CD4(+) T cells of myasthenia gravis patients are characterized by ıncreased IL-21, IL-4, and IL-17A productions and higher presence of PD-1 and ICOS

Myasthenia gravis (MG) is an autoimmune disease mediated by autoantibodies predominantly against the acetylcholine receptor (AChR). Specific T cell subsets are required for long-term antibody responses, and cytokines secreted mainly from CD4(+) T cells regulate B cell antibody production. The aim of this study was to assess the differences in the cytokine expressions of CD4(+) T cells in MG patients with AChR antibodies (AChR-MG) and the effect of immunosuppressive (IS) therapy on cytokine activity and to test these findings also in MG patients without detectable antibodies (SN-MG). Clinically diagnosed AChR-MG and SN-MG patients were included. The AChR-MG patients were grouped as IS-positive and -negative and compared with age- and sex-matched healthy controls. Peripheral blood mononuclear cells were used for ex vivo intracellular cytokine production, and subsets of CD4(+) T cells and circulating follicular helper T (cTfh) cells were detected phenotypically by the expression of the chemokine and the costimulatory receptors. Thymocytes obtained from patients who had thymectomy were also analyzed. IL-21, IL-4, IL-10, and IL-17A productions in CD4(+) T cells were increased in AChR-MG compared to those in healthy controls. IS treatment enhanced IL-10 and reduced IFN-gamma production in AChR-MG patients compared to those in IS-negative patients. Increased IL-21 and IL-4 productions were also demonstrated in SN-MG patients. Among CD4(+) T cells, Th17 cells were increased in both disease subgroups. Treatment induced higher proportions of Th2 cells in AChR-MG patients. Both CXCR5(+) and CXCR5(-) CD4(+) T cells expressed higher programmed cell death protein 1 (PD-1) and inducible costimulatory (ICOS) in AChR-MG and SN-MG groups, mostly irrespective of the treatment. Based on chemokine receptors on CXCR5(+)PD-1(+) in CD4(+) T (cTfh) cells, in AChR-MG patients without treatment, the proportions of Tfh17 cells were higher than those in the treated group, whereas the Tfh1 cells were decreased compared with those in the controls. The relevance of CXCR5 and PD-1 in the pathogenesis of AChR-MG was also suggested by the increased presence of these molecules on mature CD4 single-positive thymocytes from the thymic samples. The study provides further evidence for the importance of IL-21, IL-17A, IL-4, and IL-10 in AChR-MG. Disease-related CD4(+)T cells are identified mainly as PD-1(+) or ICOS+ with or without CXCR5, resembling cTfh cells in the circulation or probably in the thymus. AChR-MG and SN-MG seem to have some similar characteristics. IS treatment has distinctive effects on cytokine expression.Istanbul Universit

Genetic landscape of congenital insensitivity to pain and hereditary sensory and autonomic neuropathies

Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders exclusively or predominantly affecting the sensory and autonomic neurons. Due to the rarity of the diseases and findings based mainly on single case reports or small case series, knowledge about these disorders is limited. Here, we describe the molecular workup of a large international cohort of CIP/HSAN patients including patients from normally under-represented countries. We identify 80 previously unreported pathogenic or likely pathogenic variants in a total of 73 families in the >20 known CIP/HSAN-associated genes. The data expand the spectrum of disease-relevant alterations in CIP/HSAN, including novel variants in previously rarely recognized entities such as ATL3-, FLVCR1- and NGF-associated neuropathies and previously under-recognized mutation types such as larger deletions. In silico predictions, heterologous expression studies, segregation analyses and metabolic tests helped to overcome limitations of current variant classification schemes that often fail to categorize a variant as disease-related or benign. The study sheds light on the genetic causes and disease-relevant changes within individual genes in CIP/HSAN. This is becoming increasingly important with emerging clinical trials investigating subtype or gene-specific treatment strategies

Pembrolizumab-induced peripheral nervous system damage: A combination of myositis/myasthenia overlap syndrome and motor axonal polyneuropathy

