Showing papers by "Reinhard Hohlfeld published in 2017"

Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice.

Abstract: There is emerging evidence that the commensal microbiota has a role in the pathogenesis of multiple sclerosis (MS), a putative autoimmune disease of the CNS. Here, we compared the gut microbial composition of 34 monozygotic twin pairs discordant for MS. While there were no major differences in the overall microbial profiles, we found a significant increase in some taxa such as Akkermansia in untreated MS twins. Furthermore, most notably, when transplanted to a transgenic mouse model of spontaneous brain autoimmunity, MS twin-derived microbiota induced a significantly higher incidence of autoimmunity than the healthy twin-derived microbiota. The microbial profiles of the colonized mice showed a high intraindividual and remarkable temporal stability with several differences, including Sutterella, an organism shown to induce a protective immunoregulatory profile in vitro. Immune cells from mouse recipients of MS-twin samples produced less IL-10 than immune cells from mice colonized with healthy-twin samples. IL-10 may have a regulatory role in spontaneous CNS autoimmunity, as neutralization of the cytokine in mice colonized with healthy-twin fecal samples increased disease incidence. These findings provide evidence that MS-derived microbiota contain factors that precipitate an MS-like autoimmune disease in a transgenic mouse model. They hence encourage the detailed search for protective and pathogenic microbial components in human MS.

Inflammatory CNS disease caused by immune checkpoint inhibitors: status and perspectives

Abstract: Cancer treatment strategies based on immune stimulation have recently entered the clinical arena, with unprecedented success. Immune checkpoint inhibitors (ICIs) work by indiscriminately promoting immune responses, which target tumour-associated antigens or tumour-specific mutations. However, the augmented immune response, most notably the T cell response, can cause either direct neurotoxicity or, more commonly, indirect neurotoxic effects through systemic or local inflammatory mechanisms or autoimmune mechanisms. Consequently, patients treated with ICIs are susceptible to CNS disease, including paraneoplastic neurological syndromes, encephalitis, multiple sclerosis and hypophysitis. In this Opinion article, we introduce the mechanisms of action of ICIs and review their adverse effects on the CNS. We highlight the importance of early detection of these neurotoxic effects, which should be distinguished from brain metastasis, and the need for early detection of neurotoxicity. It is crucial that physicians are well informed of these neurological adverse effects, given the anticipated increase in the use of immunotherapies to treat cancer.

Human Plasmacytoid Dendritic Cells Display and Shed B Cell Maturation Antigen upon TLR Engagement.

Abstract: The BAFF-APRIL system is best known for its control of B cell homeostasis, and it is a target of therapeutic intervention in autoimmune diseases and lymphoma. By analyzing the expression of the three receptors of this system, B cell maturation Ag (BCMA), transmembrane activator and CAML interactor, and BAFF receptor, in sorted human immune cell subsets, we found that BCMA was transcribed in plasmacytoid dendritic cells (pDCs) in both blood and lymphoid tissue. Circulating human pDCs contained BCMA protein without displaying it on the cell surface. After engagement of TLR7/8 or TLR9, BCMA was detected also on the cell surface of pDCs. The display of BCMA on the surface of human pDCs was accompanied by release of soluble BCMA (sBCMA); inhibition of γ-secretase enhanced surface expression of BCMA and reduced the release of sBCMA by pDCs. In contrast with human pDCs, murine pDCs did not express BCMA, not even after TLR9 activation. In this study, we extend the spectrum of BCMA expression to human pDCs. sBCMA derived from pDCs might determine local availability of its high-affinity ligand APRIL, because sBCMA has been shown to function as an APRIL-specific decoy. Further, therapeutic trials targeting BCMA in patients with multiple myeloma should consider possible effects on pDCs.

Patient-to-patient transmission of natalizumab-associated PML?

Abstract: The two stepsisters described by Bacchetta et al.1 had close contact before and after the first patient developed PML. After PML was diagnosed in the first patient, her stepsister insisted that her neurologist ordered a magnetic resonance imaging (MRI) scan to reassure she had not PML. MRI showed a highly suggestive clinically asymptomatic lesion in her cerebellum, and PML was confirmed by CSF John Cunningham polyomavirus-polymerase chain reaction in the cerebrospinal fluid (JCV-PCR). After natalizumab was discontinued, she developed symptomatic immune reconstitution inflammatory syndrome (IRIS).1

Stop inflammation and you stop neurodegeneration in MS - Commentary.

Abstract: However, to test the hypothesis that inflammation is the sole causal factor of MS-related structural and functional loss, experimental work studying long-term impact of early and complete elimination of inflammation is needed. This proves to be an extremely difficult task, as subclinical inflammation is often present during the pre-clinical disease stages. The apparently imperfect association between inflammation and neurodegeneration (and their clinical correlates) provides an intriguing food for thought, suggesting that additional pathognomonic factors may be involved. If this proves to be true, then no sooner will MS be conquered than we learn to control all of its multiple causative factors.