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1.
J Autoimmun ; 133: 102914, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36183584

RESUMO

INTRODUCTION: Macrophages are key players in the immunopathology of anti-neutrophil cytoplasmic antibody (ANCA) mediated-vasculitis (AAV) with glomerulonephritis (ANCA GN). Different macrophage phenotypes are expected to play distinct roles in ANCA GN. Macrophages expressing CD163 and CD206 are found in lesions associated with ANCA GN. Hence, we aimed to investigate the clinicopathological significance of CD206 and CD163 in ANCA GN in a multicenter retrospective cohort study. MATERIAL AND METHODS: Patients with ANCA-associated vasculitis, with clinical data, serum and urine samples were included from three cohorts. Serum soluble CD206 (ssCD206) and urinary soluble CD163 (usCD163) levels were measured. Human kidney tissue samples (n = 53) were stained for CD206 and CD163 using immunohistochemistry and immunofluorescence, and findings were correlated with clinical and pathological data. RESULTS: In total, 210 patients were included (i.e., ANCA GN, n = 134; AAV without GN, n = 24; AAV in remission n = 52). Increased levels of both ssCD206 and usCD163 were seen in ANCA GN. High levels of ssCD206 declined after reaching remission, however, ssCD206 did not improve the accuracy of usCD163 to detect ANCA GN. Soluble markers correlated with histopathological findings. CD163+CD206- macrophages were found in the glomerulus and may play pivotal roles in glomerulonephritis, whereas CD206+CD163- and CD206+CD163+ macrophages were located tubulointerstitially and likely play a more prominent role in ANCA-associated tubulointerstitial inflammation. In ANCA GN patients increasing levels of ssCD206 increased the risk for end-stage renal disease and mortality. CONCLUSIONS: Our results confirm and extend the notion that CD206+ and CD163+ macrophages are prominent components of the cellular infiltrate in ANCA GN. We found distinct macrophage phenotypes that may play distinct roles in the immunopathology of ANCA GN and elaborate on a potential mechanism underlying the findings of this study. usCD163 remains an excellent marker to detect active ANCA GN, whereas ssCD206 seems a more prominent marker for risk prediction.


Assuntos
Anticorpos Anticitoplasma de Neutrófilos , Macrófagos , Humanos , Estudos Retrospectivos
2.
Nephrol Dial Transplant ; 34(2): 234-242, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29506265

RESUMO

Background: Early detection of renal involvement in anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is of major clinical importance to allow prompt initiation of treatment and limit renal damage. Urinary soluble cluster of differentiation 163 (usCD163) has recently been identified as a potential biomarker for active renal vasculitis. However, a significant number of patients with active renal vasculitis test negative using usCD163. We therefore studied whether soluble CD25 (sCD25), a T cell activation marker, could improve the detection of renal flares in AAV. Methods: sCD25 and sCD163 levels in serum and urine were measured by enzyme-linked immunosorbent assay in 72 patients with active renal AAV, 20 with active extrarenal disease, 62 patients in remission and 18 healthy controls. Urinary and blood CD4+ T and CD4+ T effector memory (TEM) cell counts were measured in 22 patients with active renal vasculitis. Receiver operating characteristics (ROC) curves were generated and recursive partitioning was used to calculate whether usCD25 and serum soluble CD25 (ssCD25) add utility to usCD163. Results: usCD25, ssCD25 and usCD163 levels were significantly higher during active renal disease and significantly decreased after induction of remission. A combination of usCD25, usCD163 and ssCD25 outperformed all individual markers (sensitivity 84.7%, specificity 95.1%). Patients positive for sCD25 but negative for usCD163 (n = 10) had significantly higher C-reactive protein levels and significantly lower serum creatinine and proteinuria levels compared with the usCD163-positive patients. usCD25 correlated positively with urinary CD4+ T and CD4+ TEM cell numbers, whereas ssCD25 correlated negatively with circulating CD4+ T and CD4+ TEM cells. Conclusion: Measurement of usCD25 and ssCD25 complements usCD163 in the detection of active renal vasculitis.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/sangue , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/urina , Antígenos CD/sangue , Antígenos CD/urina , Antígenos de Diferenciação Mielomonocítica/sangue , Antígenos de Diferenciação Mielomonocítica/urina , Subunidade alfa de Receptor de Interleucina-2/sangue , Nefropatias/sangue , Nefropatias/urina , Receptores de Superfície Celular/sangue , Adulto , Idoso , Anticorpos Anticitoplasma de Neutrófilos/sangue , Anticorpos Anticitoplasma de Neutrófilos/urina , Autoanticorpos , Biomarcadores/sangue , Biomarcadores/urina , Linfócitos T CD4-Positivos/imunologia , Estudos de Coortes , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Sensibilidade e Especificidade
3.
J Am Soc Nephrol ; 27(9): 2906-16, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-26940094

