Laboratory of Autoimmune and Musculoskeletal Disorders
Betty Diamond, MD 350 Community Drive |
The Diamond Laboratory is interested in the regulation of the B cell repertoire and the pathogenicity of autoantibodies.
These are many diseases characterized by the presence of autoantibodies although the contribution of the autoreactive B cells and autoantibodies to tissue injury in these diseases are often unclear. In particular, we study DNA-reactive B cells in the autoimmune disease systemic lupus erythematosus. We are interested in the alterations within B cells that lead to the survival and activation of DNA-reactive B cells and in the alterations in other cells of the immune system that affect B cell function and can also lead to the survival and activation of DNA-reactive B cells. We are especially interested in the regulation of autoreactive B cells that acquire their autoreactivity by somatic mutation during a germinal center response and in determining whether the processes that govern the selection of the B cell repertoire early in B cell development are the same as those that govern selection after activation. These studies are designed to provide new strategies to protect against autoimmune disease.
We are also interested in whether autoantibodies in individuals with autoimmune disease, or, indeed, protective antibodies in non-autoimmune individuals might frequently cause brain injury if they penetrate the blood-brain barrier. It is our hypothesis that antibodies may frequently contribute to acquired changes in cognition or behavior.
Research Description
Regulation of B cell repertoire
We are interested in the regulation autoreactive B cells as they mature to immunocompetence. We are particularly interested in the B cell receptor signaling pathway. It is our hypothesis that B cell hyporesponsiveness to antigen during early development allows autoreactive B cell to enter the native B cell repertoire. We have evidence that antigen mediates positive selection as well as negative selection of transitional B cells. We are interested in delineating those conditions in which positive selection predominates and those conditions in which negative selection is triumphant.
We are investigating the regulation of B cells that respond to antigen and acquire autoreactivity. We have shown that a process termed receptor editing causes post-germinal center B cells to express a new light chain in an effort to transform an autoreactive B cell receptor into one that is not autoreactive.
Hormonal effects on B cell development and selection
Most autoimmune disease are more common in women and there is strong evidence that estrogen contributes to this female predisposition to autoimmune disease. We are studying the impact of estrogen on B cell receptor signaling and B cell maturation to a marginal zone phenotype. We are further trying to understand if estrogen alters the germinal center response as it has been shown to regulate both RAG and AID expression.
Dendritic cell regulation of B cell function
We have been studying how alterations in function of dendritic cells can determine B cell selection and maturation. These studies provide information on a important link between the innate and the adaptive immune systems and will help identify new pathways for therapeutic intervention in autoimmune disease.
Antibodies and brain function
We have become very interested in a subset of anti-DNA antibodies that cross-reacts with NMDA receptors and alters function in adult brain following a breach in the blood-brain barrier and alters fetal brain development as a consequence of in utero exposure to maternal antibodies. We have recently extended our studies of anti-brain antibodies to ask whether these might account for some cases of autism and post-traumatic stress disorder.
Lab Members:
Name: Giovanni Franchin, MD, PhD
Position: Assistant Investigator
Research: Studies the role of leptin in the immune system. The hormone plays a direct role in B cell function and may serve as a potential target in autoimmune disorders including lupus.
E-mail: gfranchi@nshs.edu
Name: Czeslawa Kowal, PhD
Position: Assistant Investigator
Research: Studies how human lupus autoantibodies against NMDA receptors mediate cognitive impairment.
E-mail: ckowal@nshs.edu
Name: Dun Zhou, PhD
Position: Postdoctoral Research Fellow
Research: Studies antibodies that target the NMDA receptor.
Name: Hajime Yoshifuji, MD, PhD
Position: Postdoctoral Research Fellow
Research: Studies systemic lupus erythematosus and other autoimmune diseases.
E-mail: hyoshifuji@nshs.edu
Name: Joel Cohen-Solal, PhD
Position: Postdoctoral Research Fellow
Research: Studies the genetics of estrogen responsiveness in the immune system and Rheumatoid Arthritis.
E-mail: jcohenso@nshs.edu
Name: Paola Mina-Osorio, MD, PhD
Position: Postdoctoral Research Fellow
Research: Studies blood brain barrier inflammatory mediators in autoimmune diseases.
