Shu Man Fu

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Primary Appointment

Professor, Medicine- Rheumatology and Immunology

Education

  • MD, Stanford Medical School
  • PhD, Immunology, Rockefeller University, New York, NY
  • Residency, Internal Medicine, Stanford University

Research Interests

Human lymphocyte biology and autoimmunity

Research Description

Autoimmunity plays an important role in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). The emphasis of my laboratory is on the genetic and environmental factors important for these disorders. We have been focused on the mouse model NZM2328 for SLE. This model was characterized by our laboratory and was used to identify genetic loci for susceptibility of SLE. A locus controlling nephritis and anti-dsDNA antibody production was identified. The disassociation of ANA and lupus nephritis was demonstrated in a congenic strain (NZM2328.C57L/J.c4).
The laboratory is focused on identification of the genes involved in the pathogenesis of SLE. In addition, autoantigens which are the target for nephritis in NZM2328.C57L/J.c4 are to be identified. Separate loci for acute and chronic glomerulonephritis (GN) were identified on the distal portion of chromosome 1. The genetic data were confirmed by the phenotypes of a congenic strain (NZM238.C574Jc1). Further mapping by the generation of intrachromosomal recombinant strains of the C1 congenic resulted in an informative strain NZM2328.R27, showing that acute GN need not progress to chronic GN and that acute GN and chronic GN are under separate genetic control.
Current efforts are to elucidate the genes controlling these phenotypes. In addition, the hypothesis that molecular mimicry initiates the initial autoimmune response, which diversifies to multiple autoantigen, resulting in end organ damage in suitable hosts is being tested. The role of MHC in this process in both mice and men is being investigated. In this regard, bacterial and viral agents sharing cross reactive T and B cell epitopes with human auto antigens are logical candidates for molecular mimics in this process.
In collaboration, the laboratory is interested in the mechanisms of autoantibody diversification and the role of T cells in the pathogenesis of glomerulonephritis. Recently we have focused our attention on the role of molecular mimicry to environmental antigens at the T cell level in the generation of lupus related autoantibodies. Our laboratory findings let us put forward a new hypothesis on the pathogenesis of SLE.

Personal Statement

As a medical student and house staff at Stanford University School of Medicine and Stanford University Hospital, I was exposed to research in immunology and systemic lupus erythematosus. As a student and faculty member associated with the late Dr. Henry Kunkel at the Rockefeller University, I was deeply involved in various aspects of human immunological research. During this period, I continued to care for a few patients with SLE and was instrumental in organizing the serum bank in the laboratory. I was primarily responsible for the mapping of the C2 gene (the second complement component) within the MHC. I was involved in the identification of the two chain structures of the HLA-DR molecule and the generation of the homozygous cell line for typing of the HLA-D region. I also developed an interest in the role of MHC as a disease susceptibility gene in autoimmune diseases such as multiple sclerosis (MS), SLE and rheumatoid arthritis. At the Oklahoma Medical Research Foundation (OMRF), I collaborated with Dr. M. Reichlin and Dr. J. Harley to study the linkage of HLA-D region genes to autoantibody production. During the past 15 years, I have adopted NZM2328 as a lupus-nephritis model and have done extensive studies on the mechanisms of autoantibody diversification. We have demonstrated endogenous autoantigens play a crucial role on epitope spreading at the B cell level. This process involved autoreactive T cells to various T cell epitopes within the autoantigen of interest. From these studies, we have gained great insight into the role of crossreactive T cells to autoantigens and conventional environmental antigens in the induction of an autoimmune response to SmD and its peptides.

Training

  • Interdisciplinary Training Program in Immunology

Selected Publications

2022

Zhao, Z., Xu, B., Wang, S., Zhou, M., Huang, Y., Guo, C., . . . Fu, S. M. (2022). Tfh cells with NLRP3 inflammasome activation are essential for high-affinity antibody generation, germinal centre formation and autoimmunity. ANNALS OF THE RHEUMATIC DISEASES, 81(7), 1006-1012. doi:10.1136/annrheumdis-2021-221985

2021

Zhao, Z., Qiao, H., Ge, Y., Kannapel, C. C., Sung, S. -S. J., Gaskin, F., . . . Fu, S. M. (2021). Autoimmune experimental orchitis and chronic glomerulonephritis with end stage renal disease are controlled by Cgnz1 for susceptibility to end organ damage. CLINICAL IMMUNOLOGY, 224. doi:10.1016/j.clim.2021.108675

2020

Sung, S. -S. J., & Fu, S. M. (2020). A novel immunofluorescence detection method for renal cell-type specific in situ cytokine production by confocal microscopy. METHODSX, 7. doi:10.1016/j.mex.2020.100935

