Publications by authors named "Kenneth S Tung"

46 Publications

Autoimmune experimental orchitis and chronic glomerulonephritis with end stage renal disease are controlled by Cgnz1 for susceptibility to end organ damage.

Clin Immunol 2021 Mar 19;224:108675. Epub 2021 Jan 19.

Division of Rheumatology, Center for Immunity, Inflammation and Regenerative Medicine, Charlottesville, VA, USA; Department of Medicine, University of Virginia, Charlottesville, VA, USA; Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, USA. Electronic address:

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 advantage of the published observation that Cgnz1 is derived from NZW and that NZW is susceptible to orchitis, epididymitis and vasitis while C57L/J is resistant to these diseases, the possibility that this genetic region also confers germ cells susceptible to damage with aspermatogenesis and sterility in an active experimental autoimmune orchitis (EAO) model was investigated. Male mice from multiple intrachromosome (chromosome 1) recombinant strains were subjected to immunization with a sperm homogenate in CFA with concomitant administration of Bordetella pertussis toxin. There was concordance of the progression from aGN to cGN, severe proteinuria and end stage renal disease with susceptibility of EAO in NZM2328 and its congenic strains with various chromosome 1 genetic intervals introgressed from C57L/J to NZM2328. Both resistant and susceptible strains made comparable anti-testis and anti-sperm Abs. Thus the genetic interval that determines susceptibility to EAO is identical to that of Cgnz1 and mapped to the 1.34 Mb region in chromosone 1. This region likely confers germ cells in the male gonad susceptible to damage by immunologically mediated inflammation. This region has been tentatively renamed Cgnz1/Eaoz1. These observations further emphasize the importance of end organ susceptibility to damage in the pathogenesis of both systemic and organ specific autoimmune diseases.
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http://dx.doi.org/10.1016/j.clim.2021.108675DOI Listing
March 2021

Cutaneous Exposure to Clinically Relevant Lone Star Ticks Promotes IgE Production and Hypersensitivity through CD4 T Cell- and MyD88-Dependent Pathways in Mice.

J Immunol 2019 08 3;203(4):813-824. Epub 2019 Jul 3.

Beirne B. Carter Center for Immunology Research, University of Virginia School of Medicine, Charlottesville, VA 22908;

Tick-borne allergies are a growing public health concern and have been associated with the induction of IgE-mediated food allergy to red meat. However, despite the increasing prevalence of tick bite-induced allergies, the mechanisms by which cutaneous exposure to ticks leads to sensitization and the production of IgE Abs are poorly understood. To address this question, an in vivo approach was used to characterize the IgE response to lone star tick proteins administered through the skin of mice. The results demonstrated that tick sensitization and challenge induced a robust production of IgE Abs and supported a role for IgE-mediated hypersensitivity reactions in sensitized animals following oral administration of meat. The induction of IgE responses was dependent on cognate CD4 T cell help during both the sensitization phase and challenge phase with cutaneous tick exposure. In addition, IgE production was dependent on B cell-intrinsic MyD88 expression, suggesting an important role for TLR signaling in B cells to induce IgE responses to tick proteins. This model of tick-induced IgE responses could be used to study the factors within tick bites that cause allergies and to investigate how sensitization to food Ags occurs through the skin that leads to IgE production.
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http://dx.doi.org/10.4049/jimmunol.1801156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684363PMC
August 2019

Preexisting Commensal Dysbiosis Is a Host-Intrinsic Regulator of Tissue Inflammation and Tumor Cell Dissemination in Hormone Receptor-Positive Breast Cancer.

Cancer Res 2019 Jul 7;79(14):3662-3675. Epub 2019 May 7.

Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia.

It is unknown why some patients with hormone receptor-positive (HR) breast cancer present with more aggressive and invasive disease. Metastatic dissemination occurs early in disease and is facilitated by cross-talk between the tumor and tissue environment, suggesting that undefined host-intrinsic factors enhance early dissemination and the probability of developing metastatic disease. Here, we have identified commensal dysbiosis as a host-intrinsic factor associated with metastatic dissemination. Using a mouse model of HR mammary cancer, we demonstrate that a preestablished disruption of commensal homeostasis results in enhanced circulating tumor cells and subsequent dissemination to the tumor-draining lymph nodes and lungs. Commensal dysbiosis promoted early inflammation within the mammary gland that was sustained during HR mammary tumor progression. Furthermore, dysbiosis enhanced fibrosis and collagen deposition both systemically and locally within the tumor microenvironment and induced significant myeloid infiltration into the mammary gland and breast tumor. These effects were recapitulated both by directly targeting gut microbes using nonabsorbable antibiotics and by fecal microbiota transplantation of dysbiotic cecal contents, demonstrating the direct impact of gut dysbiosis on mammary tumor dissemination. This study identifies dysbiosis as a preexisting, host-intrinsic regulator of tissue inflammation, myeloid recruitment, fibrosis, and dissemination of tumor cells in HR breast cancer. SIGNIFICANCE: Identification of commensal dysbiosis as a host-intrinsic factor mediating evolution of metastatic breast cancer allows for development of interventions or diagnostic tools for patients at highest risk for developing metastatic disease..
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http://dx.doi.org/10.1158/0008-5472.CAN-18-3464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983951PMC
July 2019

Infectious, inflammatory and 'autoimmune' male factor infertility: how do rodent models inform clinical practice?

Hum Reprod Update 2018 07;24(4):416-441

Institute of Anatomy and Cell Biology, Unit of Reproductive Biology, Aulweg 123, Giessen, Germany.

Background: Infection and inflammation of the reproductive tract are significant causes of male factor infertility. Ascending infections caused by sexually transmitted bacteria or urinary tract pathogens represent the most frequent aetiology of epididymo-orchitis, but viral, haematogenous dissemination is also a contributory factor. Limitations in adequate diagnosis and therapy reflect an obvious need for further understanding of human epididymal and testicular immunopathologies and their contribution to infertility. A major obstacle for advancing our knowledge is the limited access to suitable tissue samples. Similarly, the key events in the inflammatory or autoimmune pathologies affecting human male fertility are poorly amenable to close examination. Moreover, the disease processes generally have occurred long before the patient attends the clinic for fertility assessment. In this regard, data obtained from experimental animal models and respective comparative analyses have shown promise to overcome these restrictions in humans.

