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© The Author(s). Recent findings indicate that the ubiquitin-proteasome system is involved in the pathogenesis of cancer as well as autoimmune and several neurodegenerative diseases, and is thus a target for novel therapeutics. One disease that is related to aberrant protein degradation is multiple sclerosis, an autoimmune disorder involving the processing and presentation of myelin autoantigens that leads to the destruction of axons. Here, we show that brainderived proteasomes from SJL mice with experimental autoimmune encephalomyelitis (EAE) in an ubiquitinindependent manner generate significantly increased amounts of myelin basic protein peptides that induces cytotoxic lymphocytes to target mature oligodendrocytes ex vivo. Ten times enhanced release of immunogenic peptides by cerebral proteasomes from EAE-SJL mice is caused by a dramatic shift in the balance between constitutive and β1ihigh immunoproteasomes in the CNS of SJL mice with EAE. We found that during EAE, β1i is increased in resident CNS cells, whereas β5i is imported by infiltrating lymphocytes through the blood-brain barrier. Peptidyl epoxyketone specifically inhibits brain-derived β1ihigh immunoproteasomes in vitro (kobs/[I] = 240 M-1s-1), and at a dose of 0.5 mg/kg, it ameliorates ongoing EAE in vivo. Therefore, our findings provide novel insights into myelin metabolism in pathophysiologic conditions and reveal that the β1i subunit of the immunoproteasome is a potential target to treat autoimmune neurologic diseases.

International audience; Multiple sclerosis (MS) is a severe inflammatory and neurodegenerative disease with an autoimmune background. Despite the variety of therapeutics available against MS, the development of novel approaches to its treatment is of high importance in modern pharmaceutics. In this study, experimental autoimmune encephalomyelitis (EAE) in Dark Agouti rats has been treated with immunodominant peptides of the myelin basic protein (MBP) encapsulated in mannosylated small unilamellar vesicles. The results show that liposome-encapsulated MBP(46-62) is the most effective in reducing maximal disease score during the first attack, while MBP(124-139) and MBP(147-170) can completely prevent the development of the exacerbation stage. Both mannosylation of liposomes and encapsulation of peptides are critical for the therapeutic effect, since neither naked peptides nor nonmannosylated liposomes, loaded or empty, have proved effective. The liposome-mediated synergistic effect of the mixture of 3 MBP peptides significantly suppresses the progression of protracted EAE, with the median cumulative disease score being reduced from 22 to 14 points, compared to the placebo group; prevents the production of circulating autoantibodies; down-regulates the synthesis of Th1 cytokines; and induces the production of brain-derived neurotrophic factor in the central nervous system. Thus, the proposed formulation ameliorates EAE, providing for a less severe first attack and rapid recovery from exacerbation, and offers a promising therapeutic modality in MS treatment.

Recent studies suggest that developmental check-points in B-lymphopoiesis are set in order to test the B cell receptor signaling competence. In these checkpoints ligand-independent and ligand-dependent receptor signals confer B-lymphopoiesis with positive and negative selection events. As a consequence, Blymphocytes are forced to make crucial fate decisions to determine developmental progression, survival or apoptosis. In here we review recent progress in unraveling molecular and cellular mechanisms for the role of B cell receptor signaling competence in determination of the B cell fate.

Homeostasis in the B cell compartment (as well as in T cells) is controlled by tightly regulated selection events. Throughout their life span, B cells are subjected to selection signals determining not only developmental progression, but also maturation and survival. It is now clear that most of these signals require the expression of B cell antigen receptor (or preB receptor) with functional signaling capacity. The administration of numerous mutations into the mouse germline enabled us to identify several checkpoints along the B cell developmental pathway, and provided us with powerful experimental tools to probe for selection events regulating developmental progression. In here, we will discuss recent studies in this field.