Publications by authors named "Cory Teuscher"

90 Publications

Lysosomal β-glucuronidase regulates Lyme and rheumatoid arthritis severity.

J Clin Invest 2014 Jan 16;124(1):311-20. Epub 2013 Dec 16.

Lyme disease, caused by the spirochete Borrelia burgdorferi, is the most prevalent arthropod-borne illness in the United States and remains a clinical and social challenge. The spectrum of disease severity among infected patients suggests that host genetics contribute to pathogenic outcomes, particularly in patients who develop arthritis. Using a forward genetics approach, we identified the lysosomal enzyme β-glucuronidase (GUSB), a member of a large family of coregulated lysosomal enzymes, as a key regulator of Lyme-associated arthritis severity. Severely arthritic C3H mice possessed a naturally occurring hypomorphic allele, Gusbh. C57BL/6 mice congenic for the C3H Gusb allele were prone to increased Lyme-associated arthritis severity. Radiation chimera experiments revealed that resident joint cells drive arthritis susceptibility. C3H mice expressing WT Gusb as a transgene were protected from severe Lyme arthritis. Importantly, the Gusbh allele also exacerbated disease in a serum transfer model of rheumatoid arthritis. A known GUSB function is the prevention of lysosomal accumulation of glycosaminoglycans (GAGs). Development of Lyme and rheumatoid arthritis in Gusbh-expressing mice was associated with heightened accumulation of GAGs in joint tissue. We propose that GUSB modulates arthritis pathogenesis by preventing accumulation of proinflammatory GAGs within inflamed joint tissue, a trait that may be shared by other lysosomal exoglycosidases.
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http://dx.doi.org/10.1172/JCI72339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871255PMC
January 2014

Regulatory T cells and vasectomy.

J Reprod Immunol 2013 Nov 8;100(1):66-75. Epub 2013 Sep 8.

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

CD4+ CD25+ regulatory T cells (Tregs) strongly influence the early and late autoimmune responses to meiotic germ cell antigens (MGCA) and the gonadal immunopathology in vasectomized mice. This is supported by the published and recently acquired information presented here. Within 24h of unilateral vasectomy (uni-vx) the ipsilateral epididymis undergoes epithelial cell apoptosis followed by necrosis, severe inflammation, and granuloma formation. Unexpectedly, vasectomy alone induced MGCA-specific tolerance. In contrast, uni-vx plus simultaneous Treg depletion resulted in MGCA-specific autoimmune response and bilateral autoimmune orchitis. Both tolerance and autoimmunity were strictly linked to the early epididymal injury. We now discovered that testicular autoimmunity in uni-vx mice did not occur when Treg depletion was delayed by one week. Remarkably, this delayed Treg depletion also prevented tolerance induction. Therefore, tolerance depends on a rapid de novo Treg response to MGCA exposed after vasectomy. Moreover, tolerance was blunted in mice genetically deficient in PD-1 ligand, suggesting the involvement of induced Treg. We conclude that pre-existing natural Treg prevents post-vasectomy autoimmunity, whereas vasectomy-induced Treg maintains post-vasectomy tolerance. We further discovered that vasectomized mice were still resistant to autoimmune orchitis induction for at least 12-16 months; thus, tolerance is long-lasting. Although significant sperm autoantibodies of low titers became detectable in uni-vx mice at 7 months, the antibody titers fluctuated over time, suggesting a dynamic "balance" between the autoimmune and tolerance states. Finally, we observed severe epididymal fibrosis and hypo-spermatogenesis at 12 months after uni-vx: findings of highly critical clinical significance.
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http://dx.doi.org/10.1016/j.jri.2013.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3965253PMC
November 2013

Environmental factors acting during development to influence MS risk: insights from animal studies.

Mult Scler 2013 Nov 27;19(13):1684-9. Epub 2013 Sep 27.

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

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system with an increasing incidence in females. Epidemiological data strongly implicate environmental factors acting at the population level during gestation, childhood and adulthood in the increasing incidence of MS. Several such factors are implicated in disease risk, but their causality remains unproven, while other factors remain unknown. An understanding of the risk factors acting during development is particularly limited. Animal studies could potentially bridge the gap between observational epidemiology and clinical intervention, providing not only direct evidence of causality for a given environmental agent, but also an opportunity to dissect the underlying molecular mechanisms. Given a rodent's short gestational and developmental period, the effects of developmental exposure can also be readily addressed. Nonetheless, studies in this area so far are few. In this review, we summarize the insights gleaned from studies that test environmental influences in animal models of MS, with a particular focus on gestational and early life exposures.
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http://dx.doi.org/10.1177/1352458513506954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3833345PMC
November 2013

Sex-specific control of central nervous system autoimmunity by p38 mitogen-activated protein kinase signaling in myeloid cells.

Ann Neurol 2014 Jan;75(1):50-66

Department of Medicine, Immunobiology Program, University of Vermont, Burlington, VT.

Objective: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), characterized by a global increasing incidence driven by relapsing-remitting disease in females. Investigators have described p38 mitogen-activated protein kinase (MAPK) as a key regulator of inflammatory responses in autoimmunity, but its role in the sexual dimorphism in MS or MS models remains unexplored.