Objective And Rationale: This narrative review will focus on male fertility disturbances caused by infection and inflammation, and the usefulness of the most frequently applied animal models to study these conditions.

Search Methods: An extensive search in Medline database was performed without restrictions until January 2018 using the following search terms: 'infection' and/or 'inflammation' and 'testis' and/or 'epididymis', 'infection' and/or 'inflammation' and 'male genital tract', 'male infertility', 'orchitis', 'epididymitis', 'experimental autoimmune' and 'orchitis' or 'epididymitis' or 'epididymo-orchitis', antisperm antibodies', 'vasectomy'. In addition to that, reference lists of primary and review articles were reviewed for additional publications independently by each author. Selected articles were verified by each two separate authors and discrepancies discussed within the team.

Outcomes: There is clear evidence that models mimicking testicular and/or epididymal inflammation and infection have been instructive in a better understanding of the mechanisms of disease initiation and progression. In this regard, rodent models of acute bacterial epididymitis best reflect the clinical situation in terms of mimicking the infection pathway, pathogens selected and the damage, such as fibrotic transformation, observed. Similarly, animal models of acute testicular and epididymal inflammation using lipopolysaccharides show impairment of reproduction, endocrine function and histological tissue architecture, also seen in men. Autoimmune responses can be studied in models of experimental autoimmune orchitis (EAO) and vasectomy. In particular, the early stages of EAO development showing inflammatory responses in the form of peritubular lymphocytic infiltrates, thickening of the lamina propria of affected tubules, production of autoantibodies against testicular antigens or secretion of pro-inflammatory mediators, replicate observations in testicular sperm extraction samples of patients with 'mixed atrophy' of spermatogenesis. Vasectomy, in the form of sperm antibodies and chronic inflammation, can also be studied in animal models, providing valuable insights into the human response.

Wider Implications: This is the first comprehensive review of rodent models of both infectious and autoimmune disease of testis/epididymis, and their clinical implications, i.e. their importance in understanding male infertility related to infectious and non-infectious/autoimmune disease of the reproductive organs.
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http://dx.doi.org/10.1093/humupd/dmy009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6016649PMC
July 2018

Egress of sperm autoantigen from seminiferous tubules maintains systemic tolerance.

J Clin Invest 2017 Mar 20;127(3):1046-1060. Epub 2017 Feb 20.

Autoimmune responses to meiotic germ cell antigens (MGCA) that are expressed on sperm and testis occur in human infertility and after vasectomy. Many MGCA are also expressed as cancer/testis antigens (CTA) in human cancers, but the tolerance status of MGCA has not been investigated. MGCA are considered to be uniformly immunogenic and nontolerogenic, and the prevailing view posits that MGCA are sequestered behind the Sertoli cell barrier in seminiferous tubules. Here, we have shown that only some murine MGCA are sequestered. Nonsequestered MCGA (NS-MGCA) egressed from normal tubules, as evidenced by their ability to interact with systemically injected antibodies and form localized immune complexes outside the Sertoli cell barrier. NS-MGCA derived from cell fragments that were discarded by spermatids during spermiation. They egressed as cargo in residual bodies and maintained Treg-dependent physiological tolerance. In contrast, sequestered MGCA (S-MGCA) were undetectable in residual bodies and were nontolerogenic. Unlike postvasectomy autoantibodies, which have been shown to mainly target S-MGCA, autoantibodies produced by normal mice with transient Treg depletion that developed autoimmune orchitis exclusively targeted NS-MGCA. We conclude that spermiation, a physiological checkpoint in spermatogenesis, determines the egress and tolerogenicity of MGCA. Our findings will affect target antigen selection in testis and sperm autoimmunity and the immune responses to CTA in male cancer patients.
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http://dx.doi.org/10.1172/JCI89927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5330742PMC
March 2017

C5 inhibition prevents renal failure in a mouse model of lethal C3 glomerulopathy.

Kidney Int 2017 06 27;91(6):1386-1397. Epub 2017 Jan 27.

Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. Electronic address:

C3 glomerulopathy is a potentially life-threatening disease of the kidney caused by dysregulated alternative pathway complement activation. The specific complement mediator(s) responsible for kidney injury in C3 glomerulopathy are yet to be defined and no specific therapy is currently available. We previously developed a mouse model of lethal C3 glomerulopathy with factor H and properdin gene double mutations. Therefore, we used this model to examine the role of C5 and C5a receptor (C5aR) in the pathogenesis of the disease. Disease severity in these factor H/properdin double-mutant mice was found to be correlated with plasma C5 levels, and prophylactic anti-C5 mAb therapy was effective in preventing lethal C3 glomerulopathy. When given to these double-mutant mice that had already developed active disease with severe proteinuria, anti-C5 mAb treatment also prevented death in half of the mice. Deficiency of C5aR significantly reduced disease severity, suggesting that C5aR-mediated inflammation contributed to C3 glomerulopathy. Thus, C5 and C5aR have a critical role in C3 glomerulopathy. Hence, early intervention targeting these pathways may be an effective therapeutic strategy for patients with C3 glomerulopathy.
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http://dx.doi.org/10.1016/j.kint.2016.11.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5429978PMC
June 2017

Influenza A induces dysfunctional immunity and death in MeCP2-overexpressing mice.

JCI Insight 2017 01 26;2(2):e88257. Epub 2017 Jan 26.

Center for Brain Immunology and Glia.

