B cells reach a critical threshold. T cells, the cells that cause inflammation in MS, become activated by antigen presenting cells (APCs). It is believed that two kinds of cells, dendritic cells (DCs) and B cells, activate these antigen-specific T cells, where the contribution from the latter has been less well characterized. Using a model of MS disease, researchers sought to characterize the relative importance of these two kinds of APCs. They found that B cells in combination with DCs induce severe disease, and that increasing the number of antigen-specific B cells also led to increased disease. They also found, as was previously reported, that antigen presentation by B cells alone was not enough to cause disease unless a critical number of B cells was reached. This is important because this demonstrates a key role for both cell types, where B cells may be more important in sustaining inflammation during chronic disease and DCs are important in initiating disease. Rituximab, an antibody that depletes B cells, has shown success for treatment in some patients. The results of this study might suggest that B cell targeted treatment may be beneficial to patients who are at later disease stages, and DC targeting treatments could be explored for earlier phases of disease. Future work should aim to address more clearly the role of these APCs in humans, as well as better characterize their relative importance at different disease stages.
STAT4 regulates GM-CSF production in mouse model of MS. GM-CSF is a cytokine produced by T cells that is thought to mediate MS disease. These T cells also produce the cytokines IFNγ and IL-17, where all three cytokines are implicated in causing and propagating disease to varying degrees. The authors of this study sought to determine, using a mouse model of MS, what transcription factor controls the production of GM-CSF. A transcription factor is a protein that controls the production of other proteins, therefore it is important in controlling what a cell does by controlling the proteins it makes. Identifying transcription factors that ultimately lead to the production of inflammatory molecules that cause disease can ultimately lead to a better understanding of how these cells operate and lead to very specific drug or therapeutic targets. The authors found that one transcription factor, called STAT4, controls the production of GM-CSF. Mice that could not make STAT4 did not get disease, their T cells were unable to make GM-CSF, and the number of T cells that produce all three cytokines was lower. STAT4 has previously been identified as a susceptibility loci in genome-wide association studies (GWAS) for people with MS. Taken together, this indicates that STAT4 may play a key role in MS through promoting cytokine production in T cells. Future studies should determine how STAT4 levels could be controlled and if these results are reproducible in human T cells.
TLR2 stimulation reduces effectiveness of Tregs, effect enhanced in Tregs from MS donors. Regulatory T cells are crucial for controlling and limiting immune responses and the balance between these cells and inflammatory T cells is key to immune balance. It has been shown that Tregs from persons with MS are less suppressive, meaning that they are unable to control T cell proliferation as well as their counterparts from healthy donors. The reasons why this occurs are not clearly understood. In this study, the authors show that stimulation of a surface protein called TLR2 is involved in reducing Treg function, both in MS and healthy donors. TLR2 is part of a group of proteins, called Toll-like receptors, involved in alerting the immune system that invading microbial pathogens are present. They found that Tregs from MS patients express higher levels of TLR2 and that stimulating TLR2 led Tregs to be less functional and produce more inflammatory cytokines, like IL-17 and IL-6. The authors suggest that this may provide a link between certain microbial infections and relapses in MS patients. Through their experiments, they also suggest that therapies that target IL-6 could be effective. This, coupled with previous reports showing that T cells expressing the receptor for IL-6 are less capable of being suppressed, indicate that anti-IL-6 therapy might help maintain the correct balance of Th17 to Tregs.