Anastasiya G. Trenova

Clinical and laboratory study of pro-inflammatory and anti-inflammatory cytokines in women with multiple sclerosis

Abstract Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system characterised with a complex system of interactions between proinflammatory and anti-inflammatory cytokines in its course. Aim: The aim of the present study was to investigate the serum levels of cytokines TNF-α, IFN- γ, IL- 4 and IL- 10 in female patients with MS and healthy individuals, the changes occurring in the relapse and remission phases of the disease and their correlation with the severity of the neurological deficit. Patients and methods: Thirty-five women with relapsing-remitting MS were examined. The patients’ age ranged between 18 and 50 years and MS was verified clinically and by magnetic resonance imaging according to the McDonald criteria. Thirteen of the patients were treated with interferon-β-1b. The serum concentrations of TNF-α, IFN- γ, IL- 4 and IL- 10 were determined twice - in relapse and in remission - using an enzyme-linked immunosorbent assay (EL ISA). The control group consisted of 35 age-matched healthy females. Results: The comparison of cytokine serum concentrations during the two phases of the disease showed significant elevation of the TNF-α serum levels in the relapse phase and of IL- 4 - in the remission phase. The comparison between the patients and the healthy control subjects demonstrated statistically significant lower concentrations of TNF-α in remission patients and higher concentrations of IL- 10 in relapse patients. The patients with interferon-β-1b treatment showed different profile of cytokine secretion from the patients without interferon-β-1b treatment. Interferon-β-1b-treated patients showed significantly lower serum levels of TNF-α and IFN- γ during the relapse phase and higher TNF-α and IL- 10 serum levels during the remission phase compared with the untreated patients. Conclusions: Serum levels of TNF-α and IL- 4 objectively reflect the immune response during relapse and remission of the disease. The severity of neurological deficit as estimated with the expanded disability status scale (EDSS ) does not depend on the serum levels of TNF-α, IL- 10 and IFN- γ in the two phases of MS. Резюме Введение: Множественный склероз (МС) представ- ляет собой аутоиммунное, демиелинизирующее за- болевание центральной нервной системы в ходе которого развивается сложная сеть взаимодействий между проинфляматорными и антиинфляматорными цитокинами. Цель: Исследовать сывороточные уровни TNF-α, IFN-γ, IL-4 и IL-10 у женщин с МС и у здоровых лиц, а также и изменения, наступающие во время приступа и во время ремиссии заболевания и их связь с тяжестью неврологического дефицита. Материал и методы: Обследовано 35 женщин в возрасте от 18 до 50 лет с приступно-ремитент- ным, клиническим и резонансно подтвержденным МС по критериям Мс Donald. 13 женщин лечены интерфероном β-1b. Сывороточные концентрации TNF-α, IFN-γ, IL-4 и IL-10 определены двукратно - во время приступа и во время ремиссии с помощью энзимосвязанного иммуносорбентного теста (ELISA). Контрольная группа включает 35 здоровых женщин того же возрастного интервала. Результаты: При сравнении сывороточных концен- траций цитокинов во время обеих фаз заболевания устанавливаются сигнификантно более высокие уровни TNF-α во время приступа и IL-4 - во время ремиссии. При сопоставлении результатов пациенток и здоровых женщин регистрированы статистически значимо более ниская концентрация TNF-α у больных во время ремиссии и более высокая концентрация IL-10 во время приступа. У пациенток с и без интерферона β-1b наблюдается различный профиль секреции цитокинов. Пациентки, леченные препара- том интерферон β-1b, имеют сигнификантно более ниские TNF-α и IFN-γ во время приступа и более высокие TNF-α и IL-10 в состоянии ремиссии по сравнению с нелеченными. Выводы: Сывороточные уровни TNF-α и IL-4 объ- ективно отражают активность иммунной реакции во время двух периодов клинических проявлений МС (приступ и ремиссия). Тяжесть неврологического дефицита, оцененная с помощью EDSS, не зависит от сывороточных уровней TNF-α, IL-10 и IFN-γ во время двух периодов клинических проявлений.