Loss of function or overexpression of methyl-CpG-binding protein 2 (MeCP2) results in the severe neurodevelopmental disorders Rett syndrome and MeCP2 duplication syndrome, respectively. MeCP2 plays a critical role in neuronal function and the function of cells throughout the body. It has been previously demonstrated that MeCP2 regulates T cell function and macrophage response to multiple stimuli, and that immune-mediated rescue imparts significant benefit in -null mice. Unlike Rett syndrome, MeCP2 duplication syndrome results in chronic, severe respiratory infections, which represent a significant cause of patient morbidity and mortality. Here, we demonstrate that MeCP2 mice, which overexpress MeCP2 at levels 3- to 5-fold higher than normal, are hypersensitive to influenza A/PR/8/34 infection. Prior to death, MeCP2 mice experienced a host of complications during infection, including neutrophilia, increased cytokine production, excessive corticosterone levels, defective adaptive immunity, and vascular pathology characterized by impaired perfusion and pulmonary hemorrhage. Importantly, we found that radioresistant cells are essential to infection-related death after bone marrow transplantation. In all, these results demonstrate that influenza A infection in MeCP2 mice results in pathology affecting both immune and nonhematopoietic cells, suggesting that failure to effectively respond and clear viral respiratory infection has a complex, multicompartment etiology in the context of MeCP2 overexpression.
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http://dx.doi.org/10.1172/jci.insight.88257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5256138PMC
January 2017

Macrophages redirect phagocytosis by non-professional phagocytes and influence inflammation.

Nature 2016 11 7;539(7630):570-574. Epub 2016 Nov 7.

The Center for Cell Clearance, University of Virginia, Charlottesville, Virginia 22903, USA.

Professional phagocytes (such as macrophages) and non-professional phagocytes (such as epithelial cells) clear billions of apoptotic cells and particles on a daily basis. Although professional and non-professional macrophages reside in proximity in most tissues, whether they communicate with each other during cell clearance, and how this might affect inflammation, is not known. Here we show that macrophages, through the release of a soluble growth factor and microvesicles, alter the type of particles engulfed by non-professional phagocytes and influence their inflammatory response. During phagocytosis of apoptotic cells or in response to inflammation-associated cytokines, macrophages released insulin-like growth factor 1 (IGF-1). The binding of IGF-1 to its receptor on non-professional phagocytes redirected their phagocytosis, such that uptake of larger apoptotic cells was reduced whereas engulfment of microvesicles was increased. IGF-1 did not alter engulfment by macrophages. Macrophages also released microvesicles, whose uptake by epithelial cells was enhanced by IGF-1 and led to decreased inflammatory responses by epithelial cells. Consistent with these observations, deletion of IGF-1 receptor in airway epithelial cells led to exacerbated lung inflammation after allergen exposure. These genetic and functional studies reveal that IGF-1- and microvesicle-dependent communication between macrophages and epithelial cells can critically influence the magnitude of tissue inflammation in vivo.
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http://dx.doi.org/10.1038/nature20141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5799085PMC
November 2016

Regulatory T Cells Control Th2-Dominant Murine Autoimmune Gastritis.

J Immunol 2016 07 3;197(1):27-41. Epub 2016 Jun 3.

Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908; Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908; and Department of Pathology, University of Virginia, Charlottesville, VA 22908

Pernicious anemia and gastric carcinoma are serious sequelae of autoimmune gastritis (AIG). Our study indicates that in adult C57BL/6-DEREG mice expressing a transgenic diphtheria toxin receptor under the Foxp3 promoter, transient regulatory T cell (Treg) depletion results in long-lasting AIG associated with both H(+)K(+)ATPase and intrinsic factor autoantibody responses. Although functional Tregs emerge over time during AIG occurrence, the effector T cells rapidly become less susceptible to Treg-mediated suppression. Whereas previous studies have implicated dysregulated Th1 cell responses in AIG pathogenesis, eosinophils have been detected in gastric biopsy specimens from patients with AIG. Indeed, AIG in DEREG mice is associated with strong Th2 cell responses, including dominant IgG1 autoantibodies, elevated serum IgE, increased Th2 cytokine production, and eosinophil infiltration in the stomach-draining lymph nodes. In addition, the stomachs exhibit severe mucosal and muscular hypertrophy, parietal cell loss, mucinous epithelial cell metaplasia, and massive eosinophilic inflammation. Notably, the Th2 responses and gastritis severity are significantly ameliorated in IL-4- or eosinophil-deficient mice. Furthermore, expansion of both Th2-promoting IFN regulatory factor 4(+) programmed death ligand 2(+) dendritic cells and ILT3(+) rebounded Tregs was detected after transient Treg depletion. Collectively, these data suggest that Tregs maintain physiological tolerance to clinically relevant gastric autoantigens, and Th2 responses can be a pathogenic mechanism in AIG.
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http://dx.doi.org/10.4049/jimmunol.1502344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912916PMC
July 2016

BAFF regulates follicular helper t cells and affects their accumulation and interferon-γ production in autoimmunity.

Arthritis Rheumatol 2015 Mar;67(3):773-84

University of Virginia, Charlottesville.

Objective: Follicular helper T (Tfh) cells are critical for the development of protective antibodies via germinal center (GC) B cell responses; however, uncontrolled Tfh cell expansion activates autoreactive B cells to produce antibodies that cause autoimmunity. The mechanisms that control Tfh cell homeostasis remain largely unknown. The aim of this study was to determine the contribution of BAFF to Tfh cell responses in autoimmunity.

Methods: We analyzed the properties of Tfh cells in lupus-prone mice sufficient or deficient in BCMA. Adoptive transfer studies and mixed bone marrow chimeras were used to test BCMA signaling in T cells. We assessed BAFF stimulation of Tfh cells through in vitro cell cocultures and in vivo depletion studies using flow cytometry.

Results: In Nba2 mice, Tfh cells expressed the BAFF receptors BCMA and B lymphocyte stimulator receptor 3 (BR-3) and accumulated in the spleen when BCMA was absent. BCMA deficiency in T cells promoted the expansion of Tfh cells, GC formation, autoantibody production, and interferon-γ (IFNγ) production by Tfh cells through BR-3. IFNγ-producing Tfh cells increased BAFF expression in dendritic cells. Blocking BAFF or IFNγ in vivo reduced Tfh cell accumulation and reduced autoimmunity in BCMA-deficient animals. Moreover, circulating Tfh-like cells that expressed BR-3 (but not BCMA) were elevated in patients with systemic lupus erythematosus, and this correlated with serum BAFF and IFNγ levels.

Conclusion: In Nba2 mice, BCMA negatively regulates Tfh cell expansion, while BAFF signaling through BR-3 promotes Tfh cell accumulation. Our findings suggest that the balance between BCMA and BR-3 signaling in Tfh cells serves as a checkpoint of immune tolerance.
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http://dx.doi.org/10.1002/art.38950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342294PMC
March 2015

Neutrophils contribute to excess serum BAFF levels and promote CD4+ T cell and B cell responses in lupus-prone mice.