E-mail: pminaoso@nshs.edu
Name: Sunjung Kim, PhD
Position: Postdoctoral Research Fellow
Research: Studies dendritic cell function and the impact of altered dendritic cell function in B-cell response.
E-mail: sjkim@nshs.edu
Name: Myoungsun Son, PhD
Position: Postdoctoral Research Fellow
Education: Ph.D. in Immune biology at Molecular Life Science, Ewha Women’s University, Seoul Korea
Research: In the study of the role of IgG or IgM anti-DNA antibodies in SLE.
E-mail: mson@nshs.edu
Name: Li Wang, PhD
Position: Postdoctoral Research Fellow
Education: Ph.D.in the Department of Genetics, School of Medicine, Case Western Reserve University, Cleveland
Research: My research is about whether anti-DNA, anti-NMDA antibodies play a role in determining sex ratio and the mechanism.
E-mail: lwang4@nshs.edu
Name: Nataly Manjarrez Orduno, PhD
Position: Postdoctoral Research Fellow
Education: Ph.D. in Molecular Biomedicine, CINVESTAV, Dept. of Molecular Biomedicine, Mexico
Research: In the study of the genetic variants that confer susceptibility to SLE.
E-mail: nmanjarrez@nshs.edu
Name: Yi Yan, PhD
Position: Postdoctoral Research Fellow
Education: Ph.D. in Biochemistry at Graduate Center of City University of New York, New York
Research: My research is focused on the modulation of the receptor editing in antigen-activated B cells.
E-mail: yyan@nshs.edu
Name: Eitan Giat, MD
Position: Postdoctoral Research Fellow
Education: M.D. in Medical at Hadassa Medical School, Ein Karem, Jerusalem
Research: I am studying pathogenesis-targeted therapy for lupus, by targeting specifically anti-dsDNA producing cells, using SLE mouse models and SLE patient sera.
E-mail: egiat@nshs.edu
Name: Venkatesh Jeganathan, PhD
Position: Research Associate
Research: Studies the effects of estrogen on B cell repertoire, and antigen-specific therapies in lupus.
E-mail: vjeganat@nshs.edu
Name: Eva Bertini
Position: Elmezzi Scholar
Research: Studies the induction and pathology of autoantibodies in rheumatoid arthritis.
E-mail: ebertini@nshs.edu
Name: Oladunni (Dunni) Adeniji
Position: Research Assistant - Technician
E-mail: oadeniji@nshs.edu
Name: Eugene Lee
Position: Research Assistant - Technician
E-mail: elee7@nshs.edu
Name: Jackie Dubuque
Position: Research Assistant
E-mail: jdubuque@nshs.edu
Name: Mei Qi
Position: Research Assistant
E-mail: mqi@nshs.edu
Name: Shanon Loncar
Position: Research Assistant
E-mail: sloncar@nshs.edu
Name: Emiliano Marasco
Position: Research Assistant
E-mail: emarasco@nshs.edu
Publications: (Select Publications since 2000)
Bynoe, MS., Grimaldi, CM. And Diamond, B. Estrogen upregulates Bcl-2 and blocks tolerance induction of naïve B cells. Proc. Natl. Acad. Sci. 97:2703 (2000).
Kuan, AP., Zuckier, L., Liao, L., Factor, SM. and Diamond, B. Immunoglobulin isotype determines pathogenicity in antibody-mediated myocarditis in naïve mice. Circulation Research 86:281 (2000).
Trolle, S., Chachaty, E., Kassis-chikhan, N., Wang, C., Fattal, E., Couvreur, P., Diamond., Alonso, JM. and Andremont, A. Intranasal immunization with protein-linked phosphorylcholine protects mice against a lethal intranasal challenge with Streptococcus pneumoniae. Vaccine. 18:2991 (2000).
Putterman, C., Deocharan, B. and Diamond, B. Molecular analysis of the autoantibody response in peptide-induced autoimmunity. J. Immunol. 164: 2542 (2000).
Malkiel, S., Liao, L., Cunningham, MW. And Diamond, B. The T cell dependent antibody response to the dominant epitope of streptococcal polysaccharide, N-acetyl-glucosamine, is cross-reactive with cardiac myosin. Infection & Immunity 68:5803 (2000).