Sung, S. -S. J., & Fu, S. M. (2020). Interactions among glomerulus infiltrating macrophages and intrinsic cells via cytokines in chronic lupus glomerulonephritis. JOURNAL OF AUTOIMMUNITY, 106. doi:10.1016/j.jaut.2019.102331

2019

Guo, C., Fu, R., Zhou, M., Wang, S., Huang, Y., Hu, H., . . . Fu, S. M. (2019). Pathogenesis of lupus nephritis: RIP3 dependent necroptosis and NLRP3 inflammasome activation. JOURNAL OF AUTOIMMUNITY, 103. doi:10.1016/j.jaut.2019.05.014

Stremska, M. E., Dai, C., Venkatadri, R., Wang, H., Sabapathy, V., Kumar, G., . . . Sharma, R. (2019). IL233, an IL-2-IL-33 hybrid cytokine induces prolonged remission of mouse lupus nephritis by targeting Treg cells as a single therapeutic agent. JOURNAL OF AUTOIMMUNITY, 102, 133-141. doi:10.1016/j.jaut.2019.05.005

Guo, C., Zhou, M., Zhao, S., Huang, Y., Wang, S., Fu, R., . . . Fu, S. M. (2019). Innate lymphoid cell disturbance with increase in ILC1 in systemic lupus erythematosus. CLINICAL IMMUNOLOGY, 202, 49-58. doi:10.1016/j.clim.2019.03.008

Zhao, Z., Ren, J., Dai, C., Kannapell, C. C., Wang, H., Gaskin, F., & Fu, S. M. (2019). Nature of T cell epitopes in lupus antigens and HLA-DR determines autoantibody initiation and diversification. ANNALS OF THE RHEUMATIC DISEASES, 78(3), 380-390. doi:10.1136/annrheumdis-2018-214125

2017

Fu, S. M., Wang, H., Dai, C., Sung, S. -S. J., & Gaskin, F. (2017). Pathogenesis of proliferative lupus nephritis from a historical and personal perspective. CLINICAL IMMUNOLOGY, 185, 51-58. doi:10.1016/j.clim.2016.07.024

Xu, B., Wang, S., Zhou, M., Huang, Y., Fu, R., Guo, C., . . . Yang, N. (2017). The ratio of circulating follicular T helper cell to follicular T regulatory cell is correlated with disease activity in systemic lupus erythematosus. CLINICAL IMMUNOLOGY, 183, 46-53. doi:10.1016/j.clim.2017.07.004

Fu, R., Guo, C., Wang, S., Huang, Y., Jin, O., Hu, H., . . . Fu, S. M. (2017). Podocyte Activation of NLRP3 Inflammasomes Contributes to the Development of Proteinuria in Lupus Nephritis. ARTHRITIS & RHEUMATOLOGY, 69(8), 1636-1646. doi:10.1002/art.40155

Sung, S. -S. J., Ge, Y., Dai, C., Wang, H., Fu, S. M., Sharma, R., . . . Lawler, J. R. (2017). Dependence of Glomerulonephritis Induction on Novel Intraglomerular Alternatively Activated Bone Marrow-Derived Macrophages and Mac-1 and PD-L1 in Lupus-Prone NZM2328 Mice. JOURNAL OF IMMUNOLOGY, 198(7), 2589-2601. doi:10.4049/jimmunol.1601565

2016

Fu, S. M., & Winchester, R. (2016). A special issue to commemorate the 100th birthday of Henry G. Kunkel, father of clinical immunology: A continuing appreciation of the man, his scientific contributions and his insights to clinical investigation and mentoring. CLINICAL IMMUNOLOGY, 172, 2-20. doi:10.1016/j.clim.2016.07.016

Fu, S. M. (2016). Reflections on my association with Henry G. Kunkel. CLINICAL IMMUNOLOGY, 172, 23-26. doi:10.1016/j.clim.2016.08.005

Chan, A. Y., Punwani, D., Kadlecek, T. A., Cowan, M. J., Olson, J. L., Mathes, E. F., . . . Puck, J. M. (2016). A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70. JOURNAL OF EXPERIMENTAL MEDICINE, 213(2), 155-165. doi:10.1084/jem.20150888

2015

Zhang, H., Huang, Y., Wang, S., Fu, R., Guo, C., Wang, H., . . . Fu, S. M. (2015). Myeloid-derived suppressor cells contribute to bone erosion in collagen-induced arthritis by differentiating to osteoclasts. JOURNAL OF AUTOIMMUNITY, 65, 82-89. doi:10.1016/j.jaut.2015.08.010

Chowdhary, V. R., Dai, C., Tilahun, A. Y., Hanson, J. A., Smart, M. K., Grande, J. P., . . . David, C. S. (2015). A Central Role for HLA-DR3 in Anti-Smith Antibody Responses and Glomerulonephritis in a Transgenic Mouse Model of Spontaneous Lupus. JOURNAL OF IMMUNOLOGY, 195(10), 4660-4667. doi:10.4049/jimmunol.1501073

