RESUMO
Severe SARS-CoV-2 infection is associated with strong inflammation and autoantibody production against diverse self-antigens, suggesting a system-wide defect in B cell tolerance. BND cells are a B cell subset in healthy individuals harboring autoreactive but anergic B lymphocytes. In vitro evidence suggests inflammatory stimuli can breach peripheral B cell tolerance in this subset. We asked whether SARS-CoV-2-associated inflammation impairs BND cell peripheral tolerance. To address this, PBMCs and plasma were collected from healthy controls, individuals immunized against SARS-CoV-2, or subjects with convalescent or severe SARS-CoV-2 infection. We demonstrate that BND cells from severely infected individuals are significantly activated, display reduced inhibitory receptor expression, and restored BCR signaling, indicative of a breach in anergy during viral infection, supported by increased levels of autoreactive antibodies. The phenotypic and functional BND cell alterations significantly correlate with increased inflammation in severe SARS-CoV-2 infection. Thus, autoreactive BND cells are released from peripheral tolerance with SARS-CoV-2 infection, likely as a consequence of robust systemic inflammation.
Assuntos
COVID-19 , Tolerância Periférica , Anticorpos Antivirais , Linfócitos B , Humanos , Inflamação/metabolismo , SARS-CoV-2RESUMO
Abstract The gut is the main organ that mediates the contact between antigens with our organism, controlling the immune response against environmental factors, such as microbiota and food. Innate lymphoid cells participate in the gut-associated lymphoid tissue (GALT) maturation during the prenatal and early postnatal periods. After birth, breast milk provides the essential elements for the continuity of development of this tissue, leading to structural changes and healthy microbiota installation. The microbiota participates in the organogenesis of the GALT, as in the formation of intestinal villi, stimulating the proliferation of stem cells and maintaining the integrity of epithelial barrier. Foods are also involved in maturation of the GALT, where the protein source depletion reduced the number of resident lymphocytes. This unique microenvironment present in the intestinal lamina propria (LP) and mesenteric lymph nodes (mLN) induce tolerance to innocuous antigens from the diet, known as Oral Tolerance. Antigens sampled by intestinal epithelium cells are transferred to specialized dendritic cells, residing in the LP, which migrate to the mesenteric lymph nodes where they participate in the induction of regulatory T cells (Treg). Understanding these phenomena may establish the intestinal mucosa as a tool in therapy of inflammatory bowel diseases and immunological disorders.
Assuntos
Tolerância Periférica , Microbiota , Sistema Imunitário , Intestinos/fisiologiaRESUMO
Abstract: introduction: regulatory T-cells are the main component of peripheral tolerance and their level is decreased in autoimmunity. In dental amalgam, a mixture of metals is used as a restorative material. During daily a ctivities, these metals are ingested and affect renal, neurosensory and immune systems. Studies have demonstrated an increased risk of autoimmune diseases in patients with dental amalgam fillings. It was hypothesized that the percentage of regulatory T-cells decreases in individuals with amalgam fillings. Therefore this study was designed to determine and compare the percentage of regulatory T-cells in individuals with and without amalgam fillings. Material and Methods: This was a cross-sectional study. Subjects were divided into two groups with each group consisting of 40 individuals. Group I (study group) comprised individuals with amalgam fillings, and Group II (control group), individuals without amalgam fillings in their teeth. Blood samples of all the participants were collected and tagged with CD4 FITC, CD25 PE and CD127 PerCP-Cy monoclonal antibodies for the detection of regulatory T-cells, FACSCalibur was used for this purpose. Results: The percentage of regulatory T-cells in the control group was high (77.77 +/- 5.54 percent) compared to the study group (76.09 +/- 7.68 percent), however, on comparison, the difference was not statistically significant (p=0.25). Conclusion: Dental amalgam fillings did not show a declining effect on the percentage of regulatory T-cells.
