<i>eae36</i>, a Locus on Mouse Chromosome 4, Controls Susceptibility to Experimental Allergic Encephalomyelitis in Older Mice and Mice Immunized in the Winter

Teuscher, Cory; Doerge, R. W.; Fillmore, Parley D.; Blankenhorn, Elizabeth P.

doi:10.1534/genetics.105.049049

Cited by 18 publications

(11 citation statements)

References 70 publications

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“…Seasonal differences in EAE incidence and severity have been reported in SJL-derived mice (22, 23). In the present studies, both male and female SJL/J mice were more likely to develop EAE in April, May and July compared to November (supplemental Table I and II).…”

Section: Resultsmentioning

confidence: 96%

Cutting Edge: The Y Chromosome Controls the Age-Dependent Experimental Allergic Encephalomyelitis Sexual Dimorphism in SJL/J Mice

Spach¹,

Blake²,

Bunn³

et al. 2009

The Journal of Immunology

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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. M ultiple sclerosis (MS)3 is a chronic, demyelinating disease of the CNS that results in substantial disability and paralysis. Although MS prevalence is ϳ3-fold higher in women than in men, MS in men is characterized by a more rapid clinical course and typically presents as severe progressive disease (1). Interestingly, the female-biased sexual dimorphism has been found to be on the rise within the past 50 years, presumably due to gene-environment interactions (2, 3).Experimental allergic encephalomyelitis (EAE) is the principal autoimmune model of MS. EAE in the inbred SJL/J mouse strain has been used as a model of the sexual dimorphism seen in MS, as SJL/J females are considered more susceptible to EAE than males. However, this gender bias in the EAE sexual dimorphism of SJL/J mice is unique in that it is age dependent, reflecting changes in EAE susceptibility of male mice, not female mice. Compared with young female SJL/J mice, young (4 -8 wk) male SJL/J mice show significantly impaired delayed type hypersensitivity responses (4, 5) and are significantly less susceptible to EAE (6 -10). In contrast, EAE susceptibility in older (Ն12 wk) SJL/J males is equivalent to that seen in 6-wk-old SJL/J females (6). Consequently, this gives rise to a female-biased EAE sexual dimorphism when female mice of any age are compared only with young (4 -8 wk) males. Both gonadal hormones (11-14) and sex chromosome (Chr) effects (15, 16) have been postulated to cause the sexual dimorphism. In young SJL/J mice, male gonadal hormones (12, 17) have been implicated in EAE resistance because castration of young SJL/J mice significantly increases EAE incidence and severity (6, 14) and induces the female predominant relapsing-remitting form of the disease (12, 17). Collectively, these published reports show that the gender bias of the EAE sexual dimorphism in SJL/J mice is a function of a testes-dependent, age-related transition in the EAE susceptibility of SJL/J males and is not due to an inherent steady-state increase in the EAE susceptibility of female SJL/J mice.Using C57BL/6J Y Chr substitution strains (consomic mice), we previously demonstrated that a gene or genes on the Y Chr, termed Yeae, influence EAE (18). This was the first experimental evidence demonstrating the existence of a Y Chr polymorphism capable of modifying EAE susceptibility. Because the age-dependent change in EAE susceptibility of...

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Section: Resultsmentioning

confidence: 96%

Cutting Edge: The Y Chromosome Controls the Age-Dependent Experimental Allergic Encephalomyelitis Sexual Dimorphism in SJL/J Mice

Spach¹,

Blake²,

Bunn³

et al. 2009

The Journal of Immunology

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“…The locus on chromosome 4 contains overlapping QTL for the autoimmune diseases experimental autoimmune encephalomyelitis (EAE), insulin dependent diabetes, systemic lupus erythematosus (SLE), and psoriasis (27–30) and has several candidate genes implicated in immune signaling and regulation, including the signaling proteins LCK and map3k6, as well the α-chain of the IL-22 receptor. This locus corresponds to a region on human chromosome 1, 45 Mb apart from the D1S252 marker that demonstrated linkage with infection levels of S. mansoni in humans (31).…”

Section: Discussionmentioning

confidence: 99%

Genetic Control of Severe Egg-Induced Immunopathology and IL-17 Production in Murine Schistosomiasis