Zhao, J., Wang, H., Huang, Y., Zhang, H., Wang, S., Gaskin, F., . . . Fu, S. M. (2015). Glycogen Synthase Kinase 3 beta Promotion of Renal Damage Through Activation of the NLRP3 Inflammasome in Lupus-Prone Mice. ARTHRITIS & RHEUMATOLOGY, 67(4), 1036-1044. doi:10.1002/art.38993

Zhang, H., Wang, S., Huang, Y., Wang, H., Zhao, J., Gaskin, F., . . . Fu, S. M. (2015). Myeloid-derived suppressor cells are proinflammatory and regulate collagen-induced arthritis through manipulating Th17 cell differentiation. CLINICAL IMMUNOLOGY, 157(2), 175-186. doi:10.1016/j.clim.2015.02.001

Fu, S. M., Dai, C., Zhao, Z., & Gaskin, F. (2015). Anti-dsDNA Antibodies are one of the many autoantibodies in systemic lupus erythematosus.. F1000Research, 4(F1000 Faculty Rev), 939. doi:10.12688/f1000research.6875.1

2014

Dai, C., Deng, Y., Quinlan, A., Gaskin, F., Tsao, B. P., & Fu, S. M. (2014). Genetics of systemic lupus erythematosus: immune responses and end organ resistance to damage. CURRENT OPINION IN IMMUNOLOGY, 31, 87-96. doi:10.1016/j.coi.2014.10.004

Dai, C., Wang, H., Sung, S. -S. J., Sharma, R., Kannapell, C., Han, W., . . . Fu, S. M. (2014). Interferon alpha on NZM2328.Lc1R27: Enhancing autoimmunity and immune complex-mediated glomerulonephritis without end stage renal failure. CLINICAL IMMUNOLOGY, 154(1), 66-71. doi:10.1016/j.clim.2014.06.008

Fu, S. M., Cunningham-Rundles, C., Diamond, B., Rotrosen, D., Stohl, W., & Terhorst, C. (2014). Lloyd Mayer, MD, 1952-2013, In Memoriam. CLINICAL IMMUNOLOGY, 150(2), A1-A2. doi:10.1016/j.clim.2014.01.001

Szymula, A., Rosenthal, J., Szczerba, B. M., Bagavant, H., Fu, S. M., & Deshmuk, U. S. (2014). T cell epitope mimicry between Sjogren's syndrome Antigen A (SSA)/Ro60 and oral, gut, skin and vaginal bacteria. CLINICAL IMMUNOLOGY, 152(1-2), 1-9. doi:10.1016/j.clim.2014.02.004

2013

Zhao, J., Wang, H., Dai, C., Wang, H., Zhang, H., Huang, Y., . . . Fu, S. M. (2013). P2X(7) Blockade Attenuates Murine Lupus Nephritis by Inhibiting Activation of the NLRP3/ASC/Caspase 1 Pathway. ARTHRITIS AND RHEUMATISM, 65(12), 3176-3185. doi:10.1002/art.38174

Ge, Y., Jiang, C., Sung, S. -S. J., Bagavant, H., Dai, C., Wang, H., . . . Fu, S. M. (2013). Cgnz1 allele confers kidney resistance to damage preventing progression of immune complex-mediated acute lupus glomerulonephritis. JOURNAL OF EXPERIMENTAL MEDICINE, 210(11), 2387-2401. doi:10.1084/jem.20130731

Lewis, J. E., Fu, S. M., & Gaskin, F. (2013). Autoimmunity, End Organ Damage, and the Origin of Autoantibodies and Autoreactive T Cells in Systemic Lupus Erythematosus. DISCOVERY MEDICINE, 15(81), 85-92. Retrieved from https://www.webofscience.com/

2012

Szymula, A., Szczerba, B., Bagavant, H., Fu, S. -M., & Deshmukh, U. (2012). Oral and Gut Microbiota Influence Immune Responses to Sjogren's Syndrome Associated Antigen Ro60.. ARTHRITIS AND RHEUMATISM, 64(10), S1135. Retrieved from https://www.webofscience.com/

Chowdhary, V. R., Dai, C., Fu, S. M., & David, C. S. (2012). HLA-DR3 Controls Autoantibody Response to Sm in NZM2328. DR3+.AE0 Transgenic Mice.. ARTHRITIS AND RHEUMATISM, 64(10), S620-S621. Retrieved from https://www.webofscience.com/

Ju, S. -T., Sharma, R., Gaskin, F., & Fu, S. M. (2012). IL-2 controls trafficking receptor gene expression and Th2 response for skin and lung inflammation. CLINICAL IMMUNOLOGY, 145(1), 82-88. doi:10.1016/j.clim.2012.07.015

