Raphael Schneider

IL‐27 increases the proliferation and effector functions of human naïve CD8+ T lymphocytes and promotes their development into Tc1 cells

IL‐27 has been shown to exhibit both pro‐ and anti‐inflammatory properties; it favors mouse naïve CD4+T‐cell differentiation into Th1 cells to the detriment of Th17 and Th2 skewing and regulates IL‐10 and IL‐17 production by human CD4+ T cells. Moreover, IL‐27 promotes proliferation and cytotoxic functions of mouse CD8+ T lymphocytes, but no data are available on human CD8+ T cells. We investigated the impact of IL‐27 on human CD8+T cells. In contrast to mouse T cells, the IL‐27 receptor (IL‐27R), composed of T cell cytokine receptor (TCCR) and gp130, was detected on a greater percentage of human CD8+ than CD4+ T cells and these proportions increased upon polyclonal activation. IL‐27 induced rapid STAT1 and STAT3 signaling, enhanced STAT1 protein levels, and induced SOCS1 and SOCS3 expression in a STAT1‐dependent manner by human CD8+ T cells. Addition of IL‐27 to α‐CD3‐activated naïve CD8+ T cells significantly increased T‐box transcription factor expression levels, cell proliferation, and IFN‐γ and granzyme B production leading to increased CD8+ T‐cell‐mediated cytotoxicity. These results demonstrate that IL‐27, a rapidly produced cytokine by activated APC, has a profound impact on human naïve CD8+T cells, driving them to become highly efficient Tc1 cells.

Production of IL-27 in multiple sclerosis lesions by astrocytes and myeloid cells: Modulation of local immune responses

The mechanisms whereby human glial cells modulate local immune responses are not fully understood. Interleukin‐27 (IL‐27), a pleiotropic cytokine, has been shown to dampen the severity of experimental autoimmune encephalomyelitis, but it is still unresolved whether IL‐27 plays a role in the human disease multiple sclerosis (MS). IL‐27 contribution to local modulation of immune responses in the brain of MS patients was investigated. The expression of IL‐27 subunits (EBI3 and p28) and its cognate receptor IL‐27R (the gp130 and TCCR chains) was elevated within post‐mortem MS brain lesions compared with normal control brains. Moreover, astrocytes (GFAP+ cells) as well as microglia and macrophages (Iba1+ cells) were important sources of IL‐27. Brain‐infiltrating CD4 and CD8 T lymphocytes expressed the IL‐27R specific chain (TCCR) implying that these cells could respond to local IL‐27 sources. In primary cultures of human astrocytes inflammatory cytokines increased IL‐27 production, whereas myeloid cell inflammatory M1 polarization and inflammatory cytokines enhanced IL‐27 expression in microglia and macrophages. Astrocytes in postmortem tissues and in vitro expressed IL‐27R. Moreover, IL‐27 triggered the phosphorylation of the transcription regulator STAT1, but not STAT3 in human astrocytes; indeed IL‐27 up‐regulated MHC class I expression on astrocytes in a STAT1‐dependent manner. These findings demonstrated that IL‐27 and its receptor were elevated in MS lesions and that local IL‐27 can modulate immune properties of astrocytes and infiltrating immune cells. Thus, therapeutic strategies targeting IL‐27 may influence not only peripheral but also local inflammatory responses within the brain of MS patients. GLIA 2016;64:553–569

T cells with commitment issues.

Some subsets of differentiated T cells retain phenotypic plasticity. T cells are a central element of cell-mediated immunity. Host detection of infectious agents leads to antigen presentation and release of cytokines that cause naïve T cells to develop into effector T cells or regulatory T cells (Treg cells). Effector T cells act to control the invading agents and mediate tissue inflammation. Treg cells maintain immune homeostasis by suppressing effector T cell responses to prevent collateral damage. Until recently, T cell differentiation into distinct subsets with different functions had been considered irreversible. However, new evidence suggests that some differentiated T cell subsets are more phenotypically flexible than others. Studying the plasticity of T cells and the underlying signaling mechanisms may lead to important clues for understanding immunity and autoimmunity.