PLoS One 2014 10;9(7):e102284. Epub 2014 Jul 10.

Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia, United States of America; Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia, United States of America.

Despite increased frequencies of neutrophils found in autoimmune diseases such as systemic lupus erythematosus (SLE), how they contribute to disease pathogenesis and the mechanisms that affect the accumulation of neutrophils are poorly understood. The aim of this study was to identify factors in autoantibody-mediated autoimmunity that controls the accumulation of spleen resident neutrophils and to determine whether neutrophils contribute to abnormal B cell responses. Increased levels of the cytokine BAFF have been linked to loss of B cell tolerance in autoimmunity, but the cellular source responsible for excess BAFF is unknown. B cell maturation antigen (BCMA) is a receptor for BAFF and is critical for the survival of bone marrow plasma cells. Paradoxically, BCMA deficiency exacerbates the formation of autoantibody-secreting plasma cells in spleens of lupus-prone mice and the reasons for this effect are not understood. Here we analyzed the phenotype, localization and function of neutrophils in spleens of healthy mice and congenic lupus-prone mice, and compared mice sufficient or deficient in BCMA expression. Neutrophils were found to be significantly increased in frequency and activation status in spleens of lupus-prone mice when BCMA was absent. Furthermore, neutrophils localized within T cell zones and enhanced CD4(+) T cell proliferation and IFNγ production through the production of BAFF. Reduced BAFF and IFNγ serum levels, decreased frequencies of IFNγ-producing T cells, germinal center B cells, and autoantibody production after neutrophil depletion indicated the involvement of neutrophils in these autoimmune traits. Thus, we have identified a novel role for BCMA to control excess BAFF production in murine lupus through restraining the accumulation of BAFF-producing neutrophils. Our data suggests that devising therapeutic strategies to reduce neutrophils in autoimmunity may decrease BAFF levels and ameliorate disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0102284PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4092127PMC
November 2015

The unique neonatal NK cells: a critical component required for neonatal autoimmune disease induction by maternal autoantibody.

Front Immunol 2014 28;5:242. Epub 2014 May 28.

Departments of Pathology and Microbiology, Beirne Carter Center for Immunology Research, University of Virginia , Charlottesville, VA , USA.

Human maternal autoantibodies can trigger autoimmune diseases such as congenital heart block (CHB) in the progeny of women with lupus or Sjogren's disease. The pathogenic effect of early autoantibody (autoAb) exposure has been investigated in a murine neonatal autoimmune ovarian disease (nAOD) model triggered by a unique ZP3 antibody. Although immune complexes (IC) are formed in adult and neonatal ovaries, ZP3 antibody triggers severe nAOD only in <7-day-old neonatal mice. Propensity to nAOD is due to the uniquely hyper-responsive neonatal natural killer (NK) cells that lack the inhibitory Ly49C/I receptors. In nAOD, the neonatal NK cells directly mediate ovarian inflammation and oocyte depletion while simultaneously promoting de novo pathogenic ovarian-specific T cell responses. Resistance to nAOD in older mice results from the emergence of the Ly49C/I(+) NK cells that regulate effector NK cells and from CD25(+) regulatory T cell control. In preliminary studies, FcγRIII(+) NK cells as well as the ovarian resident FcγRIII(+) macrophages and/or dendritic cells were found to be as indispensable players. Activated by ovarian IC, they migrate to lymphoid organs where NK cell priming occurs. Remarkably, the findings in nAOD are very similar to those reported for neonatal responses to a retrovirus and its cognate antibody that lead to long-lasting immunity. Studies on nAOD therefore provide insights into maternal autoAb-mediated neonatal autoimmunity, including CHB, while simultaneously uncovering new properties of the neonatal innate and adaptive responses, lethality of premature infant infection, and novel neonatal antiviral vaccine design.
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http://dx.doi.org/10.3389/fimmu.2014.00242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4035566PMC
June 2014

Isocitrate ameliorates anemia by suppressing the erythroid iron restriction response.

J Clin Invest 2013 Aug 25;123(8):3614-23. Epub 2013 Jul 25.

Department of Pathology, University of Virginia, School of Medicine, Charlottesville, Virginia, USA.

The unique sensitivity of early red cell progenitors to iron deprivation, known as the erythroid iron restriction response, serves as a basis for human anemias globally. This response impairs erythropoietin-driven erythropoiesis and underlies erythropoietic repression in iron deficiency anemia. Mechanistically, the erythroid iron restriction response results from inactivation of aconitase enzymes and can be suppressed by providing the aconitase product isocitrate. Recent studies have implicated the erythroid iron restriction response in anemia of chronic disease and inflammation (ACDI), offering new therapeutic avenues for a major clinical problem; however, inflammatory signals may also directly repress erythropoiesis in ACDI. Here, we show that suppression of the erythroid iron restriction response by isocitrate administration corrected anemia and erythropoietic defects in rats with ACDI. In vitro studies demonstrated that erythroid repression by inflammatory signaling is potently modulated by the erythroid iron restriction response in a kinase-dependent pathway involving induction of the erythroid-inhibitory transcription factor PU.1. These results reveal the integration of iron and inflammatory inputs in a therapeutically tractable erythropoietic regulatory circuit.
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http://dx.doi.org/10.1172/JCI68487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3726169PMC
August 2013

Identification of Orch3, a locus controlling dominant resistance to autoimmune orchitis, as kinesin family member 1C.

PLoS Genet 2012 27;8(12):e1003140. Epub 2012 Dec 27.

Department of Medicine/Immunobiology Program, University of Vermont, Burlington, Vermont, United States of America.

