Research

Job opportunity

Post-doctoral research scholar position is available In the Tsokos Lab. Self-motivated scholars that demonstrate a passion for research along with a comprehensive working knowledge of common laboratory techniques in Immunology are encouraged to apply. Expertise in flow cytometry and molecular biology and bioinformatics is desired. A PhD or MD/PhD in a relevant field is required. Fluency in English, strong communication skills and the ability to work independently as well as within a team of colleagues are also essential. Successful candidates will benefit from a dynamic and highly collaborative environment and the opportunity to interact with the extended scientific community at HMS. To be considered for the position please send a letter of interest and your CV to George C. Tsokos (gtsokos@bidmc.havard.edu).

Research Area

Pathogenesis of systemic lupus erythematosus

Our research has focused on the cellular and molecular pathogenesis of systemic lupus erythematosus (SLE). We opened and led the field of molecular abnormalities on immune cells in patients with SLE. Our laboratory performs biochemical, molecular biology and cellular studies of immune and kidney cells using human material and genetically engineered mice.  Molecules that are identified to contribute to immune cell malfunction are further exploited by constructing normal or lupus-prone mice engineered to express or lack each molecule to confirm their significance in vivo.  A number of targets have entered or are considered to enter clinical trials by pharma. More recently we conduct studies to understand how immune elements interact with kidney resident cells. We have been uncovering mechanisms whereby resident cells through specific molecular pathways determine whether, in the context of autoimmunity, inflammation and damage will occur.

Tsokos GC. Systemic lupus erythematosus. N Engl J Med. 2011 Dec 1;365(22):2110-21.

Pathogenesis of SLE

Individual Projects

  • Aberrant early lymphocyte signaling in SLE.  T lymphocytes from patients with SLE display increased and aberrant early signaling response because the T cell receptor is “rewired”. 
  1.   Liossis, S. N. C., Ding, X. Z., Dennis, G. J. and Tsokos, G. C.  (1998).  Altered TCR/CD3-mediated protein-tyrosyl phosphorylation in T cells from patients with systemic lupus erythematosus. Deficient expression of T-cell receptor z chain.  J. Clin Invest. 101:1448-1457. PMC508723.
  2. Moulton, V. R., Grammatikos, A.P., Fitzgerald, L. M., Tsokos, G. C. (2013). The splicing factor SF2/ASF rescues IL-2 production in T cells from SLE patients by activating IL-2 transcription.  Proc. Natl. Aca. Sci. USA. 110(5):1845-5. PMC3562779
  3. Katsuyama, E., Suarez-Fueyo, A., Bradley, S. J., Kono, M., Kyttaris, V. C., Mizui, M., Mulki, L., Malavasi, F., Tsokos. G. C.  (2020). CD38 expression in CD8 T cells compromises cytotoxic function and identifies patients with systemic lupus erythematosus prone to infections. Cell Reports. 30: 112-123.
  4. Chen, P.M., Katsuyama, E., Satyam, A., Li, H., Rubio, J., Jung, S., Andrzejewski, Becherer, D., Tsokos, M. G., Abdi, R., Tsokos, G. C. (2022). CD38 reduces mitochondrial fitness and cytotoxic T cell response against viral infection in lupus patients by suppressing mitophagy.  Science Adv. 2022 Jun 17;8(24):eabo4271.

 

 

 

 

