Felicia Gaskin

Felicia Gaskin
University of Virginia | UVa · Department of Psychiatry and Neurobehavioral Sciences

Ph.D.

About

121
Publications
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Publications

Publications (121)
Article
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
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...
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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...
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...
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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...
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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:...
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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...
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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...
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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...
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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
Turbidity measurements are rapid and reliable methods to follow the effects of drugs, proteins, nucleotides, metals, and other factors on the assembly kinetics of tubulin into microtubules in vitro and have been in use since 1974. Improvements in spectrophotometers and software have resulted in the use of less protein, and more curves can be analyz...
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...
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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...
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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
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...
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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...
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The genetic and environmental factors that control the development of Sjögren's syndrome, an autoimmune disease mainly involving the salivary and lacrimal glands, are poorly understood. Viruses which infect the glands may act as a trigger for disease. The ability of sialotropic murine CMV (MCMV) to induce acute and chronic glandular disease was cha...
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Dendritic cells (DC) mediate airway Ag presentation and play key roles in asthma and infections. Although DC subsets are known to perform different functions, their occurrence in mouse lungs has not been clearly defined. In this study, three major lung DC populations have been found. Two of them are the myeloid and plasmacytoid DC (PDC) well-charac...
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Ab responses directed against several ribonucleoprotein (RNP) Ags are a characteristic feature of systemic lupus erythematosus (SLE). Previous work in our laboratory using mouse model systems had revealed that both epitope spreading and inherent cross-reactivity between ribonucleoproteins contributes to the observed multiple specificities in autoim...
Article
Autoantibodies reactive with several cellular antigens are present in the sera of patients with systemic lupus erythematosus. Polypeptides within the Ro-RNP complex and the snRNP complex are often targeted by these autoantibodies. One of the mechanisms responsible for their evolution is that of epitope spreading. Experimental animal model systems p...
Article
Histopathology of the kidney and clinical presentation are critical factors in the diagnosis of immune-mediated glomerulonephritis (GN). The histological manifestations of glomerular injury are shared by multiple underlying mechanisms. Work from our laboratory and from other investigators shows that antinuclear, antihistone or anti-dsDNA antibodies...
Article
The helix–coil transition of poly-γ-N-carbobenzoxy-L-α,γ-diaminobutyrate (PCLB) and poly-δ-N-carbobenzoxy-L-ornithine (PCLO) in chloroform–dichloroacetic acid mixtures was followed by optical rotatory dispersion. PCLB displays a “normal” temperature-induced transition, but PCLO an “inverse” one. The thermodynamic parameters for helix formation of t...
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Full-text available
In lupus-prone NZM2328 mice, a locus Cgnz1 on chromosome 1 was linked to chronic glomerulonephritis, severe proteinuria, and early mortality in females. A locus Adnz1 on chromosome 4 was linked to antinuclear antibody (ANA) and anti-double stranded DNA (dsDNA) antibody (Ab) production. In this investigation, two congenic strains, NZM2328.C57L/Jc1 (...
Article
Systemic lupus erythematosus is a prototype of systemic autoimmunity with autoantibodies (autoAbs) to ribonucleoproteins such as Ro/La, snRNP, dsDNA, and other cellular constituents. A/J mice were used to explore the mechanism of autoAb diversification with recombinant proteins and synthetic peptides. Previous studies showed that Ro60(316-335) indu...
Article
