Shu Man Fu

Shu Man Fu
University of Virginia | UVa · School of Medicine

MD, PhD

About

277
Publications
10,695
Reads
How we measure 'reads'
A 'read' is counted each time someone views a publication summary (such as the title, abstract, and list of authors), clicks on a figure, or views or downloads the full-text. Learn more
14,763
Citations
Citations since 2016
22 Research Items
2130 Citations
2016201720182019202020212022050100150200250300350
2016201720182019202020212022050100150200250300350
2016201720182019202020212022050100150200250300350
2016201720182019202020212022050100150200250300350
Additional affiliations
January 1988 - February 2016
University of Virginia
Position
  • Professor

Publications

Publications (277)
Article
Full-text available
HLA-DR3 (DR3) is one of the dominant HLA-DR alleles associated with systemic lupus erythematosus (SLE) susceptibility. Our previous studies showed multiple intramolecular DR3 restricted T cell epitopes in the Smith D (SmD) protein, from which we generated a non-homologous, bacterial epitope mimics library. From this library we identified ABC247-261...
Article
Full-text available
Objective NLRP3 inflammasome regulates T cell responses. This study examined the roles of NLRP3 inflammasome activation in the regulation of T follicular helper (Tfh) cells during humoral response to T dependent antigens and in systemic lupus erythematosus (SLE). Methods NLRP3 inflammasome activation of Tfh cells was studied in B6, MRL/lpr and NZM...
Article
Full-text available
Cgnz1 on chromosome 1 mapped into a 1.34 Mb region of chromosome 1 in NZM2328 confers the progression of immune complex (IC) mediated glomerulonephritis (GN) from acute GN (aGN) to chronic GN (cGN) with severe proteinuria and end stage renal disease in female mice. This genetic locus mediates podocyte susceptibility to IC mediated damage. Taking ad...
Chapter
The clinical history of SLE is interesting and torturous. It can be divided into two periods: the age of dermatology with emphasis on skin manifestation and the period of transition to systemic lupus erythematosus (SLE). The history of laboratory investigation with emphasis of the development of clinical laboratory tests is presented. Certain other...
Chapter
Lupus nephritis (LN) is a major complication in systemic lupus erythematosus with considerable mortality and morbidities. Recent genetic data support the thesis that end organ resistance to damage is under genetic control and that immune complex (IC)-mediated acute glomerulonephritis need not progress to chronic glomerulonephritis and end stage ren...
Article
Full-text available
The detection of cytokines production in tissues is subjected to significant limitations: (1) Cytokine protein production frequently does not correlate with mRNA levels. (2) Cytokines are secreted rapidly and dissipate from the cellular source, thus making detection difficult. (3) The synthetic rate of many cytokines are low. (4) Tissue fixation ab...
Article
Inflammation plays a key role in the pathogenesis of lupus nephritis (LN) and inflammatory cytokines within the glomeruli are critical in this process. However, little information is available for the identities of the cell types that are primarily responsible for the production and function of the various cytokines. We have devised a novel method...
Article
Lupus glomerulonephritis (GN) is an autoimmune disease characterized by immune complex-deposition, complement activation and glomerular inflammation. In lupus-prone NZM2328 mice, the occurrence of lupus GN was accompanied by a decrease in Treg cells and an increase in proinflammatory cytokine-producing T cells. Because IL-33 in addition to IL-2 has...
Article
RIP3 activation leads to activation of necroptosis and the NLRP3 inflammasome pathways. The activation of RIP3 in lupus nephritis (LN) has not been investigated. In this study, RIP3 and necroptosis pathway activations were demonstrated in podocytes in renal biopsies from patients with class IV LN and in the diseased kidneys from lupus-prone NZM2328...
Article
Full-text available
The innate lymphoid cell (ILC) is a group of effector cells with diverse important cellular functions in both health and disease states. In comparison with healthy controls, there were increases in circulating ILC in SLE patients. The proportion of ILC1 significantly increased with significant decreases of ILC2 in SLE patients and ILC3 in SLE patie...
Chapter
Lupus nephritis (LN) is a major cause of morbidity and mortality in systemic lupus erythematosus (SLE). The mechanisms of renal damage are complex. The majority of LN cases are immune complex (IC) mediated. This chapter intends to review the history and certain aspects of recent research on our understanding of IC-mediated LN and to provide a mecha...
Article
Objectives The generation of systemic lupus erythematosus (SLE)-related autoantibodies have been shown to be T cell dependent and antigen driven with HLA-DR restriction. In this study, the initiating antigen(s) and the mechanism of autoantibody diversification were investigated. Methods T cell epitopes (T-epitopes) of SmD1 (SmD) were mapped by T-T...
