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1.
Arthritis Rheumatol ; 2022 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-35644031

RESUMO

OBJECTIVE: To investigate the immune cell profiling and their longitudinal changes in systemic lupus erythematosus (SLE). METHODS: We employed mass cytometry with three different 38-39 marker panels (Immunophenotyping, T cell/monocyte, and B cell) in cryopreserved peripheral blood mononuclear cells (PBMCs) from nine patients with early SLE, 15 patients with established SLE, and 14 non-inflammatory controls. We used machine learning-driven clustering, FlowSOM (Flow Self-Organizing Maps) and dimensional reduction with tSNE (t-distributed Stochastic Neighbor Embedding) to identify unique cell populations in early and established SLE. For the nine early SLE patients, longitudinal mass cytometry analysis was applied to PBMCs at enrollment, six months post-enrollment, and one year post-enrollment. Serum samples were also assayed for 65 cytokines by Luminex multiplex assay, and associations between cell types and cytokines/chemokines assessed. RESULTS: T peripheral helper cells (Tph cells), T follicular helper cells (Tfh cells) and several Ki67+ proliferating subsets (ICOS+ Ki67+ CD8 T cells, Ki67+ regulatory T cells, CD19int Ki67hi plasmablasts, and Ki67hi PU.1hi monocytes) were increased in early SLE patients, with more prominent alterations than were seen in early rheumatoid arthritis (RA) patients. Longitudinal mass cytometry and multiplex serum cytokine assays of samples from early SLE patients revealed that Tfh cells and CXCL10 decreased at one year post-enrollment. CXCL13 correlated positively with several of the expanded cell populations in early SLE. CONCLUSIONS: Two major helper T cell subsets and unique Ki67+ proliferating immune cell subsets were expanded in the early phase of SLE, and the immunologic features characteristic of early SLE evolved over time.

2.
Blood ; 2022 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-35714308

RESUMO

Gout is a common inflammatory arthritis caused by precipitation of monosodium urate (MSU) crystals in individuals with hyperuricemia. Acute flares are accompanied by secretion of pro-inflammatory cytokines, including interleukin-1 beta (IL-1B). Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition predisposing to hematologic cancers and cardiovascular disease. CHIP is associated with elevated IL-1B, thus we investigated CHIP as a risk factor for gout. To test the clinical association between CHIP and gout, we analyzed whole exome sequencing data from 177,824 individuals in the MGB Biobank (MGBB) and UK Biobank (UKB). In both cohorts, the frequency of gout was higher among individuals with CHIP than without CHIP (MGBB, CHIP with variant allele fraction [VAF] ≥2%: OR, 1.69; 95% CI, 1.09-2.61; P=0.0189; UKB, CHIP with VAF ≥10%: OR, 1.25; 95% CI, 1.05-1.50; P=0.0133). Moreover, individuals with CHIP and a VAF ≥10% had an increased risk of incident gout (UKB: HR, 1.28; 95% CI, 1.06-1.55; P=0.0107). In murine models of gout pathogenesis, animals with Tet2 knockout hematopoietic cells had exaggerated IL-1B secretion and paw edema upon administration of MSU crystals. Tet2 knockout macrophages elaborated higher levels of IL-1B in response to MSU crystals in vitro, and this was ameliorated through genetic and pharmacologic Nlrp3 inflammasome inhibition. These studies show that TET2-mutant CHIP is associated with an increased risk of gout in humans and that MSU crystals lead to elevated IL-1B levels in Tet2 knockout murine models. We identify CHIP as an amplifier of NLRP3-dependent inflammatory responses to MSU crystals in gout patients.

