Absence of miRNA-146a Differentially Alters Microglia Function and Proteome

Background: MiR-146a is an important regulator of innate inflammatory responses and is also implicated in cell death and survival. Methods: By sorting CNS resident cells, microglia were the main cellular source of miR-146a. Therefore, we investigated microglia function and phenotype in miR-146a knock-out (KO) mice, analyzed the proteome of KO and wild-type (WT) microglia by LC-MS/MS, and examined miR-146a expression in different brain lesions of patients with multiple sclerosis (MS). Results: When stimulated with LPS or myelin in vitro, microglia from KO mice expressed higher levels of IL-1β, TNF, IL-6, IL-10, CCL3, and CCL2 compared to WT. Stimulation increased migration and phagocytosis of WT but not KO microglia. CD11c+ microglia were induced by cuprizone (CPZ) in the WT mice but less in the KO. The proteome of ex vivo microglia was not different in miR-146a KO compared to WT mice, but CPZ treatment induced differential and reduced protein responses in the KO: GOT1, COX5b, CRYL1, and cystatin-C were specifically changed in KO microglia. We explored discriminative features of microglia proteomes: sparse Partial Least Squares-Discriminant Analysis showed the best discrimination when control and CPZ-treated conditions were compared. Cluster of ten proteins separated WT and miR-146a KO microglia after CPZ: among them were sensomes allowing to perceive the environment, Atp1a3 that belongs to the signature of CD11c+ microglia, and proteins related to inflammatory responses (S100A9, Ppm1g). Finally, we examined the expression of miR-146a and its validated target genes in different brain lesions of MS patients. MiR-146 was upregulated in all lesion types, and the highest expression was in active lesions. Nineteen of 88 validated target genes were significantly changed in active lesions, while none were changed in NAWM. Conclusion: Our data indicated that microglia is the major source of miR-146a in the CNS. The absence of miR-146a differentially affected microglia function and proteome, and miR-146a may play an important role in gene regulation of active MS lesions

Multiple sclerosis in Iceland, with observations on the alleged epidemic in the Faroe Islands

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldThe profile of multiple sclerosis (MS) in Iceland based on a total population study from 1900 to 1990 is reviewed. The first survey in the late 1950s was a retrospective one. Since then, there has been a continuous prospective study that extends over a period of 40 years. The incidence of MS, which was 2.5/100,000 in the 1930s, rose to 3.5 to 4.1/100,000 between 1975 and 1990, but the data from the 1930s must be considered unreliable. There was a similar stepwise increase in prevalence from 30 to approximately 100/100,000 in 1990. It is most likely that the changes in prevalence are the result of improved case ascertainment, the growing number of well-trained neurologists in the country, and the greater awareness of the disease due to the activities of the Icelandic MS Society. No local or regional clusters were identified, but from 1900 to 1980 there was a steady and unexpected increase in the number of cases in rural areas, both by date of clinical onset and date of putative disease acquisition. No evidence was found to support the hypothesis that an epidemic of MS had occurred in Iceland following the arrival of British, Canadian, and American troops during the Second World War. The proposed epidemic in the Faroe Islands was also reexamined, in particular because of the identical ethnic, historical, demographic, and geographical similarities with Iceland. The available data are not supportive of that idea

Road with Wilson House? in background, Castlecrag, New South Wales, ca. 1922, [2] [picture].

Title from acquisition documentation.; Part of the collection: Eric Milton Nicholls collection.; Condition: Fair.; Also available in electronic version via the Internet at: http://nla.gov.au/nla.pic-vn3993515; Purchased from Marie and Glynn Nicholls, 2006

The chair placed where Hughes stood each year to watch the march, ANZAC Day, 1954 [picture] .

Title from caption on mount.; Condition: Good.; Part of the William Morris Hughes Collection.; Also available in an electronic version via the Internet at: http://nla.gov.au/nla.pic-vn4199843; William Morris Hughes Collection; Located at; National Library of Australia Manuscript collection MS 1538

Evidence for a complex role of HLA class II genotypes in susceptibility to multiple sclerosis in Iceland

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldWe analyzed the association of HLA-DR and -DQ haplotypes and alleles with multiple sclerosis (MS) in 91 patients and 91 controls from Iceland using the relative predispositional effect method. The aim was to establish whether there is heterogeneity in HLA associations with MS, whether there are both predispositional and protective haplotypes, and whether sequence motifs also contribute to MS susceptibility. MS was positively associated with a DR2 haplotype (DRB5*0101-DQA1*0102-DQB1*0602), and empirical logistic analysis indicated that this haplotype is MS-associated because of a primary MS association with the DR2 allele. A DR13 haplotype (DRB1*1302-DQA1*0102-DQB1*0604) was negatively associated with MS, i.e., protective. Study of DR2-negative patients and controls confirmed this negative association and identified a second protective DR haplotype (DRB1*0701-DQA1*0201-DQB1*0201). Within these protective haplotypes in DR2-negative individuals, both DQA1 alleles and one DQB1 allele (*0604) were protective, but neither DR allele was protective, i.e., DQ loci may be more important than DR loci in encoding molecules protective against MS. Predispositional (Phe67) and protective (Ile67) DR beta sequence motifs were present in the total and DR2-negative patient and control groups. Since DQ but not DR alleles appear to be protective, DR beta Ile67 may confer additional protection against MS. Study of family-normal controls confirmed the MS association with the DR2 haplotype, and the transmission-disequilibrium test showed cosegregation and linkage of DR2 alleles and MS in families

Evidence for a complex role of HLA class II genotypes in susceptibility to multiple sclerosis in Iceland

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldWe analyzed the association of HLA-DR and -DQ haplotypes and alleles with multiple sclerosis (MS) in 91 patients and 91 controls from Iceland using the relative predispositional effect method. The aim was to establish whether there is heterogeneity in HLA associations with MS, whether there are both predispositional and protective haplotypes, and whether sequence motifs also contribute to MS susceptibility. MS was positively associated with a DR2 haplotype (DRB5*0101-DQA1*0102-DQB1*0602), and empirical logistic analysis indicated that this haplotype is MS-associated because of a primary MS association with the DR2 allele. A DR13 haplotype (DRB1*1302-DQA1*0102-DQB1*0604) was negatively associated with MS, i.e., protective. Study of DR2-negative patients and controls confirmed this negative association and identified a second protective DR haplotype (DRB1*0701-DQA1*0201-DQB1*0201). Within these protective haplotypes in DR2-negative individuals, both DQA1 alleles and one DQB1 allele (*0604) were protective, but neither DR allele was protective, i.e., DQ loci may be more important than DR loci in encoding molecules protective against MS. Predispositional (Phe67) and protective (Ile67) DR beta sequence motifs were present in the total and DR2-negative patient and control groups. Since DQ but not DR alleles appear to be protective, DR beta Ile67 may confer additional protection against MS. Study of family-normal controls confirmed the MS association with the DR2 haplotype, and the transmission-disequilibrium test showed cosegregation and linkage of DR2 alleles and MS in families