Methods: Toward this end, we used experimental autoimmune encephalomyelitis (EAE), the principal animal model of MS, combined with pharmacologic and genetic inhibition of p38 MAPK activity and transcriptomic analyses.

Results: Pharmacologic inhibition of p38 MAPK selectively ameliorated EAE in female mice. Conditional deletion studies demonstrated that p38α signaling in macrophages/myeloid cells, but not T cells or dendritic cells, mediated this sexual dimorphism, which was dependent on the presence of adult sex hormones. Analysis of CNS inflammatory infiltrates showed that female but not male mice lacking p38α in myeloid cells exhibited reduced immune cell activation compared with controls, whereas peripheral T-cell priming was unaffected in both sexes. Transcriptomic analyses of myeloid cells revealed differences in p38α-controlled transcripts comprising female- and male-specific gene modules, with greater p38α dependence of proinflammatory gene expression in females.

Interpretation: Our findings demonstrate a key role for p38α in myeloid cells in CNS autoimmunity and uncover important molecular mechanisms underlying sex differences in disease pathogenesis. Taken together, our results suggest that the p38 MAPK signaling pathway represents a novel target for much needed disease-modifying therapies for MS.
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http://dx.doi.org/10.1002/ana.24020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3945470PMC
January 2014

The emerging role of p38 mitogen-activated protein kinase in multiple sclerosis and its models.

Mol Cell Biol 2013 Oct 29;33(19):3728-34. Epub 2013 Jul 29.

Department of Medicine, Immunobiology Program, University of Vermont, Burlington, Vermont, USA.

Multiple sclerosis (MS), the most common disabling neurologic disease of young adults, is considered a classical T cell-mediated disease and is characterized by demyelination, axonal damage, and progressive neurological dysfunction. The currently available disease-modifying therapies are limited in their efficacy, and improved understanding of new pathways contributing to disease pathogenesis could reveal additional novel therapeutic targets. The p38 mitogen-activated protein kinase (MAPK) signaling pathway is known to be triggered by stress stimuli and to contribute to inflammatory responses. Importantly, a number of recent studies have identified this signaling pathway as a central player in MS and its principal animal model, experimental allergic encephalomyelitis. Here, we review the evidence from mouse and human studies supporting the role of p38 MAPK in regulating key immunopathogenic mechanisms underlying autoimmune inflammatory disease of the central nervous system and the potential of targeting this pathway as a disease-modifying therapy in MS.
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http://dx.doi.org/10.1128/MCB.00688-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3811866PMC
October 2013

Histamine H(3) receptor integrates peripheral inflammatory signals in the neurogenic control of immune responses and autoimmune disease susceptibility.

PLoS One 2013 22;8(7):e62743. Epub 2013 Jul 22.

Department of Medicine, Immunobiology Program, University of Vermont, Burlington, Vermont, USA.

Histamine H(3) receptor (Hrh3/H(3)R) is primarily expressed by neurons in the central nervous system (CNS) where it functions as a presynaptic inhibitory autoreceptor and heteroreceptor. Previously, we identified an H(3)R-mediated central component in susceptibility to experimental allergic encephalomyelitis (EAE), the principal autoimmune model of multiple sclerosis (MS), related to neurogenic control of blood brain barrier permeability and peripheral T cell effector responses. Furthermore, we identified Hrh3 as a positional candidate for the EAE susceptibility locus Eae8. Here, we characterize Hrh3 polymorphisms between EAE-susceptible and resistant SJL and B10.S mice, respectively, and show that Hrh3 isoform expression in the CNS is differentially regulated by acute peripheral inflammatory stimuli in an allele-specific fashion. Next, we show that Hrh3 is not expressed in any subpopulations of the immune compartment, and that secondary lymphoid tissue is anatomically poised to be regulated by central H(3)R signaling. Accordingly, using transcriptome analysis, we show that, inflammatory stimuli elicit unique transcriptional profiles in the lymph nodes of H(3)RKO mice compared to WT mice, which is indicative of negative regulation of peripheral immune responses by central H(3)R signaling. These results further support a functional link between the neurogenic control of T cell responses and susceptibility to CNS autoimmune disease coincident with acute and/or chronic peripheral inflammation. Pharmacological targeting of H(3)R may therefore be useful in preventing the development and formation of new lesions in MS, thereby limiting disease progression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0062743PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3718788PMC
February 2014

The Y chromosome as a regulatory element shaping immune cell transcriptomes and susceptibility to autoimmune disease.

Genome Res 2013 Sep 25;23(9):1474-85. Epub 2013 Jun 25.

