Dualities of the vitamin D in systemic sclerosis: a systematic literature review.

BACKGROUND: Systemic sclerosis (SSc) is a chronic disease characterized by autoimmunity, vasculopathy, and visceral and cutaneous fibrosis. Vitamin D has several functions in the immunological system, and different studies have suggested a potential role in triggering autoimmune diseases. Patients with SSc may present with low serum levels of vitamin D, but the association between hypovitaminosis D and disease onset or any clinical manifestation is still obscure. Our goal was to verify the causal relationship between hypovitaminosis D and SSc onset or any particular clinical manifestation in the literature. METHODS: A systematic literature review was performed through February 24th, 2021 on Pubmed, Lilacs/BIREME, and Cochrane databases. The eligible studies were read in full text, and, in the absence of exclusion criteria, were included in this review after consensus between two reviewers. RESULTS: Forty articles met the eligibility criteria and the main results of each study are described. In most studies, SSc patients showed a higher prevalence of vitamin D deficiency and insufficiency compared to controls. Additionally, in some reports serum levels of vitamin D were inversely correlated with the severity of SSc. Oral supplementation did not seem to affect serum levels of vitamin D. Four of the included studies were with experimental models. CONCLUSION: In conclusion, vitamin D deficiency seems to have a role in susceptibility to SSc, as well as in the clinical manifestations of the disease.

Flow cytometry evaluation of CD14/CD16 monocyte subpopulations in systemic sclerosis patients: a cross sectional controlled study.

BACKGROUND: Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by vasculopathy and fibrosis, which can be subclassified into diffuse cutaneous (dSSc) and limited cutaneous (lSSc) subtypes. Previous studies suggest that an increase in monocytes can be a hallmark of various inflammatory diseases, including SSc. Our aim was to evaluate circulating blood monocyte subpopulations (classical, intermediate and non-classical) of SSc patients and their possible association with disease manifestations. METHODS: Fifty consecutive patients fulfilling the 2013 ACR/EULAR classification criteria for SSc were included in a cross-sectional study. Monocyte subpopulations were identified based on their expression of CD64, CD14 and CD16, evaluated by flow cytometry, and were correlated with the clinical characteristics of the patients; furthermore, the expression of HLA-DR, CD163, CD169 and CD206 in the monocytes was studied. Thirty-eight age- and sex-matched healthy individuals were recruited as a control group. RESULTS: SSc patients had an increased number of circulating peripheral blood monocytes with an activated phenotypic profile compared to healthy subjects. Absolute counts of CD16+ (intermediary and non-classical) monocyte subpopulations were higher in SSc patients. There was no association between monocyte subpopulations and the clinical manifestations evaluated. CONCLUSION: We identified higher counts of all monocyte subpopulations in SSc patients compared to the control group. There was no association between monocyte subpopulations and major fibrotic manifestations. CD169 was shown to be more representative in dSSc, being a promising marker for differentiating disease subtypes.

Flow cytometry evaluation of CD14/CD16 monocyte subpopulations in systemic sclerosis patients: a cross sectional controlled study

Abstract Background: Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by vasculopathy and fibrosis, which can be subclassified into diffuse cutaneous (dSSc) and limited cutaneous (lSSc) subtypes. Previous studies suggest that an increase in monocytes can be a hallmark of various inflammatory diseases, including SSc. Our aim was to evaluate circulating blood monocyte subpopulations (classical, intermediate and non-classical) of SSc patients and their possible association with disease manifestations. Methods: Fifty consecutive patients fulfilling the 2013 ACR/EULAR classification criteria for SSc were included in a cross-sectional study. Monocyte subpopulations were identified based on their expression of CD64, CD14 and CD16, evaluated by flow cytometry, and were correlated with the clinical characteristics of the patients; furthermore, the expression of HLA-DR, CD163, CD169 and CD206 in the monocytes was studied. Thirty-eight age- and sex-matched healthy individuals were recruited as a control group. Results: SSc patients had an increased number of circulating peripheral blood monocytes with an activated phenotypic profile compared to healthy subjects. Absolute counts of CD16+ (intermediary and non-classical) monocyte subpopulations were higher in SSc patients. There was no association between monocyte subpopulations and the clinical manifestations evaluated. Conclusion: We identified higher counts of all monocyte subpopulations in SSc patients compared to the control group. There was no association between monocyte subpopulations and major fibrotic manifestations. CD169 was shown to be more representative in dSSc, being a promising marker for differentiating disease subtypes.

