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JCI Insight ; 5(12)2020 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-32396533


Lupus nephritis, one of the most serious manifestations of systemic lupus erythematosus (SLE), has a heterogeneous clinical and pathological presentation. For example, proliferative nephritis identifies a more aggressive disease class that requires immunosuppression. However, the current classification system relies on the static appearance of histopathological morphology, which does not capture differences in the inflammatory response. Therefore, a biomarker grounded in the disease biology is needed in order to understand the molecular heterogeneity of lupus nephritis and identify immunologic mechanism and pathways. Here, we analyzed the patterns of 1000 urine protein biomarkers in 30 patients with active lupus nephritis. We found that patients stratify over a chemokine gradient inducible by IFN-γ. Higher values identified patients with proliferative lupus nephritis. After integrating the urine proteomics with the single-cell transcriptomics of kidney biopsies, we observed that the urinary chemokines defining the gradient were predominantly produced by infiltrating CD8+ T cells, along with natural killer and myeloid cells. The urine chemokine gradient significantly correlated with the number of kidney-infiltrating CD8+ cells. These findings suggest that urine proteomics can capture the complex biology of the kidney in lupus nephritis. Patient-specific pathways could be noninvasively tracked in the urine in real time, enabling diagnosis and personalized treatment.

Nat Immunol ; 20(7): 902-914, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209404


Lupus nephritis is a potentially fatal autoimmune disease for which the current treatment is ineffective and often toxic. To develop mechanistic hypotheses of disease, we analyzed kidney samples from patients with lupus nephritis and from healthy control subjects using single-cell RNA sequencing. Our analysis revealed 21 subsets of leukocytes active in disease, including multiple populations of myeloid cells, T cells, natural killer cells and B cells that demonstrated both pro-inflammatory responses and inflammation-resolving responses. We found evidence of local activation of B cells correlated with an age-associated B-cell signature and evidence of progressive stages of monocyte differentiation within the kidney. A clear interferon response was observed in most cells. Two chemokine receptors, CXCR4 and CX3CR1, were broadly expressed, implying a potentially central role in cell trafficking. Gene expression of immune cells in urine and kidney was highly correlated, which would suggest that urine might serve as a surrogate for kidney biopsies.

Rim/imunologia , Nefrite Lúpica/imunologia , Biomarcadores , Biópsia , Análise por Conglomerados , Biologia Computacional/métodos , Células Epiteliais/metabolismo , Citometria de Fluxo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Imunofenotipagem , Interferons/metabolismo , Rim/metabolismo , Rim/patologia , Leucócitos/imunologia , Leucócitos/metabolismo , Nefrite Lúpica/genética , Nefrite Lúpica/metabolismo , Nefrite Lúpica/patologia , Linfócitos/imunologia , Linfócitos/metabolismo , Anotação de Sequência Molecular , Células Mieloides/imunologia , Células Mieloides/metabolismo , Análise de Célula Única , Transcriptoma
Nat Immunol ; 20(7): 928-942, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31061532


To define the cell populations that drive joint inflammation in rheumatoid arthritis (RA), we applied single-cell RNA sequencing (scRNA-seq), mass cytometry, bulk RNA sequencing (RNA-seq) and flow cytometry to T cells, B cells, monocytes, and fibroblasts from 51 samples of synovial tissue from patients with RA or osteoarthritis (OA). Utilizing an integrated strategy based on canonical correlation analysis of 5,265 scRNA-seq profiles, we identified 18 unique cell populations. Combining mass cytometry and transcriptomics revealed cell states expanded in RA synovia: THY1(CD90)+HLA-DRAhi sublining fibroblasts, IL1B+ pro-inflammatory monocytes, ITGAX+TBX21+ autoimmune-associated B cells and PDCD1+ peripheral helper T (TPH) cells and follicular helper T (TFH) cells. We defined distinct subsets of CD8+ T cells characterized by GZMK+, GZMB+, and GNLY+ phenotypes. We mapped inflammatory mediators to their source cell populations; for example, we attributed IL6 expression to THY1+HLA-DRAhi fibroblasts and IL1B production to pro-inflammatory monocytes. These populations are potentially key mediators of RA pathogenesis.

Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Perfilação da Expressão Gênica , Membrana Sinovial/metabolismo , Transcriptoma , Artrite Reumatoide/patologia , Autoimunidade/genética , Biomarcadores , Biologia Computacional/métodos , Estudos Transversais , Citocinas/metabolismo , Fibroblastos/metabolismo , Citometria de Fluxo , Expressão Gênica , Perfilação da Expressão Gênica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Leucócitos/imunologia , Leucócitos/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Transdução de Sinais , Análise de Célula Única/métodos , Membrana Sinovial/patologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Fluxo de Trabalho
Dermatol Surg ; 35(1): 98-107, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19076188