Shainheit

Bazzone²,

Rutitzky³

et al. 2009

The Journal of Immunology

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Infection with the trematode parasite Schistosoma mansoni results in a distinct heterogeneity of disease severity, both in humans and in an experimental mouse model. Severe disease is characterized by pronounced hepatic egg-induced granulomatous inflammation in a proinflammatory cytokine environment, whereas mild disease corresponds with reduced hepatic inflammation in a Th2 skewed cytokine environment. This marked heterogeneity indicates that genetic differences play a significant role in disease development, yet little is known about the genetic basis of dissimilar immunopathology. To investigate the role of genetic susceptibility in murine schistosomiasis, quantitative trait loci analysis was performed on F2 progeny derived from SJL/J and C57BL/6 mice, which develop severe and mild pathology, respectively. In this study, we show that severe liver pathology in F2 mice 7 wk after infection significantly correlated with an increase in the production of the proinflammatory cytokines IL-17, IFN-γ, and TNF-α by schistosome egg Ag-stimulated mesenteric lymph node cells. Quantitative trait loci analysis identified several genetic intervals controlling immunopathology as well as IL-17 and IFN-γ production. Egg granuloma size exhibited significant linkage to two loci, D4Mit203 and D17Mit82, both of which were inherited in a BL/6 dominant manner. Furthermore, a significant reduction of hepatic granulomatous inflammation and IL-17 production in interval-specific congenic mice demonstrated that the two identified genetic loci have a decisive effect on the development of immunopathology in murine schistosomiasis.

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“…QTL analysis identified two loci that were highly significantly linked to granulomatous inflammation, located on chromosomes 4 and 17. The locus on chromosome 4 contains a number of overlapping QTL for several autoimmune diseases with similar pathogenic mechanisms to schistosomiasis, including EAE and systemic lupus erythematosus (SLE) [138, 139], with several candidate genes implicated in immune functions including the signaling proteins, lck and map3k6, as well as IL-22ra1. The locus on chromosome 17 has also been linked with EAE and SLE and contains additional overlapping QTL with resistance to malaria (Char3) and leishmaniasis (Lmr1) [140, 141].…”

Section: Genetic Control Of Murine Schistosomiasismentioning

confidence: 99%

Induction and regulation of pathogenic Th17 cell responses in schistosomiasis

et al. 2012

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Schistosomiasis is a major tropical disease caused by trematode helminths in which the host mounts a pathogenic immune response against tissue-trapped parasite eggs. The immunopathology consists of egg antigen-specific CD4 T cell-mediated granulomatous inflammation that varies greatly in magnitude in humans and among mouse strains in an experimental model. New evidence, covered in this review, intimately ties the development of severe pathology to CD4 T helper 17 cells, a finding that adds a new dimension to the traditional CD4 Th1 vs. Th2 cell paradigm. Most examined mouse strains, in fact, develop severe immunopathology with substantial Th17 as well as Th1 and Th2 cell responses; a Th2 polarized response is an exception that is only observed in low-pathology strains such as the C57BL/6.The ability to mount pathogenic Th17 cell responses is genetically determined and depends on the ability of antigen presenting cells to produce IL-23 and IL-1â following recognition of egg antigens; analyses of several F2 progenies of (high × low)-pathology strain crosses demonstrated that quantitative trait loci governing IL-17 levels and disease severity vary substantially from cross to cross. Low pathology is dominant, which may explain the low incidence of severe disease in humans; however, coinfection with nematodes can also dampen pathogenic Th17 responses by promoting regulatory mechanisms such as those afforded by alternatively activated macrophages and T regulatory cells. A better understanding of the pathways conducive to severe forms of schistosomiasis and their regulation should lead to interventions similar to those presently used to manage other immune-mediated diseases.

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eae36, a Locus on Mouse Chromosome 4, Controls Susceptibility to Experimental Allergic Encephalomyelitis in Older Mice and Mice Immunized in the Winter

Cited by 18 publications

References 70 publications

Cutting Edge: The Y Chromosome Controls the Age-Dependent Experimental Allergic Encephalomyelitis Sexual Dimorphism in SJL/J Mice

Cutting Edge: The Y Chromosome Controls the Age-Dependent Experimental Allergic Encephalomyelitis Sexual Dimorphism in SJL/J Mice

Genetic Control of Severe Egg-Induced Immunopathology and IL-17 Production in Murine Schistosomiasis

Induction and regulation of pathogenic Th17 cell responses in schistosomiasis

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