Unaffected mosaicC9orf72case: RNA foci, dipeptide proteins, but upregulated C9orf72 expression

Objective Suggested C9orf72 disease mechanisms for amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration include C9orf72 haploinsufficiency, G4C2/C4G2 RNA foci, and dipeptide repeat (DPR) proteins translated from the G4C2 expansion; however, the role of small expansions (e.g., 30–90 repeats) is unknown and was investigated here. Methods We conducted a molecular and pathology study of a family in which the father (unaffected at age 90) carried a 70-repeat allele in blood DNA that expanded to ≈1,750 repeats in his children, causing ALS. Results Southern blotting revealed different degrees of mosaicism of small and large expansions in the fathers tissues from the CNS. Surprisingly, in each mosaic tissue, C9orf72 mRNA levels were significantly increased compared to an ALS-affected daughter with a large expansion. Increased expression correlated with higher levels of the 70-repeat allele (the upregulation was also evident at the protein level). Remarkably, RNA foci and DPR burdens were similar or even significantly increased (in cerebellum) in the unaffected father compared to the daughter with ALS. However, the father did not display TDP-43 pathology and signs of neurodegeneration. Conclusion The presence of RNA foci and DPR pathology was insufficient for disease manifestation and TDP-43 pathology in the mosaic C9orf72 carrier with upregulated C9orf72 expression. It is important to conduct an investigation of similar cases, which could be found among unaffected parents of sporadic C9orf72 patients (e.g., 21% among Finnish patients with ALS). Caution should be taken when consulting carriers of small expansions because disease manifestation could be dependent on the extent of the somatic instability in disease-relevant tissues.

Clinical Reasoning: A 64-year-old man with progressive paraspinal muscle weakness

A 64-year-old man was referred with a 5-month history of progressive muscle weakness. He first noted a stooped posture and gait difficulties, followed by difficulty climbing and descending stairs and lifting dishes up onto high shelves. The progressive severity of his weakness led him to require a wheelchair by the time of his presentation. He was unable to sit unaided, presumably because of axial weakness. In addition, he had recently started to experience bulbar symptoms, including dysphagia and voice changes, along with shortness of breath on exertion or when lying flat. He denied visual symptoms, ptosis, and facial weakness. There was no diurnal fluctuation of symptoms. He had no sensory symptoms or sphincter disturbance. There was no family history of muscle disease. However, his family history was positive for a child with chronic inflammatory demyelinating polyneuropathy, starting at age 16, with good response to periodic IV immunoglobulin (IVIg), and another child with acute inflammatory demyelinating polyneuropathy, who recovered fully.

Strains of Pathological Protein Aggregates in Neurodegenerative Diseases

The presence of protein aggregates in the brain is a hallmark of neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Considerable evidence has revealed that the pathological protein aggregates in many neurodegenerative diseases are able to self-propagate, which may enable pathology to spread from cell-to-cell within the brain. This property is reminiscent of what occurs in prion diseases such as Creutzfeldt-Jakob disease. A widely recognized feature of prion disorders is the existence of distinct strains of prions, which are thought to represent unique protein aggregate structures. A number of recent studies have pointed to the existence of strains of protein aggregates in other, more common neurodegenerative illnesses such as AD, PD, and related disorders. In this review, we outline the pathobiology of prion strains and discuss how the concept of protein aggregate strains may help to explain the heterogeneity inherent to many human neurodegenerative disorders.

Journal Club: Intrathecal effects of daclizumab treatment of multiple sclerosis

The topic of this Journal Club is a study by Bielekova et al., 1 who assessed whether daclizumab monotherapy reduces contrast-enhancing lesions (CEL) in patients with relapsing-remitting multiple sclerosis (RRMS). Furthermore, they evaluated the effects of daclizumab on clinical outcome measures and on NK cell populations in the CSF and blood of treated patients. BACKGROUND AND SIGNIFICANCE Multiple

Clinical Reasoning: A 34-year-old man with headache, diplopia, and hemiparesis

A 34-year-old right-handed man awoke with lethargy, headache, diplopia, bilateral facial numbness, mild right hemiparesis, and right arm numbness. A few weeks prior, he had received vaccines for influenza and hepatitis. His history was significant for chronic sinusitis. Family history was negative for neurologic and autoimmune disease.