Autoantibody diversification to a variety of autoantigens is a hallmark for systemic autoimmunity. SLE represents a prototype. In this article the roots of the important questions probed by the Kunkel laboratory in SLE research are traced. Data from the recent animal work by the laboratory of Shu Man Fu are summarized to emphasize the importance of...
Article
Among NZB/W-derived New Zealand mixed (NZM) strains, only NZM/Aeg2410 (NZM2410) has been well characterized. In contrast to NZM2410, NZM2328 mice develop autoantibodies and acute and severe chronic glomerulonephritis (GN) with female predominance similarly to NZB/WF1 and humans with systemic lupus erythematosus (SLE). Chronic GN with glomerular scl...
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The coexistence of autoantibodies to ribonucleoproteins (RNP) in sera of patients with systemic lupus erythematosus has been attributed to intermolecular determinant spreading among physically associated proteins. Recently, we showed that murine Ab responses to rRo60 or Ro60 peptides were diversified unexpectedly to small nuclear RNP. In this inves...
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Full-text available
Anti-Ro60 autoantibodies are found in a variety of autoimmune disorders including systemic lupus erythematosus (SLE), Sjögren's syndrome, primary biliary cirrhosis, and active hepatitis. They are the most prevalent autoantibodies in normal individuals and in asymptomatic mothers of infants afflicted with neonatal lupus. In the present study, immune...
Article
Tubulin assembly studies with GTPαS diastereoisomers have shown that there is stereoselectivity at the α-phosphate binding region of tubulin. GTPαS(S(p)) bound tighter than GTPαS(R(p)) and promoted nucleation and assembly better than GTP and GTPαS(R(p)). ATP and dATP have been reported to bind weakly to tubulin and to be less effective than GTP and...
Article
During the past several years, evidence has been accumulated to support the thesis that immunological factors may play some role in Alzheimer's disease (AD). We have characterized the reactive antigens detected by certain monoclonal antibodies secreted by Epstein-Barr virus (EBV)-transformed B cell lines from the peripheral blood of AD patients and...
Article
In a previous study, four human IgM kappa monoclonal antibodies (mAbs) secreted by Epstein-Barr-virus-transformed B cell lines independently derived from the peripheral blood of a patient with Alzheimer's disease (AD) were found to react with a conformational epitope of beta-amyloid protein and to stain amyloid plaques in AD brain. Three of these m...
Article
The exchangeable nucleotide-binding site of tubulin has been studied using diastereoisomers A (Sp) and B (Rp) of guanosine 5'-O-(1-thiotriphosphate) (GTP alpha S) in which the phosphorus atom to which sulfur is attached is chiral. GTP alpha S(A) (10 microM) nucleated assembly of purified tubulin (20 microM) into microtubules in buffer containing 0....
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CD40 plays an important role in B cell activation, proliferation, and Ig class switching. The signal transduction pathway mediated by CD40 was studied using monoclonal antibody (mAb) 626.1 to CD40. Burkitt's lymphoma and Epstein-Barr virus-transformed B cell lines and tonsilar B lymphocytes were treated with the anti-CD40 mAb for various lengths of...
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To determine the molecular and functional properties of human rheumatoid factors (RF), we established stable hybridomas and Epstein-Barr virus-transformed B cell lines from the synovial fluid or peripheral blood of three patients with rheumatoid arthritis and one patient with systemic lupus erythematosus. 17 cell lines were obtained that produced h...
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Four human B cell lines established by Epstein-Barr viral transformation of B cells from a patient with a clinical diagnosis of Alzheimer's disease (AD) were found to secrete antibodies that react with plaques and cerebrovascular blood vessels in AD brain in a staining profile characteristic of beta-amyloid protein (beta-AP) in AD brain. Two of the...
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Full-text available
Four human B cell lines established by Epstein-Barr viral transformation of B cells from a patient with a clinical diagnosis of Alzheimer's disease (AD) were found to secrete antibodies that react with plaques and cerebrovascular blood vessels in AD brain in a staining profile characteristic of B-amyloid protein (flAP) in AD brain. Two of these ant...
Article
To gain insight into the immunoglobulin variable-region repertoire of anti-IgG antibodies (rheumatoid factors [RF]), we characterized the VH and V kappa gene segments utilized in an IgM-RF-secreting lymphoblastoid cell line (SSH23) isolated from a normal individual. The cell line SSH23 was established by Epstein-Barr virus transformation of periphe...
Article
Ethacrynic acid (ECA) is a sulfhydryl reactive diuretic drug. Recent studies show that ocular administration of ECA may have potential efficacy for treatment of glaucoma. ECA affects cell shape in cultured cells from the eye outflow pathway and the microtubule system is disrupted. We have studied the effect of ECA on microtubule protein (MTP) (tubu...