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

Circum-Arctic distribution of chemical anti-herbivore compounds suggests biome-wide trade-off in defence strategies in Arctic shrubs

Spatial variation in plant chemical defence towards herbivores can help us understand variation in herbivore top-down control of shrubs in the Arctic and possibly also shrub responses to global warming. Less defended, non-resinous shrubs could be more influenced by herbivores than more defended, resinous shrubs. However, sparse field measurements limit our current understanding of how much of the circum-Arctic variation in defence compounds is explained by taxa or defence functional groups (resinous/non-resinous). We measured circum-Arctic chemical defence and leaf digestibility in resinous (Betula glandulosa, B. nana ssp. exilis) and non-resinous (B. nana ssp. nana, B. pumila) shrub birches to see how they vary among and within taxa and functional groups. Using liquid chromatography-mass spectrometry (LC-MS) metabolomic analyses and in vitro leaf digestibility via incubation in cattle rumen fluid, we analysed defence composition and leaf digestibility in 128 samples from 44 tundra locations. We found biogeographical patterns in anti-herbivore defence where mean leaf triterpene concentrations and twig resin gland density were greater in resinous taxa and mean concentrations of condensing tannins were greater in non-resinous taxa. This indicates a biome-wide trade-off between triterpene- or tannin-dominated defences. However, we also found variations in chemical defence composition and resin gland density both within and among functional groups (resinous/non-resinous) and taxa, suggesting these categorisations only partly predict chemical herbivore defence. Complex tannins were the only defence compounds negatively related to in vitro digestibility, identifying this previously neglected tannin group as having a potential key role in birch anti-herbivore defence. We conclude that circum-Arctic variation in birch anti-herbivore defence can be partly derived from biogeographical distributions of birch taxa, although our detailed mapping of plant defence provides more information on this variation and can be used for better predictions of herbivore effects on Arctic vegetation

Circum-Arctic distribution of chemical anti-herbivore compounds suggests biome-wide trade-off in defence strategies in Arctic shrubs

Spatial variation in plant chemical defence towards herbivores can help us understand variation in herbivore top-down control of shrubs in the Arctic and possibly also shrub responses to global warming. Less defended, non-resinous shrubs could be more influenced by herbivores than more defended, resinous shrubs. However, sparse field measurements limit our current understanding of how much of the circum-Arctic variation in defence compounds is explained by taxa or defence functional groups (resinous/non-resinous). We measured circum-Arctic chemical defence and leaf digestibility in resinous (Betula glandulosa, B. nana ssp. exilis) and non-resinous (B. nana ssp. nana, B. pumila) shrub birches to see how they vary among and within taxa and functional groups. Using liquid chromatography-mass spectrometry (LC-MS) metabolomic analyses and in vitro leaf digestibility via incubation in cattle rumen fluid, we analysed defence composition and leaf digestibility in 128 samples from 44 tundra locations. We found biogeographical patterns in anti-herbivore defence where mean leaf triterpene concentrations and twig resin gland density were greater in resinous taxa and mean concentrations of condensing tannins were greater in non-resinous taxa. This indicates a biome-wide trade-off between triterpene- or tannin-dominated defences. However, we also found variations in chemical defence composition and resin gland density both within and among functional groups (resinous/non-resinous) and taxa, suggesting these categorisations only partly predict chemical herbivore defence. Complex tannins were the only defence compounds negatively related to in vitro digestibility, identifying this previously neglected tannin group as having a potential key role in birch anti-herbivore defence. We conclude that circum-Arctic variation in birch anti-herbivore defence can be partly derived from biogeographical distributions of birch taxa, although our detailed mapping of plant defence provides more information on this variation and can be used for better predictions of herbivore effects on Arctic vegetation.Peer reviewe

Circum-Arctic distribution of chemical anti-herbivore compounds suggests biome-wide trade-off in defence strategies in Arctic shrubs

Spatial variation in plant chemical defence towards herbivores can help us understand variation in herbivore top?down control of shrubs in the Arctic and possibly also shrub responses to global warming. Less defended, non-resinous shrubs could be more influenced by herbivores than more defended, resinous shrubs. However, sparse field measurements limit our current understanding of how much of the circum-Arctic variation in defence compounds is explained by taxa or defence functional groups (resinous/non-resinous). We measured circum-Arctic chemical defence and leaf digestibility in resinous (Betula glandulosa, B. nana ssp. exilis) and non-resinous (B. nana ssp. nana, B. pumila) shrub birches to see how they vary among and within taxa and functional groups. Using liquid chromatography?mass spectrometry (LC?MS) metabolomic analyses and in vitro leaf digestibility via incubation in cattle rumen fluid, we analysed defence composition and leaf digestibility in 128 samples from 44 tundra locations. We found biogeographical patterns in anti-herbivore defence where mean leaf triterpene concentrations and twig resin gland density were greater in resinous taxa and mean concentrations of condensing tannins were greater in non-resinous taxa. This indicates a biome-wide trade-off between triterpene- or tannin-dominated defences. However, we also found variations in chemical defence composition and resin gland density both within and among functional groups (resinous/non-resinous) and taxa, suggesting these categorisations only partly predict chemical herbivore defence. Complex tannins were the only defence compounds negatively related to in vitro digestibility, identifying this previously neglected tannin group as having a potential key role in birch anti-herbivore defence. We conclude that circum-Arctic variation in birch anti-herbivore defence can be partly derived from biogeographical distributions of birch taxa, although our detailed mapping of plant defence provides more information on this variation and can be used for better predictions of herbivore effects on Arctic vegetation

