Laquinimod, a prototypic quinoline-3-carboxamide and aryl hydrocarbon receptor agonist, utilizes a CD155-mediated natural killer/dendritic cell interaction to suppress CNS autoimmunity

Abstract Background Quinoline-3-carboxamides, such as laquinimod, ameliorate CNS autoimmunity in patients and reduce tumor cell metastasis experimentally. Previous studies have focused on the immunomodulatory effect of laquinimod on myeloid cells. The data contained herein suggest that quinoline-3-carboxamides improve the immunomodulatory and anti-tumor effects of NK cells by upregulating the adhesion molecule DNAX accessory molecule-1 (DNAM-1). Methods We explored how NK cell activation by laquinimod inhibits CNS autoimmunity in experimental autoimmune encephalomyelitis (EAE), the most utilized model of MS, and improves immunosurveillance of experimental lung melanoma metastasis. Functional manipulations included in vivo NK and DC depletion experiments and in vitro assays of NK cell function. Clinical, histological, and flow cytometric read-outs were assessed. Results We demonstrate that laquinimod activates natural killer (NK) cells via the aryl hydrocarbon receptor and increases their DNAM-1 cell surface expression. This activation improves the cytotoxicity of NK cells against B16F10 melanoma cells and augments their immunoregulatory functions in EAE by interacting with CD155+ dendritic cells (DC). Noteworthy, the immunosuppressive effect of laquinimod-activated NK cells was due to decreasing MHC class II antigen presentation by DC and not by increasing DC killing. Conclusions This study clarifies how DNAM-1 modifies the bidirectional crosstalk of NK cells with CD155+ DC, which can be exploited to suppress CNS autoimmunity and strengthen tumor surveillance

Soziale Organisation, soziales Lernen und Differenzierung

Bernhardt M, Edelhoff C, Faulstich-Wieland H, et al. Soziale Organisation, soziales Lernen und Differenzierung. Die deutsche Schule. Zeitschrift für Erziehungswissenschaft, Bildungspolitik und pädagogische Praxis. 1975;67(7):489-512

Genome-wide association reveals contribution of MRAS to painful temporomandibular disorder in males

