Analysis of CNS autoimmunity in genetically diverse mice reveals unique phenotypes and mechanisms.

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).

Probing the basis of disease heterogeneity in multiple sclerosis using genetically diverse mice.

Unlabelled: 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).

Host Genetic Variation Has a Profound Impact on Immune Responses Mediating Control of Viral Load in Chronic Gammaherpesvirus Infection.

Chronic infection with the gammaherpesvirus EBV is a risk factor for several autoimmune diseases, and poor control of EBV viral load and enhanced anti-EBV responses elevate this risk further. However, the role of host genetic variation in the regulation of immune responses to chronic gammaherpesvirus infection and control of viral replication remains unclear. To address this question, we infected C57BL/6J (B6) and genetically divergent wild-derived inbred PWD/PhJ (PWD) mice with murine gammaherpesvirus-68 (MHV-68), a gammaherpesvirus similar to EBV, and determined the effect of latent gammaherpesvirus infection on the CD4 T cell transcriptome.

A genetic locus complements resistance to Bordetella pertussis-induced histamine sensitization.

Histamine plays pivotal role in normal physiology and dysregulated production of histamine or signaling through histamine receptors (HRH) can promote pathology. Previously, we showed that Bordetella pertussis or pertussis toxin can induce histamine sensitization in laboratory inbred mice and is genetically controlled by Hrh1/HRH1. HRH1 allotypes differ at three amino acid residues with P-V-L and L-M-S, imparting sensitization and resistance respectively.

Sex differences in susceptibility to influenza A virus infection depend on host genotype.

Infection with the respiratory pathogen influenza A virus (IAV) causes significant morbidity and mortality each year. While host genotype is thought to contribute to severity of disease, naturally occurring genetic determinants remain mostly unknown. Moreover, more severe disease is seen in women compared with men, but genetic mechanisms underlying this sex difference remain obscure.

The Cdkn2a gene product p19 alternative reading frame (p19ARF) is a critical regulator of IFNβ-mediated Lyme arthritis.

Type I interferon (IFN) has been identified in patients with Lyme disease, and its abundant expression in joint tissues of C3H mice precedes development of Lyme arthritis. Forward genetics using C3H mice with severe Lyme arthritis and C57BL/6 (B6) mice with mild Lyme arthritis identified the Borrelia burgdorferi arthritis-associated locus 1 (Bbaa1) on chromosome 4 (Chr4) as a regulator of B. burgdorferi-induced IFNβ expression and Lyme arthritis severity.

Interactions between host genetics and gut microbiota determine susceptibility to CNS autoimmunity.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system. The etiology of MS is multifactorial, with disease risk determined by genetics and environmental factors. An emerging risk factor for immune-mediated diseases is an imbalance in the gut microbiome.

Identification of novel loci controlling inflammatory bowel disease susceptibility utilizing the genetic diversity of wild-derived mice.

Inflammatory bowel disease (IBD) is a complex disorder that imposes a growing health burden. Multiple genetic associations have been identified in IBD, but the mechanisms underlying many of these associations are poorly understood. Animal models are needed to bridge this gap, but conventional laboratory mouse strains lack the genetic diversity of human populations.

The sex-specific role of p38 MAP kinase in CNS autoimmunity is regulated by estrogen receptor alpha.

Biological sex is a critical factor in regulating immune function. A striking example of this is the higher prevalence of autoimmune diseases such as multiple sclerosis (MS) and lupus in females compared to males. While many studies have implicated the role of sex hormones such as estrogens and androgens in these sex differences, surprisingly little is known about other molecular pathways that underlie sex differences or interact with sex hormones.

Erratum: Author Correction: A natural mouse model reveals genetic determinants of systemic capillary leak syndrome (Clarkson disease).

[This corrects the article DOI: 10.1038/s42003-019-0647-4.].

A natural mouse model reveals genetic determinants of systemic capillary leak syndrome (Clarkson disease).

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.

Network-Based Functional Prediction Augments Genetic Association To Predict Candidate Genes for Histamine Hypersensitivity in Mice.

Genetic mapping is a primary tool of genetics in model organisms; however, many quantitative trait loci (QTL) contain tens or hundreds of positional candidate genes. Prioritizing these genes for validation is often and biased by previous findings. Here we present a technique for prioritizing positional candidates based on computationally inferred gene function.

Tuberculosis and impaired IL-23-dependent IFN-γ immunity in humans homozygous for a common missense variant.

Inherited IL-12Rβ1 and TYK2 deficiencies impair both IL-12- and IL-23-dependent IFN-γ immunity and are rare monogenic causes of tuberculosis, each found in less than 1/600,000 individuals. We show that homozygosity for the common P1104A allele, which is found in about 1/600 Europeans and between 1/1000 and 1/10,000 individuals in regions other than East Asia, is more frequent in a cohort of patients with tuberculosis from endemic areas than in ethnicity-adjusted controls ( = 8.37 × 10; odds ratio, 89.

