Pro-inflammatory autoantigen-specific CD4+ T helper (auto-Th) cells are central orchestrators of autoimmune diseases (AIDs). We aimed to characterize these cells in human AIDs with defined autoantigens by combining human leukocyte antigen (HLA)-tetramer-based and activation-based multidimensional ex vivo analyses. In aquaporin4-antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) patients, auto-Th cells expressed CD154, but proliferative capacity and pro-inflammatory cytokines were strongly reduced. Instead, exhaustion-associated co-inhibitory receptors were expressed together with FOXP3, the canonical regulatory T cell (Treg) transcription factor. Auto-Th cells responded in vitro to checkpoint inhibition and provided potent B cell help. Cells with the same exhaustion-like (ThEx) phenotype were identified in soluble liver antigen (SLA)-antibody-autoimmune hepatitis and BP180-antibody-positive bullous pemphigoid, AIDs of the liver and skin, respectively. While originally described in cancer and chronic infection, our data point to T cell exhaustion as a common mechanism of adaptation to chronic (self-)stimulation across AID types and link exhausted CD4+ T cells to humoral autoimmune responses, with implications for therapeutic targeting.

BACKGROUND: Neuromyelitis Optica Spectrum Disorders (NMOSD) is a neuroinflammatory condition characterized by optic neuritis and transverse myelitis. While the current approach to NMOSD focuses on relapse-associated worsening (RAW), recent evidence indicates Relapse-Independent Disease Activity (RIDA) in patients.
METHODS: Databases including Embase, PubMed, Scopus, and Web of Sciences were systematically searched up to December 2023. No restrictions were applied. Inclusion criteria focused on studies reporting evidence of RIDA in NMOSD patients. Data extraction involved details such as study title, author, participant characteristics, treatment, evaluation methods, positive findings according to RIDA, and prevalence of findings in NMOSD patients. This study is conducted following the PRISMA guidelines with a registered protocol on PROSPERO (ID = CRD42023492352).
RESULTS: Of 802 studies, 38 were included in the systematic review, covering 1881 NMOSD patients. AQP4-IGg status was positive in 90.6 % of the patients. Ocular findings indicative of RIDA were reported in 23 studies, including thinning of GCIPL, RNFL, GCC, and GCL layers, foveal and macular shape and volume abnormalities, vessel loss, and visual evoked potentials (VEPs) abnormalities. MRI findings supporting the RIDA were reported in 13 studies, including new lesion incidence and brain and spinal cord atrophy. Serum and CSF RIDA-supporting findings were reported in five studies, including elevation in sGFAP and sNFL. Biopsies and autopsies suggested inflammatory processes in relapse-free patients in 2 studies. The predominant manifestation of RIDA in NMOSD was identified in the visual system, suggesting the impaired retinal glial cells like Müller cells during the relapse-free period in NMOSD.
CONCLUSIONS: Our systematic review provides valuable insights into RIDA in NMOSD. Establishing guidelines for the diagnosis and treatment of RIDA is crucial. Further studies are needed to provide robust evidence on RIDA in NMOSD patients.

暂无摘要。

This study aimed to identify the prevalence, clinical and radiographic characteristics, and risk factors for cognitive dysfunction in patients with Neuromyelitis optica spectrum disorder (NMOSD). Eighty-three participants who were diagnosed with NMOSD were recruited. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) and Frontal Assessment Battery (FAB). The mean age of the patients was 47.78 ± 13.14 years, with an average of 12.05 ± 4.62 years of formal education. The majority (54%) exhibited cognitive impairment, defined by a MoCA score < 25 (mean: 22.96 ± 3.82). Disease severity (evaluated by the Expanded Disability Status Scale) and lower formal education levels were associated with cognitive impairment (p = 0.011 and < 0.001, respectively). The annualized relapse rate, disease duration, and AQP4 antibody status were not associated with cognitive impairment. Interestingly, informant-reported cognitive decline was associated with poorer cognitive performance (p = 0.027). Radiographic findings of lesion location and severity were associated with MoCA-assessed cognitive performance, particularly for lesions in the right parietal lobes (p = 0.023). Hippocampal atrophy was negatively correlated with FAB scores. In conclusion, approximately half of the Thai patients with NMOSD exhibited cognitive impairment, which was associated with age, formal education level, disease severity, relative perception, and specific radiological findings. Further studies incorporating comprehensive neuropsychological tests and subjective cognitive complaints are warranted.

