Cory Teuscher

Multiple sclerosis (MS) is a complex disease with significant heterogeneity in disease course and progression. Genetic studies have identified numerous loci associated with MS risk, but the genetic basis of disease progression remains elusive. To address this, we leveraged the Collaborative Cross (CC), a genetically diverse mouse strain panel, and experimental autoimmune encephalomyelitis (EAE). The 32 CC strains studied captured a wide spectrum of EAE severity, trajectory, and presentation, including severe-progressive, monophasic, relapsing remitting, and axial rotary–EAE (AR-EAE), accompanied by distinct immunopathology. Sex differences in EAE severity were observed in 6 strains. Quantitative trait locus analysis revealed distinct genetic linkage patterns for different EAE phenotypes, including EAE severity and incidence of AR-EAE. Machine learning–based approaches prioritized candidate genes for loci underlying EAE severity ( Abcc4 and Gpc6 ) and AR-EAE ( Yap1 and Dync2h1 ). This work expands the EAE phenotypic repertoire and identifies potentially novel loci controlling unique EAE phenotypes, supporting the hypothesis that heterogeneity in MS disease course is driven by genetic variation.

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The systemic capillary leak syndrome (SCLS, Clarkson disease) is a disorder of unknown etiology characterized by recurrent episodes of vascular leakage of proteins and fluids into peripheral tissues, resulting in whole-body edema and hypotensive shock. The pathologic mechanisms and genetic basis for SCLS remain elusive. Here we identify an inbred mouse strain, SJL, which recapitulates cardinal features of SCLS, including susceptibility to histamine- and infection-triggered vascular leak. We named this trait “Histamine hypersensitivity” (Histh/Histh) and mapped it to Chromosome 6.Histhis syntenic to the genomic locus most strongly associated with SCLS in humans (3p25.3), revealing that the predisposition to develop vascular hyperpermeability has a strong genetic component conserved between humans and mice and providing a naturally occurring animal model for SCLS. Genetic analysis ofHisthmay reveal orthologous candidate genes that contribute not only to SCLS, but also to normal and dysregulated mechanisms underlying vascular barrier function more generally.

Vitamin D3 (VitD) insufficiency is postulated to represent a major modifiable risk factor for multiple sclerosis (MS). While low VitD levels strongly correlate with higher MS risk in white populations, this is not the case for other ethnic groups, suggesting the existence of a genetic component. Moreover, VitD supplementation studies in MS so far have not shown a consistent benefit. We sought to determine whether direct manipulation of VitD levels modulates central nervous system autoimmune disease in a sex-by-genotype-dependent manner. To this end, we used a dietary model of VitD modulation, together with the autoimmune animal model of MS, experimental autoimmune encephalomyelitis (EAE). To assess the impact of genotype-by-VitD interactions on EAE susceptibility, we utilized a chromosome substitution (consomic) mouse model that incorporates the genetic diversity of wild-derived PWD/PhJ mice. High VitD was protective in EAE in female, but not male C57BL/6J (B6) mice, and had no effect in EAE-resistant PWD/PhJ (PWD) mice. EAE protection was accompanied by sex- and genotype-specific suppression of proinflammatory transcriptional programs in CD4 T effector cells, but not CD4 regulatory T cells. Decreased expression of proinflammatory genes was observed with high VitD in female CD4 T effector cells, specifically implicating a key role of MHC class II genes, interferon gamma, and Th1 cell-mediated neuroinflammation. In consomic strains, effects of VitD on EAE were also sex- and genotype dependent, whereby high VitD: (1) was protective, (2) had no effect, and (3) unexpectedly had disease-exacerbating effects. Systemic levels of 25(OH)D differed across consomic strains, with higher levels associated with EAE protection only in females. Analysis of expression of key known VitD metabolism genes between B6 and PWD mice revealed that their expression is genetically determined and sex specific and implicated Cyp27b1 and Vdr as candidate genes responsible for differential EAE responses to VitD modulation. Taken together, our results support the observation that the association between VitD status and MS susceptibility is genotype dependent and suggest that the outcome of VitD status in MS is determined by gene-by-sex interactions.

Month‐season of birth (M‐SOB) is a risk factor in multiple chronic diseases, including multiple sclerosis (MS), where the lowest and greatest risk of developing MS coincide with the lowest and highest birth rates, respectively. To determine whether M‐SOB effects in such chronic diseases as MS can be experimentally modeled, we examined the effect of M‐SOB on susceptibility of C57BL/6J mice to experimental autoimmune encephalomyelitis (EAE). As in MS, mice that were born during the M‐SOB with the lowest birth rate were less susceptible to EAE than mice born during the M‐SOB with the highest birth rate. We also show that the M‐SOB effect on EAE susceptibility is associated with differential production of multiple cytokines/chemokines by neuroantigen‐specific T cells that are known to play a role in EAE pathogenesis. Taken together, these results support the existence of an M‐SOB effect that may reflect seasonally dependent developmental differences in adaptive immune responses to self‐antigens independent of external stimuli, including exposure to sunlight and vitamin D. Moreover, our documentation of an M‐SOB effect on EAE susceptibility in mice allows for modeling and detailed analysis of mechanisms that underlie the M‐SOB effect in not only MS but in numerous other diseases in which M‐SOB impacts susceptibility.—Reynolds, J. D., Case, L. K., Krementsov, D. N., Raza, A., Bartiss, R., Teuscher, C. Modeling month‐season of birth as a risk factor in mouse models of chronic disease: from multiple sclerosis to autoimmune encephalomyelitis. FASEB J. 31, 2709–2719 (2017). www.fasebj.org

Significance: Including sex and gender into preclinical research is central to delineating the mechanisms contributing to sex differences in health and disease. The majority of sex differences in susceptibility to infectious diseases, such as influenza A virus (IAV), are believed to be due to the influence of sex hormones on the immune system; however, the idea that sex chromosomes also may influence infectious disease susceptibility is being increasingly recognized. Our finding that genetic variation in chromosome Y (ChrY) influences the survival of male mice following IAV infection, and the associated sex differences in IAV susceptibility, further establishes a critical role for ChrY in controlling the male-specific regulatory genome related to infectious disease susceptibility.