Resumen: introducción: las células T reguladoras son el principal componente de la tolerancia periférica y su nivel se reduce en la autoinmunidad. En las obturaciones de amalgama, una mezcla de metales se utiliza como un material de restauración. Durante las actividades diarias, estos metales se ingieren y afectan el sistema renal, neurosensorial e inmunológico. Los estudios han demostrado un aumento del riesgo de enfermedades autoinmunes en pacientes con amalgamas dentales. Se planteó la hipótesis que el porcentaje de células T reguladoras disminuye en individuos con obturaciones de amalgama. Por tanto, este estudio fue diseñado para determinar y comparar el porcentaje de células T reguladoras en individuos con y sin obturaciones de amalgama. Material y Métodos: Se realizó un estudio de corte transversal. Los sujetos fueron divididos en dos grupos, cada uno con 40 individuos. El grupo I (de estudio) estuvo conformado por individuos con obturaciones de amalgama y el grupo II (de control) por individuos sin obturaciones de amalgma. Se colectaron muestras de sangre, las que fueron marcadas con anticuerpos monoclonales CD4 FITC, CD25 PE y CD127 PerCP-C para detectar las células T reguladoras, se utilizó FACSCalibur para este propósito. Resultados: El porcentaje de células T reguladoras en el grupo control fue alta (77,77 +/- 5,54 por ciento) en comparación con el grupo de estudio (76,09 +/- 7,68 por ciento), pero esta diferencia no fue estadísticamente significativa (p=0,25). Conclusión: Las obturaciones de amalgama no se asociaron con una disminución en el porcentaje de células T reguladoras.
Assuntos
Masculino , Feminino , Humanos , Adulto , Autoimunidade , Amálgama Dentário , Tolerância Periférica , Linfócitos T Reguladores , Estudos Transversais , PaquistãoRESUMO
Fibroblastic reticular cells (FRCs) are stromal cells found in secondary lymphoid organ. Despite its structural function in the lymph nodes being well established, recent studies indicate that the FRCs also play a key role in immunological processes, associated with cell transit, immune response, and cells activation quality, and contribute to peripheral tolerance. To this end, we focus this review on lymph nodes FRC characterization and discuss functional aspects such as production of cytokines and chemokines and their involvement in the immune response, seeking to establish whether certain subsets have a more functional specialization.
Assuntos
Células do Tecido Conjuntivo/metabolismo , Fibroblastos/metabolismo , Animais , Movimento Celular , Sobrevivência Celular , Células do Tecido Conjuntivo/citologia , Células do Tecido Conjuntivo/imunologia , Fibroblastos/citologia , Fibroblastos/imunologia , Humanos , Tecido Linfoide/citologia , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Tolerância Periférica/imunologia , Fenótipo , PrimatasRESUMO
OBJECTIVE: To analyze whether the expression and modulation of T cell receptor (TCR) signaling is dependent on Casitas B lineage lymphoma b (Cbl-b) in T cells from patients with systemic lupus erythematosus (SLE) upon stimulation with a tolerogenic substance. METHODS: Peripheral blood mononuclear cells were obtained from 20 patients with SLE (active disease or in remission) and 20 healthy controls. Levels of Cbl-b expression were measured using reverse transcription-polymerase chain reaction and Western blotting in peripheral CD4+ T cells from SLE patients and healthy controls upon anergy induction. Cell proliferation was measured using the carboxyfluorescein diacetate succinimidyl ester dilution method. Cytokine production was analyzed by luminometry, and surface expression of activation markers was assessed by flow cytometry. Transfection assays were performed to induce overexpression of Cbl-b, and phosphorylation of TCR-associated kinases was evaluated. RESULTS: CD4+ T cells from SLE patients displayed resistance to anergy (as evidenced by increased cell proliferation, interleukin-2 production, and expression of activation and costimulatory markers), and this was associated with altered Cbl-b expression. Upon ionomycin treatment, primary T cells showed enhanced MAPK activity and decreased Akt phosphorylation, which was representative of the anergic state. In T cells from lupus patients, Cbl-b overexpression led to increased expression of phosphorylated MAPK, thus indicating the reversibility of anergy resistance. CONCLUSION: These findings suggest that abnormal peripheral tolerance in SLE is caused by a deficiency in Cbl-b, and that this ubiquitin ligase plays a key role in regulating TCR signaling during the induction of peripheral tolerance.