http://dosequis.colorado.edu/Courses/BrainWeb/papers/MG1.pdf

Myasthenia gravis: a comprehensive review of immune dysregulation and etiological mechanisms.

The end of twentieth century has introduced some changes into T helper (Th) cells division. The identification of the new subpopulation of T helper cells producing IL-17 modified model of Th1–Th2 paradigm and it was named Th17. High abilities to stimulate acute and chronic inflammation made these cells ideal candidate for crucial player in development of autoimmune disorders. Numerous publications based on animal and human models confirmed their pivotal role in pathogenesis of human systemic and organ-specific autoimmune diseases. These findings made Th17 cells and pathways regulating their development and function a good target for therapy. Therapies based on inhibition of Th17-dependent pathways are associated with clinical benefits, but on the other hand are frequently inducing adverse effects. In this review, we attempt to summarize researches focused on the importance of Th17 cells in development of human autoimmune diseases as well as effectiveness of targeting IL-17 and its pathways in pre-clinical and clinical studies.

/pdf/the-role-of-il-17-and-th17-lymphocytes-in-autoimmune-5g0l160shj.pdf

The Role of IL-17 and Th17 Lymphocytes in Autoimmune Diseases

Myasthenia Gravis: Paradox versus paradigm in autoimmunity

No consensus has been reached on the ideal therapeutic algorithm for myasthenia gravis (MG). Most patients with MG require induction therapy with high doses of corticosteroids and maintenance with an immunosuppressant. Severe cases and acute worsening require intravenous immunoglobulin or plasmapheresis before oral immunosuppressants start having an effect. However, biologics are emerging as important therapeutic tools that promise to provide better corticosteroid sparing effects than standard treatments and can even induce remission. In particular, eculizumab, a monoclonal antibody against complement C5, has been approved by the FDA for refractory MG on the basis of a phase III trial. Rituximab, an anti-CD20 monoclonal antibody that depletes peripheral B cells, has also been effective in many large uncontrolled series, although was not in a small phase III trial. Whether the newer anti-CD20 agents ocrelizumab, ofatumumab, obinutuzumab, ublituximab or inebilizumab will be more effective remains unclear. Belimumab, an antibody against the B cell trophic factor BAFF, was ineffective in phase III trials, and efgartigimod, which depletes antibodies, was effective in a phase II study. Some anti-cytokine agents relevant to MG immunopathogenesis also seem promising. Checkpoint inhibitors can trigger MG in some patients, necessitating early intervention. Increased availability of new biologics provides targeted immunotherapies and the opportunities to develop more specific therapies.

Immunotherapy in myasthenia gravis in the era of biologics.

Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction (NMJ). Autoantibodies target key molecules at the NMJ, such as the nicotinic acetylcholine receptor (AChR), muscle-specific kinase (MuSK), and low-density lipoprotein receptor-related protein 4 (Lrp4), that lead by a range of different pathogenic mechanisms to altered tissue architecture and reduced densities or functionality of AChRs, reduced neuromuscular transmission, and therefore a severe fatigable skeletal muscle weakness. In this review, we give an overview of the history and clinical aspects of MG, with a focus on the structure and function of myasthenic autoantigens at the NMJ and how they are affected by the autoantibodies’ pathogenic mechanisms. Furthermore, we give a short overview of the cells that are implicated in the production of the autoantibodies and briefly discuss diagnostic challenges and treatment strategies.

https://www.mdpi.com/2073-4409/8/7/671/pdf

Myasthenia Gravis: Pathogenic Effects of Autoantibodies on Neuromuscular Architecture.

It has been suggested that interleukin-17 (IL-17) plays a crucial role in the development of several autoimmune diseases. However, there are no data about the relationship between myasthenia gravis and IL-17. The aim of this study was to measure the concentration of IL-17 and determine whether levels depend on the severity of MG. Serum IL-17 concentrations were measured in 25 patients. IL-17 concentrations were higher in generalized MG compared with controls and correlated with anti-acetylcholinesterase receptor antibody titers.

Increased serum interleukin‐17 levels in patients with myasthenia gravis

Accumulation of galactosphingolipids is a general characteristic of Fabry disease, a lysosomal storage disorder caused by the deficient activity of α-galactosidase A encoded by the GLA gene. Although many polymorphic GLA haplotypes have been described, it is still unclear whether some of these variants are causative of disease symptoms. We report the study of an inheritance of a complex intronic haplotype (CIH) (c.-10C > T, c.369 + 990C > A, c.370-81_370-77delCAGCC, c.640-16A > G, c.1000-22C > T) within the GLA gene associated with Fabry-like symptoms and galactosphingolipid accumulation. We analysed α-Gal A activity in plasma, leukocytes and skin fibroblasts in patients, and measured accumulation of galactosphingolipids by enzymatic methods and immunofluorescence techniques. Additionally, we evaluated GLA expression using quantitative PCR, EMSA, and cDNA cloning. CIH carriers had an altered GLA expression pattern, although most of the carriers had high residual enzyme activity in plasma, leukocytes and in skin fibroblasts. Nonetheless, CIH carriers had significant galactosphingolipid accumulation in fibroblasts in comparison with controls, and also glycolipid deposits in renal tubules and glomeruli. EMSA assays indicated that the c.-10C > T variant in the promoter affected a nuclear protein binding site. Thus, inheritance of the CIH caused an mRNA deregulation altering the GLA expression pattern, producing a tissue glycolipid storage.