Female sex hormones and cytokine secretion in women with multiple sclerosis

Abstract Data from experimental and clinical research suggest that sex hormones may influence the autoimmune process in multiple sclerosis (MS). Studies on the hormonal profile of patients with MS and its relation to the disease activity provide heterogeneous results. Objectives: The aim of this study is to investigate the changes in serum levels of estradiol and progesterone and their correlations with the cytokine profile and the degree of disability in women with relapsing-remitting MS (RRMS). Methods: The serum concentrations of estradiol, progesterone, tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukine-4 (IL-4) and interleukine-10 (IL-10) were measured and the degree of disability was determined in 35 women with RRMS, during relapse and remission. Serum levels of hormones were measured by micro-particle enzyme immunoassay and ELISA was used for the cytokines concentrations. The degree of disability was assessed by the Expanded Disability Status Scale and the Scripps Neurological Rating Scale. Results: Sixty per cent of patients had serum concentrations of estradiol and/or progesterone below the lower limit of normal in one or both phases of MS. Hormonal levels increased significantly during remission in these patients. Women with and without hormonal abnormalities differed in terms of cytokine profile during relapse and remission. Significantly higher TNF-alpha in both phases and IFN-gamma in remission was found for the patients with hormonal disturbances compared to these with normal hormonal status. Conclusions: Our study finds high frequency of hormonal disturbances among female patients with RRMS. Abnormally low concentrations of sex hormones are associated with higher serum levels of TNF-alpha and IFN-gamma, which could suggest suppressive effect of estradiol and progesterone on pro-inflammatory cytokine secretion.

Alterations in serum levels of IL-17 in contrast to TNF-alpha correspond to disease-modifying treatment in relapsing-remitting multiple sclerosis

Abstract Cytokines of different types play an important role in multiple sclerosis (MS) pathogenesis as mediators and regulators of the immune processes in the central nervous system. The aim of the study was to determine the effect of interferon-beta and glatiramer acetate on serum concentrations of TNF-alpha and IL-17 A and their correlation with the degree of disability in clinically stable patients with relapsing-remitting MS. A cross-sectional, case-control study of 220 patients (68 treatment naïve; 152 treated with interferon-beta or glatiramer acetate) and 99 clinically healthy age-gender-body mass index-matched subjects were performed. Serum cytokine concentrations were measured during remission of the disease by means of ELISA. Treatment naïve patients showed significantly higher levels of IL-17 A than the treated individuals (p = .000109) and controls (p = .000044). Within the treated group, only patients with interferon-beta had significantly higher serum IL-17 than the controls (p = .023). TNF-alpha concentrations were significantly higher in the treated patients compared to the healthy controls (p = .000013), regardless of the type of the therapy. Treatment naïve individuals did not differ from the controls according to their serum TNF-alpha (p = .922). No correlation was found between the serum cytokine concentrations and Expanded Disability Status Scale (EDSS) score (p > .05). Serum concentrations of these cytokines could not be regarded as reliable predictors for the severity of the residual neurological deficit during disease-modifying treatment. Our data suggest that suppression of IL-17 A production as one of the mechanisms underlying the beneficial effect of first-line disease-modifying treatments is stronger in glatiramer acetate than in interferon-beta.

Cognitive Impairment in Multiple Sclerosis

Abstract Multiple sclerosis (MS) is a socially significant immune-mediated disease, characterized by demyelination, axonal transection and oligodendropathy in the central nervous system. Inflammatory demyelination and neurodegeneration lead to brain atrophy and cognitive deficit in up to 75% of the patients. Cognitive dysfunctions impact significantly patients’ quality of life, independently from the course and phase of the disease. The relationship between pathological brain findings and cognitive impairment is a subject of intensive research. Summarizing recent data about prevalence, clinical specificity and treatment of cognitive disorders in MS, this review aims to motivate the necessity of early diagnosis and complex therapeutic approach to these disturbances in order to reduce the social burden of the disease.

