Estudio del compartimento T CD4+ en la fibromialgia y en su asociación con el Síndrome de Sjogren
- Autores: Atusa Movasat Hajkhan
- Directores de la Tesis: Melchor Álvarez de Mon Soto (dir. tes.), Jorge Monserrat Sanz (codir. tes.)
- Lectura: En la Universidad de Alcalá ( España ) en 2024
- Idioma: español
- Tribunal Calificador de la Tesis: Agustín Albillos Martínez (presid.), Ana Isabel Turrión Nieves (secret.), Patricia E. Carreira (voc.)
- Programa de doctorado: Programa de Doctorado en Ciencias de la Salud por la Universidad de Alcalá
- Calificación: Sobresaliente
- Materias:
- Enlaces
- Resumen
- español
Introducción: La fibromialgia (FM) es un síndrome caracterizado por un estado doloroso crónico y generalizado, sin alteraciones orgánicas demostrables y asociado con una gran variedad de síntomas. La etiopatogenia de la FM no está establecida, considerándose multifactorial. Por otro lado, el síndrome de Sjögren (SS) es una enfermedad inmunológica, autoinmune y sistémica caracterizada por la infiltración de linfocitos T a nivel de las glándulas Exocrinas y otras manifestaciones extraglandulares, que condicionan el pronóstico de la enfermedad. La etiopatogenia del SS es multifactorial: hormonales, genéticos e inmunológicos, infecciones virales, etc. El resultado es la estimulación autorreactiva linfocitaria, la producción de autoanticuerpos y la inflamación crónica de las glándulas salivales y lagrimales y de otros tejidos. El SS y la FM comparten muchas características clínicas comunes, como la fatiga y las mialgias, de tal manera que entre el 10 y el 30 % de los pacientes con SS cumplen criterios de FM. Debido a estas características superpuestas comunes, es imposible establecer si la FM ocurre tras la aparición del SS o no. Así mismo, no queda clara la coexistencia de las dos enfermedades conjuntamente, o más bien, si los síntomas de dolor osteomuscular generalizado y la fatiga podrían ser parte de síntomas de SS.
Hipótesis: En este estudio nos planteamos que la FM podría estar relacionada con alteraciones del sistema inmune y que éstas se pueden detectar en sangre periférica. Debido a la implicación de los linfocitos T CD4+ en la regulación y desarrollo de la respuesta inmune, les convierte en una población de potencial relevancia para detectar una disfunción del sistema inmune en procesos considerados sistémicos. En el SS es previsible proponer la existencia de alteraciones linfocitarias y de los niveles de citocinas circulantes. Por su marcada asociación con FM constituye un modelo clínico para investigar la persistencia o variación de las disfunciones inmunitarias de la FM primaria en cuadros secundarios a otras enfermedades.
Objetivos: El objetivo de este estudio es investigar las posibles alteraciones del sistema inmune en el compartimento T CD4+ en pacientes con FM y FM asociada a SS, así como en SS aislado y controles sanos.
Material y métodos: Se realizó un estudio en 20 pacientes con FM, 15 pacientes con FM asociada a SS, 15 pacientes con SS y 15 controles sanos, mediante una muestra de sangre periférica. Los distintos parámetros inmunológicos se analizaron mediante inmunofluorescencia con anticuerpos monoclonales y citometría de flujo policromática cuantitativa.
Resultados: la FM se asocia con un aumento relativo y absoluto de los linfocitos T CD4+, con un aumento de linfocitos TN y TMC, y una concomitante disminución porcentual de los linfocitos T CD8+. El SS cursa con marcada linfopenia T por un evidente descenso de los linfocitos T CD8+. Así mismo, en la FM se observa un incremento de los linfocitos T CD4+ recién diferenciados CD31+ con predominio en los linfocitos TMC con expansión de las células T CD4+ CD127+ en los linfocitos TN y TMC y menor activación crónica con reducción de los linfocitos T CD4+CD28- con especial énfasis en los linfocitos TME y TE. Este patrón de afectación del compartimento linfocitario T CD4+ no se detecta en el SS ni en el asociado a FM. En cuanto a los linfocitos Treg, la FM cursa con una expansión de estos linfocitos, que por el contrario no se detecta en el SS ni en el asociado a FM.
