T Lymphocytes are normally tolerant to the cells, tissues and molecules that characterize our self-constituents as a result of “education” processes associated with T cell development in the thymus. However, in autoimmune diseases such as systemic lupus erythematosus T cells appear that react to various self-molecules, indicating that T cell tolerance mechanisms have failed. A lupus-like disease can also be induced by chronic exposure to certain medications (“xenobiotics”), and our studies suggest that these drugs act to prevent the acquisition of self-tolerance during positive selection as T cells undergo development in the thymus (figure).
We have investigated the cellular and molecular basis for the capacity of lupus-inducing drugs to disrupt central T cell tolerance. This was done using an in vitro model system that mimics some of the process taking place during T cell development in the thymus, and we developed a mouse model for drug-induced lupus in which autoreactive T cells and anti-chromatin autoantibodies develop after injection of a lupus-inducing drug into the thymus. This animal model is useful in understanding the origin and pathogenesis of this type of autoimmune disease as well as the role of autoreactive B cells that have the same specificity as those is systemic lupus erythematosus.
Autoantibodies are characteristic of patients with autoimmune diseases and are useful biomarkers for the diagnosis and management of patients. Currently, tests for autoantibodies are performed in centralized clinical laboratories, delaying results and physician action. We are developing a biosensor with an electrochemical-based digital readout that measures autoantibodies in less than thirty minutes. This point-of-care device is inexpensive and portable, making it suitable for use in clinics, and is undergoing further refinements.
Selected PublicationsLink to PubMed
Kretz-Rommel, A. and Rubin, R. L. (1999) Persistence of autoreactive T cell drive is required to elicit anti-chromatin antibodies in a murine model of drug-induced lupus. J. Immunol. 162, 813-820.
Kretz-Rommel, A. and Rubin, R. L. (2000) Disruption of positive selection of thymocytes causes autoimmunity. Nature Medicine 6, 298-305.
Kretz-Rommel, A. and Rubin, R. L. (2001) Early cellular events in systemic autoimmunity driven by chromatin-reactive T cells. Cellular Immunology 208, 125-136.
Rubin, R. L., Salomon, D. R. and Guerrero, R. S. (2001) Thymus function in drug-induced lupus. Lupus 10, 795-801.
Rubin, R.L. and Kretz-Rommel, A. (2001) A non-deletional mechanism for central T cell tolerance. Critical Reviews in Immunology, 21, 29-40.
Rubin, R. L., Teodorescu, M., Beutner, E. H., and Plunkett, R.W. (2004) Complement-fixing properties of antinuclear antibodies distinguish drug-induced lupus from systemic lupus erythematosus, Lupus 13: 249-256.
Rubin, R. L. and Kretz-Rommel, A. (2004) Drug-Induced Autoimmunity. In Stem Cell Therapy of Autoimmune Disease, R.K. Burt and A. Marmont, eds, R.G. Landes Biosciences, Georgetown, TX, 173-181.
Rubin, R. L. Antihistone antibodies. (2004) In Systemic Lupus Erythematosus, 4th edition, R.G. Lahita, ed., Elsevier Academic Press, San Diego, 325-348.
Teodorescu, M., Ustiyan V., Russo, K. and Rubin, R. L. (2004) Binding to histone of an anomalous IgG from patients with SLE and drug-induced lupus, J. Clin. Immunol. 110:145-153.
Rubin, R. L. and. Hermanson, T. M. (2005) Plasticity in the positive selection of T cells: affinity of the selecting antigen and IL-7 affect T cell responsiveness, International Immunology 17: 959-971.
Rubin, R. L. (2005) Drug-induced lupus, Toxicology, 209: 135-147.
Rubin, R. L., Hermanson, T. M., Bedrick, E. J., McDonald, J. D., Burchiel, S.W., Reed, M. D. and Sibbitt, W. L. (2005) Effect of cigarette smoke on autoimmunity in murine and human systemic lupus erythematosus, Toxicological Sciences, 87: 86-96.
Rubin, R. L. (2006) Central and peripheral tolerance, In Autoantibodies and Autoimmunity: Molecular Mechanisms in Health and Disease, K. M. Pollard, ed., Wiley-VCH.
Konstantinov, K. N., Sitdikov, R. A., Lopez, G. P., Atanassov, P., and Rubin, R. L. (2009) Rapid detection of anti-chromatin autoantibodies in human serum using a portable electrochemical biosensor, Biosensors and Bioelectronics, 24, 1949-1954.
Rubin, R. L. (2010) Lupus erythematosus syndrome induced by drugs In Drug-Induced and Iatrogenic Lung Disease, Ph. Camus and E. C. Rosenow, eds., Hodder Arnold, London, 297-307.
Konstantinov, K., Tzamaloukas, A., and Rubin, R.L., (2013) Detection of autoantibodies in a point-of-care rheumatology setting, Autoimmunity Highlights, 4: 55-61.
Rubin, R.L., Wall, D., and Konstantinov, K.N., (2014) Electrochemical biosensor for quantitation of anti-DNA autoantibodies in human serum, Biosensors and Bioelectronics, 51, 177-183.