Estudio del compartimento T CD4+ en la fibromialgia y en su asociación con el Síndrome de Sjogren

Resum

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.