Experimental autoimmune orchitis (EAO), the principal model of non-infectious testicular inflammatory disease, can be induced in susceptible mouse strains by immunization with autologous testicular homogenate and appropriate adjuvants. As previously established, the genome of DBA/2J mice encodes genes that are capable of conferring dominant resistance to EAO, while the genome of BALB/cByJ mice does not and they are therefore susceptible to EAO. In a genome scan, we previously identified Orch3 as the major quantitative trait locus controlling dominant resistance to EAO and mapped it to chromosome 11. Here, by utilizing a forward genetic approach, we identified kinesin family member 1C (Kif1c) as a positional candidate for Orch3 and, using a transgenic approach, demonstrated that Kif1c is Orch3. Mechanistically, we showed that the resistant Kif1c(D2) allele leads to a reduced antigen-specific T cell proliferative response as a consequence of decreased MHC class II expression by antigen presenting cells, and that the L(578) → P(578) and S(1027) → P(1027) polymorphisms distinguishing the BALB/cByJ and DBA/2J alleles, respectively, can play a role in transcriptional regulation. These findings may provide mechanistic insight into how polymorphism in other kinesins such as KIF21B and KIF5A influence susceptibility and resistance to human autoimmune diseases.
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http://dx.doi.org/10.1371/journal.pgen.1003140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3531464PMC
May 2013

Combination of factor H mutation and properdin deficiency causes severe C3 glomerulonephritis.

J Am Soc Nephrol 2013 Jan 30;24(1):53-65. Epub 2012 Nov 30.

Department of Pharmacology and Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.

Factor H (fH) and properdin both modulate complement; however, fH inhibits activation, and properdin promotes activation of the alternative pathway of complement. Mutations in fH associate with several human kidney diseases, but whether inhibiting properdin would be beneficial in these diseases is unknown. Here, we found that either genetic or pharmacological blockade of properdin, which we expected to be therapeutic, converted the mild C3 GN of an fH-mutant mouse to a lethal C3 GN with features of human dense deposit disease. We attributed this phenotypic change to a differential effect of properdin on the dynamics of alternative pathway complement activation in the fluid phase and the cell surface in the fH-mutant mice. Thus, in fH mutation-related C3 glomerulopathy, additional factors that impact the activation of the alternative pathway of complement critically determine the nature and severity of kidney pathology. These results show that therapeutic manipulation of the complement system requires rigorous disease-specific target validation.
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http://dx.doi.org/10.1681/ASN.2012060570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3537216PMC
January 2013

Lymphatic endothelial cells induce tolerance via PD-L1 and lack of costimulation leading to high-level PD-1 expression on CD8 T cells.

Blood 2012 Dec 19;120(24):4772-82. Epub 2012 Sep 19.

Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.

Lymphatic endothelial cells (LECs) induce peripheral tolerance by direct presentation to CD8 T cells (T(CD8)). We demonstrate that LECs mediate deletion only via programmed cell death-1 (PD-1) ligand 1, despite expressing ligands for the CD160, B- and T-lymphocyte attenuator, and lymphocyte activation gene-3 inhibitory pathways. LECs induce activation and proliferation of T(CD8), but lack of costimulation through 4-1BB leads to rapid high-level expression of PD-1, which in turn inhibits up-regulation of the high-affinity IL-2 receptor that is necessary for T(CD8) survival. Rescue of tyrosinase-specific T(CD8) by interference with PD-1 or provision of costimulation results in autoimmune vitiligo, demonstrating that LECs are significant, albeit suboptimal, antigen-presenting cells. Because LECs express numerous peripheral tissue antigens, lack of costimulation coupled to rapid high-level up-regulation of inhibitory receptors may be generally important in systemic peripheral tolerance.
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http://dx.doi.org/10.1182/blood-2012-04-427013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3520619PMC
December 2012

Impaired natural killer cell self-education and "missing-self" responses in Ly49-deficient mice.

Blood 2012 Jul 1;120(3):592-602. Epub 2012 Jun 1.

Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada.

Ly49-mediated recognition of MHC-I molecules on host cells is considered vital for natural killer (NK)-cell regulation and education; however, gene-deficient animal models are lacking because of the difficulty in deleting this large multigene family. Here, we describe NK gene complex knockdown (NKC(KD)) mice that lack expression of Ly49 and related MHC-I receptors on most NK cells. NKC(KD) NK cells exhibit defective killing of MHC-I-deficient, but otherwise normal, target cells, resulting in defective rejection by NKC(KD) mice of transplants from various types of MHC-I-deficient mice. Self-MHC-I immunosurveillance by NK cells in NKC(KD) mice can be rescued by self-MHC-I-specific Ly49 transgenes. Although NKC(KD) mice display defective recognition of MHC-I-deficient tumor cells, resulting in decreased in vivo tumor cell clearance, NKG2D- or antibody-dependent cell-mediated cytotoxicity-induced tumor cell cytotoxicity and cytokine production induced by activation receptors was efficient in Ly49-deficient NK cells, suggesting MHC-I education of NK cells is a single facet regulating their total potential. These results provide direct genetic evidence that Ly49 expression is necessary for NK-cell education to self-MHC-I molecules and that the absence of these receptors leads to loss of MHC-I-dependent "missing-self" immunosurveillance by NK cells.
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http://dx.doi.org/10.1182/blood-2012-02-408732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3976224PMC
July 2012

Autoimmune epididymoorchitis is essential to the pathogenesis of male-specific spondylarthritis in HLA-B27-transgenic rats.

Arthritis Rheum 2012 Aug;64(8):2518-28

Rheumatic Diseases Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8884, USA.

Objective: Male rats transgenic for HLA-B27 and human β(2) -microglobulin (hβ(2) m) spontaneously develop epididymoorchitis (EO) preceding the development of spondylarthritis (SpA). In the specific B27/hβ(2) m-transgenic rat cross-strain (21-3 × 382-2)F(1) , only the males develop SpA, and neither sex develops gut inflammation. This study was undertaken to determine whether EO and SpA in male (21-3 × 382-2)F(1) rats are causally related. In addition, the primary characteristics of EO in this rat arthritis model were assessed.

Methods: Male B27/hβ(2) m-transgenic (21-3 × 382-2)F(1) rats underwent bilateral, unilateral, or sham epididymoorchiectomy between ages 36 and 125 days. The castrated rats were given testosterone replacement. Alternatively, the 21-3 and 283-2 transgene loci were crossed with a transgene inducing aspermatogenesis. Rats were observed for the development of EO, arthritis, and spondylitis.