  • cAMP response element modulator alpha.  A gene and function study unveils the molecular underpinnings of antithetic production of IL-2 and IL-17 in SLE. 
  1. Hedrich C. M., Crispin, J. C. Rauen, T., Ioannidis, C., Lo, M. S., Kyttaris, V. C., and Tsokos, G. C. (2012).  cAMP responsive element modulator (CREM) a mediates CpG-DNA methylation of IL-2 and IL17A during CD4 lineage commitment and contributes to T cells subset distribution in SLE.  Proc. Natl. Aca. Sci. USA.  109:16606-11. PMC3478624.
  2. Yoshida, N., Comte, D., Mizui, M., Otomo, K., Rosetti, F., Mayadas, T. N., Crispín, J. C., Bradley, S., Koga, T., Kono, M., Tenbrock, K., Karampetsou, M., Kyttaris, V. C., and Tsokos, G. C.  (2016). ICER controls Th17 cell differentiation and regulates autoimmune pathology. Nature Commun. 29;7:12993. doi: 10.1038/ncomms12993. 
  3. Kono, M., Yoshida, N., Maeda, K.,  Tsokos, G. C. (2018). Transcriptional factor ICER promotes Glutaminolysis and the generation of Th17 cells. Proc. Natl. Aca. Sci. USA. 115(10):2478-2483.
  4. Li,  P., Jiang, M., Li, K., Xiao, X., Zhou, Y., Li, H., Xu, Y., Krisfield, S, Lipsky, P. E., Tsokos, G.C. (corresponding author),  Zhang, X. (2021). Glutathione peroxidase 4 regulated neutrophil ferroptosis induces systemic autoimmunity. Nature Immunol. 22(9):1107-1117. Research highlights in:  Ohl, K., Rauen, T., Tenbrock, K., Dysregulated neutrophilic cell death in SLE: a spotlight on ferroptosis.  Signal Transduction and Targeted Therapy (2021)6:392;Pan, Z., Naowarojna, N., Wang, Y. et al. Neutrophil ferroptotic death promotes autoimmune pathogenesis. Sci. China Life Sci. (2021). https://doi.org/10.1007/s11427-021-2014-4; Mao, C., Lei, G., Zhuang, L., Gan, B. Ferroptosis as an important driver of lupus. Protein & Cell, https://doi.org/10.1007/s13238-021-00892-1

 

 

  • Double Negative (DN) Cells.   CD3positive but CD4 and CD8 negative T cells are expanded in patients with SLE and provide help to B cells to produce anti-DNA antibodies and produce IL-17 and infiltrate the kidney
  1. Hedrich, C. M., Crispin, J. C., Rauen, T., Ioannidis, C., Koga, T., Rodriguez Rodriguez, N., Apostolidis, S. A., Kyttaris, V. C., Tsokos, G. C.   (2014).  cAMP responsive element modulator (CREM)α mediates chromatin remodeling of CD8 during the generation of CD3+CD4-CD8- T cells.  J. Biol. Chem. 289(4):2361-70. PMC3900979
  2. Li, H., Tsokos, M. G., Bickerton, S., Sharabi, A., Li, Y., Moulton, V. R. Fahmy, T. M., Tsokos, G. C. Precision DNA demethylation ameliorates disease in lupus-prone mice. JCI (Insight) doi.org/101172/jci.insight.120880.
  3. Li H, Adamopoulos IE, Moulton VR, Stillman IE, Herbert Z, Moon JJ, Sharabi A, Krishfield S, Tsokos MG, Tsokos GC. Systemic lupus erythematosus favors the generation of IL-17 producing double negative T cells. Nature Commun. 2020 Jun 5;11(1):2859. doi: 10.1038/s41467-020-16636-4. PubMed PMID: 32503973.
  4. Li, H., Tsokos, M. G., Bhargava, R., Adamopoulos, I. E., Menn-Josephy, H., Stillman, I, E., Jordan, J., Rosenstiel, P.,  Tsokos, G. C.  IL-23 acts renal tubular epithelial cells to drive lymphoid follicle formation in the kidney independent of IL-17.  J. Clin. Invest. 2021 May 6:142428. doi: 10.1172/JCI142428

 

 

  • Calcium Calmodulin Kinase 4 in SLE. A treatment target - CaMK4 is increased in SLE T cells and tissue resident cells.
  1. Juang, Y. T., Wang, Y., Solomou, E. E., Mawrin, C., Tenbrock, K., Kyttaris, V. C., and Tsokos, G. C.  (2005). Systemic lupus erythematosus serum Ig increases CREM binding to the IL-2 promoter and suppress IL-2 production through CaMKIV.  J. Clin. Invest. 115: 996-1005. PMC1070410.
  2. Koga, T., Hedrich, C., Mizui, M., Yoshida, N., Lieberman, L. A., Rauen, T., Crispín, J. C.  Tsokos, G. C. (2014). CaMK4 promotes TH17 related autoimmune pathology though Akt/mTOR and CREM-a.  J. Clin. Invest. 124(5):2234-45. PMC4001553.
  3. Maeda, K., Otomo, K., Yoshida, N., Abu-Asab, A. S., Ichinose, K., Nishino, T., Kono, M., Ferretti, A., Maruyama, S., Bickerton, S., Fahmy, T. M., Tsokos, M. G., Tsokos, G. C. 2018. Podocyte-specific delivery of calcium/calmodulin kinase inhibitor prevents autoimmune and drug-induced kidney damage.  J. Clin. Invest. 128(8):3445-345.
  4. Scherlinger, M., Pan, W., Hisada, R., Boulougoura, A., Yoshida, N., Vukelic, M., Umeda, M., Krishfield, S., Tsokos, M. G., Tsokos, G. C. Phosphofructokinase P fine-tunes T regulatory cell metabolism, function and stability in systemic autoimmunity. Science Adv. 8, eadc9657 (2022)
  5. Scherlinger M, Li H, Pan W, Li W, Karino K, Vichos T, Boulougoura A, Yoshida N, Tsokos MG, Tsokos GC. CaMK4 controls follicular helper T cell expansion and function during normal and autoimmune T-dependent B cell responses. Nat Commun. 2024;15(1):840.