Dualities of the vitamin D in systemic sclerosis: a systematic literature review

Abstract Background: Systemic sclerosis (SSc) is a chronic disease characterized by autoimmunity, vasculopathy, and visceral and cutaneous fibrosis. Vitamin D has several functions in the immunological system, and different studies have suggested a potential role in triggering autoimmune diseases. Patients with SSc may present with low serum levels of vitamin D, but the association between hypovitaminosis D and disease onset or any clinical manifestation is still obscure. Our goal was to verify the causal relationship between hypovitaminosis D and SSc onset or any particular clinical manifestation in the literature. Methods: A systematic literature review was performed through February 24th, 2021 on Pubmed, Lilacs/BIREME, and Cochrane databases. The eligible studies were read in full text, and, in the absence of exclusion criteria, were included in this review after consensus between two reviewers. Results: Forty articles met the eligibility criteria and the main results of each study are described. In most studies, SSc patients showed a higher prevalence of vitamin D deficiency and insufficiency compared to controls. Additionally, in some reports serum levels of vitamin D were inversely correlated with the severity of SSc. Oral supplementation did not seem to affect serum levels of vitamin D. Four of the included studies were with experimental models. Conclusion: In conclusion, vitamin D deficiency seems to have a role in susceptibility to SSc, as well as in the clinical manifestations of the disease.

Vitamin D and Cytokine Profiles in Patients With Systemic Sclerosis.

INTRODUCTION: Hypovitaminosis D has been frequently described in systemic sclerosis (SSc). Cytokines are important mediators of tissue damage and clinical dysfunction in SSc and may be influenced by vitamin D levels. OBJECTIVE: To evaluate the serum levels of vitamin D and its correlation with the clinical features and cytokine profiles in SSc patients. METHODS: Case-control study, including 50 SSc patients and 35 healthy non matched controls. Serum levels of 25(OH) vitamin D were measured by chemiluminescence assay, and serum concentrations of interleukin 2 (IL-2), IL-4, IL-6, IL-10, tumor necrosis factor, and interferon γ were determined by flow cytometry. RESULTS: Fourteen patients (28%) had diffuse cutaneous SSc, 94% were female, 80% European derived, with a mean age of 57.2 ± 12.8 years. The serum vitamin D levels in SSc patients were 23.9 ± 8.5 ng/mL and 30.2 ± 6.2 ng/mL in the control group (standardized mean difference -6.19; 95% confidence interval, -9.9 to -2.3; p = 0.002), despite the more frequent supplementation of vitamin D in SSc patients (p = 0.014). No significant associations were found among vitamin D concentrations and cytokine levels. Serum levels of IL-6 were significantly elevated in SSc patients (p = 0.024) and were positively correlated with the modified Rodnan skin score (rs = 0.291, p =0.041). CONCLUSIONS: Despite lower vitamin D levels in SSc patients, there was no clear association with any cytokine. Serum levels of IL-6 were significantly elevated and positively correlated with the extent of skin involvement in SSc patients.

Polyclonal B-cell lymphocytosis: Report of three cases.

BACKGROUND: Persistent polyclonal B-cell lymphocytosis (PPBL) is a rare benign condition characterized by a polyclonal B-cell lymphocytosis with binucleated lymphocytes. We hereby report three cases of PPBL. METHODS: Flow cytometry immunophenotyping was performed in peripheral blood samples from three patients with clinical suspicion of lymphoproliferative disease. RESULTS: Case 1 was a female middle-aged smoker; Case 2 was an elderly male; and Case 3 was a non-smoker female. Flow cytometry evaluation of all cases revealed an expansion of mature B-cells, with a normal Kappa/Lambda light chain ratio; B-cell lymphocytes of Cases 2 and 3 had CD5 coexpression; Case 3 also had monocytosis. CONCLUSIONS: Diagnose of PPBL is important in order to avoid unnecessary diagnostic procedures and therapy. © 2018 International Clinical Cytometry Society.

Correlation between cellular expression of complement regulatory proteins with depletion and repopulation of B-lymphocytes in peripheral blood of patients with rheumatoid arthritis treated with rituximab.