- English
Introduction: Fibromyalgia (FM) is a syndrome characterized by a chronic, generalized painful state, without demonstrable organic alterations and associated with a wide variety of symptoms including persistent asthenia, unrefreshing sleep, generalized stiffness, anxious-depressive symptoms, cognitive dysfunction, headache, digestive and sensory alterations. FM has a prevalence of 2,45 % in the adult population. Regarding the hypothesis of the involvement of the immune system, although FM is not considered a disease of inflammatory origin, there are many studies that suggest the existence of alterations of the immune system, and specifically, its involvement in the generation of an imbalance between proinflammatory and anti-inflammatory cytokines that could be related to the pathogenesis of the disease. On the other hand, Sjögren's syndrome (SS) is a chronic systemic, autoimmune, immunologic disease characterized by T lymphocyte infiltration at the level of the exocrine glands, with an adult prevalence of 0.1 - 0.6 %. In addition, one third of patients may present different extraglandular manifestations, more active and severe than the glandular ones, which condition the prognosis of the disease. The etiopathogenesis of SS is multifactorial due to the interaction of various factors such as hormonal, genetic and immunological, which condition a certain individual susceptibility, together with external factors, possibly viral infections. The result is autoreactive lymphocyte stimulation, production of autoantibodies and chronic inflammation of the salivary and lacrimal glands and often other tissues. SS and FM share many common clinical features such as fatigue and myalgias, among other clinical manifestations, such that 10 - 30 % of patients with SS meet criteria for FM. Because of these common overlapping features, in many cases, it is often impossible to establish whether FM is after the onset of SS or not. Likewise, it is unclear whether the two diseases coexist together, or rather, whether the symptoms of widespread musculoskeletal pain and fatigue could be part of a spectrum.
Hypothesis: In this study we posit that FM could be related to alterations of the immune system and that these can be detected in peripheral blood. Due to the involvement of CD4+ T lymphocytes in the regulation and development of the immune response, they are a potentially relevant population to detect immune system dysfunction in processes considered systemic. In secondary forms it is feasible to consider that these possible dysfunctions are modified or persist in an overt manner. In SS it is foreseeable to propose the existence of lymphocyte alterations and circulating cytokine levels. Because of its marked association with FM, it constitutes an ideal clinical model to investigate the persistence or variation of the immune dysfunctions of primary FM in cases secondary to other diseases.
Objectives: The main objective of this study is to investigate possible alterations of the immune system in the CD4+ T lymphocyte T compartment in patients with FM and FM associated with SS, as well as in isolated SS and healthy controls.
Material and methods: A cross-sectional study was performed in 65 women: 20 patients with FM, 15 patients with FM associated with SS, 15 patients with SS and 15 healthy controls. Sociodemographic characteristics, clinical manifestations of the disease and a general blood test were collected from each participant included in the study. At the same time, the participants completed different questionnaires on the symptoms of the disease and its characteristics in order to obtain a complete description of the patients. The questionnaires on specific aspects of FM or SS were completed only by the patients diagnosed with these pathologies, while those on general and non-specific aspects of the disease were completed by both the patients and the control group. The different immunological parameters were studied by immunofluorescence with monoclonal antibodies and quantitative polychromatic flow cytometry. The Luminex technique was used to study the concentration of circulating cytokines, with a highly sensitive kit (Milliplex MAP kit, from the Merck laboratory). The statistical analysis of the variables studied was performed with SPSS 19 software. The study of normality was performed using the Kolmogorov-Smirnov test, obtaining the result of non-normality for most of the variables, so the non-parametric MannWhitney U test was used to compare the different study groups and the level of statistical significance was set at 0.05.
Results: The study of clinical questionnaires performed on patients shows that FM alone or associated with SS, is associated with higher scores of depression, anxiety, insomnia and fatigue, and worse quality of sleep and quality of life. Regarding immunological parameters, FM is associated with a relative and absolute increase in CD4+ T lymphocytes, with an increase in TN and TMC lymphocytes, and a concomitant percentage decrease in CD8+. SS presents with marked T lymphopenia due to a marked decrease in CD8+ T lymphocytes. Likewise, in FM there is an increase in newly differentiated CD31+CD4+ T lymphocytes with predominance in TMC lymphocytes with expansion of CD4+ CD127+ T cells in TN and TMC lymphocytes and less chronic activation with reduction of CD4+ CD28- T lymphocytes with special emphasis on TME and TE lymphocytes. This pattern of involvement of the CD4+ T lymphocyte compartment is not detected in SS or in FM associated with SS. As for Treg lymphocytes, FM presents with an expansion of these lymphocytes, which, on the contrary, is not detected in SS or in FM associated with SS. Regarding the pattern of cytokine production by CD4+ T lymphocytes, increased intracellular expression of IFN-γ and IL-17A is observed in patients with FM, which are decreased and normal, respectively, in patients with SS and FM associated with SS. Simultaneously, elevated TNF-α, IL4 and IL-9 production is detected in FM and also in SS associated or not with FM. Finally, FM presents with normal circulating levels of IL-4, IL-7, INF-γ and TNF-α and decreased levels of INF-γ, IL-17A and IL-10. In SS and FM associated with this disease, no alterations in serum concentrations of these cytokines are detected.
Conclusions: FM is associated with a marked involvement of the CD4+ T lymphocyte population with a significant redistribution of its main subpopulations, activation status and its capacity to secrete proinflammatory and anti-inflammatory cytokines. However, the alterations found in patients with FM are different from those found in the presence of a disease of immunologic pathogenesis such as SS, suggesting that in patients with the joint presence of FM with SS, the immunologic pattern we found is due to SS and not to FM.
- español