 

 

Media Select

  • The first Ser/Thr Phosphatase (PP2A) in autoimmunity. 
  1. Katsiari, C. G., Kyttaris, V. C., Juang, Y. T. and Tsokos, G. C.   (2005).  Protein phosphatase 2A is a negative regulator of IL-2 production in patients with systemic lupus erythematosus. J. Clin. Invest. 115: 3193–3204 PMC1253625
  2. Crispin, J. C. Apostolidis, S. Finnell, M. and Tsokos, G. C. (2011). Induction of PP2A Bb, a novel regulator of IL-2 deprivation-induced T cell apoptosis, is deficient in systemic lupus erythematosus.  Proc. Natl. Aca. Sci. USA.108: 12443-12448. PMC3145691
  3. Apostolidis, S. A., Rodriguez-Rodriguez, N., Fueyo-Suarez, A., Dioufa, N., Crispin, J. C., Ezcan, E., Tsokos, M. and Tsokos, G. C.  (2016).  Protein phosphatase 2a is requisite for the function of regulatory T cells.  Nature Immunol.  17; 556- 564.    Commentary by G. M. Delgoffe PP2A’s restraint on mTOR is critical for Treg cell activity.Nature Immunol. 17: 478-479.  Commentary in The Rheumatologist.
  4. Pan, W., Nagpal, K., Suarez-Fueyo, A., Ferretti, A., Tsokos, M. G., Tsokos, G. C. (2021). The regulatory subunit PPP2R2A of PP2A enhances Th1 and Th17 differentiation through activation of the GEF-H1/RhoA/ROCK signaling pathway. J. Immunol.  206(8):1719-1728

 

 

 

  • Immunopathogenesis of lupus neprhritis. Little is known about the pathogenesis of lupus nephritis (LN), particularly as it relates to the initiation and propagation of the inflammatory response which accounts for the development or end stage renal disease. LN may complicate up to two thirds of patients with systemic lupus erythematosus with higher rates commonly seen among minorities and children.   Besides the needle kidney biopsy, we lack tools that reflect tissue pathology with fidelity. Although two drugs have been recently approved to treat patients with LN, all treatment protocols involve systemic administration of drugs or biologics which are laden with side effects and limited clinical efficacy.    Ample evidence has revealed that kidney resident cells and newly formed high endothelial venules in the presence of an autoinflammatory environment, upregulate molecules which account for the ensuing inflammation and cell damage, while in their absence, kidney damage is averted.  These molecular changes can be recorded in parallel in podocytes and tubular epithelial cells in the urine.  This project will test the hypothesis that interaction of constituents of the immune system with kidney resident cells and the  ectopically formed high endothelial venules, determines the development of inflammation and injury in the setting of LN: 1) Interplay between autoimmune effectors and kidney resident cells in lupus nephritis and 2) Newly formed high endothelial cells in the kidney- pathogenesis and implications in lupus nephritis.

a. Tsokos, G. C. Autoimmunity and organ damage in systemic autoimmunity.  Nature Immunol.  21, 605-614, 2020.

b. Tsokos, G. C.  Boulougoura, A., Kasinath, V., Abdi, R., Li, H. The immunoregulatory roles of non-haematopoietic cells in the kidney. Nature Rev. Nephrol. 2023 Nov 20. doi: 10.1038/s41581-023-00786-x

 

 

 

  • Abend, A. H., He, I., Bahroos, N., Christianakis, S., Crew, A. B., Wise, L. M., Lipori, G. P., He, X., Murphy, S. N., Herrick, C. D., Avasarala, J., Weiner, M. G., Zelko, J. S., Matute-Arcos, E., Abajian, M., Payne, P. R., Lai, A. M., Davis, H. A., Hoberg, A. A., … Fairweather, D. (2024). Estimation of prevalence of autoimmune diseases in the United States using electronic health record data.. The Journal of Clinical Investigation. https://doi.org/10.1172/JCI178722 (Original work published 2024)
    Publisher's Version

    BACKGROUND: Previous epidemiologic studies of autoimmune diseases in the United States (US) have included a limited number of diseases or used meta-analyses that rely on different data collection methods and analyses for each disease.

