Multiple sclerosis (OMIM 126200) 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.1 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;2,3 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.4 Modestly powered Genome-Wide Association Studies (GWAS)5-10 have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects play a key role in disease susceptibility.11 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 9772 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 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 over-represented amongst those mapping close to the identified loci and particularly implicate T helper cell differentiation in the pathogenesis of multiple sclerosis.

The Wiskott-Aldrich syndrome protein (WASp) is mutated in the severe immunodeficiency disease Wiskott-Aldrich syndrome (WAS). The function of B cells and the physiologic alterations in WAS remain unclear. We show that B cells from WAS patients exhibited decreased motility and had reduced capacity to migrate, adhere homotypically, and form long protrusions after in vitro culture. WASpdeficient murine B cells also migrated less well to chemokines. Upon antigen challenge, WASp-deficient mice mounted a reduced and delayed humoral immune response to both T-cell-dependent and -independent antigens. This was at least in part due to deficient migration and homing of B cells. In addition, the germi- The Wiskott-Aldrich syndrome (WAS) is caused by mutations in the Wiskott-Aldrich syndrome protein (WASp). 2 WAS patients display increased susceptibility to pyogenic, viral, and opportunistic infections and are predisposed to develop eczema, autoimmune, or lymphoproliferative disease. 3,4 Exclusively expressed in hematopoietic cells, WASp normally exists in an inactive state caused by intramolecular protein folding that prevents its activation. 5 Upon association with guanosine triphosphate (GTP)-bound Cdc42 and phosphatidylinositol-4,5-bisphosphate (PIP2), the C-terminus of WASp interacts with the Arp2/3 complex and with actin monomers, resulting in actin polymerization and consequent changes of cell shape and structure. 5 Many different mutations in WASp have been characterized, leading to expression of truncated fragments or to lack of expression. A novel type of mutation (L270P) has been identified in patients suffering from severe congenital neutropenia. 6 This mutation disrupts the critical autoinhibiting conformation of WASp and renders WASp constitutively active.Early evidence for a cytoskeletal role of WASp in immune cells came from thorough analysis of patient blood lymphocytes, revealing abnormal cell surface architecture. [7][8][9] However, a recent report suggests that fresh peripheral blood lymphocytes from WAS patients have normal numbers of microvillli. 10 Results from WASpnull mice have shown significant impairment in T-cell activation and formation of the immunologic synapse. 11-14 Natural killer cells, dendritic cells, macrophages, and hematopoietic stem cells have altered cytoskeletal responses. [15][16][17][18][19][20][21][22] The evidence for malfunction of WASp-deficient B cells is contradictory. WAS patients respond poorly to T-cell-independent antigens, suggesting a role for B cells in disease development. 3,4 One report shows impaired B-cell receptor triggering, 23 whereas 3 others indicate normal activation. 11,12,24 B-cell lines derived from WAS patients have reduced levels of F-actin, 25 and B cells from WASp-null mice exhibit a lower cell polarization and spreading response. 26 The B-cell contribution to development of WAS remains elusive. Furthermore, it is unclear how the absence of WASp in hematopoietic cells leads to immunodeficiency. In this paper, we have investigated the function of WASp-d...

Nonsecretors and Lea+b- individuals are significantly less prone to be infected with GGII noroviruses. This new information extends previous knowledge and supports the hypothesis that nonsecretors are relatively but not absolutely resistant to norovirus infections.