Painful temporomandibular disorders (TMDs) are the leading cause of chronic orofacial pain, but its underlying molecular mechanisms remain obscure. Although many environmental factors have been associated with higher risk of developing painful TMD, family and twin studies support a heritable genetic component as well. We performed a genome-wide association study assuming an additive genetic model of TMD in a discovery cohort of 999 cases and 2031 TMD-free controls from the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study. Using logistic models adjusted for sex, age, enrollment site, and race, we identified 3 distinct loci that were significant in combined or sex-segregated analyses. A single-nucleotide polymorphism on chromosome 3 (rs13078961) was significantly associated with TMD in males only (odds ratio = 2.9, 95% confidence interval: 2.02-4.27, P = 2.2 x 10(-8)). This association was nominally replicated in a meta-analysis of 7 independent orofacial pain cohorts including 160,194 participants (odds ratio - 1.16, 95% confidence interval: 1.0-1.35, P = 2.3 x 10(-2)). Functional analysis in human dorsal root ganglia and blood indicated this variant is an expression quantitative trait locus, with the minor allele associated with decreased expression of the nearby muscle RAS oncogene homolog (MRAS) gene (beta = -0.51, P = 2.43 x 10(-5)). Male mice, but not female mice, with a null mutation of Mras displayed persistent mechanical allodynia in a model of inflammatory pain. Genetic and behavioral evidence support a novel mechanism by which genetically determined MRAS expression moderates the resiliency to chronic pain. This effect is male-specific and may contribute to the lower rates of painful TMD in men1603579591National Institute of Dental and Craniofacial Research (NIDCR)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Dental & Craniofacial Research (NIDCR) [U01DE017018]; NIDCRUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Dental & Craniofacial Research (NIDCR) [U01DE017018, HHSN268201200008I]; Canadian Excellence Research Chairs (CERC) Program grant [CERC09]; US Cancer Pain Relief Committee (Career Development Award "Neurochemistry and Physiology of Human Pain-Processing Nuclei"); Federal Ministry of Education and ResearchFederal Ministry of Education & Research (BMBF) [01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg-West Pomerania; network "Greifswald Approach to Individualized Medicine (GANI_MED)" - Federal Ministry of Education and Research [03IS2061A]; Siemens Healthcare (Erlangen, Germany); Federal State of Mecklenburg-West Pomerania; Academy of FinlandAcademy of Finland [104781, 120315, 129269, 1114194, 24300796]; University Hospital Oulu; University of Oulu [75617]; NHLBI grant through the STAMPEED program [5R01HL087679-02, 1RL1MH083268-01]; NIH/National Institute of Mental Health (NIMH) [5R01MH63706: 02]; ENGAGE project; EUEuropean Union (EU) [277849]; Medical Research CouncilMedical Research Council UK (MRC) [G0500539, G0600705, G1002319]; MRC, Centenary Early Career Award; Academy of Finland EGEAproject [285547]; Biocentrum Helsinki; European Commission (EURO-BLCS)European Commission Joint Research Centre [QLG1-CT-2000-01643]; Sigrid Juselius FoundationSigrid Juselius Foundation; US National Institute of Mental HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH) [5R01 MH 63706: 02]; Sao Paulo Research FoundationFundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2006/56019-8R, 2009/02520-6]; Canadian Excellence Research Chairs (CERC) Program [CERC09]; NIH/National Institute of Neurological Disorders and Stroke (NINDS)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) [NS045685]; National Heart, Lung, and Blood Institute (NHLBI)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [HHSN268201300001I/N01-HC-65233, HHSN268201300004I/N01-HC-65234, HHSN268201300002I/N01-HC-65235, HHSN268201300003I/N01-HC-65236 Northwestern Univ, HHSN268201300005I/N01-HC-65237]; ENGAGE grant [HEALTH-F4-2007-201413]; Intramural Research Program of the NIH, National Institute of Environmental Health SciencesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Environmental Health Sciences (NIEHS); Biocenter; [K12DE022793]; [H2020-633595

Genome-wide association reveals contribution of MRAS to painful temporomandibular disorder in males

Abstract Painful temporomandibular disorders (TMDs) are the leading cause of chronic orofacial pain, but its underlying molecular mechanisms remain obscure. Although many environmental factors have been associated with higher risk of developing painful TMD, family and twin studies support a heritable genetic component as well. We performed a genome-wide association study assuming an additive genetic model of TMD in a discovery cohort of 999 cases and 2031 TMD-free controls from the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study. Using logistic models adjusted for sex, age, enrollment site, and race, we identified 3 distinct loci that were significant in combined or sex-segregated analyses. A single-nucleotide polymorphism on chromosome 3 (rs13078961) was significantly associated with TMD in males only (odds ratio = 2.9, 95% confidence interval: 2.02–4.27, P = 2.2 × 10⁻⁸). This association was nominally replicated in a meta-analysis of 7 independent orofacial pain cohorts including 160,194 participants (odds ratio = 1.16, 95% confidence interval: 1.0–1.35, P = 2.3 × 10⁻²). Functional analysis in human dorsal root ganglia and blood indicated this variant is an expression quantitative trait locus, with the minor allele associated with decreased expression of the nearby muscle RAS oncogene homolog (MRAS) gene (beta = −0.51, P = 2.43 × 10⁻⁵). Male mice, but not female mice, with a null mutation of Mras displayed persistent mechanical allodynia in a model of inflammatory pain. Genetic and behavioral evidence support a novel mechanism by which genetically determined MRAS expression moderates the resiliency to chronic pain. This effect is male-specific and may contribute to the lower rates of painful TMD in men