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

Understanding the DNA elements that constitute and control the regulatory genome is critical for the appropriate therapeutic management of complex diseases. Here, using chromosome Y (ChrY) consomic mouse strains on the C57BL/6J (B6) background, we show that susceptibility to two diverse animal models of autoimmune disease, experimental allergic encephalomyelitis (EAE) and experimental myocarditis, correlates with the natural variation in copy number of Sly and Rbmy multicopy ChrY genes. On the B6 background, ChrY possesses gene regulatory properties that impact genome-wide gene expression in pathogenic CD4(+) T cells. Using a ChrY consomic strain on the SJL background, we discovered a preference for ChrY-mediated gene regulation in macrophages, the immune cell subset underlying the EAE sexual dimorphism in SJL mice, rather than CD4(+) T cells. Importantly, in both genetic backgrounds, an inverse correlation exists between the number of Sly and Rbmy ChrY gene copies and the number of significantly up-regulated genes in immune cells, thereby supporting a link between copy number variation of Sly and Rbmy with the ChrY genetic element exerting regulatory properties. Additionally, we show that ChrY polymorphism can determine the sexual dimorphism in EAE and myocarditis. In humans, an analysis of the CD4(+) T cell transcriptome from male multiple sclerosis patients versus healthy controls provides further evidence for an evolutionarily conserved mechanism of gene regulation by ChrY. Thus, as in Drosophila, these data establish the mammalian ChrY as a member of the regulatory genome due to its ability to epigenetically regulate genome-wide gene expression in immune cells.
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http://dx.doi.org/10.1101/gr.156703.113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759723PMC
September 2013

Studies in experimental autoimmune encephalomyelitis do not support developmental bisphenol a exposure as an environmental factor in increasing multiple sclerosis risk.

Toxicol Sci 2013 Sep 23;135(1):91-102. Epub 2013 Jun 23.

Department of Medicine, Immunobiology Program, University of Vermont, Burlington, Vermont 05405, USA.

Multiple sclerosis (MS), a demyelinating immune-mediated central nervous system disease characterized by increasing female penetrance, is the leading cause of disability in young adults in the developed world. Epidemiological data strongly implicate an environmental factor, acting at the population level during gestation, in the increasing incidence of female MS observed over the last 50 years, yet the identity of this factor remains unknown. Gestational exposure to bisphenol A (BPA), an endocrine disruptor used in the manufacture of polycarbonate plastics since the 1950s, has been reported to alter a variety of physiological processes in adulthood. BPA has estrogenic activity, and we hypothesized that increased gestational exposure to environmental BPA may therefore contribute to the increasing female MS risk. To test this hypothesis, we utilized two different mouse models of MS, experimental autoimmune encephalomyelitis (EAE) in C57BL/6J mice (chronic progressive) and in SJL/J mice (relapsing-remitting). Dams were exposed to physiologically relevant levels of BPA in drinking water starting 2 weeks prior to mating and continuing until weaning of offspring. EAE was induced in adult offspring. No significant changes in EAE incidence, progression, or severity were observed with BPA exposure, despite changes in cytokine production by autoreactive T cells. However, endocrine disruption was evidenced by changes in testes development, and transcriptomic profiling revealed that BPA exposure altered the expression of several genes important for testes development, including Pdgfa, which was downregulated. Overall, our results do not support gestational BPA exposure as a significant contributor to the increasing female MS risk.
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http://dx.doi.org/10.1093/toxsci/kft141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3748766PMC
September 2013

Systemic lack of canonical histamine receptor signaling results in increased resistance to autoimmune encephalomyelitis.

J Immunol 2013 Jul 14;191(2):614-22. Epub 2013 Jun 14.

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

Histamine (HA) is a key regulator of experimental allergic encephalomyelitis (EAE), the autoimmune model of multiple sclerosis. HA exerts its effects through four known G-protein-coupled receptors: H1, H2, H3, and H4 (histamine receptors; H(1-4)R). Using HR-deficient mice, our laboratory has demonstrated that H1R, H2R, H3R, and H4R play important roles in EAE pathogenesis, by regulating encephalitogenic T cell responses, cytokine production by APCs, blood-brain barrier permeability, and T regulatory cell activity, respectively. Histidine decarboxylase-deficient mice (HDCKO), which lack systemic HA, exhibit more severe EAE and increased Th1 effector cytokine production by splenocytes in response to myelin oligodendrocyte gp35-55. In an inverse approach, we tested the effect of depleting systemic canonical HA signaling on susceptibility to EAE by generating mice lacking all four known G-protein-coupled-HRs (H(1-4)RKO mice). In this article, we report that in contrast to HDCKO mice, H(1-4)RKO mice develop less severe EAE compared with wild-type animals. Furthermore, splenocytes from immunized H(1-4)RKO mice, compared with wild-type mice, produce a lower amount of Th1/Th17 effector cytokines. The opposing results seen between HDCKO and H1-4RKO mice suggest that HA may signal independently of H1-4R and support the existence of an alternative HAergic pathway in regulating EAE resistance. Understanding and exploiting this pathway has the potential to lead to new disease-modifying therapies in multiple sclerosis and other autoimmune and allergic diseases.
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http://dx.doi.org/10.4049/jimmunol.1203137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3747232PMC
July 2013

Genetic control of estrogen-regulated transcriptional and cellular responses in mouse uterus.

FASEB J 2013 May 31;27(5):1874-86. Epub 2013 Jan 31.