Results: In unmanipulated transgenic rats, inflammation was first evident in the ductuli efferentes (DE; ducts linking the rete testis to epididymis) as early as age 30 days. The inflammation was initially neutrophilic, and later became granulomatous. Antisperm and anti-testis cell antibodies appeared in the rat serum after age 70 days. Cells infiltrating the testes were predominantly CD4+ T cells and CD68+ or CD163+ macrophages. Quantitative polymerase chain reaction of the DE, epididymis, and testis showed elevations in the levels of interferon-γ, interleukin-10 (IL-10), and IL-17A. In addition, levels of IL-12A, IL-22, IL-23A, and IL-23 receptor were found to be elevated in the DE. Remarkably, castration of the rats before age 91 days completely prevented the subsequent onset of arthritis and spondylitis, as did transgene-induced azospermia.

Conclusion: Autoimmune EO develops spontaneously in HLA-B27/hβ(2) m-transgenic (21-3 × 283-2)F(1) rats at age 30 days, the age when antigen-positive meiotic germ cells first exit the testis. Persistent testicular inflammation and/or antigenic stimulation are essential prerequisites for the subsequent development of SpA. Thus, dysregulated innate immunity at immune-privileged sites may be an essential mechanism triggering the onset of SpA.
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http://dx.doi.org/10.1002/art.34480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3396784PMC
August 2012

The tyrosine phosphatase SHP-1 dampens murine Th17 development.

Blood 2012 May 20;119(19):4419-29. Epub 2012 Mar 20.

Beirne Carter Center for Immunology Research and Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA.

Th17 cells represent a subset of CD4+ T helper cells that secrete the proinflammatory cytokine IL-17. Th17 cells have been ascribed both a beneficial role in promoting clearance of pathogenic fungi and bacteria, and a pathogenic role in autoimmune diseases. Here we identify the tyrosine phosphatase SHP-1 as a critical regulator of Th17 development, using 3 complementary approaches. Impaired SHP-1 activity through genetic deletion of SHP-1, transgenic expression of an inducible dominant negative SHP-1, or pharmacologic inhibition of SHP-1 strongly promotes the development of Th17. Ex vivo Th17 skewing assays demonstrate that genetic or pharmacologic disruption of SHP-1 activity in T cells results in a hyper-response to stimulation via IL-6 and IL-21, 2 cytokines that promote Th17 development. Mechanistically, we find that SHP-1 decreases the overall cytokine-induced phosphorylation of STAT3 in primary CD4+ T cells. These data identify SHP-1 as a key modifier of IL-6-and IL-21-driven Th17 development via regulation of STAT3 signaling and suggest SHP-1 as a potential new therapeutic target for manipulating Th17 differentiation in vivo.
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http://dx.doi.org/10.1182/blood-2011-09-377069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3362360PMC
May 2012

Natural killer cells regulate murine cytomegalovirus-induced sialadenitis and salivary gland disease.

J Virol 2012 Feb 7;86(4):2132-42. Epub 2011 Dec 7.

Department of Microbiology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.

The transmission of herpesviruses depends on viral shedding at mucosal surfaces. The salivary gland represents a major site of persistent viral replication for many viruses, including cytomegalovirus. We established a mouse model of salivary gland dysfunction after acute viral infection and investigated the cellular requirements for the loss of secretion. Murine cytomegalovirus (MCMV) infection severely impaired saliva secretion independently of salivary gland virus levels. Lymphocytes or circulating monocytes/macrophages were not required for secretory dysfunction. Dysfunction occurred before glandular inflammation, suggesting that a soluble mediator initiated the disruption of acinar cell function. Despite genetic differences in innate resistance to MCMV, NK cells protected the host against acinar atrophy and the loss of secretions under conditions of an exceedingly low virus inoculum. NK cells also modulated the type of glandular inflammation after infection, as they prevented an influx of Siglec-F(+) polymorphonuclear leukocytes (PMNs). Therefore, beyond their recognized role in controlling MCMV replication, NK cells preserve organ integrity and function and regulate the innate inflammatory response within the gland.
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http://dx.doi.org/10.1128/JVI.06898-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3302420PMC
February 2012

Pathogenesis of gastritis in ileitis-prone SAMP1/Yit mice.

Keio J Med 2011 ;60(2):65-8

Department of Medicine, University of Virginia, Virginia, USA.

Inflammatory bowel disease is a chronic inflammatory disease of the gut which manifests as ulcerative colitis or Crohn's disease. One of the most studied animal models of spontaneous Crohn's disease is the senescence-accelerated mouse (SAMP1/Yit strain) model. In SAMP1/Yit mice, although many immunological responses are perturbed, some evidence suggests that the primary defect lies in the epithelial cell barrier. In the process of studying epithelial permeability, we observed that the stomach in SAMP1/Yit mice also had increased permeability. Upon further examination, these mice were shown to have marked, chronic gastritis with focal to diffuse aggregates of mononuclear cells of mixed lineages. These aggregates were located predominantly in the oxyntic mucosa, with occasional lesions in the forestomach but with relatively fewer cellular infiltrates in the antral mucosa. Real-time RT PCR showed an increase in several helper T cell (Th cell)-derived pro-inflammatory cytokines in the gastric mucosa of SAMP1/Yit mice. However, many of the cells in the aggregates of SAMP1/Yit mice were B cells. SAMP1/Yit B cells exacerbate ileitis when co-transferred into immunodeficient recipients. The gastritis also reflects a contribution by B cells. As SAMP1/Yit mice were derived from AKR mice, we examined AKR mice and determined that they too have an increased occurrence of gastritis, although they do not develop ileitis. B cells contributed to the gastric inflammation in these mice also. Thus, SAMP1/Yit mice display gastritis as well as ileitis, and B cells appear to play a role in the pathogenesis of inflammation at both sites. This review will discuss some of the mechanisms that may account for these different manifestations of gastrointestinal disease.
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http://dx.doi.org/10.2302/kjm.60.65DOI Listing
October 2011

B cell maturation antigen deficiency exacerbates lymphoproliferation and autoimmunity in murine lupus.

J Immunol 2011 Jun 2;186(11):6136-47. Epub 2011 May 2.

Department of Microbiology, University of Virginia, Charlottesville, VA 22908, USA.

