Pathogenic mechanisms and experimental models of multiple sclerosis.

Multiple sclerosis (MS) is a devastating autoimmune disease that affects more than 1 million people worldwide and severely compromises motor and sensory function through demyelination and axonal loss. This review covers current therapies, lessons learned from failed clinical trials, genetic susceptibility, key cell types involved, animal models, gene expression, and biomarker information. The current first-line therapies for MS include the type I interferons (IFN-I) and glatiramer acetate (GA) but because of their limited effectiveness new therapeutic modalities are required. Tysabri is an anti very late antigen-4 antibody that antagonizes the migration of multiple cell types and appears more efficacious as compared to the IFNs or GA. Tysabri blocks the transmigration of T cells and monocytes, which indicates that blocking multiple cell types may increase the effectiveness of the therapy. However, this therapy may increase the risk of progressive multifocal leukoencephalopathy. The major cell types hypothesized to be pathogenic include T cells and antigen-presenting cells, including B cells. The correlation of the animal model experimental autoimmune encephalomyelitis (EAE) of MS and its predictive value to determine efficacy in the clinic appears limited. However, all current therapies do demonstrate efficacy in EAE models. There are also examples of mechanisms that have worked in EAE but have failed in the clinic, such as the TNFα antagonists and anti-p40 (a subunit of IL-12 and IL-23). The MS field would benefit if clinical biomarkers were available to monitor clinical efficacy. The etiology of MS remains elusive but additional understanding of mechanisms involved in the pathogenesis of MS may guide us to more effective treatment and management of this autoimmune disease.

MafB restricts M-CSF-dependent myeloid commitment divisions of hematopoietic stem cells.

While hematopoietic stem cell (HSC) self-renewal is well studied, it remains unknown whether distinct control mechanisms enable HSC divisions that generate progeny cells with specific lineage bias. Here, we report that the monocytic transcription factor MafB specifically restricts the ability of M-CSF to instruct myeloid commitment divisions in HSCs. MafB deficiency specifically enhanced sensitivity to M-CSF and caused activation of the myeloid master-regulator PU.1 in HSCs in vivo. Single-cell analysis revealed that reduced MafB levels enabled M-CSF to instruct divisions producing asymmetric daughter pairs with one PU.1(+) cell. As a consequence, MafB(-/-) HSCs showed a PU.1 and M-CSF receptor-dependent competitive repopulation advantage specifically in the myelomonocytic, but not T lymphoid or erythroid, compartment. Lineage-biased repopulation advantage was progressive, maintained long term, and serially transplantable. Together, this indicates that an integrated transcription factor/cytokine circuit can control the rate of specific HSC commitment divisions without compromising other lineages or self-renewal.