Neuromyelitis optic spectrum diseases (NMOSD) are a group of rare neuroimmunological diseases involving mainly the optic nerves and spinal cord, to a lesser extent the brain, and causing severe exacerbations that lead to persistent disability of patients. For many years, opticoneuromyelitis was considered a prognostically unfavorable variant of the course of multiple sclerosis (MS), however, in 2004, specific autoantibodies to aquaporin-4 were found in such patients, which made it possible to isolate NMOSD into a separate group of demyelinating diseases other than MS. Due to similar clinical signs and the predominantly remitting course of diseases, it is often difficult to make a correct diagnosis and, accordingly, prescribe effective therapy, which often leads to incorrectly selected therapy with incorrect diagnosis. In some cases, this leads to a worsening of the course of NMOSD. We present a case of late diagnosis of NMOSD that confirms the development of exacerbation in the patient 2 months after the first course of therapy with alemtuzumab prescribed as a highly effective therapy for highly active remitting MS. Timely diagnosis of NMOSD makes it possible to exclude such cases.
Заболевания спектра оптиконейромиелита (ЗСОНМ) представляют собой группу редких нейроиммунных заболеваний, вовлекающих преимущественно зрительные нервы и спинной мозг, в меньшей степени — головной мозг, и вызывающие тяжелые обострения, которые приводят к стойкой инвалидизации больных. В течение многих лет оптиконейромиелит считался прогностически неблагоприятным вариантом течения рассеянного склероза (РС), однако в 2004 г. у таких пациентов были обнаружены специфические аутоантитела к аквапорину-4, что позволило выделить ЗСОНМ в отдельную группу демиелинизирующих заболеваний, отличную от РС. Из-за аналогичных клинических признаков и преимущественно ремиттирующего течения заболеваний часто бывает трудно поставить правильный диагноз и, соответственно, назначить эффективную терапию, что нередко приводит к неправильно подобранной терапии при неверной постановке диагноза. В некоторых случаях это является причиной ухудшения течения ЗСОНМ. Описанный нами клинический случай поздней диагностики ЗСОНМ подтверждает развитие обострения у пациентки спустя 2 мес после проведенного первого курса терапии алемтузумабом, назначенного в качестве высокоэффективной терапии высокоактивного ремиттирующего РС. Своевременная диагностика ЗСОНМ позволяет исключить подобные случаи.

Posterior reversible encephalopathy syndrome (PRES) is characterized by nonspecific symptoms, including not only pronounced non-focal and various focal neurological signs but also specific neuroimaging features, including vasogenic edema affecting predominantly the posterior area. PRES usually develops in the setting of acute arterial hypertension. However, it is not uncommon for PRES to develop in non-hypertensive patients, including people with autoimmune disorders (multiple sclerosis, neuromyelitis optica spectrum disorder, etc). PRES could also be due to the toxic effects of drugs or other substances. The pathophysiological mechanisms of PRES include impaired autoregulation of cerebral blood flow due to acute arterial hypertension and toxic endotheliotropic effects of endogenous and exogenous factors.
Синдром задней обратимой энцефалопатии (PRES) характеризуется неспецифической симптоматикой в виде выраженных общемозговых и разнообразных очаговых неврологических симптомов, сопровождается характерными нейровизуализационными изменениями (вазогенный отек, поражающий преимущественно теменно-затылочную область). PRES как правило развивается на фоне острой артериальной гипертензии, однако нередки случаи его развития у пациентов с нормальным артериальным давлением, в том числе и при аутоиммунных расстройствах, включая рассеянный склероз, заболевания спектра оптиконейромиелита, а также вследствие токсического воздействия ряда лекарственных препаратов или иных веществ. Патофизиологические механизмы PRES включают нарушение ауторегуляции мозгового кровотока на фоне острой артериальной гипертензии и токсическое эндотелиотропное воздействие эндогенных и экзогенных факторов.