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

The uterotropic response of the uterus to 17β-estradiol (E2) is genetically controlled, with marked variation observed depending on the mouse strain studied. Previous genetic studies from our laboratory using inbred mice that are high [C57BL/6J (B6)] or low [C3H/HeJ (C3H)] responders to E2 led to the identification of quantitative trait (QT) loci associated with phenotypic variation in uterine growth and leukocyte infiltration. The mechanisms underlying differential responsiveness to E2, and the genes involved, are unknown. Therefore, we used a microarray approach to show association of distinct E2-regulated transcriptional signatures with genetically controlled high and low responses to E2 and their segregation in (C57BL/6J×C3H/HeJ) F1 hybrids. Among the 6664 E2-regulated transcripts, analysis of cellular functions of those that were strain specific indicated C3H-selective enrichment of apoptosis, consistent with a 7-fold increase in the apoptosis indicator CASP3, and a 2.4-fold decrease in the apoptosis inhibitor Naip1 (Birc1a) in C3H vs. B6 following treatment with E2. In addition, several differentially expressed transcripts reside within our previously identified QT loci, including the ERα-tethering factor Runx1, demonstrated to enhance E2-mediated transcript regulation. The level of RUNX1 in uterine epithelial cells was shown to be 3.5-fold greater in B6 compared to C3H. Our novel insights into the mechanisms underlying the genetic control of tissue sensitivity to estrogen have great potential to advance understanding of individualized effects in physiological and disease states.
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http://dx.doi.org/10.1096/fj.12-213462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3633824PMC
May 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

H(1)R expression by CD11B(+) cells is not required for susceptibility to experimental allergic encephalomyelitis.

Cell Immunol 2012 Jul-Aug;278(1-2):27-34. Epub 2012 Jul 14.

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

The histamine H(1) receptor (Hrh1/H(1)R) was identified as an autoimmune disease gene in experimental allergic encephalomyelitis (EAE), the principal autoimmune model of multiple sclerosis (MS). Previously, we showed that selective re-expression of H(1)R by endothelial cells or T cells in H(1)RKO mice significantly reduced or complemented EAE severity and cytokine responses, respectively. H(1)R regulates innate immune cells, which in turn influences peripheral and central nervous system CD4(+) T cell effector responses. Therefore, we selectively re-expressed H(1)R in CD11b(+) cells of H(1)RKO mice to test the hypothesis that H(1)R signaling in these cells contributes to EAE susceptibility. We demonstrate that transgenic re-expression of H(1)R by H(1)RKO-CD11b(+) cells neither complements EAE susceptibility nor T cell cytokine responses highlighting the cell-specific effects of Hrh1 in the pathogenesis of EAE and MS, and the need for cell-specific targeting in optimizing therapeutic interventions based on such genes.
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http://dx.doi.org/10.1016/j.cellimm.2012.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3490133PMC
January 2013

Inheritance of coronary artery disease in men.

Lancet 2012 Jun;379(9835):2424-2425

Department of Medicine, University of Vermont, Burlington, VT 05405, USA; Department of Pathology, University of Vermont, Burlington, VT, USA; Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, USA. Electronic address:

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http://dx.doi.org/10.1016/S0140-6736(12)61060-5DOI Listing
June 2012

Combinatorial roles for histamine H1-H2 and H3-H4 receptors in autoimmune inflammatory disease of the central nervous system.

Eur J Immunol 2012 Jun;42(6):1536-46

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

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system in which histamine (HA) and its receptors have been implicated in disease pathogenesis. HA exerts its effects through four different G protein-coupled receptors designated H(1)-H(4). We previously examined the effects of traditional single HA receptor (HR) knockouts (KOs) in experimental allergic encephalomyelitis (EAE), the autoimmune model of MS. Our results revealed that H(1) R and H(2) R are propathogenic, while H(3) R and H(4) R are antipathogenic. This suggests that combinatorial targeting of HRs may be an effective disease-modifying therapy (DMT) in MS. To test this hypothesis, we generated H(1) H(2) RKO and H(3) H(4) RKO mice and studied them for susceptibility to EAE. Compared with wild-type (WT) mice, H(1) H(2) RKO mice developed a less severe clinical disease course, whereas the disease course of H(3) H(4) RKO mice was more severe. H(1) H(2) RKO mice also developed less neuropathology and disrupted blood brain barrier permeability compared with WT and H(3) H(4) RKO mice. Additionally, splenocytes from immunized H(1) H(2) RKO mice produced less interferon(IFN)-γ and interleukin(IL)-17. These findings support the concept that combined pharmacological targeting of HRs may be an appropriate ancillary DMT in MS and other immunopathologic diseases.
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http://dx.doi.org/10.1002/eji.201141859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3508704PMC
June 2012

High-throughput genotyping of advanced congenic lines by high resolution melting analysis for identification of Bbaa2, a QTL controlling Lyme arthritis.

Biotechniques 2012 Mar;52(3):183-90

Department of Pathology, University of Utah, Salt Lake City, UT, USA.