OBJECTIVES: To correlate the basal expression of complement regulatory proteins (CRPs) CD55, CD59, CD35, and CD46 in B-lymphocytes from the peripheral blood of a cohort of 10 patients with rheumatoid arthritis (RA) initiating treatment with rituximab (RTX) with depletion and time repopulation of such cells. METHODS: Ten patients with RA received two infusions of 1g of RTX with an interval of 14 days. Immunophenotypic analysis for the detection of CD55, CD59, CD35, and CD46 on B-lymphocytes was carried out immediately before the first infusion. The population of B-lymphocytes was analyzed by means of basal CD19 expression and after 1, 2, and 6 months after the infusion of RTX, and then quarterly until clinical relapse. Depletion of B-lymphocytes in peripheral blood was defined as a CD19 expression <0.005×109/L. RESULTS: Ten women with a median of 49 years and a baseline DAS28=5.6 were evaluated; 9 were seropositive for rheumatoid factor. Five patients showed a repopulation of B-lymphocytes after 2 months, and the other five after 6 months. There was a correlation between the basal expression of CD46 and the time of repopulation (correlation coefficient=-0.733, p=0.0016). A similar trend was observed with CD35, but without statistical significance (correction coefficient=-0.522, p=0.12). CONCLUSION: The increased CD46 expression was predictive of a faster repopulation of B-lymphocytes in patients treated with RTX. Studies involving a larger number of patients will be needed to confirm the utility of basal expression of CRPs as a predictor of clinical response.

Correlation between cellular expression of complement regulatory proteins with depletion and repopulation of B-lymphocytes in peripheral blood of patients with rheumatoid arthritis treated with rituximab / Correlação entre expressão celular de proteínas reguladoras do complemento com a depleção e repopulação de linfócitos B no sangue periférico de pacientes com artrite reumatoide tratada com rituximabe

Abstract Objectives: To correlate the basal expression of complement regulatory proteins (CRPs) CD55, CD59, CD35, and CD46 in B-lymphocytes from the peripheral blood of a cohort of 10 patients with rheumatoid arthritis (RA) initiating treatment with rituximab (RTX) with depletion and time repopulation of such cells. Methods: Ten patients with RA received two infusions of 1 g of RTX with an interval of 14 days. Immunophenotypic analysis for the detection of CD55, CD59, CD35, and CD46 on B-lymphocytes was carried out immediately before the first infusion. The population of B-lymphocytes was analyzed by means of basal CD19 expression and after 1, 2, and 6 months after the infusion of RTX, and then quarterly until clinical relapse. Depletion of B-lymphocytes in peripheral blood was defined as a CD19 expression <0.005 × 109/L. Results: Ten women with a median of 49 years and a baseline DAS28 = 5.6 were evaluated; 9 were seropositive for rheumatoid factor. Five patients showed a repopulation of B-lymphocytes after 2 months, and the other five after 6 months. There was a correlation between the basal expression of CD46 and the time of repopulation (correlation coefficient = −0.733, p = 0.0016). A similar trend was observed with CD35, but without statistical significance (correction coefficient = −0.522, p = 0.12). Conclusion: The increased CD46 expression was predictive of a faster repopulation of B-lymphocytes in patients treated with RTX. Studies involving a larger number of patients will be needed to confirm the utility of basal expression of CRPs as a predictor of clinical response.

Resumo Objetivos: Correlacionar a expressão basal das proteínas reguladoras do complemento (PRC) CD55, CD59, CD35 e CD46 nos linfócitos B do sangue periférico de uma coorte de 10 pacientes com artrite reumatoide (AR) iniciando tratamento com rituximabe (RTX) com a depleção e tempo de repopulação dessas células. Métodos: Dez pacientes com AR receberam duas infusões de 1 g de RTX com intervalo de 14 dias. Análises imunofenotípicas para detecção de CD55, CD59, CD35 e CD46 nos linfócitos B foram feitas imediatamente antes da primeira infusão. A população de linfócitos B foi analisada por meio da expressão de CD19 basal e após um, dois e seis meses após a infusão de RTX e então trimestralmente até a recaída clínica. Depleção de linfócitos B no sangue periférico foi definida como expressão de CD19 < 0,005 × 109/l. Resultados: Dez mulheres com mediana de 49 anos e DAS 28 basal de 5,6 foram avaliadas; nove eram soropositivas para o fator reumatoide. Cinco pacientes apresentaram repopulação de linfócitos B após dois meses e as outras cinco aos seis meses. Houve correlação entre a expressão basal de CD46 e o tempo de repopulação (coeficiente de correlação -0,733, p = 0,0016). Tendência semelhante foi observada com CD35, porém sem significância estatística (coeficiente de correção 0,522, p = 0,12). Conclusão: Expressão aumentada de CD46 foi preditora de repopulação mais rápida de linfócitos B em pacientes tratados com RTX. Estudos com um número maior de pacientes serão necessários para confirmar a utilidade da expressão basal das PRC como preditora de resposta clínica.

Exercise on Progenitor Cells in Healthy Subjects and Patients with Type 1 Diabetes.

