γδ T cells enhance autoimmunity by restraining regulatory T cell responses via an interleukin-23-dependent mechanism.

Mice that lack interleukin-23 (IL-23) are resistant to T cell-mediated autoimmunity. Although IL-23 is a maturation factor for T helper 17 (Th17) cells, a subset of γδ T cells expresses the IL-23 receptor (IL-23R) constitutively. Using IL-23R reporter mice, we showed that γδ T cells were the first cells to respond to IL-23 during experimental autoimmune encephalomyelitis (EAE). Although γδ T cells produced Th17 cell-associated cytokines in response to IL-23, their major function was to prevent the development of regulatory T (Treg) cell responses. IL-23-activated γδ T cells rendered αß effector T cells refractory to the suppressive activity of Treg cells and also prevented the conversion of conventional T cells into Foxp3(+) Treg cells in vivo. Thus, IL-23, which by itself has no direct effect on Treg cells, is able to disarm Treg cell responses and promote antigen-specific effector T cell responses via activating γδ T cells.

Mitochondrial membrane protein associated neurodegenration: a novel variant of neurodegeneration with brain iron accumulation.

BACKGROUND: Recently, mutations in an open-reading frame on chromosome 19 (C19orf12) were identified as a novel genetic factor in neurodegeneration with brain iron accumulation (NBIA). Because of the mitochondrial localization of the derived protein, this variant is referred to as mitochondrial membrane protein-associated neurodegeneration with brain iron accumulation (MPAN). METHODS/RESULTS: We describe the clinical phenotype and MRI of 3 newly identified individuals with MPAN due to either previously reported or novel homozygous or compound heterozygous genetic alterations in C19orf12. CONCLUSIONS: MPAN is characterized by a juvenile-onset, slowly progressive phenotype with predominant lower limb spasticity, generalized dystonia, and cognitive impairment. Typical additional features include axonal motor neuropathy and atrophy of the optic nerve. MRI showed iron deposition in the globus pallidus and substantia nigra without the eye-of-the-tiger sign, which is typical for PKAN, the most frequent form of NBIA.

Immune mechanisms of new therapeutic strategies in MS: teriflunomide.

At present, a series of oral disease-modifying agents is being introduced for the treatment of multiple sclerosis. With the exception of laquinimod, the "new" oral compounds have already been approved for other indications such as organ transplantation (FTY720), psoriasis (dimethylfumarate), hairy cell leukemia (cladribine), and rheumatoid arthritis (leflunomide). Leflunomide is the prodrug of teriflunomide which is the latest compound that has successfully been tested in a large phase III clinical trial in relapsing MS. Due to its favorable safety profile and its efficacy in rheumatoid arthritis where the aberrant immune response is in various aspects similar to the autoimmune reaction in MS patients, teriflunomide is a promising treatment option for MS patients. Here, we review the most important cell biological and immunological modes of action of teriflunomide, report on the available data on its pharmacokinetics in humans, and summarize the recent clinical trials of teriflunomide in relapsing MS.

Active immunization with amyloid-beta 1-42 impairs memory performance through TLR2/4-dependent activation of the innate immune system.

Active immunization with amyloid-ß (Aß) peptide 1-42 reverses amyloid plaque deposition in the CNS of patients with Alzheimer's disease and in amyloid precursor protein transgenic mice. However, this treatment may also cause severe, life-threatening meningoencephalitis. Physiological responses to immunization with Aß(1-42) are poorly understood. In this study, we characterized cognitive and immunological consequences of Aß(1-42)/CFA immunization in C57BL/6 mice. In contrast to mice immunized with myelin oligodendrocyte glycoprotein (MOG)(35-55)/CFA or CFA alone, Aß(1-42)/CFA immunization resulted in impaired exploratory activity, habituation learning, and spatial-learning abilities in the open field. As morphological substrate of this neurocognitive phenotype, we identified a disseminated, nonfocal immune cell infiltrate in the CNS of Aß(1-42)/CFA-immunized animals. In contrast to MOG(35-55)/CFA and PBS/CFA controls, the majority of infiltrating cells in Aß(1-42)/CFA-immunized mice were CD11b(+)CD14(+) and CD45(high), indicating their blood-borne monocyte/macrophage origin. Immunization with Aß(1-42)/CFA was significantly more potent than immunization with MOG(35-55)/CFA or CFA alone in activating macrophages in the secondary lymphoid compartment and peripheral tissues. Studies with TLR2/4-deficient mice revealed that the TLR2/4 pathway mediated the Aß(1-42)-dependent proinflammatory cytokine release from cells of the innate immune system. In line with this, TLR2/4 knockout mice were protected from cognitive impairment upon immunization with Aß(1-42)/CFA. Thus, this study identifies adjuvant effects of Aß(1-42), which result in a clinically relevant neurocognitive phenotype highlighting potential risks of Aß immunotherapy.

Prevalence and Risk Factors of Psychiatric Symptoms among Swiss Elite Athletes during the First Lockdown of the COVID-19 Pandemic.

The COVID-19 pandemic and the associated first lockdown measures may have had a relevant impact on the mental health of competitive athletes. This study aimed to evaluate the prevalence of various mental health issues in a Swiss elite athletes' cohort during the first lockdown of the pandemic, and to assess their association with different potential risk factors. Elite athletes from different disciplines were interviewed during the first lockdown in spring 2020 by means of an online questionnaire on symptoms of existing anxieties, depression and sleep disorders, as well as on training circumstances and physical performance before and during the lockdown. Additionally, the economic situation, secondary occupations and current physical health problems were surveyed. A total of 203 (92 female, 111 male) athletes met the inclusion criteria and participated in the survey. Training volume and intensity decreased significantly during lockdown from 3.1 to 2.7 h/day. Financial existential fears increased and were associated with higher training volumes and higher trait anxiety scores. Depressive symptoms and insomnia were present but not exceptionally frequent during the lockdown. Depressive symptoms were associated with higher anxiety scores, higher insomnia severity scores, lower training intensity and worse coping with the measures taken by the authorities against the pandemic. Changes in training and daily habits due to the first lockdown may have affected the mental health of elite athletes. Longitudinal studies should, however, further investigate the long-term effects of the pandemic on mental health.

Th17 lymphocytes traffic to the central nervous system independently of α4 integrin expression during EAE.

The integrin α4ß1 (VLA-4) is used by encephalitogenic T cells to enter the central nervous system (CNS). However, both Th1 and Th17 cells are capable of inducing experimental autoimmune encephalomyelitis (EAE), and the molecular cues mediating the infiltration of Th1 versus Th17 cells into the CNS have not yet been defined. We investigated how blocking of α4 integrins affected trafficking of Th1 and Th17 cells into the CNS during EAE. Although antibody-mediated inhibition of α4 integrins prevented EAE when MOG(35-55)-specific Th1 cells were adoptively transferred, Th17 cells entered the brain, but not the spinal cord parenchyma, irrespective of α4 blockade. Accordingly, T cell-conditional α4-deficient mice were not resistant to actively induced EAE but showed an ataxic syndrome with predominantly supraspinal infiltrates of IL-23R(+)CCR6(+)CD4(+) T cells. The entry of α4-deficient Th17 cells into the CNS was abolished by blockade of LFA-1 (αLß2 integrin). Thus, Th1 cells preferentially infiltrate the spinal cord via an α4 integrin-mediated mechanism, whereas the entry of Th17 cells into the brain parenchyma occurs in the absence of α4 integrins but is dependent on the expression of αLß2. These observations have implications for the understanding of lesion localization, immunosurveillance, and drug design in multiple sclerosis.