3.
Sci Transl Med ; 14(649): eabo0686, 2022 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-35704599

RESUMO

T cell-derived pro-inflammatory cytokines are a major driver of rheumatoid arthritis (RA) pathogenesis. Although these cytokines have traditionally been attributed to CD4 T cells, we have found that CD8 T cells are notably abundant in synovium and make more interferon (IFN)-γ and nearly as much tumor necrosis factor (TNF) as their CD4 T cell counterparts. Furthermore, using unbiased high-dimensional single-cell RNA-seq and flow cytometric data, we found that the vast majority of synovial tissue and synovial fluid CD8 T cells belong to an effector CD8 T cell population characterized by high expression of granzyme K (GzmK) and low expression of granzyme B (GzmB) and perforin. Functional experiments demonstrate that these GzmK+ GzmB+ CD8 T cells are major cytokine producers with low cytotoxic potential. Using T cell receptor repertoire data, we found that CD8 GzmK+ GzmB+ T cells are clonally expanded in synovial tissues and maintain their granzyme expression and overall cell state in blood, suggesting that they are enriched in tissue but also circulate. Using GzmK and GzmB signatures, we found that GzmK-expressing CD8 T cells were also the major CD8 T cell population in the gut, kidney, and coronavirus disease 2019 (COVID-19) bronchoalveolar lavage fluid, suggesting that they form a core population of tissue-associated T cells across diseases and human tissues. We term this population tissue-enriched expressing GzmK or TteK CD8 cells. Armed to produce cytokines in response to both antigen-dependent and antigen-independent stimuli, CD8 TteK cells have the potential to drive inflammation.


Assuntos
COVID-19 , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Citocinas/metabolismo , Granzimas/metabolismo , Humanos
4.
JCI Insight ; 7(8)2022 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-35290245

RESUMO

Cutaneous lupus is commonly present in patients with systemic lupus erythematosus (SLE). T cells have been strongly suspected to contribute to the pathology of cutaneous lupus; however, our understanding of the relevant T cell phenotypes and functions remains incomplete. Here, we present a detailed single-cell RNA-Seq profile of T and NK cell populations present within lesional and nonlesional skin biopsies of patients with cutaneous lupus. T cells across clusters from lesional and nonlesional skin biopsies expressed elevated levels of IFN-simulated genes (ISGs). Compared with T cells from control skin, however, T cells from cutaneous lupus lesions did not show elevated expression profiles of activation, cytotoxicity, or exhaustion. Integrated analyses indicated that skin lymphocytes appeared less activated and lacked the expanded cytotoxic populations prominent in lupus nephritis kidney T/NK cells. Comparison of skin T cells from lupus and systemic sclerosis skin biopsies further revealed an elevated ISG signature specific to cells from lupus biopsies. Overall, these data represent the first detailed transcriptomic analysis to our knowledge of the T and NK cells in cutaneous lupus at the single-cell level and have enabled a cross-tissue comparison that highlights stark differences in composition and activation of T/NK cells in distinct tissues in lupus.


Assuntos
Lúpus Eritematoso Cutâneo , Nefrite Lúpica , Feminino , Humanos , Rim/patologia , Células Matadoras Naturais/metabolismo , Lúpus Eritematoso Cutâneo/patologia , Nefrite Lúpica/genética , Nefrite Lúpica/patologia , Masculino , Linfócitos T/metabolismo , Transcriptoma
6.
Ann Rheum Dis ; 81(6): 805-814, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35168946

RESUMO

OBJECTIVE: Neutrophils are typically the most abundant leucocyte in arthritic synovial fluid. We sought to understand changes that occur in neutrophils as they migrate from blood to joint. METHODS: We performed RNA sequencing of neutrophils from healthy human blood, arthritic blood and arthritic synovial fluid, comparing transcriptional signatures with those from murine K/BxN serum transfer arthritis. We employed mass cytometry to quantify protein expression and sought to reproduce the synovial fluid phenotype ex vivo in cultured healthy blood neutrophils. RESULTS: Blood neutrophils from healthy donors and patients with active arthritis showed largely similar transcriptional signatures. By contrast, synovial fluid neutrophils exhibited more than 1600 differentially expressed genes. Gene signatures identified a prominent response to interferon gamma (IFN-γ), as well as to tumour necrosis factor, interleukin-6 and hypoxia, in both humans and mice. Mass cytometry confirmed that healthy and arthritic donor blood neutrophils are largely indistinguishable but revealed a range of neutrophil phenotypes in synovial fluid defined by downregulation of CXCR1 and upregulation of FcγRI, HLA-DR, PD-L1, ICAM-1 and CXCR4. Reproduction of key elements of this signature in cultured blood neutrophils required both IFN-γ and prolonged culture. CONCLUSIONS: Circulating neutrophils from patients with arthritis resemble those from healthy controls, but joint fluid cells exhibit a network of changes, conserved across species, that implicate IFN-γ response and ageing as complementary drivers of the synovial fluid neutrophil phenotype.