PURPOSE: To evaluate the acute effect of aerobic exercise (AE) and resistance exercise (RE) on the release of endothelial progenitor cell (EPCs, CD34+/KDR+/CD45 dim) and vascular function in type 1 diabetes (T1DM). METHODS: Fourteen men with T1DM and 5 nondiabetic controls were randomly assigned to 40-min AE (60% VO 2peak) and RE sessions (60% 1-RM). The study had a crossover design, and interventions were 1 wk apart. Venous occlusion plethysmography (blood flow, reactive hyperemia, and vascular resistance) and blood collection (EPC levels, flow cytometry) were done immediately before and after exercise sessions. RESULTS: Patients were 30.3 ± 1.6 yr-old, HbA1c 7.7% ± 0.2%; controls were 26.8 ± 2.3 yr-old. Groups did not differ in EPC levels at baseline or in relation to exercise. Over time, exercise did not induce changes in patients with T1DM, whereas, in controls, EPCs were decreased after AE (-10.7%, P = 0.017) and increased after RE (+12.2%, P = 0.004). Compared with baseline, blood flow increased and vascular resistance decreased after RE in both groups. Reactive hyperemia was increased 10 min after AE and RE sessions in patients with T1DM (36.5% and 42.0%, respectively) and in controls (35.4% and 74.3%), but no group differences were observed between groups in response to exercise. CONCLUSIONS: Despite the increased vascular reactivity in both groups after both exercise sessions, EPCs were only influenced by exercise in controls. The unchanged number of EPCs in T1DM after exercise sessions might indicate a blunted endothelium regenerating capacity, revealing an early deterioration of the functional arterial characteristics not disclosed by only evaluating vascular functional variables.

Vitamin D and systemic lupus erythematosus: state of the art.

Systemic lupus erythematosus (SLE) is a systemic inflammatory disease associated with genetic, environmental, hormonal, and immunological factors. One of these factors is vitamin D deficiency. Vitamin D plays many roles in the immune system. Several studies have suggested a potential role in the development of autoimmune diseases. SLE patients have low serum levels of vitamin D, which increase the possibility of an association between vitamin deficiency and disease onset and evolution. This review of the literature presents an analysis of the aspects related to the immunoregulatory effects of vitamin D and its importance for SLE, as well as the recommendations for vitamin D supplementation in these patients.

The role of complement regulatory proteins in peripheral blood cells of patients with systemic lupus erythematosus: review.

CD55, CD59, CD35 and CD46 are cell membrane proteins that have regulatory properties on the activation of the complement cascade. Deficiency in the expression of these proteins may be associated with lower protection of healthy cells against complement mediated lysis and also with the accumulation of immune complexes in tissues. Few studies assess the expression of these proteins in patients with SLE and the mechanisms that regulate reduction in cellular expression, whereas its impact on manifestations of systemic lupus erythematosus is still unknown.

Diminished expression of complement regulatory proteins on peripheral blood cells from systemic lupus erythematosus patients.

CD55, CD59, CD46, and CD35 are proteins with complement regulatory (Creg) properties that ensure cell and tissue integrity when this system is activated. The aim of this study was to evaluate the Creg expression on peripheral blood cells from SLE patients and its association with cytopenia and disease activity. Flow cytometric analyses were performed on blood cells from 100 SLE patients and 61 healthy controls. Compared with healthy controls, we observed in SLE patients with lymphopenia and neutropenia decreased expression of CD55, CD59, and CD46 (P < 0.05). In SLE patients with anemia, CD59 and CD35 were decreased on red blood cells. Furthermore, there was a negative correlation between CD55 and CD59 on neutrophils and the disease activity. The results suggest there is an altered pattern of Creg expression on the peripheral blood cells of SLE patients, and the expression is correlated with disease activity and/or with activation of the complement system.

Expressão de proteínas reguladoras do complemento CD55, CD59, CD35 e CD46 na artrite reumatoide / Expression of complement regulatory proteins CD55, CD59, CD35, and CD46 in rheumatoid arthritis

A artrite reumatoide (AR) é uma doença autoimune, associada à sinovite poliarticular inflamatória, que acomete principalmente as articulações periféricas. Cerca de 1 por cento da população mundial é afetada, sendo duas a três vezes mais prevalente em mulheres. Apresenta patogênese complexa e multifatorial. A sinóvia das articulações afetadas é infiltrada por linfócitos T e B, macrófagos e granulócitos. A sinóvia reumatoide adquire características proliferativas, formando o pannus, e invade a cartilagem articular e o osso, levando à destruição da arquitetura normal da articulação e à perda de função. A diminuição da expressão de proteínas reguladoras do complemento (PCR) parece desempenhar papel importante na atividade da AR, associada ao agravamento dos sintomas clínicos. A superativação do sistema complemento (SC) é a causa da exacerbação da doença em vários modelos de doenças autoimunes. O presente artigo tem por objetivo revisar os principais aspectos relacionados à regulação do SC na AR, a fim de propiciar melhor compreensão do potencial papel desse sistema na fisiopatologia e na atividade da doença.