Introduction – Immune-checkpoint inhibi- tors (ICI) are effective drugs in cancer treat- ment that block immune checkpoints and stimulate an attack on cancer cells. However, various side effects were reported with ICIs. Peripheral nervous system (PNS) side effects are three times more frequent than those in the central nervous system. Case report – A 63-year-old male patient was admitted to our department with a 10-day history of dyspnea, diplopia, and generalized weakness. He had a diagnosis of non-small cell lung cancer, which was treated with pembrolizumab. His neuro- logical symptoms appeared one week after the second course of pembrolizumab, and gradually worsened. His neurological exam- ination showed nasal speech, bilateral ptosis, tongue and neck flexor weakness, prominent asymmetrical upper limb weakness, and mild lower limb weakness. Deep tendon reflex- es and sensory examination were normal. He had an elevated creatine kinase level (4430 U/L). Needle electromyography (EMG) showed a myopathic pattern, and single fiber EMG demonstrated an increased jitter in the right frontal muscle. Pembrolizumab treat- ment was discontinued, and intravenous methylprednisolone followed by intravenous immunoglobulin (IVIg) were initiated. His symptoms gradually improved. However, his weakness began to worsen after a month, and repeated nerve conduction studies showed a predominantly motor axonal polyneuropathy. Thereafter, the patient was treated with IVIg infusions (0.4 g/every two weeks) to maintain his motor function. Conclusion – Our case showed that ICIs could simultaneously or sequentially cause damage in multiple domains of the PNS. Early recognition of these adverse events is essential since the outcome is favorable with rapid cessation of the causative ICI and administration of immune-modulator treatment

Transthyretin-Related Familial Amyloid Polyneuropathy: In the Light of New Developments

Transthyretin-related familial amyloid polyneuropathy (TTR-FAP) is caused by gain-of-toxic-function of TTR, which dissociates from its native tetramer form to a monomer form and aggregates in several tissues and organs. Mutations in the TTR gene lead to this amyloidogenic transformation and cause autosomal dominant disease. TTR-FAP typically causes sensorimotor FAP accompanied by autonomic involvement, but considerable phenotypic diversity is noted between different mutation types. In the event of clinical suspicion, TTR gene sequencing and pathologic confirmation are the recommended paths to follow. Significant improvement has been achieved in treating the disease over the past 20 years, starting with liver transplantation, followed by tetramer stabilizers and TTR-lowering therapies. Although there are still some uncertainties in diagnosing and treating TTR-FAP, recent advances are promising, especially in the field of treatmen

Transthyretin-Related Familial Amyloid Polyneuropathy: In the Light of New Developments

Transthyretin-related familial amyloid polyneuropathy (TTR-FAP) is caused by gain-of-toxic-function of TTR, which dissociates from its native tetramer form to a monomer form and aggregates in several tissues and organs. Mutations in the TTR gene lead to this amyloidogenic transformation and cause autosomal dominant disease. TTR-FAP typically causes sensorimotor FAP accompanied by autonomic involvement, but considerable phenotypic diversity is noted between different mutation types. In the event of clinical suspicion, TTR gene sequencing and pathologic confirmation are the recommended paths to follow. Significant improvement has been achieved in treating the disease over the past 20 years, starting with liver transplantation, followed by tetramer stabilizers and TTR-lowering therapies. Although there are still some uncertainties in diagnosing and treating TTR-FAP, recent advances are promising, especially in the field of treatmen

Aquaporin-4 Gene Polymorphisms in Neuromyelitis Optica and Recurrent Optic Neuritis

Objective: Although Aquaporin-4 (Aqp-4) gene polymorphisms have been extensively studied in neuromyelitis optica spectrum disorder (NMOSD), there is little evidence on the involvement of Aqp-4 in the pathogenesis of relapsing optic neuritis (RON). Materials and Methods: In our study, we recruited patients who were followed by Istanbul University, Istanbul Faculty of Medicine, Department of Neurology, Multiple Sclerosis and Myelin Disorders Unit between 1979 and 2015. Blood samples of the patients were genotyped for potential variants in the exons and the nearby regions of Aqp-4 gene. Results: The Aqp-4 gene was sequenced in 15 patients with RON who were seronegative, 33 patients with NMOSD, and 30 healthy controls. None of the patients showed previously described single nucleotide polymorphisms (SNPs). Three new SNPs were identified in non-exonic regions of the gene. One intronic SNP located in close proximity to the fifth exon had a higher prevalence in patients with RON than patients with NMOSD and healthy controls. Conclusion: Aqp-4 SNPs show a considerable heterogeneous geographic distribution and might be involved in RON pathogenesis