Assuntos
Artrite , Neutrófilos , Envelhecimento , Animais , Artrite/metabolismo , Humanos , Interferon gama/metabolismo , Camundongos , Neutrófilos/metabolismo , Fenótipo , Líquido Sinovial/metabolismo
7.
Immunol Rev ; 307(1): 191-202, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35103314

RESUMO

Pathologic T cell-B cell interactions underlie many autoimmune diseases. The T cells that help B cells in autoimmune diseases vary in phenotype and include T cells that lack typical features of T follicular helper cells, such as expression of CXCR5 and BCL6. A population of PD-1hi CXCR5- T peripheral helper (Tph) cells has now been recognized in multiple autoantibody-associated diseases. Tph cells display a distinctive set of features, merging the ability to provide B cell help with the capacity to migrate to inflamed peripheral tissues. Here, we review the scope of immune-related conditions in which Tph cells have been implicated and provide a perspective on their potential contributions to pathologic B cell activation in autoimmune diseases. We discuss Tph cells as a promising therapeutic strategy in autoimmunity and consider the utility of tracking Tph cells in blood as a biomarker to quantify aberrant T cell-B cell activation in patients with autoimmune diseases.


Assuntos
Doenças Autoimunes , Linfócitos T Auxiliares-Indutores , Doenças Autoimunes/metabolismo , Linfócitos B , Humanos , Ativação Linfocitária , Receptores CXCR5/metabolismo
8.
Nat Immunol ; 23(3): 446-457, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35177831

RESUMO

T cells acquire a regulatory phenotype when their T cell antigen receptors (TCRs) experience an intermediate- to high-affinity interaction with a self-peptide presented via the major histocompatibility complex (MHC). Using TCRß sequences from flow-sorted human cells, we identified TCR features that promote regulatory T cell (Treg) fate. From these results, we developed a scoring system to quantify TCR-intrinsic regulatory potential (TiRP). When applied to the tumor microenvironment, TiRP scoring helped to explain why only some T cell clones maintained the conventional T cell (Tconv) phenotype through expansion. To elucidate drivers of these predictive TCR features, we then examined the two elements of the Treg TCR ligand separately: the self-peptide and the human MHC class II molecule. These analyses revealed that hydrophobicity in the third complementarity-determining region (CDR3ß) of the TCR promotes reactivity to self-peptides, while TCR variable gene (TRBV gene) usage shapes the TCR's general propensity for human MHC class II-restricted activation.


Assuntos
Receptores de Antígenos de Linfócitos T alfa-beta , Receptores de Antígenos de Linfócitos T , Linhagem da Célula , Regiões Determinantes de Complementaridade/genética , Peptídeos , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Linfócitos T Reguladores
9.
Artigo em Inglês | MEDLINE | ID: mdl-35212719

