Cooper Medical School of Rowan University
Department of Biomedical Sciences
401 South Broadway, Suite 542
Camden, NJ 08103
Education and Training:
1993 PhD in Human Genetics, University of Torino, Italy
1991-1997 Research training/post-doctoral work at Columbia University College of Physicians and Surgeons
NYC and Harvard Medical School, Boston MA
1993-1995: Junior faculty, University of Siena, Italy
1998-2012: Assistant Professor-Associate Professor of Medicine at the University of Rochester School Medicine, Rochester, NY
2012-current: Professor - Cooper Medical School of Rowan University, Camden, NJ
B lymphocytes, inflammation and autoimmunity
The Bottaro lab has focused for many years on the role of B lymphocytes in normal immune responses and disease states such as autoimmunity and cancer. B lymphocytes are the cells of the adaptive immune system best known for producing antibodies that bind to and inactivate foreign substances (antigens) and invading pathogens. In recent years, a wealth of evidence has also emerged indicating that B cells play more subtle, but critical regulatory roles on immune responses, based on their ability to secrete soluble factors (cytokines) and to directly influence the behavior of other immune system components, such as T cells. The same mechanisms have been implicated in autoimmune diseases, such as rheumatoid arthritis, type I diabetes and lupus, in which the immune system directs its activity against the organism's own ("self") tissues and cells, causing inflammation and damage to target organs.
Far less well understood are the mechanisms by which inflammatory processes exert effects on B lymphocytes that modulate their functional properties, and in turn modify the outcome of immune activation. Based on published work in a mouse model of rheumatoid arthritis, and parallel human studies, our lab has identified significant changes in expression of surface proteins as well as functional properties in B lymphocytes exposed to proinflammatory signals in lymph nodes draining arthritic joints or other sites of inflammation. We have hypothesized that these changes can have dramatic effects on immune responsiveness, as well as on the onset and progression of autoimmune disease (see figure 1).
Figure 1 - Effects on inflammatory signals on lymph node-resident B cells. Inflammatory signals are carried from peripheral sites into the draining lymph nodes via multiple pathways, including cytokine-mediated signals, inflammatory molecular patterns from pathogens (PAMPs) or damaged cells (DAMPs), through the immigration of cells (eg, dendritic cells , DCs, neutrophils, NFs), and/or indirectly via activation of resident cells such as macrophages (MFs) and lymph node stromal cells. We have shown that a major outcome of these signals is the induction of changes in resident B cells, resulting in accumulation of a novel B cell population (B cells in inflamed nodes, or Bin cells) with increased expression of functionally significant surface markers such asCD21/35 and CD1d. We have shown that up-regulation of CD21/35, a receptor for complement components, allows Bin cells to capture and process antigen-containing immune complexes, and likely present these antigens to helper T cell (Th) via anon-conventional ("non-cognate") pathway. We propose that in typical, transient acute inflammatory conditions (blue boxes) this non-cognate presentation mechanism serves to enhance and accelerate immune responsiveness to potentially harmful antigens, but that in chronic inflammation its long-term persistence can result in a breakdown of the regulatory mechanisms (tolerance) that prevent response of the immune system against "self" antigens, and therefore promote the onset of autoimmune disease. This is a new hypothesis compared to conventional models of autoimmunity in which tolerance breakdown precedes the onset of inflammation.
Our current research utilizes state-of-the-art in vivo immunological assays, cell and molecular approaches, and in vitro culture systems in both human samples and mouse disease models to characterize the proinflammatory cytokines involved in these B cells changes,establish their long-term immunological implications, and extend their significance with regard to human disease.
1: Fischer BD, Ho C, Kuzin I, Bottaro A, O'Leary ME. Chronic exposure to tumor necrosis factor in vivo induces hyperalgesia, upregulates sodium channel gene expression and alters the cellular electrophysiology of dorsal root ganglion neurons. Neurosci Lett. 2017;653:195-201. PMID: 28118521
2: Bouta EM, Kuzin I, de Mesy Bentley K, Wood RW, Rahimi H, Ji RC, Ritchlin CT, Bottaro A, Xing L, Schwarz EM. Brief Report: Treatment of Tumor Necrosis Factor-Transgenic Mice With Anti-Tumor Necrosis Factor Restores Lymphatic Contractions, Repairs Lymphatic Vessels, and May Increase Monocyte/Macrophage Egress. Arthritis Rheumatol. 2017;69:1187-1193. PMID: 28118521; PMC5449211.
3: Kuzin II, Kates SL, Ju Y, Zhang L, Rahimi H, Wojciechowski W, Bernstein SH, Burack R, Schwarz EM, Bottaro A. Increased numbers of CD23(+) CD21(hi) Bin-like B cells in human reactive and rheumatoid arthritis lymph nodes. Eur J Immunol. 2016; 46:1752-7. PMID: 27105894; PMCID: PMC4942352.
4: Han BK, Olsen NJ, Bottaro A. The CD27-CD70 pathway and pathogenesis of autoimmune disease. Semin Arthritis Rheum. 2016;45:496-501. PMID: 26359318.
5: Han BK, Kuzin I, Gaughan JP, Olsen NJ, Bottaro A. Baseline CXCL10 and CXCL13 levels are predictive biomarkers for tumor necrosis factor inhibitor therapy in patients with moderate to severe rheumatoid arthritis: a pilot, prospective study. Arthritis Res Ther. 2016;18:93. PMID: 27102921; PMCID: PMC4840903.
6: Kuzin II, Bouta EM, Schwarz EM, Bottaro A. TNF signals are dispensable for the generation of CD23+ CD21/35-high CD1d-high B cells in inflamed lymph nodes. Cell Immunol. 2015;296:133-7. PMID: 25959608; PMCID: PMC4509818.