Congenic mapping is a powerful strategy to identify genomic loci regulating quantitative traits. Generating congenic lines is an iterative process of refinement that is both time and resource intensive. Here we report an alternative to traditional microsatellite marker analysis or costly high-density oligonucleotide single nucleotide polymorphism (SNP) arrays for congenic genotyping. The identification of inherited SNP variability in congenic lines using high resolution melting analysis (HRMA) represents a novel application of the method. The blocked probe HRMA approach offers a scalable, low cost, closed-tube system that benefits from rapid turnaround times, and unequivocal interpretation. The markedly higher prevalence of SNPs relative to microsatellites in the genome allows much greater flexibility for the identification of new genotyping landmarks as congenic intervals are refined. We have adopted this approach in our development of B6.C3-Bbaa2 congenic lines for the identification of loci regulating murine Lyme arthritis severity. As a result, we have been able to fully genotype individuals prior to weaning age, and expand our number of breeding cages without increasing our colony budget. Thus far, 26 SNP markers have been successfully mapped to the Bbaa2 locus. This has facilitated the identification of 20 novel B6.C3-Bbaa2 congenic lines spanning the original interval.
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http://dx.doi.org/10.2144/000113838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3329127PMC
March 2012

Chromosome y regulates survival following murine coxsackievirus b3 infection.

G3 (Bethesda) 2012 Jan 1;2(1):115-21. Epub 2012 Jan 1.

Coxsackievirus B3 (CVB3) contributes to the development of myocarditis, an inflammatory heart disease that predominates in males, and infection is a cause of unexpected death in young individuals. Although gonadal hormones contribute significantly to sex differences, sex chromosomes may also influence disease. Increasing evidence indicates that Chromosome Y (ChrY) genetic variants can impact biological functions unrelated to sexual differentiation. Using C57BL/6J (B6)-ChrY consomic mice, we show that genetic variation in ChrY has a direct effect on the survival of CVB3-infected animals. This effect is not due to potential Sry-mediated differences in prenatal testosterone exposure or to differences in adult testosterone levels. Furthermore, we show that ChrY polymorphism influences the percentage of natural killer T cells in B6-ChrY consomic strains but does not underlie CVB3-induced mortality. These data underscore the importance of investigating not only the hormonal regulation but also ChrY genetic regulation of cardiovascular disease and other male-dominant, sexually dimorphic diseases and phenotypes.
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http://dx.doi.org/10.1534/g3.111.001610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3276194PMC
January 2012

Genetics of experimental allergic encephalomyelitis supports the role of T helper cells in multiple sclerosis pathogenesis.

Ann Neurol 2011 Dec;70(6):887-96

Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA.

Objective: The major histocompatibility complex (MHC) is the primary genetic contributor to multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE), but multiple additional interacting loci are required for genetic susceptibility. The identity of most of these non-MHC genes is unknown. In this report, we identify genes within evolutionarily conserved genetic pathways leading to MS and EAE.

Methods: To identify non-MHC binary and quantitative trait loci (BTL/QTL) important in the pathogenesis of EAE, we generated phenotype-selected congenic mice using EAE-resistant B10.S and EAE-susceptible SJL mice. We hypothesized that genes linked to EAE BTL/QTL and MS-GWAS can be identified if they belong to common evolutionarily conserved pathways, which can be identified with a bioinformatic approach using Ingenuity software.

Results: Many known BTL/QTL were retained and linked to susceptibility during phenotype selection, the most significant being a region on chromosome 17 distal to H2 (Eae5). We show in pathway analysis that T helper (T(H))-cell differentiation genes are critical for both diseases. Bioinformatic analyses predicted that Eae5 is important in CD4 T-effector and/or Foxp3(+) T-regulatory cells (Tregs), and we found that B10.S-Eae5(SJL) congenic mice have significantly greater numbers of lymph node CD4 and Tregs than B10.S mice.

Interpretation: These results support the polygenic model of MS/EAE, whereby MHC and multiple minor loci are required for full susceptibility, and confirm a critical genetic dependence on CD4 T(H)-cell differentiation and function in the pathogenesis of both diseases.
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http://dx.doi.org/10.1002/ana.22642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4122509PMC
December 2011

Histamine H4 receptor optimizes T regulatory cell frequency and facilitates anti-inflammatory responses within the central nervous system.

J Immunol 2012 Jan 5;188(2):541-7. Epub 2011 Dec 5.