RESUMO

A specific biomarker that can separate active renal vasculitis from other causes of renal dysfunction is lacking, with a kidney biopsy often being required. Soluble CD163 (sCD163), shed by monocytes and macrophages, has been reported as a potential biomarker in diseases associated with excessive macrophage activation. Thus, we hypothesized that urinary sCD163 shed by crescent macrophages correlates with active glomerular inflammation. We detected sCD163 in rat urine early in the disease course of experimental vasculitis. Moreover, microdissected glomeruli from patients with small vessel vasculitis (SVV) had markedly higher levels of CD163 mRNA than did those from patients with lupus nephritis, diabetic nephropathy, or nephrotic syndrome. Both glomeruli and interstitium of patients with SVV strongly expressed CD163 protein. In 479 individuals, including patients with SVV, disease controls, and healthy controls, serum levels of sCD163 did not differ between the groups. However, in an inception cohort, including 177 patients with SVV, patients with active renal vasculitis had markedly higher urinary sCD163 levels than did patients in remission, disease controls, or healthy controls. Analyses in both internal and external validation cohorts confirmed these results. Setting a derived optimum cutoff for urinary sCD163 of 0.3 ng/mmol creatinine for detection of active renal vasculitis resulted in a sensitivity of 83%, specificity of 96%, and a positive likelihood ratio of 20.8. These data indicate that urinary sCD163 level associates very tightly with active renal vasculitis, and assessing this level may be a noninvasive method for diagnosing renal flare in the setting of a known diagnosis of SVV.


Assuntos
Antígenos CD/urina , Antígenos de Diferenciação Mielomonocítica/urina , Nefropatias/urina , Rim/irrigação sanguínea , Vasculite/urina , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/urina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptores de Superfície Celular , Adulto Jovem
4.
Ned Tijdschr Geneeskd ; 1672023 03 16.
Artigo em Holandês | MEDLINE | ID: mdl-36943167

RESUMO

BACKGROUND: In 15-25% of patients with rheumatoid arthritis, the presence of pathognomonic autoantibodies (anti-citrullinated protein (aCCP) or rheumafactor (RF) is lacking. In these cases of seronegative rheumatoid arthritis, diagnosis is based on clinical presentation. However, some of the patients with seronegative rheumatoid arthritis are misdiagnosed. CASE DESCRIPTION: Here we discuss a case of a 64 year old female, with a diagnoses of seronegative rheumatoid arthritis for 18 years. Although extensively treated with immunosuppressive medication, she did not reach remission. After second opinion in our hospital we diagnosed Whipple's disease. CONCLUSION: This case report illustrates the importance of a broad differential diagnosis of seronegative arthritis as well as the importance of re-assessment of patients diagnosed with seronegative rheumatoid arthritis, who do not reach remission upon immunosuppressive treatment.


Assuntos
Artrite Reumatoide , Doença de Whipple , Feminino , Humanos , Pessoa de Meia-Idade , Doença de Whipple/complicações , Doença de Whipple/diagnóstico , Doença de Whipple/tratamento farmacológico , Artrite Reumatoide/diagnóstico , Autoanticorpos , Imunossupressores/uso terapêutico , Diagnóstico Diferencial
5.
Ned Tijdschr Geneeskd ; 1662023 03 16.
Artigo em Holandês | MEDLINE | ID: mdl-36928684

RESUMO

BACKGROUND: In 15-25% of patients with rheumatoid arthritis, the presence of pathognomonic autoantibodies (anti-citrullinated protein (aCCP) or rheumafactor (RF) is lacking. In these cases of seronegative rheumatoid arthritis, diagnosis is based on clinical presentation. However, some of the patients with seronegative rheumatoid arthritis are misdiagnosed. CASE DESCRIPTION: Here we discuss a case of a 64 year old female, with a diagnoses of seronegative rheumatoid arthritis for 18 years. Although extensively treated with immunosuppressive medication, she did not reach remission. After second opinion in our hospital we diagnosed Whipple's disease. CONCLUSION: This case report illustrates the importance of a broad differential diagnosis of seronegative arthritis as well as the importance of re-assessment of patients diagnosed with seronegative rheumatoid arthritis, who do not reach remission upon immunosuppressive treatment.


