Thierry Vincent

Long-term Outcomes of CLIPPERS (Chronic Lymphocytic Inflammation With Pontine Perivascular Enhancement Responsive to Steroids) in a Consecutive Series of 12 Patients

BACKGROUND Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a central nervous system inflammatory disease. OBJECTIVE To describe the disease course of CLIPPERS. DESIGN A nationwide study was implemented to collect clinical, magnetic resonance imaging, cerebrospinal fluid, and brain biopsy specimen characteristics of patients with CLIPPERS. SETTING Academic research. PATIENTS Twelve patients with CLIPPERS. MAIN OUTCOME MEASURES The therapeutic management of CLIPPERS was evaluated. RESULTS Among 12 patients, 42 relapses were analyzed. Relapses lasted a mean duration of 2.5 months, manifested frequent cerebellar ataxia and diplopia, and were associated with a mean Expanded Disability Status Scale (EDSS) score of 4. Besides typical findings of CLIPPERS, magnetic resonance imaging showed brainstem mass effect in 5 patients, extensive myelitis in 3 patients, and closed ring enhancement in 1 patient. Inconstant oligoclonal bands were found on cerebrospinal fluid investigation in 4 patients, with an increased T-cell ratio of CD4 to CD8. Among 7 available brain biopsy specimens, staining was positive for perivascular CD4 T lymphocytes in 5 samples. Thirty-eight of 42 relapses were treated with pulse corticosteroid therapy, which led to improvement, with a mean residual EDSS score of 1.9 (range, 0-7). In 1 patient with untreated relapses, scores on the EDSS progressively increased to a score of 10 at death. Among 5 patients without long-term corticosteroid therapy, the mean annualized relapse rate was 0.5 (range, 0.25-2.8). Among 7 patients taking oral corticosteroids, no relapses occurred in those whose daily dose was 20 mg or higher. No progressive course of CLIPPERS was observed. Four patients with a final EDSS score of 4 or higher had experienced previous severe relapses (EDSS score, ≥5) and brainstem and spinal cord atrophy. CONCLUSIONS CLIPPERS is a relapsing-remitting disorder without progressive forms. Long-term disability is correlated with the severity of previous relapses. Further studies are needed to confirm that prolonged corticosteroid therapy prevents further relapses.

Impact of autoantibody glycosylation in autoimmune diseases

OBJECTIVE Recent outcomes enhanced the critical role of glycosylation pattern of autoantibodies in the pathophysiology of antibody-mediated autoimmune diseases. In this review, we discuss the critical role of immunoglobulin (Ig) glycosylation on skewing immune response towards a pro- or anti-inflammatory pathway. METHODS A comprehensive search of Pubmed references was completed by hand searching of selected articles. RESULTS We first described the impact of glycosylation on Ig immune effector functions: antibody-dependent cell-mediated cytotoxicity, complement activation, dendritic cell, macrophage or B-cell activation and maturation, neoantigen formation, or Ig-receptor binding. We then reviewed autoimmune diseases with abnormal Ig glycosylation, trying to understand its role in the pathogenic process. We then discussed the usefulness of monitoring Ig glycosylation as a biomarker of disease activity, as demonstrated in proteinase-3 anti-neutrophil cytoplasmic autoantibodies associated vasculitis. After reporting environmental and immune factors known to affect Ig glycosylation process, we finally evoked therapeutic strategies currently being developed in order to modulate Ig glycosylation pattern and autoimmune disease evolution. CONCLUSION This overview on Ig glycosylation mechanisms and impact on immune system modulation is necessary to face new therapeutic approaches of autoimmune diseases.

Lack of confirmation of anti-inward rectifying potassium channel 4.1 antibodies as reliable markers of multiple sclerosis.

Background: auto-antibodies against the potassium channel inward rectifying potassium channel 4.1 (Kir4.1) have previously been identified in 46% of patients with multiple sclerosis (MS). Objectives: to confirm these findings. Methods: we evaluated the presence of anti-Kir4.1 antibodies by enzyme-linked immunosorbent assay (ELISA) and immunofluorescence in 268 MS patients, 46 patients with other neurological diseases (OND) and 45 healthy controls. Results: anti-Kir4.1 antibodies were found in 7.5% of MS patients, 4.3% of OND patients and 4.4% of healthy controls. Immunofluorescence analysis did not identify any specific staining. Conclusions: we confirmed the presence of anti-Kir4.1 antibodies in MS patients, but at a much lower prevalence than previously reported.