Common viruses and host gene interactions in Multiple Sclerosis

Multiple sclerosis (MS) is a neurological disorder, characterised by demyelination and inflammation of the central nervous system, leading to sensory and motor symptoms. MS is thought to be complex disease, with both environmental and genetic risk factors underlying disease susceptibility. Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections are two environmental risk factors, one with a robust association to MS (EBV) and one where the results have been more inconclusive (CMV). The strongest genetic risk factors lies within the HLA genes, with HLA-DRB1*15 as the strongest susceptibility factor, and HLA-A*02, as the most protective genetic factor. In paper I, the role of EBV infection, and the interaction with HLA-DRB1*15 and HLA-A*02 was studied. Anti-EBNA1 IgG was measured, as was IgG antibodies towards 5 different epitopes of EBNA1. High levels of EBNA1 385-420 IgG antibodies were strongly associated with MS, independent of EBNA1 IgG antibody level. There was interaction on the additive scale between EBNA1 385-420 IgG and HLA-DRB1*15 and absence of HLA-A*02. In paper II, we tried to replicate findings by Simon et al, where they found interaction on the multiplicative scale between EBNA1 IgG levels and smoking (never/ever), but our analysis showed no such interaction. In paper III, the association between CMV and MS was studied, yielding a significant negative association between CMV and MS. To further validate our results, a meta-analysis of published retrospective studies was performed, which provided a similar negative association, supporting our results. In paper IV, the focus shifted from the association of viruses to MS, to dissecting the host genetic influence on anti-JCV seropositivity and anti-JCV antibody levels. JC virus is the virus responsible for Progressive multifocal leukoencephalopathy (PML), a rare but potentially fatal side-effect seen in MS-patients treated with natalizumab. A meta-analysis of three genome wide association studies performed in two sets of MS cases, one Scandinavian and one German, and a set of Swedish controls, strongly indicated that the HLA class II region was involved in regulating anti-JCV antibody response, and anti-JCV antibody levels. Analysis of classically named HLA-alleles supported these findings. The alleles in the DRB1*15- DQB1*06:02-DQA1*01:02-haplotype were all strongly negatively associated with anti-JCV antibody status and low anti-JCV antibody levels. The alleles in the DRB1*13-DQB1*06:02- DQA1*01:03-haplotype were positively associated with anti-JCV antibody status. Several non-HLA loci were suggestively associated with anti-JCV antibody status and anti-JCV antibody levels (p<0.0001). However, these findings will have to be replicated in an independent dataset. This thesis highlights the interactions between environmental and genetic factors in modulating MS risk. It also shows that the HLA genes have a central role in the susceptibility to JCV infection

UPPLEVELSEN AV ARBETSTERAPEUTISKA INTERVENTIONER FÖR VUXNA MED DEPRESSION : En litteraturstudie

Depression ökar bland Sveriges befolkning, men också över hela världen och förväntas vara den näst vanligaste sjukdomen år 2030. Arbetsterapeutiska interventioner är effektiva vid depression, och om interventionen består av en livsstilsförändring kan det minska sjukdomens symptom. Syftet med studien var att undersöka hur arbetsterapeutiska interventioner vid depression upplevs av vuxna deltagare. För att besvara syftet gjordes en systematisk litteraturstudie och vid litteratursökningen användes databaserna APA Psycinfo, Cinahl och Web of Science. Slutligen granskades sju artiklar och analysen identifierade sju underkategorier och två huvudkategorier. Studien visade en variation av upplevelser då deltagarna upplevde att de arbetsterapeutiska interventionerna ökade deras kunskap om en balanserad vardag, deras självförtroende stärktes samt att gruppinterventioner upplevdes bidra till samhörighet och social integration. Resultatet kan ge arbetsterapeuten en ökad kunskap kring olika interventioners betydelse för deltagarens upplevelse, men fler studier bör genomföras för att stärka evidensen för upplevelser av arbetsterapeutiska interventioner vid depression

UPPLEVELSEN AV ARBETSTERAPEUTISKA INTERVENTIONER FÖR VUXNA MED DEPRESSION : En litteraturstudie