    METHODS: To estimate the prevalence of autoimmune diseases in the US, we used electronic health record data from six large medical systems in the US. We developed a software program using common methodology to compute the estimated prevalence of autoimmune diseases alone and in aggregate that can be readily used by other investigators to replicate or modify the analysis over time.

    RESULTS: Our findings indicate that over 15 million people, or 4.6% of the US population, have been diagnosed with at least one autoimmune disease from January 1, 2011, to June 1, 2022, and 34% of those are diagnosed with more than one autoimmune disease. As expected, females (63% of those with autoimmune disease) were almost twice as likely as males to be diagnosed with an autoimmune disease. We identified the top 20 autoimmune diseases based on prevalence and according to sex and age.

    CONCLUSION: Thus, we provide, for the first time, a large-scale prevalence estimate of autoimmune disease in the US by sex and age.

    FUNDING: Autoimmune Registry Inc., the National Heart Lung and Blood Institute, the National Center for Advancing Translational Sciences, the Intramural Research Program of the National Institute of Environmental Health Sciences.

  • Maeda, K., Abdi, R., & Tsokos, G. C. (2024). The Role of Podocytes in Lupus Pathology.. Current Rheumatology Reports, 27(1), 10. https://doi.org/10.1007/s11926-024-01175-4 (Original work published 2024)
    Publisher's Version

    PURPOSE OF REVIEW: Kidney injury due to lupus nephritis (LN) is a severe and sometimes life-threatening sequela of systemic lupus erythematosus. Autoimmune injury to podocytes has been increasingly demonstrated to be a key driver of LN-related kidney injury because these cells play key roles in glomerular filtration barrier homeostasis. Irreparable podocyte injury impairs these processes and can lead to proteinuria, which is an indicator of poor prognosis in LN. This review highlights recent advances in our understanding of the involvement of podocytes in the pathogenesis of LN and discusses new podocyte-targeted therapeutic strategies.

    RECENT FINDINGS: Podocytes play a key role in glomerular filtration barrier homeostasis, both by helping to secrete and organize the glomerular basement membrane and by the formation of a glomerular slit diaphragm between adjacent cells. Recent studies revealed the involvement of abnormal calcium signaling, dysregulation of actin-related proteins, and mitotic catastrophe in LN progression. In addition, podocytes express many molecules related to the innate and adaptive immune responses. IgG from patients with LN induces direct injury of podocytes, inflammasome, and interactions with immune cells which have been shown to promote the development of LN. Our understanding of the role of podocytes in the pathogenesis of LN has been improved. Recent studies have shed light on potential therapeutic strategies targeting podocytes to control kidney injury.

  • Rubio, J., Humbel, M., Mulki, L., Katsuyama, E., Krishfield, S., O’Connell, J., Tsokos, G. C., & Kyttaris, V. (2024). Expanded CD8+CD38+ T Cell Population in Patients With Systemic Lupus Erythematosus Is Linked to Increased Infection Rates: A Prospective Study.. ACR Open Rheumatology. https://doi.org/10.1002/acr2.11725 (Original work published 2024)
    Publisher's Version

    OBJECTIVE: One of the leading causes of morbidity and mortality among patients with systemic lupus erythematosus (SLE) is infections. The expression of the ectonucleotidase CD38 on the surface of CD8+ T cells has been linked to compromised cytotoxic function. The aim of this prospective study was to assess whether the presence of CD8+CD38+ in the peripheral blood of patients with SLE can serve as a biomarker for infectious complications.

    METHODS: A cohort of 80 patients with SLE were recruited over 18 months. The rate of clinically significant infections and presence of CD8+CD38+ T cells in the peripheral blood were monitored at each clinic visit. The patients were classified into high CD38+ and low CD38+ CD8+ T cells using flow cytometry and a previously established cutoff rate of 28.4%.