Article
Follicular T regulatory (Tfr) cells inhibit follicular T helper (Tfh) cells mediated B cell responses. Tfh cells are involved in the pathogenesis of systemic lupus erythematosus (SLE). However, the role of Tfr cells in SLE remains unclear. The frequency of circulating Tfr and Tfh cells were examined in SLE patients and healthy controls. The frequen...
Article
Objective: Development of proteinuria in lupus nephritis (LN) is associated with podocyte dysfunction. The NLRP3 inflammasome has been implicated in the pathogenesis of LN. The purpose of this study was to investigate whether NLRP3 inflammasome activation is involved in the development of podocyte injury in LN. Methods: A fluorescence-labeled ca...
Article
Full-text available
Glomerular damage mediated by glomerulus-infiltrating myeloid-derived cells is a key pathogenic event in lupus nephritis (LN), but the process is poorly understood. Confocal microscopy of kidney sections and flow cytometry analysis of glomerular cells from magnetic bead-purified glomeruli have identified glomerulus-infiltrating leukocyte population...
Chapter
Lupus nephritis (LN) is a major complication in systemic lupus erythematosus with considerable mortality and morbidities. The mechanisms of renal damage are complex. Since LN was considered a prototype of immune complex (IC)-mediated disease, major efforts have been focused on the nature of the IC with special emphasis on the nature of the targeted...
Article
A brother and sister developed a previously undescribed constellation of autoimmune manifestations within their first year of life, with uncontrollable bullous pemphigoid, colitis, and proteinuria. The boy had hemophilia due to a factor VIII autoantibody and nephrotic syndrome. Both children required allogeneic hematopoietic cell transplantation (H...
Article
MHC, especially HLA-DR3 and HLA-DR2, is one of the most important genetic susceptibility regions for systemic lupus erythematosus. Human studies to understand the role of specific HLA alleles in disease pathogenesis have been hampered by the presence of strong linkage disequilibrium in this region. To overcome this, we produced transgenic mice expr...
Article
Full-text available
Anti-dsDNA antibodies are the most studied antibodies of the lupus-related autoantibodies. The dogma is that these are the most important autoantibodies in systemic lupus erythematosus. In this review, evidence is presented to show that these antibodies (as measured by modern clinical laboratories) are not the most important autoantibodies in the d...
Article
Myeloid-derived suppressor cells (MDSC) and Th17 cells were found to expand in collagen-induced arthritis (CIA) significantly. Two subsets of MDSC, polymorphonuclear (PMN) and mononuclear (MO), were detected and their ratios varied during the development of CIA. Depletion of MDSC in vivo resulted in suppression of T cell proliferation and decreased...
Article
Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disorder. Considerable progress has been made to delineate the genetic control of this complex disorder. In this review, selected aspects of human and mouse genetics related to SLE are reviewed with emphasis on genes that contribute to both innate and adaptive immunity and to ge...
Article
Objective Glycogen synthase kinase 3β (GSK-3β) has been demonstrated to be involved in immune and inflammatory responses via multiple signaling pathways, leading to the production of proinflammatory cytokines. The purpose of this study was to investigate the role of GSK-3β in the pathogenesis of lupus nephritis in 2 mouse models.Methods Thiadiazoli...
Article
Interferon alpha (IFNα) may play a significant role in systemic lupus erythematosus (SLE) pathogenesis. Recent literature suggests that IFNα does not correlate with disease activities and blockade of IFNα is not effective in treating SLE. This study is to delineate further the role of IFNα in SLE. 12-week old NZM2328 and its congenic NZM2328.Lc1R27...
Article
This study was undertaken to test the hypothesis that Sjogren’s syndrome Antigen A (SSA)/Ro60-reactive T cells are activated by peptides originating from oral and gut bacteria. T cell hybridomas generated from HLA-DR3 transgenic mice recognized 3 regions on Ro60, with core epitopes mapped to amino acids 228-238, 246-256 and 371-381. BLAST analysis...
Article
Full-text available
Objective: The NLRP3 inflammasome plays key roles in inflammation and autoimmunity, and purinergic receptor P2X7 has been proposed to be upstream of NLRP3 activation. The aim of the present study, using murine models, was to investigate whether the P2X7 /NLRP3 inflammasome pathway contributes to the pathogenesis of lupus nephritis (LN). Methods:...
Article
Full-text available
Cgnz1 and Agnz1 on the distal region of mouse chromosome 1 are associated with chronic glomerulonephritis (cGN) and acute GN (aGN). NZM2328.Lc1R27 (R27) was generated by introgressing a C57L/J region where Cgnz1 is located to NZM2328. R27 female mice developed aGN mediated by immune complex (IC) deposition and complement activation without progress...