PURPOSE: To evaluate the efficacy of a 1,064-nm neodymium-doped yttrium aluminium garnet (Nd:YAG) laser using lower than traditional fluences (22-40 J/cm(2)) for treatment of pseudofolliculitis barbae (PFB). METHODS: Twenty-two patients with PFB refractory to conservative therapy received five weekly treatments over the anterior neck using a 1,064-nm Nd:YAG laser at 12 J/cm(2). Pulse duration was 20 ms with 10 mm spot size. Topical anesthesia was not used. Treatments were completed 15 minutes after patient arrival. Patients presented for 2- and 4-week follow-up. Ten evaluators used a Global Assessment Scale (GAS) to assess dyspigmentation, papule counts, and cobblestoning by comparing baseline to 4-week follow-up visit photographs. Hair and papule counts were performed on five patients and compared with the GAS. Investigators recorded adverse effects using a visual analog and side effects scale. RESULTS: Eleven patients demonstrated 83% improvement on the GAS (p<.01). There was a mean reduction of 59.5% in dyspigmentation (p<.03), 91.2% in papule count (p<.01), and 75.6% in cobblestoning (p<.02). Patients reported 1 out of 10 on both adverse effects scales. CONCLUSION: Low-fluence 1,064-nm laser treatment achieved significant temporary reduction in PFB. Subjects noted minimal pain without topical anesthesia.

Foliculite/radioterapia , Remoção de Cabelo/métodos , Terapia com Luz de Baixa Intensidade/métodos , Pigmentação da Pele , Adulto , Feminino , Humanos , Lasers de Estado Sólido/uso terapêutico , Terapia com Luz de Baixa Intensidade/efeitos adversos , Masculino , Dor/etiologia , Projetos Piloto , Estudos Prospectivos
Lasers Surg Med ; 39(6): 543-50, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17659584


BACKGROUND: It has been proposed for many years that low-level laser (or light) therapy (LLLT) can ameliorate the pain, swelling, and inflammation associated with various forms of arthritis. Light is thought to be absorbed by mitochondrial chromophores leading to an increase in adenosine triphosphate (ATP), reactive oxygen species and/or cyclic AMP production and consequent gene transcription via activation of transcription factors. However, despite many reports about the positive effects of LLLT in arthritis and in medicine in general, its use remains controversial. For all indications (including arthritis) the optimum optical parameters have been difficult to establish and so far are unknown. METHODS: We tested LLLT on rats that had zymosan injected into their knee joints to induce inflammatory arthritis. We compared illumination regimens consisting of a high and low fluence (3 and 30 J/cm(2)), delivered at high and low irradiance (5 and 50 mW/cm(2)) using 810-nm laser light daily for 5 days, with the positive control of conventional corticosteroid (dexamethasone) therapy. RESULTS: Illumination with 810-nm laser was highly effective (almost as good as dexamethasone) at reducing swelling and a longer illumination time (10 or 100 minutes compared to 1 minute) was more important in determining effectiveness than either the total fluence delivered or the irradiance. LLLT induced reduction of joint swelling correlated with reduction in the inflammatory marker serum prostaglandin E2 (PGE2). CONCLUSION: LLLT with 810-nm laser is highly effective in treating inflammatory arthritis in this model. Longer illumination times were more effective than short times regardless of total fluence or irradiance. These data will be of value in designing clinical trials of LLLT for various arthritides.

Artrite/terapia , Terapia com Luz de Baixa Intensidade , Animais , Anti-Inflamatórios/uso terapêutico , Artrite/sangue , Artrite/induzido quimicamente , Dexametasona/uso terapêutico , Dinoprostona/sangue , Modelos Animais de Doenças , Relação Dose-Resposta à Radiação , Feminino , Polissacarídeos/efeitos adversos , Ratos , Ratos Endogâmicos Lew , Fatores de Tempo , Zimosan/efeitos adversos
Kidney Int ; 62(2): 611-9, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12110025


BACKGROUND: Clinical studies have shown sevelamer HCl (Renagel) to be effective for the reduction of serum phosphate in hemodialysis patients. These studies also consistently have demonstrated a significant reduction of low-density lipoprotein (LDL) cholesterol following treatment with sevelamer. METHODS: Equilibrium binding of bile acids and oleic acid was determined by incubating sevelamer with ligand containing buffer. Aliquots of the solution were filtered and the free ligand concentrations quantitated by high-pressure liquid chromatography (HPLC). Flow kinetics were determined using a cylindrical flow cell containing trapped sevelamer. Bile acid and oleic acid were pumped through the stirred cell in a manner designed to mimic the in vivo situation. Binding was monitored by HPLC. RESULTS: Sevelamer binds bile acids cooperatively and with high capacity. At low binding densities, the presence of the more hydrophobic bile acids enhances the binding of the less hydrophobic bile acids, and the presence of oleic acid enhances the binding of all bile acids. At saturating oleic acid concentrations, the bile acid binding capacity of sevelamer is reduced by only a factor of two. Moreover, the presence of oleic acid dramatically diminishes the release rate of bile acids from sevelamer. CONCLUSIONS: The favorable bile acid binding characteristics of sevelamer provide a compelling explanation for its ability to lower LDL cholesterol in hemodialysis patients and in healthy volunteers.

Ácidos e Sais Biliares/metabolismo , Compostos de Epóxi/metabolismo , Compostos de Epóxi/farmacologia , Polietilenos/metabolismo , Polietilenos/farmacologia , LDL-Colesterol/metabolismo , Humanos , Falência Renal Crônica/tratamento farmacológico , Cinética , Modelos Biológicos , Ácido Oleico/metabolismo , Ácido Oleico/farmacologia , Poliaminas , Diálise Renal , Sevelamer