Systemic lupus erythematosus and its preclinical lupus-prone mouse models are autoimmune disorders involving the production of pathogenic autoantibodies. Genetic predisposition to systemic lupus erythematosus results in B cell hyperactivity, survival of self-reactive B cells, and differentiation to autoantibody-secreting plasma cells (PCs). These corrupt B cell responses are, in part, controlled by excess levels of the cytokine BAFF that normally maintains B cell homeostasis and self-tolerance through limited production. B cell maturation Ag (BCMA) is a receptor for BAFF that, under nonautoimmune conditions, is important for sustaining enduring Ab protection by mediating survival of long-lived PCs but is not required for B cell maturation and homeostasis. Through analysis of two different lupus-prone mouse models deficient in BCMA, we identify BCMA as an important factor in regulating peripheral B cell expansion, differentiation, and survival. We demonstrate that a BCMA deficiency combined with the lpr mutation or the murine lupus susceptibility locus Nba2 causes dramatic B cell and PC lymphoproliferation, accelerated autoantibody production, and early lethality. This study unexpectedly reveals that BCMA works to control B cell homeostasis and self-tolerance in systemic autoimmunity.
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http://dx.doi.org/10.4049/jimmunol.1001931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181142PMC
June 2011

Regulatory T cells control tolerogenic versus autoimmune response to sperm in vasectomy.

Proc Natl Acad Sci U S A 2011 May 18;108(18):7511-6. Epub 2011 Apr 18.

Department of Pathology and Beirne B Carter Center of Immunology, University of Virginia, Charlottesville, VA 22908, USA.

Vasectomy is a well accepted global contraceptive approach frequently associated with epididymal granuloma and sperm autoantibody formation. To understand the long-term sequelae of vasectomy, we investigated the early immune response in vasectomized mice. Vasectomy leads to rapid epithelial cell apoptosis and necrosis, persistent inflammation, and sperm granuloma formation in the epididymis. Vasectomized B6AF1 mice did not mount autoimmune response but instead developed sperm antigen-specific tolerance, documented as resistance to immunization-induced experimental autoimmune orchitis (EAO) but not experimental autoimmune encephalomyelitis. Strikingly, tolerance switches over to pathologic autoimmune state following concomitant CD4(+)CD25(+)Foxp3(+) regulatory T cell (Treg) depletion: unilaterally vasectomized mice produce dominant autoantibodies to an orchitogenic antigen (zonadhesin), and develop CD4 T-cell- and antibody-dependent bilateral autoimmune orchitis. Therefore, (i) Treg normally prevents spontaneous organ-specific autoimmunity induction by persistent endogenous danger signal, and (ii) autoantigenic stimulation with sterile autoinflammation can lead to tolerance. Finally, postvasectomy tolerance occurs in B6AF1, C57BL/6, and A/J strains. However, C57BL/6 mice resisted EAO after 60% Treg depletion, but developed EAO after 97% Treg reduction. Therefore, variance in intrinsic Treg function--a possible genetic trait--can influence the divergent tolerogenic versus autoimmune response to vasectomy.
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http://dx.doi.org/10.1073/pnas.1017615108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3088630PMC
May 2011

H2 control of natural T regulatory cell frequency in the lymph node correlates with susceptibility to day 3 thymectomy-induced autoimmune disease.

J Immunol 2011 Jan 6;186(1):382-9. Epub 2010 Dec 6.

Department of Medicine, University of Vermont, Burlington, VT 05405, USA.

Day 3 thymectomy (D3Tx) results in a loss of peripheral tolerance mediated by natural regulatory T cells (nTregs) and development of autoimmune ovarian dysgenesis (AOD) and autoimmune dacryoadenitis (ADA) in A/J and (C57BL/6J × A/J) F(1) hybrids (B6A), but not in C57BL/6J (B6) mice. Previously, using quantitative trait locus (QTL) linkage analysis, we showed that D3Tx-AOD is controlled by five unlinked QTL (Aod1-Aod5) and H2. In this study, using D3Tx B6-Chr(A/J)/NaJ chromosome (Chr) substitution strains, we confirm that QTL on Chr16 (Aod1a/Aod1b), Chr3 (Aod2), Chr1 (Aod3), Chr2 (Aod4), Chr7 (Aod5), and Chr17 (H2) control D3Tx-AOD susceptibility. In addition, we also present data mapping QTL controlling D3Tx-ADA to Chr17 (Ada1/H2), Chr1 (Ada2), and Chr3 (Ada3). Importantly, B6-ChrX(A/J) mice were as resistant to D3Tx-AOD and D3Tx-ADA as B6 mice, thereby excluding Foxp3 as a susceptibility gene in these models. Moreover, we report quantitative differences in the frequency of nTregs in the lymph nodes (LNs), but not spleen or thymus, of AOD/ADA-resistant B6 and AOD/ADA-susceptible A/J, B6A, and B6-Chr17(A/J) mice. Similar results correlating with experimental allergic encephalomyelitis and orchitis susceptibility were seen with B10.S and SJL/J mice. Using H2-congenic mice, we show that the observed difference in frequency of LN nTregs is controlled by Ada1/H2. These data support the existence of an LN-specific, H2-controlled mechanism regulating the prevalence of nTregs in autoimmune disease susceptibility.
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http://dx.doi.org/10.4049/jimmunol.1002110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3012265PMC
January 2011

Lymph node-resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentation.

J Exp Med 2010 Apr 22;207(4):681-8. Epub 2010 Mar 22.

Department of Microbiology and Carter Immunology Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.

Peripheral immune tolerance is generally thought to result from cross-presentation of tissue-derived proteins by quiescent tissue-resident dendritic cells to self-reactive T cells that have escaped thymic negative selection, leading to anergy or deletion. Recently, we and others have implicated the lymph node (LN) stroma in mediating CD8 T cell peripheral tolerance. We demonstrate that LN-resident lymphatic endothelial cells express multiple peripheral tissue antigens (PTAs) independent of the autoimmune regulator (Aire). They directly present an epitope derived from one of these, the melanocyte-specific protein tyrosinase, to tyrosinase-specific CD8 T cells, leading to their deletion. We also show that other LN stromal subpopulations express distinct PTAs by mechanisms that vary in their Aire dependence. These results establish lymphatic endothelial cells, and potentially other LN-resident cells, as systemic mediators of peripheral immune tolerance.
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http://dx.doi.org/10.1084/jem.20092465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2856027PMC
April 2010

Cutting edge: normal regional lymph node enrichment of antigen-specific regulatory T cells with autoimmune disease-suppressive capacity.