Article
Full-text available
Systemic lupus erythematosus (SLE) is a prototype of systemic autoimmunity affecting many systems. Both antibodies and autoreactive T cells play significant roles in its pathogenesis. Experimental data and clinical observations indicate that autoimmunity and end organ damage are under separate genetic controls and that there are significant interac...
Article
Full-text available
Due to a mutation in the Foxp3 transcription factor, Scurfy mice lack regulatory T-cells that maintain self-tolerance of the immune system. They develop multi-organ inflammation (MOI) and die around four weeks old. The affected organs are skin, tail, lungs and liver. In humans, endocrine and gastrointestinal inflammation are also observed, hence th...
Article
Full-text available
Genetic and environmental factors contribute in the pathogenesis of systemic lupus erythematosus (SLE). Lupus nephritis, the most common and severe manifestation of SLE, involves inflammation in the kidney leading to loss of renal function. However, it is not clear what controls the progression of lupus nephritis; this is an important research ques...
Article
Full-text available
Both Il2(-/-) mice and Scurfy (Sf) mutant mice that are deficient in FoxP3, develop multi-organ inflammation but only the latter display severe skin and lung inflammation. In contrast, Sf.Il2(-/-) double mutant mice do not display skin inflammation and markedly reduced lung inflammation. In this review, we summarize our recent findings based on mic...
Article
The Foxp3(+)CD4(+) regulatory T-cell (Treg)-deficient Scurfy (Sf) mice rapidly develop severe inflammation in the skin and lungs with expanded Th subsets bearing increased expression of various chemokine/chemoattractant/retention receptor genes (CRG). Nine different double mutants were generated to elucidate their roles in the skin and lung inflamm...
Article
Although systemic lupus erythematosus (SLE) is a multigenic autoimmune disorder, HLA-D is the most dominant genetic susceptibility locus. This study was undertaken to investigate the hypothesis that microbial peptides bind HLA-DR3 and activate T cells reactive with lupus autoantigens. Using HLA-DR3 transgenic mice and lupus-associated autoantigen S...
Article
Systemic lupus erythematosus (SLE) is a multi-system disorder resulting from interaction of susceptibility genes and environmental factors. SLE has protean clinical presentations at the initial diagnosis and relapses. SLE-related autoantibodies have unique patterns of diversification to linked proteins such as the snRNP particle and the diversifica...
Article
The CD25(+)Foxp3(+) regulatory T-cells (Treg) that had lost CD25 and Foxp3 in vivo (ex-Treg) exist but are difficult to study. We generated antigen (Ag)-specific Treg hybridomas from iTreg clones (iTreg-hyb) using iTreg of DO11.10.Foxp3-GFP mice and presented evidence that they behave like ex-Treg. The iTreg-hyb displayed little CD25 and Foxp3-GFP...
Article
Full-text available
Scurfy (Sf) mice bear a mutation in the Foxp3 transcription factor, lack regulatory T cells (Treg), develop multiorgan inflammation, and die prematurely. The major target organs affected are skin, lungs, and liver. “Sf mice lacking the Il2 gene (Sf.Il2–/–), despite being devoid of Treg, did not develop skin and lung inflammation, but the inflammati...
Article
CD4(+) T-cell (Th) cytokines provide important regulatory and effector functions of T-cells. Among them, IL-2 plays a unique role. IL-2 is required for the generation and maintenance of regulatory T-cells (Treg) to provide lifelong protection from autoimmune disease. Whether IL-2 is also required for autoimmune disease development is less clear as...
Article
Full-text available
Eosinophils play important roles in asthma and lung infections. Murine models are widely used for assessing the functional significance and mechanistic basis for eosinophil involvements in these diseases. However, little is known about tissue eosinophils in homeostasis. In addition, little data on eosinophil chemokine production during allergic air...
Article
Full-text available
Anti-Smith (Sm) D autoantibodies are specific for systemic lupus erythematosus. In this investigation, the influence of HLA-D genes on immune responses to SmD was investigated. Mice with HLA-DR3, HLA-DR4, HLA-DQ0601, HLA-DQ0604, or HLA-DQ8 transgenes were immunized with recombinant SmD1, and their Ab responses were analyzed. Analysis by ELISA showe...
Article
Full-text available
Lupus-prone female New Zealand Mixed (NZM)2328 mice develop high titers of anti-nuclear and anti-dsDNA autoantibodies. Despite high expression of type I IFNs, these mice do not develop autoantibodies to the small nuclear ribonucleoprotein (snRNP) complex. Thus, additional genetic factors must regulate the generation of anti-snRNP autoantibodies. In...