    RESULTS: A total of 20 infections were registered over the study period. We observed that the patients with an expanded CD8+CD38+ T cell population in the peripheral blood had a higher rate of recurrent infections and a higher likelihood of infection compared with patients with a low CD8+CD38+ T cell population. The levels of CD38 in CD8+ T cells remained stable over time in the studied subjects.

    CONCLUSION: High levels of CD8+CD38+ T cells in the peripheral blood of patients with SLE identify a subgroup prone to infections for whom proper clinical measures should be applied.

  • Umeda, M., Karino, K., Satyam, A., Yoshida, N., Hisada, R., Bhargava, R., Vichos, T., Kunzler, A. L., Igawa, T., Ichinose, K., Torigoe, K., Nishino, T., Maeda, T., Owen, C. A., Abdi, R., Kawakami, A., & Tsokos, G. C. (2024). Hypoxia Promotes the Expression of ADAM9 by Tubular Epithelial Cells, Which Enhances Transforming Growth Factor β1 Activation and Promotes Tissue Fibrosis in Patients With Lupus Nephritis.. Arthritis & Rheumatology (Hoboken, N.J.). https://doi.org/10.1002/art.42987 (Original work published 2024)
    Publisher's Version

    OBJECTIVE: Enhanced expression of transforming growth factor (TGF) β in the kidneys of patients with lupus nephritis (LN) can lead to progressive fibrosis, resulting in end-organ damage. ADAM9 activates TGFβ1 by cleaving the latency-associated peptide (LAP). We hypothesized that ADAM9 in the kidney may accelerate fibrogenesis by activating TGFβ1.

    METHODS: We assessed the expression of ADAM9 in the kidneys of mice and humans who were lupus prone. In vitro experiments were conducted using tubular epithelial cells (TECs) isolated from mice and explored the mechanisms responsible for the up-regulation of ADAM9 and the subsequent activation of TGFβ1. To assess the role of ADAM9 in the development of tubular-intestinal fibrosis in individuals with LN, we generated MRL/lpr mice who were Adam9 deficient.

    RESULTS: ADAM9 was highly expressed in tubules from MRL/lpr mice. The transcription factor hypoxia-inducible factor-1α was found to promote the transcription of ADAM9 in TECs. TECs from mice who were Adam9 deficient and exposed to the hypoxia mimetic agent dimethyloxalylglycine failed to cleave the LAP to produce bioactive TGFβ1 from latent TGFβ1. Coculture of TECs from mice who were Adam9 deficient with fibroblasts in the presence of dimethyloxalylglycine and latent TGFβ1 produced decreased amounts of type I collagen and α-smooth muscle actin (SMA) by fibroblasts. MRL/lpr mice who were Adam9 deficient showed reduced interstitial fibrosis. At the translational level, ADAM9 expression in tissues and urine of patients with LN was found to increase.

    CONCLUSION: Hypoxia promotes the expression of ADAM9 by TECs, which is responsible for the development of interstitial fibrosis in patients with LN by enhancing the TGFβ1 activation, which promotes fibroblasts to produce collagen and α-SMA.

  • Katsuyama, E., Humbel, M., Suarez-Fueyo, A., Satyam, A., Yoshida, N., Kyttaris, V. C., Tsokos, M. G., & Tsokos, G. C. (2024). CD38 in SLE CD4 T cells promotes Ca2+ flux and suppresses interleukin-2 production by enhancing the expression of GM2 on the surface membrane.. Nature Communications, 15(1), 8304. https://doi.org/10.1038/s41467-024-52617-7 (Original work published 2024)
    Publisher's Version

    CD38 has emerged as a potential therapeutic target for patients with systemic lupus erythematosus (SLE) but it is not known whether CD38 alters CD4+ T cell function. Using primary human T cells and CD38-sufficient and CD38-deficient Jurkat T cells, we demonstrate that CD38 shifts the T cell lipid profile of gangliosides from GM3 to GM2 by upregulating B4GALNT1 in a Sirtuin 1-dependent manner. Enhanced expression of GM2 causes ER stress by enhancing Ca2+ flux through the PLCγ1-IP3 pathway. Interestingly, correction of the calcium overload by an IP3 receptor inhibitor, but not by a store-operated calcium entry (SOCE) inhibitor, improves IL-2 production by CD4+ T cells in SLE. This study demonstrates that CD38 affects calcium homeostasis in CD4+ T cells by controlling cell membrane lipid composition that results in suppressed IL-2 production. CD38 inhibition with biologics or small drugs should be expected to benefit patients with SLE.