Vitamin D immunomodulatory potential in multiple sclerosis.

ABSTRACT Multiple sclerosis (MS) is an autoimmune disease of unknown etiology whose treatment is of limited efficiency and therefore has a high social burden. As it has been suggested that myelin destruction model, the clinical manifestation and the potential of therapeutic response in MS are correlated, it is quite justifiable that we study various factors (genetic, hormonal, environmental) that take part in the autoimmune process in order to improve the control over the disrupted immune regulation. Results from epidemiological and clinical studies clearly suggest that changes in vitamin D serum concentrations are correlated with the magnitude of the risk of developing MS, the phases of relapse and remittance and with gender differences in vitamin D metabolism. Experimental and clinical studies also have established that 25-hydroxy vitamin D (25(OH)D) and 1,25-dihydroxy vitamin D (1,25(OH)2D) exert an immunomodulatory effect in the central nervous system and peripheral organs of the immune system. The standard reference range of vitamin D concentration in serum is 50-80 nmol/l - it provides normal calcium metabolism. Issues that are discussed include the vitamin D serum concentration needed to suppress the aberrant immune response in MS patients; a subgroup of MS patients suitable for vitamin D treatment, the vitamin D being applied in optimally effective and safe dosage. MS prevalence rate in Bulgaria has increased two-fold in 17 years but this is a rather short interval to be able to assume that the gene pool of the population changes. Thus further studies on possible interactions between different environmental factors and these factors’ role in the disease pathogenesis are justified and necessary. РЕЗЮМЕ Множественный склероз - МС - представляет собой значимое иммунообуславленное заболевание неизвест- ной этиологии, лечение которого с ограниченной эффективностью. Концепция зависимости между моделью деструкции миелина, клиническими прояв- лениями и потенциалом терапевтического ответа является основанием изучить участие различных факторов в аутоиммунном процессе - генетических, гормональных, факторов окружающей среды - с целью улучшения контроля над расстроенной им- мунной регуляцией. Результаты эпидемиологических и клинических наблюдений показывают связь изме- нений сывороточных концентраций витамина Д со степенью риска развития МС, с фазами приступа и ремиссии, с половыми различиями в метаболизме витамина Д. Иммуномодулирующая активность 25- hydroxy vitamin D (25(OH)D) и 1,25-dihydroxy vitamin D (1,25(OH)2D) в центральной нервной системе и в периферических органах иммунной системы устанавливается при экспериментальных и клинических наблюдениях. Принятый стандарт референтных границ витамина Д в сыворотке 50-80 nmol/l обеспечивает нормальный кальциевый метаболизм. Дискуссионными остаются вопросы о: сывороточной концентрации витамина Д, необходи- мой для подавления аберантного иммунного ответа у пациентов с МС; субгруппе МС пациентов, под- ходящих для лечения витамином Д, примененным в оптимально эффективной и безопасной дозе. В нашей стране заболеваемость МС повыси- лась двукратно за последние 17 лет - короткий интервал, чтобы обсуждать вопрос: возможны ли изменения в генном фоне населения. С такой точки зрения исследования взаимодействия между факто- рами окружающей среды и их роли в патогенезе болезни обоснованы и необходимы.