Rare demyelinating diseases are a group of diseases whose pathogenesis is based on the process of demyelination. This group of diseases includes acute multiple encephalomyelitis (ADEM), opticoneuromyelitis spectrum diseases (NMOSD) and anti-myelin-oligodendrocyte glycoprotein-associated diseases (MOG-antibodies-associated diseases - MOGAD). Recently, new biological drugs for pathogenetic therapy have been developed, which have shown their effectiveness and good tolerability in comparison with therapy with first- and second-line drugs. Aim of the study - analysis of modern possibilities of pathogenetic treatment of patients with ADEM, seronegative and seropositive patients with NMOSD. The analysis was carried out on the basis of English-language publications in PubMed published over the past five years. This review summarizes current ideas about the possibilities of pathogenetic treatment of rare diseases. The advantages of using ravulizumab over other representatives of a new biological therapy associated with the use of monoclonal antibodies are shown. The analyzed data allow us to conclude that there is a significant development of pathogenetic treatment options for ZSONM. However, the effectiveness of new therapeutic biological drugs is still limited due to the lack of a large amount of clinical data to confirm, which creates the need to continue analyzing the experience of their use.
Редкие демиелинизирующие заболевания представляют группу заболеваний, в основе патогенеза которых лежит процесс демиелинизации. К данной группе заболеваний относят острый рассеянный энцефаломиелит (ОРЭМ), заболевания спектра оптиконейромиелита (ЗСОНМ) и анти-миелин-олигодендроцитарный гликопротеин-ассоциированные заболевания (МОГАТАЗ). Разрабатываются новые биологические средства патогенетической терапии, которые показали более высокую эффективность и хорошую переносимость по сравнению с препаратами первой и второй линий. В статье представлен анализ современных возможностей патогенетического лечения пациентов с ОРЭМ, серонегативных и серопозитивных пациентов с ЗСОНМ. Проведен анализ англоязычных публикаций из базы PubMed, опубликованных за последние 5 лет. Суммированы современные представления о возможностях патогенетического лечения редких заболеваний. Показаны преимущества использования равулизумаба перед другими представителями новой биологической терапии, связанной с использованием моноклональных антител. Результаты анализа данных литературы позволяют сделать вывод о значительном развитии патогенетических вариантов лечения ЗСОНМ, однако данные об эффективности новых биологических препаратов по-прежнему ограничены из-за отсутствия достаточного количества клинических исследований для ее подтверждения, что диктует необходимость продолжить анализ опыта их использования.