Hyaluronan, a major non‐protein glycosaminoglycan component of the extracellular matrix in human bone marrow, mediates dexamethasone resistance in multiple myeloma

Summary. Originating from a post‐switch memory B cell or plasma cell compartment in peripheral lymphoid tissues, malignant multiple myeloma (MM) cells accumulate in the bone marrow of patients with MM. In this favourable microenvironment, their growth and survival are dependent upon both soluble factors and physical cell‐to‐cell and cell‐to‐extracellular‐matrix contacts. In this study, hyaluronan (HA), a major non‐protein glycosaminoglycan component of the extracellular matrix in mammalian bone marrow, acted as a survival factor against dexamethasone (Dex)‐induced apoptosis in MM cell lines. These effects were mediated through an interleukin 6 (IL‐6) autocrine pathway, involving signal transducers and activators of transcription‐3 phosphorylation on IL‐6‐dependent XG‐1 and XG‐6 cell lines. HA promoted accumulation of IL‐6 in the culture medium without affecting IL‐6 gene expression, suggesting that HA protects, stabilizes and concentrates IL‐6 close to its site of secretion, thus favouring its autocrine activity. In contrast, in the IL‐6‐independent RPMI8226 cell line, HA survival effect was mediated through a gp80‐IL‐6 receptor‐independent pathway, resulting in the upregulation of Bcl‐2 anti‐apoptotic protein expression and nuclear factor‐κB activation. Taken together, these data suggest that HA antagonizes Dex‐induced apoptosis of MM cells by favouring the autocrine activity of different cytokines or growth factors. As HA is a major component of the bone marrow extracellular matrix, these findings support the idea that HA could play a major role in the survival of MM cells in vivo, and could explain why MM cells accumulate in the bone marrow of patients with MM and escape conventional chemotherapy.

Neuroimmunity dynamics and the development of therapeutic strategies for amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal paralytic disorder characterized by the progressive and selective loss of both upper and lower motoneurons. The neurodegenerative process is accompanied by a sustained inflammation in the brain and spinal cord. The neuron-immune interaction, implicating resident microglia of the central nervous system and blood-derived immune cells, is highly dynamic over the course of the disease. Here, we discuss the timely controlled neuroprotective and neurotoxic cues that are provided by the immune environment of motoneurons and their potential therapeutic applications for ALS.

Extensive cerebral white matter involvement in a patient with NMO spectrum disorder

Abnormal brain MRI has been described in up to 60% of patients with NMO patients. However, white matter T2 hyperintensities have been rarely observed. We report the case of a 49-year-old woman with long-lasting neuromyelitis optica (NMO) spectrum disorder and diffuse cerebral white matter T2-weighted hyperintensities. Our case suggests that some NMO patients can progressively develop l extensive cerebral involvement.

The Neuroinflammation in the Physiopathology of Amyotrophic Lateral Sclerosis

Neuroinflammation is an inflammatory response that takes place within the central nervous system (CNS) during a neurodegenerative process or following a neuronal injury. The main effectors of neuroinflammation, which are astrocytes, microglia and immune cells can confer in a contextand time-dependent manner both neuroprotective and neurotoxic effects. It has now become evident that neuroinflammation is a prominent pathological hallmark of several neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and Amyotro‐ phic Lateral Sclerosis (ALS)(reviewed in [1, 2]). Indeed, reactive astrocytes and microglia as well as infiltrating T lymphocytes have been identified in ALS experimental models and patients. In the present chapter, we will describe the neuroinflammatory phenotype that characterizes ALS and discuss how the aberrant astrocytes, microglia and immune cells may actively participate in the neurodegenerative process. Further, we will examine the therapeutic potential of targeting neuroinflammation in both pre-clinical disease models and ALS patients.