Multiple sclerosis (MS) is a debilitating autoimmune neuroinflammatory disease influenced by genetics and the environment. MS incidence in female subjects has approximately tripled in the last centur...

Multiple sclerosis (MS) is a debilitating chronic inflammatory disease of the nervous system that affects approximately 2.3 million individuals worldwide, with higher prevalence in females, and a strong genetic component. While over 200 MS susceptibility loci have been identified in GWAS, the underlying mechanisms whereby they contribute to disease susceptibility remains ill-defined. Forward genetics approaches using conventional laboratory mouse strains are useful in identifying and functionally dissecting genes controlling disease-relevant phenotypes, but are hindered by the limited genetic diversity represented in such strains. To address this, we have combined the powerful chromosome substitution (consomic) strain approach with the genetic diversity of a wild-derived inbred mouse strain. Using experimental allergic encephalomyelitis (EAE), a mouse model of MS, we evaluated genetic control of disease course among a panel of 26 consomic strains of mice inheriting chromosomes from the wild-derived PWD strain on the C57BL/6J background, which models the genetic diversity seen in human populations. Nineteen linkages on 18 chromosomes were found to harbor loci controlling EAE. Of these 19 linkages, six were male-specific, four were female-specific, and nine were non-sex-specific, consistent with a differential genetic control of disease course between males and females. An MS-GWAS candidate-driven bioinformatic analysis using orthologous genes linked to EAE course identified sex-specific and non-sex-specific gene networks underlying disease pathogenesis. An analysis of sex hormone regulation of genes within these networks identified several key molecules, prominently including the MAP kinase family, known hormone-dependent regulators of sex differences in EAE course. Importantly, our results provide the framework by which consomic mouse strains with overall genome-wide genetic diversity, approximating that seen in humans, can be used as a rapid and powerful tool for modeling the genetic architecture of MS. Moreover, our data represent the first step towards mechanistic dissection of genetic control of sexual dimorphism in CNS autoimmunity.

The estrogens are female sex hormones that are involved in a variety of physiological processes, including reproductive development and function, wound healing, and bone growth. They are mainly known for their roles in reproductive tissues—specifically, 17β‐estradiol (E ₂ ), the primary estrogen, which is secreted by the ovaries and induces cellular proliferation and growth of the uterus and mammary glands. In addition to the role of estrogens in promoting tissue growth and development during normal physiological states, they have a well‐established role in determining susceptibility to disease, particularly cancer, in reproductive tissues. The responsiveness of various tissues to estrogen is genetically controlled, with marked quantitative variation observed across multiple species, including humans. This variation presents both researchers and clinicians with a veritable physiological puzzle, the pieces of which—many of them unknown—are complex and difficult to fit together. Although genetics is known to play a major role in determining sensitivity to estrogens, there are other factors, including parent of origin and the maternal environment, that are intimately linked to heritable phenotypes but do not represent genotype, per se. The objectives of this review article were to summarize the current knowledge of the role of genotype, and uterine and neonatal environments, in phenotypic variation in the response to estrogens; to discuss recent findings and the potential mechanisms involved; and to highlight exciting research opportunities for the future.—Wall, E. H., Hewitt, S. C., Case, L. K., Lin, C.‐Y., Korach, K. S., Teuscher, C., The role of genetics in estrogen responses: a critical piece of an intricate puzzle. FASEB J. 28, 5042–5054 (2014). www.fasebj.org

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 (C57BL6/J; B6) or low (C3H/HeJ; C3H) responders to E₂ led to the identification of quantitative trait loci (QTL) associated with phenotypic variation in uterine growth and leukocyte infiltration. Like the uterus, phenotypic variation in the responsiveness of the mammary gland to E₂ during both normal and pathologic conditions has been reported. In the current experiment, we utilized an E₂-specific model of mammary ductal growth combined with a microarray approach to determine the degree to which genotype influences the responsiveness of the mammary gland to E₂, including the associated transcriptional programs, in B6 and C3H mice. Our results reveal that E₂-induced mammary ductal growth and ductal morphology are genetically controlled. In addition, we observed a paradoxical effect of mammary ductal growth in response to E₂ compared with what has been reported for the uterus; B6 is a high responder for the uterus and was a low responder for mammary ductal growth, whereas the reverse was observed for C3H. In contrast, B6 was a high responder for mammary ductal side branching. The B6 phenotype was associated with increased mammary epithelial cell proliferation and apoptosis, and a distinct E₂-induced transcriptional program. These findings lay the groundwork for future experiments designed to investigate the genes and mechanisms underlying phenotypic variation in tissue-specific sensitivity to systemic and environmental estrogens during various physiological and disease states.