Harris, SL., Park, MK., Nahm, MH. and Diamond, B. A peptide mimic of phosphorylcholine, a dominant epitope found on Streptococcus pneumonia. Infection & Immunity 68:5778 (2000).
Sieling, PA., Porcelli, SA., Baochau, TD., Spada, F., Bloom, BR., Diamond, B. and Hahn, BH. Human double negative T cells in SLE provide help for IgG and are restricted by CD1c. J.Immunol. 165:5338 (2000).
Peeva, E., Grimaldi, C., Spatz, L., and Diamond, B. Bromocriptine restores tolerance in estrogen-treated mice. J. Clin. Invest. 106:1372 (2000).
Khalil, M., Inaba, K., Steinman, R., Ravetch, J. and Diamond, B. T cell studies in a peptideinduced model of systemic lupus erythematosus. J. Immunol. 166:1667 (2001).
Sharma, A., Isenberg, D., and Diamond, B. Crossreactivity of human anti-dsDNA antibodies to phosphorylcholine: clue to their origin. J. Autoimmunity 16:1 (2001).
Lee, HB., Diamond, BA. and Blaufox, M.D In-vivo detection of deposition of radiolabeled lupus anti-kidney antibody and its inhibition by soluble antigen. J. Nuclear Medicine 42:138 (2001).
Grimaldi, CM., Michael, DJ., and Diamond, B. Expansion and activation of a population ofautoreactive marginal zone B cells in a model of estrogen-induced lupus. Cutting Edge J. Immunol. 167:1886 (2001).
DeGiorgio, LA., Konstantinov, KN., Lee, SC., Hardin, JA., Volpe, BT., and Diamond, B. Novel mechanism for brain injury in SLE: a subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor. Nature Medicine . 7:1189-1193 (2001).
Chu, YP., Taylor, D., Yan, HG., Diamond, B., and Spatz, L. persistence of partially functional double stranded DNA binding B cells in mice transgenic for the IgM heavy chain of an anti-dsDNA antibody. Int. Immunol. 14:45-54 (2002).
Harris, S., Dagtas, AS., Chen, H., and Diamond, B. Regulating the isotypic and idiotypic profile of an anti-PC antibody response: lessons from peptide mimics. Mol. Immunol. 39:263-272 (2002).
Grimaldi, CM., Cleary, J., Dagtas, AS., Moussai, D., and Diamond, B. Estrogen alters thresholds for B cell apoptosis and activation. J. Clin. Invest. 109:1625-1633 (2002).
Newman, J., Rice, JS., Wang, C., Harris, SL., and Diamond, B. Identification of an antigen specific B cell population. J. Immunol. Methods. 272 177-18 (2003).
Sharma, A., Isenberg, D., and Diamond, B. Studies of human polyclonal and monoclonal a antibodies binding to lupus autoantigens and crossreactive antigens. Rheumatology . 42:453-463 (2003).
Peeva, E., Rice, J., Chen, ME., Cleary, J., Michael D., and Diamond, B. Prolactin modulates the naïve B cell repertoire. J. Clin. Invest. 111:275-283 (2003).
Wang, C., Khalil, M., Ravetch, J., and Diamond, B. The naïve B cell repertoire predisposes to antigen-induced systemic lupus erythematosus. J. Immunol. 170:4826-4832 (2003).
Ramanujam, N., Wang, X., Huang, W., Schiffer, L., Grimaldi, C., Akkerman, A., Diamond, B., Madaio, M., and Davidson, A. The mechanism of action of TACI-Ig in murine SLE. J. Immunol. 173: 3524-3534 (2003).
Chu, YP., Spatz, L., and Diamond, B. A second heavy chain permits survival of high affinity autoreactive B cells. Autoimmunity 37:27-32 (2004).
Kowal, C., DeGiorgio, LA., Nakaoka, T., Hetherington, H., Huerta, PT., Diamond, B., and Volpe, BT. Cognition and Immunity: Antibody impairs memory. Immunity 21:179-201(2004).