OBJECTIVE: To compare the diagnostic criteria of 2006 (DC 2006) and 2015 (DC 2015) in the Russian population of patients with suspected neuromyelitis optica spectrum disorders (NMOSD), with the calculation of their sensitivity, specificity, accuracy and predictive value.
METHODS: We reviewed medical records of suspected NMOSD patients who were therefore examined for the presence of serum autoantibodies targeting the aquaporin-4 water channel protein (AQP4-IgG) in 6 specialized Russian (Nizhny Novgorod and Moscow) medical centers. One hundred patients (78 female), aged 17 to 74 years (mean 38.1±13.3 years), were included. The follow-up period ranged from 4 to 108 months (mean 59.7±31.6 months).
RESULTS: During the follow-up the diagnosis of NMOSD was confirmed in 32 people, and 68 patients had diagnoses different from NMOSD. At the disease onset, 68.8% of patients were seropositive for AQP4-IgG. The mean time for confirming NMOSD diagnosis was 15.2±14.2 months. At the disease onset, 36% of patients fulfilled the DC 2015, the diagnosis was subsequently confirmed in 77.8% out of them. 26% of the patients fulfilled the DC 2006, the diagnosis was subsequently confirmed in 84.6% out of them. The sensitivity of DC 2006/DC 2015 was 69%/88%, specificity 94%/88%, accuracy 86%/88%, negative predictive value 85%/94%, positive predictive value 86%/78%.
CONCLUSIONS: The specificity, sensitivity and accuracy of modern diagnostic criteria for NMOSD In Russian patients is comparable to those obtained in foreign studies. DC 2015 helps to diagnose NMOSD earlier than DC 2006, but they have a lower specificity.
UNASSIGNED: Сравнительный анализ диагностических критериев 2006 г. (ДК 2006) и 2015 г. (ДК 2015) в российской популяции пациентов с подозрением на заболевание спектра оптиконейромиелита (ЗСОНМ) с расчетом их чувствительности, специфичности, точности и прогностической ценности.
UNASSIGNED: На базе шести центров специализированной медицинской помощи пациентам с воспалительными и демиелинизирующими заболеваниями ЦНС (Нижний Новгород и Москва) методом сплошной выборки проведен ретроспективный анализ медицинской документации пациентов, при первичном обращении у которых предполагалось наличие ЗСОНМ, и которые в связи с этим были обследованы на наличие в сыворотке крови аутоантител к белку водопроводящих каналов клеточных мембран аквапорину-4 (AQP4-IgG). Включено 100 пациентов (78 женщин) в возрасте от 17 до 74 лет (38,1±13,3 года). Срок наблюдения составил от 4 до 108 мес (59,7±31,6 мес).
UNASSIGNED: В процессе наблюдения диагноз ЗСОНМ был подтвержден у 32 пациентов; у 68 были диагностированы отличные от ЗСОНМ заболевания. В дебюте заболевания 68,8% пациентов были серопозитивными по AQP4-IgG. Среднее время, потребовавшееся для установления диагноза ЗСОНМ, составило 15,2±14,2 мес. В дебюте заболевания 36% пациентов удовлетворяли ДК 2015, в последующем диагноз был подтвержден у 77,8%. 26% пациентов удовлетворяли ДК 2006, диагноз в последующем был подтвержден у 84,6%. Чувствительность ДК 2006/ДК 2015 составила 69/88%, специфичность — 94/88%, точность — 86/88%, прогностичность отрицательного результата 85/94%, прогностичность положительного результата — 86/78%.
UNASSIGNED: Специфичность, чувствительность и точность современных диагностических критериев ЗСОНМ у российских пациентов сопоставима с показателями, полученным в зарубежных исследованиях. ДК 2015 в сравнении с ДК 2006 помогают раньше диагностировать ЗСОНМ, однако обладают меньшей специфичностью.

The autoimmune channelopathies represent a rapidly evolving scientific and clinical domain. The description of channels, expressed on neurons and glia, as targets of autoantibodies in neuromyelitis optica, autoimmune encephalitis, and related syndromes have revolutionized many areas of neurologic practice. To date, tens of surface antibody specificities have been described, a number that is likely to continue to increase. A central paradigm for all these disorders is that of pathogenic autoantibodies which target extracellular epitopes accessible for binding in vivo. Hence, in these disorders, the autoantibodies are causative diagnostic tools, and provide valuable reagents to model the diseases. Their production by B-lineage cells provides opportunities to study and modulate their production. Across these syndromes, early recognition and treatment are critical since most respond to immunotherapies. Yet, several unmet medical needs persist within treated patient populations, and widespread clinical under-recognition remains a challenge. In this review, we summarize the neuroscience and immunologic basis of autoantibody-mediated central nervous system channelopathies, the molecular effects of the autoantibodies, clinical phenotypes, and treatment approaches. We describe progress since the inauguration of the field through to open questions and potential future directions.

Aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) is an autoimmune disease characterized by suboptimal recovery from attacks and long-term disability. Experimental data suggest that AQP4 antibodies can disrupt neuroplasticity, a fundamental driver of brain recovery. A well-established method to assess brain LTP is through intermittent theta-burst stimulation (iTBS). This study aimed to explore neuroplasticity in AQP4-NMOSD patients by examining long-term potentiation (LTP) through iTBS. We conducted a proof-of-principle study including 8 patients with AQP4-NMOSD, 8 patients with multiple sclerosis (MS), and 8 healthy controls (HC) in which iTBS was administered to induce LTP-like effects. iTBS-induced LTP exhibited significant differences among the 3 groups (p: 0.006). Notably, AQP4-NMOSD patients demonstrated impaired plasticity compared to both HC (p = 0.01) and pwMS (p = 0.02). This pilot study provides the first in vivo evidence supporting impaired neuroplasticity in AQP4-NMOSD patients. Impaired cortical plasticity may hinder recovery following attacks suggesting a need for targeted rehabilitation strategies.