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

Histamine is a biogenic amine that mediates multiple physiological processes, including immunomodulatory effects in allergic and inflammatory reactions, and also plays a key regulatory role in experimental allergic encephalomyelitis, the autoimmune model of multiple sclerosis. The pleiotropic effects of histamine are mediated by four G protein-coupled receptors, as follows: Hrh1/H(1)R, Hrh2/H(2)R, Hrh3/H(3)R, and Hrh4/H(4)R. H(4)R expression is primarily restricted to hematopoietic cells, and its role in autoimmune inflammatory demyelinating disease of the CNS has not been studied. In this study, we show that, compared with wild-type mice, animals with a disrupted Hrh4 (H(4)RKO) develop more severe myelin oligodendrocyte glycoprotein (MOG)(35\x{2013}55)-induced experimental allergic encephalomyelitis. Mechanistically, we also show that H(4)R plays a role in determining the frequency of T regulatory (T(R)) cells in secondary lymphoid tissues, and regulates T(R) cell chemotaxis and suppressor activity. Moreover, the lack of H(4)R leads to an impairment of an anti-inflammatory response due to fewer T(R) cells in the CNS during the acute phase of the disease and an increase in the proportion of Th17 cells.
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http://dx.doi.org/10.4049/jimmunol.1101498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3253209PMC
January 2012

Histamine H(1) receptor signaling regulates effector T cell responses and susceptibility to coxsackievirus B3-induced myocarditis.

Cell Immunol 2012 15;272(2):269-74. Epub 2011 Oct 15.

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

Susceptibility to autoimmune myocarditis has been associated with histamine release by mast cells during the innate immune response to coxsackievirus B3 (CVB3) infection. To investigate the contribution of histamine H(1) receptor (H(1)R) signaling to CVB3-induced myocarditis, we assessed susceptibility to the disease in C57BL/6J (B6) H(1)R(-/-) mice. No difference was observed in mortality between CVB3-infected B6 and H(1)R(-/-) mice. However, analysis of their hearts revealed a significant increase in myocarditis in H(1)R(-/-) mice that is not attributed to increased virus replication. Enhanced myocarditis susceptibility correlated with a significant expansion in pathogenic Th1 and Vγ4(+) γδ T cells in the periphery of these animals. Furthermore, an increase in regulatory T cells was observed, yet these cells were incapable of controlling myocarditis in H(1)R(-/-) mice. These data establish a critical role for histamine and H(1)R signaling in regulating T cell responses and susceptibility to CVB3-induced myocarditis in B6 mice.
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http://dx.doi.org/10.1016/j.cellimm.2011.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3244571PMC
April 2012

Sex chromosome complement contributes to sex differences in coxsackievirus B3 but not influenza A virus pathogenesis.

Biol Sex Differ 2011 Aug 1;2. Epub 2011 Aug 1.

The W Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.

Background: Both coxsackievirus B3 (CVB3) and influenza A virus (IAV; H1N1) produce sexually dimorphic infections in C57BL/6 mice. Gonadal steroids can modulate sex differences in response to both viruses. Here, the effect of sex chromosomal complement in response to viral infection was evaluated using four core genotypes (FCG) mice, where the Sry gene is deleted from the Y chromosome, and in some mice is inserted into an autosomal chromosome. This results in four genotypes: XX or XY gonadal females (XXF and XYF), and XX or XY gonadal males (XXM and XYM). The FCG model permits evaluation of the impact of the sex chromosome complement independent of the gonadal phenotype.

Methods: Wild-type (WT) male and female C57BL/6 mice were assigned to remain intact or be gonadectomized (Gdx) and all FCG mice on a C57BL/6 background were Gdx. Mice were infected with either CVB3 or mouse-adapted IAV, A/Puerto Rico/8/1934 (PR8), and monitored for changes in immunity, virus titers, morbidity, or mortality.

Results: In CVB3 infection, mortality was increased in WT males compared to females and males developed more severe cardiac inflammation. Gonadectomy suppressed male, but increased female, susceptibility to CVB3. Infection with IAV resulted in greater morbidity and mortality in WT females compared with males and this sex difference was significantly reduced by gonadectomy of male and female mice. In Gdx FCG mice infected with CVB3, XY mice were less susceptible than XX mice. Protection correlated with increased CD4+ forkhead box P3 (FoxP3)+ T regulatory (Treg) cell activation in these animals. Neither CD4+ interferon (IFN)γ (T helper 1 (Th1)) nor CD4+ interleukin (IL)-4+ (Th2) responses differed among the FCG mice during CVB3 infection. Infection of Gdx FCG mice revealed no effect of sex chromosome complement on morbidity or mortality following IAV infection.

Conclusions: These studies indicate that sex chromosome complement can influence pathogenicity of some, but not all, viruses.
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http://dx.doi.org/10.1186/2042-6410-2-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3162877PMC
August 2011

Activation of p38 MAPK in CD4 T cells controls IL-17 production and autoimmune encephalomyelitis.

Blood 2011 Sep 25;118(12):3290-300. Epub 2011 Jul 25.

Department of Medicine, Immunobiology Program, University of Vermont, Burlington, VT, USA.

Although several transcription factors have been shown to be critical for the induction and maintenance of IL-17 expression by CD4 Th cells, less is known about the role of nontranscriptional mechanisms. Here we show that the p38 MAPK signaling pathway is essential for in vitro and in vivo IL-17 production by regulating IL-17 synthesis in CD4 T cells through the activation of the eukaryotic translation initiation factor 4E/MAPK-interacting kinase (eIF-4E/MNK) pathway. We also show that p38 MAPK activation is required for the development and progression of both chronic and relapsing-remitting forms of experimental allergic encephalomyelitis (EAE), the principal autoimmune model of multiple sclerosis. Furthermore, we show that regulation of p38 MAPK activity specifically in T cells is sufficient to modulate EAE severity. Thus, mechanisms other than the regulation of gene expression also contribute to Th17 cell effector functions and, potentially, to the pathogenesis of other Th17 cell-mediated diseases.
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http://dx.doi.org/10.1182/blood-2011-02-336552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3179398PMC
September 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

Endothelial histamine H1 receptor signaling reduces blood-brain barrier permeability and susceptibility to autoimmune encephalomyelitis.

