Meningeal Infiltration of the Spinal Cord by Non-Classically Activated B Cells is Associated with Chronic Disease Course in a Spontaneous B Cell-Dependent Model of CNS Autoimmune Disease

We characterized B cell infiltration of the spinal cord in a B cell-dependent spontaneous model of central nervous system (CNS) autoimmunity that develops in a proportion of mice with mutant T and B cell receptors specific for myelin oligodendrocyte glycoprotein. We found that, while males are more likely to develop disease, females are more likely to have a chronic rather than monophasic disease course. B cell infiltration of the spinal cord was investigated by histology and FACs. CD4+ T cell infiltration was pervasive throughout the white and in some cases gray matter. B cells were almost exclusively restricted to the meninges, often in clusters reminiscent of those described in human multiple sclerosis. These clusters were typically found adjacent to white matter lesions and their presence was associated with a chronic disease course. Extensive investigation of these clusters by histology did not identify features of lymphoid follicles, including organization of T and B cells into separate zones, CD35+ follicular dendritic cells, or germinal centers. The majority of cluster B cells were IgD+ with little evidence of class switch. Consistent with this, B cells isolated from the spinal cord were of the naïve/memory CD38hi CD95lo phenotype. Nevertheless, they were CD62Llo and CD80hi compared to lymph node B cells suggesting that they were at least partly activated and primed to present antigen. Therefore, if meningeal B cells contribute to CNS pathology in autoimmunity, follicular differentiation is not necessary for the pathogenic mechanism

Lymphocytes in MS and EAE: More than just a CD4+ World

Multiple sclerosis is degenerative disease of the central nervous system (CNS) in which myelin destruction and axon loss leads to the accumulation of physical, cognitive, and mental deficits. MS affects more than a million people worldwide and managing this chronic disease presents a significant health challenge. Multiple lines of evidence indicate that MS is an autoimmune disorder in which immune cells launch an inflammatory attack targeting myelin antigens. Indeed, myelin-reactive T cells and antibodies have been identified in MS patients and in animal models (namely experimental autoimmune encephalomyelitis, or EAE) that recapitulate many features of human disease. Animal model studies have demonstrated that T cells are both necessary and sufficient to initiate and sustain CNS autoimmunity. However, most MS animal models rely on the role played by CD4+ T cells and partially replicate the multiple aspects of MS pathogenesis. Thus, research in the past has focused heavily on the contribution of CD4+ T cells to the disease process; searching PubMed for “MS AND CD4” yields twice the results as corresponding searches for “CD8” or “B cell” and four times that for “NK cells”. While CD4+ T cells may represent the minimum requirement to mediate CNS autoimmunity, it is clear that the immune response underlying human MS is far more complex and involves numerous other immune cells and subsets. This is well illustrated by the observation that MS patients treated with an anti-CD4 depleting antibody did not gain any clinical benefits whereas removal of several lymphocyte subsets using an anti-CD52 depleting antibody has been shown to impede disease progression. In particular, the pathogenic role(s) of non-CD4+ T cell lymphocytes is relatively poorly understood and under-researched, despite evidence that these subsets contribute to disease pathology or regulation. For example, the observed oligoclonal expansion of CD8+ T cells within the CNS compartment supports a local activation. CD8+ T cells with polarized cytolytic granules are seen in close proximity to oligodendrocytes and demyelinated axons in MS tissues. The presence of B cells in inflammatory lesions and antibodies in the CSF have long been recognized as features of MS and Rituximab, a B cell depleting therapy, has been shown to be highly effective to treat MS. Intriguingly, the putative MS therapeutic reagent Daclizumab may function in part through the expansion of a subset of immunoregulatory NK cells. NKT and ?d T cells may also play a role in CNS autoimmunity, given that they respond to lipid antigens and that myelin is lipid-rich. While different animal models recapitulate some of these aspects of human disease, identifying appropriate models and measures to investigate the role of these less well-understood lymphocytes in MS remains a challenge for the field. This Frontiers research topic aims to create a platform for both animal- and human-focused researchers to share their original data, hypotheses, future perspectives and commentaries regarding the role of these less-well understood lymphocyte subsets (CD8+ T cells, B cells, NK cells, NK T cells, ?d T cells) in the pathogenesis of CNS autoimmunity

Nearshore versus offshore copper loading in Lake Superior sediments: Implications for transport and cycling

A thorough understanding of the fate and transport of metals in Lake Superior is necessary in order to predict the ability of Lake Superior to recover from anthropogenic perturbations (copper mining). Sediment cores were collected from nearshore and offshore sites in Lake Superior and used to evaluate spatial and temporal variations in copper loading associated with mining-related activities. Although both settings have been strongly affected by anthropogenic releases of copper, copper concentrations in nearshore cores are significantly greater than those found in offshore cores, implying that nearshore copper loading is dominated by simple deposition and burial of sediment generated from mining activities. Temporal variations in copper profiles in sediments from nearshore environments closely mimic copper production rates. Conversely, copper loading histories derived from offshore sediments are not well correlated to production rates. The offshore sediment cores, when compared with analogous cores from Lakes Ontario and Michigan, show that the average, lake-wide intensity of copper loading in Lake Superior is comparable to the other two lakes, despite the fact that Lake Superior has received the largest total burden of anthropogenic copper. Cu/Zn ratios, used to evaluate the amount of copper loading derived from mining discharges, vary strongly in nearshore environments in response to loading. Cu/Zn ratios in offshore sediments are much less variable, implying that copper loading may be regulated by additional mechanisms (solution chemistry and/or biologic uptake). Study of trace metal partitioning within Lake Superior sediments indicates that the organic fraction of the sediment contains the majority of the copper. Copper concentrations in offshore sediments are significantly correlated to organic carbon content of the sediment whereas copper concentrations in nearshore sediments are not. These findings support the model that transport and deposition of particles released from mining discharges dominate copper loading in nearshore sediments, whereas biologic uptake and settling of particulate organic matter may regulate copper loading in offshore sediments

Autoreactive, Low-Affinity T Cells Preferentially Drive Differentiation of Short-Lived Memory B Cells at the Expense of Germinal Center Maintenance

Summary: B cell fate decisions within a germinal center (GC) are critical to determining the outcome of the immune response to a given antigen. Here, we characterize GC kinetics and B cell fate choices in a response to the autoantigen myelin oligodendrocyte glycoprotein (MOG) and compare the response with a standard model foreign antigen. Both antigens generate productive primary responses, as evidenced by GC development, circulating antigen-specific antibodies, and differentiation of memory B cells. However, in the MOG response, the status of the cognate T cell partner drives preferential B cell differentiation to a memory phenotype at the expense of GC maintenance, resulting in a truncated GC. Reduced plasma cell differentiation is largely independent of T cell influence. Interestingly, memory-phenotype B cells formed in the MOG GC are not long lived, resulting in a failure of the B cell response to secondary challenge. : Jain et al. compare B cell responses to different antigens and find that they preferentially differentiate into short-lived memory-phenotype B cells in response to a myelin autoantigen. This was in part controlled by T cells and influenced by TCR affinity for antigen, demonstrating that antigen characteristics can determine immune outcome. Keywords: B cell, T follicular helper cell, autoimmunity, germinal center, MOG, memory B cell, plasma cell, multiple sclerosi