Depression ökar bland Sveriges befolkning, men också över hela världen och förväntas vara den näst vanligaste sjukdomen år 2030. Arbetsterapeutiska interventioner är effektiva vid depression, och om interventionen består av en livsstilsförändring kan det minska sjukdomens symptom. Syftet med studien var att undersöka hur arbetsterapeutiska interventioner vid depression upplevs av vuxna deltagare. För att besvara syftet gjordes en systematisk litteraturstudie och vid litteratursökningen användes databaserna APA Psycinfo, Cinahl och Web of Science. Slutligen granskades sju artiklar och analysen identifierade sju underkategorier och två huvudkategorier. Studien visade en variation av upplevelser då deltagarna upplevde att de arbetsterapeutiska interventionerna ökade deras kunskap om en balanserad vardag, deras självförtroende stärktes samt att gruppinterventioner upplevdes bidra till samhörighet och social integration. Resultatet kan ge arbetsterapeuten en ökad kunskap kring olika interventioners betydelse för deltagarens upplevelse, men fler studier bör genomföras för att stärka evidensen för upplevelser av arbetsterapeutiska interventioner vid depression

JC polyomavirus infection is strongly controlled by human leucocyte antigen class II variants

JC polyomavirus (JCV) carriers with a compromised immune system, such as in HIV, or subjects on immune-modulating therapies, such as anti VLA-4 therapy may develop progressive multifocal leukoencephalopathy (PML) which is a lytic infection of oligodendrocytes in the brain. Serum antibodies to JCV mark infection occur only in 50-60% of infected individuals, and high JCV-antibody titers seem to increase the risk of developing PML. We here investigated the role of human leukocyte antigen (HLA), instrumental in immune defense in JCV antibody response. Anti-JCV antibody status, as a surrogate for JCV infection, were compared to HLA class I and II alleles in 1621 Scandinavian persons with MS and 1064 population-based Swedish controls and associations were replicated in 718 German persons with MS. HLA-alleles were determined by SNP imputation, sequence specific (SSP) kits and a reverse PCR sequence-specific oligonucleotide (PCR-SSO) method. An initial GWAS screen displayed a strong HLA class II region signal. The HLA-DRB1*15 haplotype was strongly negatively associated to JCV sero-status in Scandinavian MS cases (OR = 0.42, p = 7×10(-15)) and controls (OR = 0.53, p = 2×10(-5)). In contrast, the DQB1*06:03 haplotype was positively associated with JCV sero-status, in Scandinavian MS cases (OR = 1.63, p = 0.006), and controls (OR = 2.69, p = 1×10(-5)). The German dataset confirmed these findings (OR = 0.54, p = 1×10(-4) and OR = 1.58, p = 0.03 respectively for these haplotypes). HLA class II restricted immune responses, and hence CD4+ T cell immunity is pivotal for JCV infection control. Alleles within the HLA-DR1*15 haplotype are associated with a protective effect on JCV infection. Alleles within the DQB1*06:03 haplotype show an opposite association. These associations between JC virus antibody response and human leucocyte antigens supports the notion that CD4+ T cells are crucial in the immune defence to JCV and lays the ground for risk stratification for PML and development of therapy and prevention

JC polyomavirus infection is strongly controlled by human leucocyte antigen class II variants.

JC polyomavirus (JCV) carriers with a compromised immune system, such as in HIV, or subjects on immune-modulating therapies, such as anti VLA-4 therapy may develop progressive multifocal leukoencephalopathy (PML) which is a lytic infection of oligodendrocytes in the brain. Serum antibodies to JCV mark infection occur only in 50-60% of infected individuals, and high JCV-antibody titers seem to increase the risk of developing PML. We here investigated the role of human leukocyte antigen (HLA), instrumental in immune defense in JCV antibody response. Anti-JCV antibody status, as a surrogate for JCV infection, were compared to HLA class I and II alleles in 1621 Scandinavian persons with MS and 1064 population-based Swedish controls and associations were replicated in 718 German persons with MS. HLA-alleles were determined by SNP imputation, sequence specific (SSP) kits and a reverse PCR sequence-specific oligonucleotide (PCR-SSO) method. An initial GWAS screen displayed a strong HLA class II region signal. The HLA-DRB1*15 haplotype was strongly negatively associated to JCV sero-status in Scandinavian MS cases (OR = 0.42, p = 7×10(-15)) and controls (OR = 0.53, p = 2×10(-5)). In contrast, the DQB1*06:03 haplotype was positively associated with JCV sero-status, in Scandinavian MS cases (OR = 1.63, p = 0.006), and controls (OR = 2.69, p = 1×10(-5)). The German dataset confirmed these findings (OR = 0.54, p = 1×10(-4) and OR = 1.58, p = 0.03 respectively for these haplotypes). HLA class II restricted immune responses, and hence CD4+ T cell immunity is pivotal for JCV infection control. Alleles within the HLA-DR1*15 haplotype are associated with a protective effect on JCV infection. Alleles within the DQB1*06:03 haplotype show an opposite association. These associations between JC virus antibody response and human leucocyte antigens supports the notion that CD4+ T cells are crucial in the immune defence to JCV and lays the ground for risk stratification for PML and development of therapy and prevention