Assuntos
Artrite Reumatoide , Doença de Whipple , Feminino , Humanos , Pessoa de Meia-Idade , Doença de Whipple/complicações , Doença de Whipple/diagnóstico , Doença de Whipple/tratamento farmacológico , Artrite Reumatoide/diagnóstico , Autoanticorpos , Imunossupressores/uso terapêutico , Diagnóstico Diferencial
6.
Am J Obstet Gynecol ; 207(1): 76.e1-14, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22607666

RESUMO

OBJECTIVE: During pregnancy the maternal immune system has to adapt its response to accommodate the fetus. The objective of this study was to analyze the effects of smoking on the maternal immune system. STUDY DESIGN: First-trimester decidual tissue and peripheral blood of smoking and nonsmoking women were analyzed by real time reverse transcription-polymerase chain reaction (RT-PCR) and flow cytometry. A mouse model was used to further analyze the effects of smoking. Murine tissue was analyzed by flow cytometry, real-time RT-PCR, and immunohistochemistry. RESULTS: Smoking caused lower percentages of viable pups in mice and lower birthweights in humans. Smoking mothers, both mice and human, had more natural killer cells and inflammatory macrophages locally, whereas systemically they had lower percentages of regulatory T cells than nonsmoking controls. CONCLUSION: Maternal smoke exposure during pregnancy influences local and systemic immune responses in both women and mice. Such changes may be involved in adverse pregnancy outcomes in smoking individuals.


Assuntos
Gravidez/imunologia , Fumar/imunologia , Adulto , Animais , Biomarcadores/metabolismo , Estudos de Casos e Controles , Decídua/citologia , Decídua/metabolismo , Feminino , Citometria de Fluxo , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Células Matadoras Naturais/metabolismo , Linfonodos/citologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fumar/efeitos adversos , Baço/citologia , Linfócitos T Reguladores/metabolismo
7.
Front Immunol ; 10: 2170, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31572380

RESUMO

Objectives: Regulatory T cells (Tregs) are frequently functionally impaired in patients with granulomatosis with polyangiitis (GPA). However, the mechanism underlying their impaired function is unknown. Here, we hypothesized that Treg dysfunction in GPA is due to altered microRNA (miRNA) expression. Methods: RNA isolated from FACS-sorted memory (M) Tregs (CD4+CD45RO+CD25+CD127-) of 8 healthy controls (HCs) and 8 GPA patients without treatment was subjected to miRNA microarray analysis. Five differentially expressed miRNAs were validated in a larger cohort by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). An miRNA target gene database search revealed targets that were tested with RT-qPCR in MTregs from patients and HCs. cAMP levels were measured using flow cytometry. Results: Microarray analysis revealed 19 differentially expressed miRNAs, of which miR-142-3p was confirmed to be significantly upregulated in MTregs from GPA patients compared to those from HCs (1.9-fold, p = 0.03). In vitro overexpression of miR-142-3p lowered the suppressive capacity of MTregs (2.1-fold, p = 0.03), and miR-142-3p expression correlated negatively with the suppressive capacity (rho = -0.446, p = 0.04). Overexpression of miR-142-3p significantly decreased cAMP levels (p = 0.02) and tended to decrease the mRNA levels of a predicted target gene, adenylate cyclase 9 (ADCY9; p = 0.06). In comparison to those from HCs, MTregs from GPA patients had lower ADCY9 mRNA levels (2-fold, p = 0.008) and produced significantly less cAMP after stimulation. Importantly, induction of cAMP production in miR-142-3p overexpressed MTregs by forskolin restored their suppressive function in vitro. Conclusion: Overexpression of miR-142-3p in MTregs from GPA patients might cause functional impairment by targeting ADCY9, which leads to the suppression of cAMP production.


Assuntos
Granulomatose com Poliangiite/imunologia , MicroRNAs/imunologia , Linfócitos T Reguladores/imunologia , Adenilil Ciclases/genética , AMP Cíclico/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
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