J Immunol 2009 Dec;183(12):7635-8

Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA.

Natural CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) effectively prevent autoimmune disease development, but their role in maintaining physiological tolerance against self-Ag of internal organs is not yet defined. In this study, we quantified disease-specific Treg (DS-Treg) as Treg that preferentially suppress one autoimmune disease over another in day 3 thymectomized recipients. A striking difference was found among individual lymph nodes (LN) of normal mice; Treg from draining LN were 15-50 times more efficient than those of nondraining LN at suppressing autoimmune diseases of ovary, prostate, and lacrimal glands. The difference disappeared upon auto-Ag ablation and returned upon auto-Ag re-expression. In contrast, the CD4(+)CD25(-) effector T cells from different individual LN induced multiorgan inflammation with comparable organ distribution. We propose that peripheral tolerance for internal organs relies on the control of autoreactive effector T cells by strategic enrichment of Ag-specific Treg in the regional LN.
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http://dx.doi.org/10.4049/jimmunol.0804251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2872190PMC
December 2009

The postnatal maternal environment affects autoimmune disease susceptibility in A/J mice.

Cell Immunol 2010 ;260(2):119-27

Department of Medicine, University of Vermont, Burlington, VT 05405, USA.

The postnatal maternal environment is known to increase susceptibility to a number of autoimmune diseases. Here we asked whether the postnatal maternal environment could influence autoimmune disease development to day 3 thymectomy (d3tx)-induced autoimmune ovarian disease (AOD) and experimental allergic encephalomyelitis (EAE) in cross-fostered A/J and B6 mice. A/J pups foster-nursed by B6 mothers exhibit an increase in autoimmune disease development while cross-fostering B6 pups on A/J mothers did not alter their susceptibility. The increase in AOD incidence seen in foster-nursed d3tx A/J mice correlated with a decrease in the total number of CD4(+) T cells in the lymph nodes of these animals. Analysis of the cellular composition in the milk revealed that B6 mice shed significantly more maternally derived lymphocytes into their milk compared to A/J mothers. These data suggest that there are maternally derived postnatal factors that influence the development of autoimmune disease in A/J mice.
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http://dx.doi.org/10.1016/j.cellimm.2009.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2795069PMC
January 2010

Characterizing emergent properties of immunological systems with multi-cellular rule-based computational modeling.

Trends Immunol 2008 Dec 27;29(12):589-99. Epub 2008 Oct 27.

Department of Biomedical Engineering, University of Virginia, Health System, Charlottesville, VA 22908, USA.

The immune system is comprised of numerous components that interact with one another to give rise to phenotypic behaviors that are sometimes unexpected. Agent-based modeling (ABM) and cellular automata (CA) belong to a class of discrete mathematical approaches in which autonomous entities detect local information and act over time according to logical rules. The power of this approach lies in the emergence of behavior that arises from interactions between agents, which would otherwise be impossible to know a priori. Recent work exploring the immune system with ABM and CA has revealed novel insights into immunological processes. Here, we summarize these applications to immunology and, particularly, how ABM can help formulate hypotheses that might drive further experimental investigations of disease mechanisms.
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http://dx.doi.org/10.1016/j.it.2008.08.006DOI Listing
December 2008

Cutting edge: Autoimmune disease in day 3 thymectomized mice is actively controlled by endogenous disease-specific regulatory T cells.

J Immunol 2008 Apr;180(7):4366-70

Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA.

Female B6AF1 mice thymectomized on day 3 (d3tx) develop autoimmune ovarian disease (AOD) and dacryoadenitis. It has been hypothesized that d3tx breaks tolerance by depleting late ontogeny regulatory T cells (Treg). We now report that Treg greatly expand over effector T cells in d3tx mice and adoptively suppress autoimmune disease in d3tx recipients. In the d3tx donors, Treg from ovarian lymph nodes (LN) preferentially suppress AOD and Treg from lacrimal gland LN preferentially suppress dacryoadenitis, suggesting they are strategically positioned for disease control. Indeed, the autologous disease in d3tx mice is dramatically enhanced by in vivo depletion of endogenous Treg. Moreover, normal 3-day-old mice possess Treg that suppress AOD and autoimmune gastritis as efficiently as adult cells. Thus, d3tx mice possess disease-relevant Treg of presumed neonatal origin. They accumulate in the regional LN and actively inhibit concurrent autoimmune disease; however, they cannot fully prevent autoimmune disease development.
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http://dx.doi.org/10.4049/jimmunol.180.7.4366DOI Listing
April 2008

The role of physiological self-antigen in the acquisition and maintenance of regulatory T-cell function.

Immunol Rev 2006 Aug;212:170-84

Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA.

The CD4+ CD25+ regulatory T cells (Tregs) are efficient regulators of autoimmunity, but the mechanism remains elusive. We summarize recent data for the conclusion that disease-specific Tregs respond to tissue antigens to maintain physiological tolerance and prevent autoimmunity. First, polyclonal Tregs from antigen-positive donors suppress autoimmune ovarian disease (AOD) or experimental autoimmune prostatitis in day 3 thymectomized (d3tx) mice more efficiently than Tregs from antigen-negative donors. Second, Tregs of antigen-negative adult mice respond to cognate antigen in vivo and rapidly gain disease-specific Treg function. Third, in d3tx female recipients devoid of neonatal ovarian antigens, only female Tregs suppressed AOD; the male Tregs gain AOD-suppressing function by responding to the ovarian antigen in the recipients and mask the supremacy of female Tregs in AOD suppression. Fourth, when Tregs completely suppress AOD, the ovary-draining lymph node is the only location with evidence of profound and persistent (but reversible) host T-cell suppression. Fifth, from these nodes, highly potent AOD-suppressing Tregs are retrievable. We conclude that self-tolerance involves the continuous priming of Tregs by autoantigens, and in autoimmune disease suppression, the effector T-cell response is continuously negated by potent disease-specific Tregs that accumulate at the site of autoantigen presentation.
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http://dx.doi.org/10.1111/j.0105-2896.2006.00404.xDOI Listing
August 2006