Rheumatoid arthritis (RA) is an autoimmune disease associated with polyarticular inflammatory synovitis affecting mainly peripheral joints. It affects approximately 1 percent of the world population, being two to three times more prevalent in women. Rheumatoid arthritis has a complex and multifactorial pathogenesis. The synovium of the affected joints is infiltrated by T and B lymphocytes, macrophages, and granulocytes. The rheumatoid synovium has proliferative characteristics, forming the pannus, which invades cartilage and bone, leading to normal architecture destruction and function loss. The decreased expression of complement regulatory proteins (CRP) seems to play an important role in RA activity, and is associated with worsening of the clinical symptoms. In several models of autoimmune diseases, the overactivation of the complement system (CS) is the cause of disease exacerbation. This article aimed at reviewing the main aspects related to CS regulation in RA in order to provide a better understanding of the potential role of this system in the pathophysiology and activity of the disease.

Expression of complement regulatory proteins CD55, CD59, CD35, and CD46 in rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease associated with polyarticular inflammatory synovitis affecting mainly peripheral joints. It affects approximately 1% of the world population, being two to three times more prevalent in women. Rheumatoid arthritis has a complex and multifactorial pathogenesis. The synovium of the affected joints is infiltrated by T and B lymphocytes, macrophages, and granulocytes. The rheumatoid synovium has proliferative characteristics, forming the pannus, which invades cartilage and bone, leading to normal architecture destruction and function loss. The decreased expression of complement regulatory proteins (CRP) seems to play an important role in RA activity, and is associated with worsening of the clinical symptoms. In several models of autoimmune diseases, the overactivation of the complement system (CS) is the cause of disease exacerbation. This article aimed at reviewing the main aspects related to CS regulation in RA in order to provide a better understanding of the potential role of this system in the pathophysiology and activity of the disease.

The expression of CD56 antigen is associated with poor prognosis in patients with acute myeloid leukemia

BACKGROUND: The expression of CD56 is considered a bad prognostic factor for overall survival, lower rates or short complete remission and extramedullary invasion but the results are controversial. The importance of validating new prognostic parameters in acute leukemias was the reason to investigate the CD56 expression in blast cells of patients with acute myeloid leukemia. METHODS: A cohort of 48 patients treated at Hospital de Clinicas de Porto Alegre and diagnosed with acute myeloid leukemia as classified by the French-American-British group (FAB) criteria using cell morphology, cytochemistry and flow cytometry were evaluated. RESULTS: Eight cases (16.7 percent) were CD56 positive without correlation to age or gender. The highest incidence of CD56 positivity was in FAB subtypes M4 and M5. The death rate during induction was not significantly different between patients with and without CD56 expression (62.5 percent vs. 27.5 percent; p-value = 0.097). However, patients that expressed CD56 had significantly lower overall survival than those who did not (mean 4.0 months vs. 14.5 months; p-value = 0.03). CONCLUSIONS: The data suggest that expression of CD56 in acute myeloid leukemia may be indicative of poor prognosis because it is associated with a shorter overall survival. The death rate during induction was not significantly different despite an apparent difference in proportions between groups.

The expression of CD56 antigen is associated with poor prognosis in patients with acute myeloid leukemia.

BACKGROUND: The expression of CD56 is considered a bad prognostic factor for overall survival, lower rates or short complete remission and extramedullary invasion but the results are controversial. The importance of validating new prognostic parameters in acute leukemias was the reason to investigate the CD56 expression in blast cells of patients with acute myeloid leukemia. METHODS: A cohort of 48 patients treated at Hospital de Clinicas de Porto Alegre and diagnosed with acute myeloid leukemia as classified by the French-American-British group (FAB) criteria using cell morphology, cytochemistry and flow cytometry were evaluated. RESULTS: Eight cases (16.7%) were CD56 positive without correlation to age or gender. The highest incidence of CD56 positivity was in FAB subtypes M4 and M5. The death rate during induction was not significantly different between patients with and without CD56 expression (62.5% vs. 27.5%; p-value = 0.097). However, patients that expressed CD56 had significantly lower overall survival than those who did not (mean 4.0 months vs. 14.5 months; p-value = 0.03). CONCLUSIONS: The data suggest that expression of CD56 in acute myeloid leukemia may be indicative of poor prognosis because it is associated with a shorter overall survival. The death rate during induction was not significantly different despite an apparent difference in proportions between groups.