel, L. Bregoli, M. E. Call, I. Catz, J. A. Chan, N. H. Moore, K. G. Warren, S. J. Wong, D. A. Hafler, and K. W. Wucherpfennig. 2005. Antibodies from Inflamed Central Nervous System Tissue Recognize Myelin Oligodendrocyte Glycoprotein. J Immunol 175:1974.

12. O'Connor, K. C., S. Roy, C. Becker, D. A. Hafler, and A. B. Kantor. 2006. Comprehensive Phenotyping in Multiple Sclerosis: Discovery Based Proteomics and the Current Understanding of Putative Biomarkers. Disease Markers 22(4):213-25. Pubmed Link

13. Anderson, D. A., K. Kuguchi, K. C. O'Connor, L. Glimcher, V. K. Kuchroo, and D. A. Hafler. 2006. Dysregulated T cell expression of TIM3 in multiple sclerosis. Journal of Experimental Medicine 12;203(6):1413.

14. Bradshaw, E. M., A. Orihuela, D. A. Hafler, S. A. Greenberg, and K. C. O'Connor. 2007. Evidence of an antigen driven humoral response in the inflammatory myopathies. J. Immunol. Jan 1;178(1):547-556. Pubmed Link

15. O’Connor KC, McLaughlin KA, De Jager PL, Chitnis T, Robinson WH, Cherry SV, Bar-Or A, Banwell B, Fukaura H, Tenembaum S, Wong SL, Rostasy K, Dale R, Freedman M, Steinman L, Hafler DA and Wucherpfennig KW. Self-assembling Antigen Tetramers Identify an Autoantibody-associated Form of Acute Demyelinating Encephalomyelitis.
Nat Med In press. Nature Link

16. Doris Lambracht-Washington, Kevin C. O'Connor, Elizabeth Cameron , Andrea Jowdry ,E. Sally Ward , Elliot Frohman , Michael K. Racke, Nancy L. Monson Antigen specificity of clonally expanded and receptor edited cerebrospinal fluid B cells from patients with relapsing remitting MS. Journal of Neuroimmunology (2007) inpress.

Invited Reviews

1. O'Connor, K. C., A. Bar-Or, and D. A. Hafler. 2001. The neuroimmunology of multiple sclerosis: possible roles of T and B lymphocytes in immunopathogenesis. J Clin Immunol 21:81.

2. Hafler, D. A., J. M. Slavik, D. E. Anderson, K. C. O'Connor, P. De Jager, and C. Baecher-Allan. 2005. Multiple sclerosis. Immunol Rev 204:208.

Books and Chapters

1. Bar-Or, A., K. C. O'Connor, and D. A. Hafler. 2001. Multiple Sclerosis. In Samter’s Immunologic Diseases, Vol. 2. Austen, Frank, Atkinson, and Cantor, eds. Lippencott, Williams and Wilkins, New York, p. 711.

2. O'Connor, K.C., V. Viglietta, and D. A. Hafler. 2005. Principles of Autoimmunity. In Clinical Neuroimmunology. J. Antel, ed. Oxford University Press, Oxford.

3. O'Connor, K. C., S. V. Cherry, and D. A. Hafler. 2006. Autoantibodies and B cells in multiple sclerosis and other inflammatory neurological diseases. In Immunotherapy of autoimmune disease. J. Zhang, and S. M. Skinner, eds. Springer, New York.

Links of interest

Cousin Thomas visits the laboratory