Circulating levels of interleukin-17A, tumor necrosis factor-alpha, interleukin-18, interleukin-10, and cognitive performance of patients with relapsing-remitting multiple sclerosis

Abstract Multiple sclerosis (MS) is associated with cytokine imbalance and high rate (40–70%) of cognitive impairment. The objective of this study is to investigate the relationship between serum concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-17A, IL-18, IL-10, and cognitive performance in patients with relapsing-remitting MS (RRMS). Methods The study comprised 159 patients with RRMS (mean age 40.08 ± 8.48 years) in remission phase and 86 age-, gender-, and education-matched healthy controls. Paced Auditory Serial Addition Test (PASAT), Symbol Digit Modalities test (SDMT), and Isaacs test were used for assessment of working memory, attention, visuo-perceptual abilities, information processing speed, and executive functions. Serum cytokine concentrations were measured by enzyme-linked immunosorbent assay (ELISA). Results Patients had significantly increased serum concentrations of TNF-alpha and IL-17A and decreased levels of IL-10 compared to the controls (p < 0.05). Negative correlation was found between serum TNF-alpha and SDMT score in patients with disease evolution longer than 10 years (rxy = −0.258 p = 0.033); PASAT and SDMT scores were in negative correlation with concentration of IL-17A (rxy = −0.229 p = 0.004; rxy = −0.166 p = 0.041). Cognitive impairment was established in 46.5% (n = 74) of the patients. Cognitively impaired patients had significantly higher serum IL-17A than cognitively preserved individuals (p = 0.007). Multiple linear regression analysis revealed IL-17A as a significant predictor of cognitive performance in RRMS patients. Conclusion The results from this study suggest that pro-inflammatory cytokines IL-17A and TNF-alpha simultaneously with decreased IL-10 are involved in cognitive deterioration in RRMS.

A Role of Cytokine Gene Polymorphisms in Cognitive Functioning

Abstract The changes in cognitive functions that occur with aging and in various pathological conditions are a subject of growing interest. Experimental and clinical data justify the hypothesis about the influence the immune system exerts on cognitive processes. The balance between pro-inflammatory and anti-inflammatory cytokines has been established as a necessary factor for normal cognitive functioning. Cytokine production is under strong genetic control and various single nucleotide polymorphisms (SNPs) in cytokine genes have been described. As cytokine SNPs have been demonstrated to affect the gene expression or the functional activity of the immune protein this logically led to the suggestion about the role of these polymorphisms in cognitive functioning. Studies exploring the association between different genetic variants of cytokine gene polymorphisms and cognitive abilities in healthy subjects and in demented patients show divergent results. The review of relevant literature suggests that SNPs implement their effect on cognition in large interactions with each other, as well as with many other factors, some of which still remain to be identified. This article summarizes the contemporary knowledge about the correlations between SNPs in cytokine genes and cognitive status in humans. Further research is needed to determine the precise role and the molecular mechanisms of action of the SNPs in cognitive processes.

Vitamin D and environmental factors in multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disease of unknown etiology whose treatment is of limited efficiency and therefore has a high social burden. As it has been suggested that myelin destruction model, the clinical manifestation and the potential of therapeutic response in MS are correlated, it is quite justifiable that we study various factors (genetic, hormonal, environmental) that take part in the autoimmune process in order to improve the control over the disrupted immune regulation. Results from epidemiological and clini¬cal studies clearly suggest that changes in vitamin D serum concentrations are correlated with the magnitude of the risk of developing MS, the phases of relapse and remittance and with gender differences in vitamin D metabolism. Experimental and clinical studies also have established that 25-hydroxy vitamin D (25(OH)D) and 1,25-dihydroxy vitamin D (1,25(OH)2D) exert an immunomodulatory effect in the central nervous system and peripheral organs of the immune system. The standard reference range of vitamin D con¬centration in serum is 50-80 nmol/l it provides normal calcium metabolism. Issues that are discussed include the vitamin D serum concentration needed to suppress the aberrant immune response in MS patients; a subgroup of MS patients suitable for vitamin D treat¬ment, the vitamin D being applied in optimally effective and safe dosage. MS prevalence rate in Bulgaria has increased two-fold in 17 years but this is a rather short interval to be able to assume that the gene pool of the population changes. Thus further studies on pos¬sible interactions between different environmental factors and these factors’ role in the disease pathogenesis are justified and necessary.