Article
A combination of systemic autoimmunity and tissue response to immune injury underlie renal involvement in lupus erythematosus. In this review, we discuss recent literature investigating pathogenetic mechanisms of lupus glomerulonephritis. In lupus glomerulonephritis, glomerular immune complexes were believed to be the primary mediators of renal dis...
Article
Full-text available
Scurfy (Foxp3(Sf)/Y), Il2(-/-), and Il2ralpha(-/-) mice are deficient in CD4(+)Foxp3(+) regulatory T cells (Treg), but only the latter two develop inflammation in the submandibular gland (SMG), a critical target of Sjögren's syndrome. In this study, we investigated the reason that SMG of Scurfy (Sf), Sf.Il2(-/-), Sf.Il2ralpha(-/-), and the long-liv...
Article
Full-text available
Scurfy (Sf) mice lack CD4(+)Foxp3(+) regulatory T cells and develop fatal multiorgan inflammation (MOI) mediated by CD4(+) T cells. Introducing Il2(-/-) gene into Sf mice (Sf.Il2(-/-)) inhibited inflammation in skin and lung. As a major integrin receptor for the organs, we compared CD103 expression on the CD4(+) T cells of B6, Il2(-/-), Sf, and Sf....
Article
Unlabelled: There have been several descriptions of mouse models that manifest select immunological and clinical features of autoimmune cholangitis with similarities to primary biliary cirrhosis in humans. Some of these models require immunization with complete Freund's adjuvant, whereas others suggest that a decreased frequency of T regulatory ce...
Article
Full-text available
Scurfy mice display the most severe form of multi-organ inflammation due to total lack of the CD4+Foxp3+ regulatory T cells (Treg) resulted from a mutation of the X-linked transcription factor Foxp3. A large repertoire of Treg-suppressible, inflammation-inducing T cells was demonstrated by adoptive transfer experiments using Rag1-/- mice as recipie...
Article
Full-text available
Foreign Ag-specific TCR-transgenic (Tg) mice contain a small fraction of T cells bearing the endogenous Vbeta and Valpha chains as well as a population expressing an intermediate level of Tg TCR. Importantly, these minor nonclonotypic populations contain > or = 99% of the CD4(+)Foxp3(+) regulatory T cells (Treg) and, despite low overall Treg expres...
Article
This study was undertaken to determine whether induction of systemic inflammation accelerates the development of Sjögren's syndrome (SS) in genetically susceptible mice. Female (NZB x NZW)F1 mice were treated with either Freund's incomplete adjuvant (IFA) or phosphate buffered saline (PBS) at monthly intervals. Salivary gland function was monitored...
Article
Full-text available
We hypothesize that regulatory T-cell (Treg)-deficient strains have an altered TCR repertoire in part due to the expansion of autoimmune repertoire by self-antigen. We compared the Vβ family expression profile between B6 and Treg-lacking B6.Cg-Foxp3sf/Y (B6.sf) mice using fluorescent anti-Vβ mAbs and observed no changes. However, while the spectrat...
Article
Full-text available
Mutation of the Foxp3 transcription factor in Scurfy (Sf) mice results in complete absence of the CD4+Foxp3+ regulatory T cells (Tregs), severe multiorgan autoimmune syndrome, and early death at 4 wk of age. However, Sf mice simultaneously bearing the Il2-/- (Sf.Il2-/-) or Faslpr/lpr gene (Sf.Faslpr/lpr) have extended lifespan despite totally lacki...
Article
Scurfy mice which lacks functional Foxp3 transcription factor and CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells, spontaneously develop autoimmune responses against skin, lung, liver and tail. However, many organs/tissues are spared from autoimmune attack. Here, we demonstrate that scurfy mice contain dormant autoimmune T cells that induced new di...
Article
Full-text available
Autoantibody response against the small nuclear ribonucleoprotein (snRNP) complex is a characteristic feature of systemic lupus erythematosus. The current investigation was undertaken to determine whether activation of SmD-reactive T cells by synthetic peptides harboring T cell epitopes can initiate a B cell epitope spreading cascade within the snR...
Article
Full-text available
A massive systemic expansion of CD8(+) memory T (T(M)) cells and a remarkable increase in circulating IL-2 were observed only in IL-2Ralpha (CD25) knockout (KO) mice but not in IL-2 KO and scurfy mice, although all three mutants lack regulatory T (Treg) cells. However, both phenotypes were suppressed by the transfer of Treg cells. The data presente...