Grimaldi, CM., Hill, L., Xu, H., Peeva, E., and Diamond, B. Hormonal modulation of B cell development and repertoire selection. Molecular. Immunol. 42:811-820 (2005).
Rice, JS., Newman, J., Wang, C., Michael, DJ., and Diamond, B. Receptor editing in peripheral B cell tolerance. Proc. Natl. Acad. Sci.102:1608-1613 (2005).
Forestier, C., Molano, A., Im, JS., Dutronc, Y., Diamond, B., Davidson, A., Illarionov, PA., Besra, GS., and Porcelli, SA. Expansion and hyperactivity of CD1d-restricted NKT cells during the progression of systemic lupus erythematosus in New Zealand black x New Zealand white) F1 Mice1. J. Immunol. 175:763-770 (2005).
Chowdhry, IA., Kowal, C, Hardin, J., Zhou, Z., and Diamond B. Autoantibodies that bind glomeruli: cross-reactivity with bacterial antigen. Arthritis & Rheumatism 52:2403-2410 (2005).
Peeva, E., Venkatesh, J., and Diamond B. Tamoxifen blocks estrogen-induced B cell maturation, but not survival. J. Immunol. 175:1415-1423 (2005).
Prabhakaran, S., Bramlage, M., Edgar, MA., Diamond, B., Hardin, JA., and Volpe, BT. Overwhelming leukoencephalophay as the only sign of neuropsychiatric lupus. Case Report J. Rheumatol. 32: 1843-1845 (2005).
Petri, M., Kim, M., Kalunian, KC., Grossman, J., Hahn, BH., Sammaritano, L., Lockshin, M., Merrill, JT., Belmont, HM., Askanase, AD., McCune, WJ., Hearth-Holmes, M., Dooley, MA., Feldt, JV., Friedman, A.., Tan, M., Davis, J., Cronin, M., Diamond, B., Mackay, M., Sigler, L., Fillius, M., Rupel, A., and Buyon, JP. Combined oral contraceptives in women with systemic lupus erythematosus. NEJM 353:2550-2558 (2005).
Grimaldi, C., Jeganathan, V., and Diamond, B. Hormonal regulation of B cell development: 17 beta-estradiol impairs negative selection of high affinity DNA-reactive B cells at more than one developmental checkpoint J. Immunol. 176:2703-2710 (2006).
Huerta, PT., Kowal, C., DeGiorgio, LA., Volpe, BT., and Diamond, B. Immunology and behavior: antibodies alter emotion Proc. Natl. Acad. Sci. 103:678-683 (2006).
Roebuck-Spencer, TM., Yarboro, CH., Nowak, M., Takada, K., Jacobs, G., Lapteva, L., Weickert, T., Volpe, B., Diamond, B., Illei, G. and Bleiberg, J. Use of computerized assessment to predict neuropsychological functioning and emotional distress in patients with systemic lupus erythematosus (SLE). Arthritis Care and Rheumatism 55:434-441(2006).
Lapteva, L., Nowak, M., Yarboro, CH., Takada, K., Roebuck, T., Weickert, T., Bleiberg, J., Rosenstein, D., Pao, M., Volpe, B., Diamond, B and Illei, G. Anti-N-Methyl-D-Aspartate (NMDA) Receptor antibodies, cognitive dysfunction and depression in Systemic Lupus Erythematosus. Arthritis & Rheumatism 54:2505-2514 (2006).
Venkatesh, J., Peeva, E., Xu, X. and Diamond, B. Hormonal milieu, not antigenic specificity, determines the mature phenotype of autoreactive B cells. Cutting Edge J. Immunol. 176:3311-3314 (2006).
Ramanujam, M., Wang, X., Huang, W., Liu, Z., Schiffer, L., Tao, H., Frank, D., Rice, J., Diamond, B., YU, K., Porcelli, S. and Davidson, A. Similarities and differences between selective and non-selective BAFF blockade in murine SLE. J. Clin. Invest. 116:724-734 (2006).
Peeva, E., Gonzalez,J., Hicks, R. and Diamond, B. Lupus susceptibility interval Sle3/5 confers responsiveness to prolactin in C57Bl6 mice. Cutting Edge J. Immunol. 177:1401-1405 (2006).
