Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk

Multiple sclerosis is a complex neurological disease, with 3c20% of risk heritability attributable to common genetic variants, including >230 identified by genome-wide association studies. Multiple strands of evidence suggest that much of the remaining heritability is also due to additive effects of common variants rather than epistasis between these variants or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that up to 5% of this heritability is explained by low-frequency variation in gene coding sequence. We identify four novel genes driving MS risk independently of common-variant signals, highlighting key pathogenic roles for regulatory T cell homeostasis and regulation, IFN\u3b3 biology, and NF\u3baB signaling. As low-frequency variants do not show substantial linkage disequilibrium with other variants, and as coding variants are more interpretable and experimentally tractable than non-coding variation, our discoveries constitute a rich resource for dissecting the pathobiology of MS. In a large multi-cohort study, unexplained heritability for multiple sclerosis is detected in low-frequency coding variants that are missed by GWAS analyses, further underscoring the role of immune genes in MS pathology

Sisters in arms: epic narratives in United Red Army (2007) and The Baader Meinhof Complex (2008)

The aim of this chapter is to frame contemporary films about terrorism within inclusive interpretations of the war film genre and discuss the adoption of epic narratives in the depiction of 1970s revolutionary violence. Two recent films have explored the history of notorious left-wing terrorist groups as negative sagas: United Red Army/Jitsuroku Rengo Sekigun (Wakamatsu Koji, 2007) and The Bader-Meinhof Complex/Der Baader-Meinhof Komplex (Uli Edel, 2008). In light of Robert Eberwein’s flexible definition of the ‘war film’ (2010: 45), these biopics meet his criteria by depicting the conflict itself (preparation, aftermath and actual urban guerrilla), the activities off the battlefield (radicalisation, recruitment and propaganda) and the effects on society (impact on families and the state’s response to violence).  Through a comparative contextualisation of terrorism in West Germany and Japan, this chapter also analyses one of the most striking aspects of how left-wing political violence return in the cinema of the new millennium: the high visibility and mediated spectacle of female terrorists. Female participation in politically motivated violence has been consistent in global conflicts, but during the 1970s the number of female terrorists grew rapidly in radical left-wing organisations. In order to understand gendered representational strategies and the legacy of female involvement in the armed struggle, particular attention will be paid to the threatening and threated body of the female terrorists in The Bader-Meinhof Complex and United Red Army.  The representation of terrorists is not homogeneous but tends to follow stereotypical paradigms because female combatants are seen as the worst attack to society and the patriarchal system. In these films, in fact, political violence is blamed on sexually free and naïve youngsters, mentally unstable mothers and emotionally dependant women. It will be suggested that through narratives of female hysteria and supportive of gender imbalance, these films domesticate female violence and reject all forms of action that do not re-inscribe femininity within its normative societal role