Sex-Specific Gene-by-Vitamin D Interactions Regulate Susceptibility to Central Nervous System Autoimmunity.

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.

Genetic Control of Lyme Arthritis by Arthritis-Associated Locus 1 Is Dependent on Localized Differential Production of IFN-β and Requires Upregulation of Myostatin.

Previously, using a forward genetic approach, we identified differential expression of type I IFN as a positional candidate for an expression quantitative trait locus underlying arthritis-associated locus 1 (). In this study, we show that mAb blockade revealed a unique role for IFN-β in Lyme arthritis development in B6.C3- mice.

Anti-inflammatory roles of p38α MAPK in macrophages are context dependent and require IL-10.

The p38 MAPK pathway was originally identified as a master regulator of proinflammatory cytokine production by myeloid cells. Numerous drugs targeting this kinase showed promise in preclinical models of inflammatory disease, but so far, none have shown efficacy in clinical trials. The reasons behind this are unclear, but may, in part, be explained by emerging anti-inflammatory functions of this kinase or overly refined selectivity of second-generation pharmacologic inhibitors.

Modeling month-season of birth as a risk factor in mouse models of chronic disease: from multiple sclerosis to autoimmune encephalomyelitis.

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.

Genetic variation in chromosome Y regulates susceptibility to influenza A virus infection.

Males of many species, ranging from humans to insects, are more susceptible than females to parasitic, fungal, bacterial, and viral infections. One mechanism that has been proposed to account for this difference is the immunocompetence handicap model, which posits that the greater infectious disease burden in males is due to testosterone, which drives the development of secondary male sex characteristics at the expense of suppressing immunity. However, emerging data suggest that cell-intrinsic (chromosome X and Y) sex-specific factors also may contribute to the sex differences in infectious disease burden.

Vaccine draining lymph nodes are a source of antigen-specific B cells.

Purpose: Our research is focused on using vaccine draining lymph nodes as a source of immune cells to better understand the immune response and to attempt to generate new anti-cancer reagents. Following a vaccine, harvesting the lymph node can only be done once. We endeavored to determine the range of times that B cells secreting anti-KLH antibodies were present in the node of KLH-vaccinated mice.

Accelerated remyelination during inflammatory demyelination prevents axonal loss and improves functional recovery.

Demyelination in MS disrupts nerve signals and contributes to axon degeneration. While remyelination promises to restore lost function, it remains unclear whether remyelination will prevent axonal loss. Inflammatory demyelination is accompanied by significant neuronal loss in the experimental autoimmune encephalomyelitis (EAE) mouse model and evidence for remyelination in this model is complicated by ongoing inflammation, degeneration and possible remyelination.

Pharmacological inhibitors of TRPV4 channels reduce cytokine production, restore endothelial function and increase survival in septic mice.

Sepsis is characterized by systemic inflammation, edema formation and hypo-perfusion leading to organ dysfunction and ultimately death. Activation of the transient receptor potential vanilloid type 4 (TRPV4) channel is associated with edema formation and circulatory collapse. Here, we show that TRPV4 channels are involved in the hyper-inflammatory response and mortality associated with sepsis.

Inactivation of nuclear GSK3β by Ser(389) phosphorylation promotes lymphocyte fitness during DNA double-strand break response.

Variable, diversity and joining (V(D)J) recombination and immunoglobulin class switch recombination (CSR) are key processes in adaptive immune responses that naturally generate DNA double-strand breaks (DSBs) and trigger a DNA repair response. It is unclear whether this response is associated with distinct survival signals that protect T and B cells. Glycogen synthase kinase 3β (GSK3β) is a constitutively active kinase known to promote cell death.

β-Glucuronidase, a Regulator of Lyme Arthritis Severity, Modulates Lysosomal Trafficking and MMP-9 Secretion in Response to Inflammatory Stimuli.

The lysosomal enzyme β-glucuronidase (Gusb) is a key regulator of Lyme-associated and K/B×N-induced arthritis severity. The luminal enzymes present in lysosomes provide essential catabolic functions for the homeostatic degradation of a variety of macromolecules. In addition to this essential catabolic function, lysosomes play important roles in the inflammatory response following infection.

Mitochondrial Ca²⁺ and membrane potential, an alternative pathway for Interleukin 6 to regulate CD4 cell effector function.

IL-6 plays an important role in determining the fate of effector CD4 cells and the cytokines that these cells produce. Here we identify a novel molecular mechanism by which IL-6 regulates CD4 cell effector function. We show that IL-6-dependent signal facilitates the formation of mitochondrial respiratory chain supercomplexes to sustain high mitochondrial membrane potential late during activation of CD4 cells.

Exacerbation of autoimmune neuroinflammation by dietary sodium is genetically controlled and sex specific.

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 century, suggesting a sex-specific environmental influence. Recent animal and human studies have implicated dietary sodium as a risk factor in MS, whereby high sodium augmented the generation of T helper (Th) 17 cells and exacerbated experimental autoimmune encephalomyelitis (EAE), the principal model of MS.