Proc Natl Acad Sci U S A 2010 Nov 18;107(44):18967-72. Epub 2010 Oct 18.

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

Disruption of the blood-brain barrier (BBB) underlies the development of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis. Environmental factors, such as Bordetella pertussis, are thought to sensitize central endothelium to biogenic amines like histamine, thereby leading to increased BBB permeability. B. pertussis-induced histamine sensitization (Bphs) is a monogenic intermediate phenotype of EAE controlled by histamine H(1) receptor (Hrh1/H(1)R). Here, we transgenically overexpressed H(1)R in endothelial cells of Hrh1-KO (H(1)RKO) mice to test the role of endothelial H(1)R directly in Bphs and EAE. Unexpectedly, transgenic H(1)RKO mice expressing endothelial H(1)R under control of the von Willebrand factor promoter (H(1)RKO-vWF(H1R) Tg) were Bphs-resistant. Moreover, H(1)RKO-vWF(H1R) Tg mice exhibited decreased BBB permeability and enhanced protection from EAE compared with H(1)RKO mice. Thus, contrary to prevailing assumptions, our results show that endothelial H(1)R expression reduces BBB permeability, suggesting that endothelial H(1)R signaling may be important in the maintenance of cerebrovascular integrity.
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http://dx.doi.org/10.1073/pnas.1008816107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2973887PMC
November 2010

Slam haplotypes modulate the response to lipopolysaccharide in vivo through control of NKT cell number and function.

J Immunol 2010 Jul 7;185(1):144-56. Epub 2010 Jun 7.

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

CD1d-restricted NKT cells make up an innate-like T cell subset that plays a role in amplifying the response of innate immune leukocytes to TLR ligands. The Slam locus contains genes that have been implicated in innate and adaptive immune responses. In this study, we demonstrate that divergent Slam locus haplotypes modulate the response of macrophages to the TLR4 ligand LPS through their control of NKT cell number and function. In response to LPS challenge in vivo, macrophage TNF production in Slam haplotype-2(+) 129S1/SvImJ and 129X1/SvJ mice was significantly impaired in comparison with macrophage TNF production in Slam haplotype-1(+) C57BL/6J mice. Although no cell-intrinsic differences in macrophage responses to LPS were observed between strains, 129 mice were found to be deficient in liver NKT cell number, in NKT cell cytokine production in response to the CD1d ligand alpha-galactosylceramide, and in NKT cell IFN-gamma production after LPS challenge in vivo. Using B6.129c1 congenic mice and adoptive transfer, we found that divergent Slam haplotypes controlled the response to LPS in vivo, as well as the diminished NKT cell number and function, and that these phenotypes were associated with differential expression of signaling lymphocytic activation molecule family receptors on NKT cells. These data suggest that the polymorphisms that distinguish two Slam haplotypes significantly modulate the innate immune response in vivo through their effect on NKT cells.
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http://dx.doi.org/10.4049/jimmunol.0902658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055558PMC
July 2010

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

A single nucleotide polymorphism in Tyk2 controls susceptibility to experimental allergic encephalomyelitis.

J Immunol 2009 Jun;182(12):7776-83

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

Genes controlling immunopathologic diseases of differing etiopathology may also influence susceptibility to autoimmune disease. B10.D1-H2(q)/SgJ mice with a 2538 G-->A missense mutation in the tyrosine kinase-2 gene (Tyk2) are susceptible to Toxoplasma gondii yet resistant to autoimmune arthritis, unlike the wild-type B10.Q/Ai substrain. To understand whether Tyk2 is also important in a second autoimmune model, experimental allergic encephalomyelitis (EAE) was induced in B10.D1-H2(q)/SgJ (Tyk2(A)) and B10.Q/Ai (Tyk2(G)) mice with the myelin oligodendrocyte glycoprotein peptide 79-96. B10.D1-H2(q)/SgJ mice were resistant to EAE whereas B10.Q/Ai mice were susceptible, and a single copy of the Tyk2(G) allele conferred EAE susceptibility in F(1) hybrids. Furthermore, EAE resistance in B10.D1-H2(q)/SgJ mice was overridden when pertussis toxin (PTX) was used to mimic the effects of environmental factors derived from infectious agents. Numerous cytokines and chemokines were increased when PTX was included in the immunization protocol. However, only RANTES, IL-6, and IFN-gamma increased significantly with both genetic compensation and PTX treatment. These data indicate that Tyk2 is a shared autoimmune disease susceptibility gene whose genetic contribution to disease susceptibility can be modified by environmental factors. Single nucleotide polymorphisms like the one that distinguishes Tyk2 alleles are of considerable significance given the potential role of gene-by-environment interactions in autoimmune disease susceptibility.
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http://dx.doi.org/10.4049/jimmunol.0900142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3008628PMC
June 2009

Interval-specific congenic lines reveal quantitative trait Loci with penetrant lyme arthritis phenotypes on chromosomes 5, 11, and 12.