Mackay, M., Stanevsky, A., Wang, T., Aranow, C., Li, M., Koening, S., Ravech, JV. and Diamond, B. Selective dysregulation of the FC (gamma)IIB receptor on memory B cells in SLE. J. Exp. Med. 203:2157-2164 (2006).
Kowal, C., DeGiorgio, LA., Lee, JY., Edgard, ME., Huerta, PT., Volpe, BT. and Diamond B. Human lupus autoantibodies against NMDA receptors mediate cognitive impairment. Proc. Natl. Acad. Sci. 103:19854-19859 (2006).
Tseng, CE., Buyon, JP., Kim, M., Belmont, HM., Mackay, M., Diamond, B.,Marer, G., Rosenthal, P., Haines, K., Ilie, V. and Abramson, SB. The effect of moderate-dose corticosteroids in preventing severe flares in patients with serologically active, but clinically stable, systemic lupus erythematosus: findings of a prospective, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 54:3623-3632 (2006).
Boder, J., Fehervari, Z., Diamond, B and Sakaguchi, S. ICER/CREM-mediated transcriptional attenuation of IL-2 and its role in suppression by regulatory T cells. Eur. I Immunol. 37:884-895 (2007).
Looney, RJ., Diamond, B., Hoers, VM., Levesque, MC., Moreland, L., Nahm, MN. and St. Clair,EW. Guidelines for assessing immunocompetency in clinical trials for autoimmune disease. Clinical Immunol. 123:235-243 (2007).
Kim, SJ. and Diamond, B. Generation and maturation of bone marrow-derived DCs under serum-free conditions. J. Immunol Methods. 323:101-108 (2007).
Batova, I., Kowal, C., May, R., Scharff, MD. and Diamond, B Human recombinant fab fragments with sub-nanomolar affinities for acetylated histones. J. Immunol Methods. 329:1-10 (2008).
Jacobi, AN., Reiter, K., Mackay, M., Aranow, C., Hiepe, F., Radbruch, A., Hansen, A., Burmester, GR., Diamond, B., Lipsky, PE. and Dorner. T. Activated memory B cell sub-sets correlate with disease activity in SLE: Delineation by expression of CD27, IgD, and CD95. Arthritis & Rheumatism 58:1768-1773 (2008).
Wang, Y. and Diamond, B. B cell receptor revision diminishes the autoreactive B cell response after antigen activation in mice. JCI 118:2896-2907 (2008) PMC2467385.
Kim, SJ., Caton, M., Wang, C., Khalil, M., Zhou, ZJ., Hardin, J. and Diamond, B. Increased IL-12 inhibits B cells differentiation to germinal center cells and promotes differentiation to short lived plasmablasts. J Exp Med. 205:2437-2448 (2008) PMC2556778.
Zhang, J., Jacobi, AM., Mackay, M., Aranow, C., Wang, T., Chinnasamy, P. and Diamond, B. Identification of DNA-reactive B cells in patients with SLE. J. Immunol. Methods 338:79-84 (2008). PMC2577778.
Zhang, J., Jacobi, AM., Wang, T. and Diamond, B. Pathogenic autoantibodies in systemic lupus erythematosus are derived from both self-reactive and non-self-reactive B cells. Molecular Med. 14:675-681(2008) PMC2493535.
Fragoso-Loyo, H., Cabiedes, J., Orozco-Narvaez, O., Davila-Maldonado, L., Atisha-Fregoso, Y., Diamond, B., Llorente, L, Sanchez-Guerrero, J. Serum and cerebrospinal fluid autoantibodies in patients with neuropsychiatric lupus erythematosus. Implications for diagnosis and pathogenesis PloS One 10:3347-54 (2008) PMC2556096.
Venkatesh, J., Kawabata, D., Kim, Xu, X., Chinnasamy, P., Paul, E., Diamond, B. and Grimaldi, CM. Selective regulation of autoreactive B cells by FcγRIIB J. Autoimmunity (in press).
Lee, YI., Huerta, PT., Zhang, J., Kowal, C., Bertini, E., Volpe, BT. and Diamond, B. Maternal lupus and congenital cortical impairment Nature Med 15:91-96 (2009). PMC2615794.