Sharma, R., Sung, S. -S. J., Gaskin, F., Fu, S. M., & Ju, S. -T. (2012). A novel function of IL-2: Chemokine/chemoattractant/retention receptor genes induction in Th subsets for skin and lung inflammation. JOURNAL OF AUTOIMMUNITY, 38(4), 322-331. doi:10.1016/j.jaut.2012.02.001

Szymula, A., Szczerba, B., Bagavant, H., Fu, S. M., & Deshmukh, U. (2012). A case for microbial involvement in the activation of lupus-antigen reactive T cells. JOURNAL OF IMMUNOLOGY, 188. Retrieved from https://www.webofscience.com/

Ju, S. -T., Sharma, R., Gaskin, F., Kung, J. T., & Fu, S. M. (2012). The Biology of Autoimmune Response in the Scurfy Mice that Lack the CD4+Foxp3+ Regulatory T-Cells.. Biology, 1(1), 18-42. doi:10.3390/biology1010018

Ge, Y., Brown, M. G., Wang, H., & Fu, S. M. (2012). Genetic approach to study lupus glomerulonephritis.. Methods in molecular biology (Clifton, N.J.), 900, 271-290. doi:10.1007/978-1-60761-720-4_13

2011

Deshmukh, U. S., Sim, D. L., Dai, C., Kannapell, C. J., Gaskin, F., Rajagopalan, G., . . . Fu, S. M. (2011). HLA-DR3 restricted T cell epitope mimicry in induction of autoimmune response to lupus-associated antigen SmD. JOURNAL OF AUTOIMMUNITY, 37(3), 254-262. doi:10.1016/j.jaut.2011.07.002

Sharma, R., Sung, S. -S. J., Ju, C. -Y. A., Deshmukh, U. S., Fu, S. M., & Ju, S. -T. (2011). Regulatory T-Cell (Treg) hybridoma as a novel tool to study Foxp3 regulation and Treg fate. JOURNAL OF AUTOIMMUNITY, 37(2), 113-121. doi:10.1016/j.jaut.2011.05.008

Fu, S. M., Deshmukh, U. S., & Gaskin, F. (2011). Pathogenesis of systemic lupus erythematosus revisited 2011: End organ resistance to damage, autoantibody initiation and diversification, and HLA-DR. JOURNAL OF AUTOIMMUNITY, 37(2), 104-112. doi:10.1016/j.jaut.2011.05.004

Sharma, R., Sharma, P. R., Kim, Y. -C., Leitinger, N., Lee, J. K., Fu, S. M., & Ju, S. -T. (2011). IL-2-controlled expression of multiple T cell trafficking genes and Th2 cytokines in the regulatory T cell-deficient scurfy mice: implication to multiorgan inflammation and control of skin and lung inflammation (vol 186, pg 1268, 2011). JOURNAL OF IMMUNOLOGY, 186(8), 5012-5013. doi:10.4049/jimmunol.1190010

Sharma, R., Fu, S. M., & Ju, S. -T. (2011). IL-2: A two-faced master regulator of autoimmunity. JOURNAL OF AUTOIMMUNITY, 36(2), 91-97. doi:10.1016/j.jaut.2011.01.001

Sharma, R., Sharma, P. R., Kim, Y. -C., Leitinger, N., Lee, J. K., Fu, S. M., & Ju, S. -T. (2011). IL-2-Controlled Expression of Multiple T Cell Trafficking Genes and Th2 Cytokines in the Regulatory T Cell-Deficient Scurfy Mice: Implication to Multiorgan Inflammation and Control of Skin and Lung Inflammation. JOURNAL OF IMMUNOLOGY, 186(2), 1268-1278. doi:10.4049/jimmunol.1002677

2010

Jr, R. C. E., Lannigan, J. A., Kim, P., Lee, J. J., Fu, S. M., & Sung, S. -S. J. (2010). Murine lung eosinophil activation and chemokine production in allergic airway inflammation. CELLULAR & MOLECULAR IMMUNOLOGY, 7(5), 361-374. doi:10.1038/cmi.2010.31

Jiang, C., Deshmukh, U. S., Gaskin, F., Bagavant, H., Hanson, J., David, C. S., & Fu, S. M. (2010). Differential Responses to Smith D Autoantigen by Mice with HLA-DR and HLA-DQ Transgenes: Dominant Responses by HLA-DR3 Transgenic Mice with Diversification of Autoantibodies to Small Nuclear Ribonucleoprotein, Double-Stranded DNA, and Nuclear Antigens. JOURNAL OF IMMUNOLOGY, 184(2), 1085-1091. doi:10.4049/jimmunol.0902670