/pdf/increased-glycolipid-storage-produced-by-the-inheritance-of-4x2muc7on7.pdf

Increased glycolipid storage produced by the inheritance of a complex intronic haplotype in the α-galactosidase A ( GLA ) gene

Introduction Data on polyneuropathy rates in Parkinson’s disease vary between studies. Our purpose was to determine its prevalence and the factors associated with that entity. Material and methods Presence of polyneuropathy was determined using the Utah Early Neuropathy Scale and a nerve conduction study in patients with Parkinson’s disease. We established 2 subgroups of patients with polyneuropathy by clinical relevance: patients scoring ≥5 on the Utah Early Neuropathy Scale, and patients scoring Results Eighty-four subjects were included in the study. Prevalence of polyneuropathy was 30.9%; 21.4% of the patients scored ≥5 and 9.5% scored 12 for the subgroup scoring ≥5, but only age at disease onset for the subgroup with lower scores. Conclusions Polyneuropathy may have a primary neurodegenerative origin in relationship with older age at onset of Parkinson’s disease and more advanced stages of the disease. Decreases in vitamin B 12 levels may contribute to exacerbation of polyneuropathy in these patients.

Prevalence and factors associated with polyneuropathy in Parkinson’s disease

Reply: Idiopathic hypertrophic pachymeningitis mimicking neurosarcoidosis.

Ocular flutter (OF) is a burst of to-and-fro horizontal saccades without an intersaccadic interval. OF has been considered to be a subtype of opsoclonus-myoclonus syndrome (OMS). In fact, when these saccades are strictly horizontal they are called OF and when any direction they are called opsoclonus. In this case, they can be associated with myoclonus and truncal or limb ataxia forming opsoclonus-myoclonus syndrome. The most common aetiologies are paraneoplastic, postinfectious, multiple sclerosis, toxic-metabolic and idiopathic [1]. This disorder is due to a loss of omnipause neuron inhibition on burst neurons within the paramedian pontine reticular formation. When it occurs, the burst neurons produce an off-time saccadic eye movement [2]. We describe a 39-year-old woman who developed OF in the fifth month of pregnancy. The patient presented with blurred vision for 1 week and the inability to read. The patient did not have oscillopsia or problems with coordination. She did not have a previous infectious disease or report use of any relevant drugs. On examination, the patient showed rapid, low-amplitude, horizontal saccades without an intersaccadic interval (Supplementary video). Saccades occurred in a neutral position and increased with fixation [3]. The remaining neurological and physical examinations were normal. Blood count, routine biochemistry was normal. Serological tests on blood and cerebrospinal fluid were normal as well. Antineural antibodies (anti-RI, antiYo, anti-Hu, anti-Ma2, anti-Ma1, anti-CV2 and anti-Tr) and anti-ganglioside antibodies (GM1, GM2, GM3, GD1a, GD1b, GQ1b, GT1b) were absent. The cerebrospinal fluid was normal except for a slight rise in the IgG-index (0.74; normal range 0.20–0.70). Oligoclonal bands were negative. The symptoms resolved gradually within 10 weeks without treatment. Pregnancy continued without any complications. Brain magnetic resonance imaging was performed after the delivery. It was normal without evidence of demyelination. Despite the fact that opsoclonus and OF are both very rare disorders, OMS has been reported in three pregnant women [4]. This may suggest a likely relationship between these ocular disorders and pregnancy. All cases occurred in the middle to late stages of pregnancy, as with our case. Moreover, OF has been associated with autoimmune disorders, such as multiple sclerosis. Curiously, in demyelinating diseases, it has been well documented that the number of relapses decreased at the end of pregnancy due to low immunological activity. On the other hand, during pregnancy, the maternal immune system reacts to the foreign fetal tissue. Instead of attacking, however, it tolerates and supports fetal growth. However, several factors could alter maternal immunological mechanisms and produce pregnancy disorders; e.g., infertility or miscarriage disorders. For example, in preeclampsia, which occurs after the 20th week of gestation, there may be an excessive inflammatory response against foreign fetal antigens. There could be cross-reactivity with embryogenic targets. In children, the most frequent association with opsoclonus is a paraneoplastic disorder, frequently a neuroblastoma, which is an embryonic neoplasm originating from the neural crest [5]. Therefore, a pregnant woman could react against the cells of her fetus that have similar epitopes to troncoencephalic (OF and myoclonus) and cerebellar (trunk ataxia) cells, causing this oculomotor syndrome. Our case description strengthens the hypothesis that pregnancy influences the development of this rare disorder, Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s1376 0-019-01080 -z) contains supplementary material, which is available to authorized users.

Jose C. Roche

Papers

Increased serum interleukin‐17 levels in patients with myasthenia gravis

Increased glycolipid storage produced by the inheritance of a complex intronic haplotype in the α-galactosidase A ( GLA ) gene

Prevalence and factors associated with polyneuropathy in Parkinson’s disease

Reply: Idiopathic hypertrophic pachymeningitis mimicking neurosarcoidosis.

Can ocular flutter be due to pregnancy