Infect Immun 2009 Aug 1;77(8):3302-11. Epub 2009 Jun 1.

Department of Pathology, University of Utah, Salt Lake City, 84112, USA.

The observation that Borrelia burgdorferi-induced arthritis is severe in C3H mice and milder in C57BL/6 (B6) mice has allowed a forward genetics approach for the identification of genetic elements that regulate the arthritis response. Quantitative trait loci (QTL) on five chromosomes (Chr) were identified previously in segregating crosses between C3H and B6 mice and collectively designated B. burgdorferi arthritis-associated (Bbaa) QTL. Reciprocal interval-specific congenic lines (ISCL) that encompass Bbaa1, Bbaa2-Bbaa3, Bbaa4, Bbaa6, and Bbaa12 on Chr 4, 5, 11, 12, and 1, respectively, have now been generated. Bidirectional transfer of the arthritis severity phenotype in association with Bbaa2-Bbaa3 and Bbaa4 was observed, and unidirectional transfer with the B6 allele of Bbaa6 was noted. These findings confirm the existence of polymorphic loci within Bbaa2-Bbaa3, Bbaa4, and Bbaa6 that regulate the severity of B. burgdorferi-induced arthritis. ISCL were used to assess the regulation of a previously identified interferon transcriptional profile associated with severe disease in C3H mice. The regulation of this transcriptional signature was found to be independent of penetrant Bbaa QTL, both in joint tissues and in isolated macrophages. These results clearly demonstrate the utility of forward genetics for the discovery of novel genes and pathways involved in the regulation of the severity of Lyme arthritis and predict the involvement of regulatory elements not evident from other experimental approaches.
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http://dx.doi.org/10.1128/IAI.00396-09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715682PMC
August 2009

Cutting edge: the Y chromosome controls the age-dependent experimental allergic encephalomyelitis sexual dimorphism in SJL/J mice.

J Immunol 2009 Feb;182(4):1789-93

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

Multiple sclerosis is a sexually dimorphic, demyelinating disease of the CNS, and experimental allergic encephalomyelitis (EAE) is its principal autoimmune model. Young male SJL/J mice are relatively resistant to EAE whereas older males and SJL/J females of any age are susceptible. By comparing a wide age range of proteolipid protein peptide 139-151 immunized mice, we found that female disease severity remains constant with age. In contrast, EAE disease severity increases with age in SJL/J males, with young males having significantly less severe disease and older males having significantly more disease than equivalently aged females. To determine whether the Y chromosome contributes to this sexual dimorphism, EAE was induced in consomic SJL/J mice carrying a B10.S Y chromosome (SJL.Y(B10.S)). EAE was significantly more severe in young male SJL.Y(B10.S) mice compared with young male SJL/J mice. These studies show that a Y chromosome-linked polymorphism controls the age-dependent EAE sexual dimorphism observed in SJL/J mice.
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http://dx.doi.org/10.4049/jimmunol.0803200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2658649PMC
February 2009

Resistance to lipopolysaccharide-induced preterm delivery mediated by regulatory T cell function in mice.

Biol Reprod 2009 May 14;80(5):874-81. Epub 2009 Jan 14.

Department of Obstetrics, University of Vermont College of Medicine, Burlington, Vermont, USA.

Intrauterine or intraperitoneal administration of lipopolysaccharide (LPS) into normal mice at midgestation induces preterm delivery (PTD) within 24 h through a mechanism dependent on Toll-like receptor signaling and expression of inflammatory cytokines. The exact participants in the cellular network involved in PTD are not known. Although the activities of innate immune cells are thought to be important, the extent to which this process depends on T and B cells has yet to be examined. Mice deficient in T and B cells due to genetic deficiency in the recombination activating gene 1 (Rag1(-/-)) were given LPS intraperitoneally on Day 15 of gestation and found to be susceptible to LPS-induced PTD. This was found to involve many of the inflammatory mediators reported as important in normal mice. Moreover, at a low dose (3 microg), pregnant Rag1(-/-) mice were found to be more susceptible to PTD than a cohort of normal mice on the same genetic background. This increased susceptibility was partially reversed by transfer, on Day 10 of gestation, of whole lymphocytes or purified CD4(+) T cells. Transfer of purified CD4(+) T cells to Rag1(-/-) mice resulted in a uterine draining node population of FOXP3(+) cells, suggesting that these cells may contribute to resistance to LPS-induced PTD. Overall, the data suggest that, although T and B lymphocytes are not critical positive regulators of LPS-induced PTD, CD4(+) T cells play a protective and regulatory role, and thus could be a target for preventive or therapeutic manipulation.
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http://dx.doi.org/10.1095/biolreprod.108.074294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2804837PMC
May 2009