RESUMO

OBJECTIVE: Delayed detection of lupus nephritis associates with worse outcomes. There are conflicting recommendations regarding a threshold level of proteinuria at which biopsy will likely yield actionable management. This study addressed the association of urine protein creatinine ratios (UPCR) with clinical characteristics and investigated the incidence of proliferative and membranous histology in patients with a UPCR between 0.5 and 1. METHODS: 275 SLE patients (113 first biopsy, 162 repeat) were enrolled in the multicentre multi-ethnic/racial Accelerating Medicines Partnership across 15 U.S. sites at the time of a clinically indicated renal biopsy. Patients were followed for 1 year. RESULTS: At biopsy, 54 patients had UPCR <1 and 221 had UPCR >1. Independent of UPCR or biopsy number, a majority (92%) of patients had class III, IV, V or mixed histology. Moreover, patients with UPCR <1 and class III, IV, V, or mixed had a median activity index of 4.5 and chronicity index of 3, yet 39% of these patients had an inactive sediment. Neither anti-dsDNA nor low complement distinguished class I or II from III, IV, V, or mixed in patients with UPCR <1. Of 29 patients with baseline UPCR <1 and class III, IV, V or mixed, 23 (79%) had a UPCR <0.5 at one year. CONCLUSION: In this prospective study three quarters of patients with UPCR <1 had histology showing class III, IV, V or mixed with accompanying activity and chronicity despite an inactive sediment or normal serologies. These data support renal biopsy at thresholds lower than a UPCR of 1.

10.
Sci Immunol ; 7(68): eabf2846, 2022 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-35148199

RESUMO

Macrophages regulate protective immune responses to infectious microbes, but aberrant macrophage activation frequently drives pathological inflammation. To identify regulators of vigorous macrophage activation, we analyzed RNA-seq data from synovial macrophages and identified SLAMF7 as a receptor associated with a superactivated macrophage state in rheumatoid arthritis. We implicated IFN-γ as a key regulator of SLAMF7 expression and engaging SLAMF7 drove a strong wave of inflammatory cytokine expression. Induction of TNF-α after SLAMF7 engagement amplified inflammation through an autocrine signaling loop. We observed SLAMF7-induced gene programs not only in macrophages from rheumatoid arthritis patients but also in gut macrophages from patients with active Crohn's disease and in lung macrophages from patients with severe COVID-19. This suggests a central role for SLAMF7 in macrophage superactivation with broad implications in human disease pathology.


Assuntos
Inflamação/imunologia , Ativação de Macrófagos/imunologia , Família de Moléculas de Sinalização da Ativação Linfocitária/imunologia , Transcriptoma/imunologia , Doença Aguda , Adulto , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , COVID-19/genética , COVID-19/imunologia , COVID-19/metabolismo , COVID-19/virologia , Células Cultivadas , Doença Crônica , Doença de Crohn/genética , Doença de Crohn/imunologia , Doença de Crohn/metabolismo , Feminino , Humanos , Inflamação/genética , Inflamação/metabolismo , Ativação de Macrófagos/genética , RNA-Seq/métodos , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologia , Família de Moléculas de Sinalização da Ativação Linfocitária/genética , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Análise de Célula Única/métodos , Membrana Sinovial/imunologia , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , Transcriptoma/genética
11.
Arthritis Rheumatol ; 74(3): 441-452, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34435471

RESUMO

OBJECTIVE: Findings from recent transcriptome analyses of the synovium of patients with rheumatoid arthritis (RA) have revealed that 15-fold expanded HLA-DR+CD90+ synovial fibroblasts potentially act as key mediators of inflammation. The reasons for the expansion of HLA-DR+CD90+ synovial fibroblasts are unclear, but genetic signatures indicate that interferon-γ (IFNγ) plays a central role in the generation of this fibroblast subset. The present study was undertaken to investigate the generation, function and therapeutically intended blockage of HLA-DR+CD90+ synovial fibroblasts. METHODS: We combined functional assays using primary human materials and focused bioinformatic analyses of mass cytometry and transcriptomics patient data sets. RESULTS: We detected enriched and activated Fcγ receptor type IIIa-positive (CD16+) NK cells in the synovial tissue from patients with active RA. Soluble immune complexes were recognized by CD16 in a newly described reporter cell model, a mechanism that could be contributing to the activation of natural killer (NK) cells in RA. In vitro, NK cell-derived IFNγ induced HLA-DR on CD90+ synovial fibroblasts, leading to an inflammatory, cytokine-secreting HLA-DR+CD90+ phenotype. HLA-DR+CD90+ synovial fibroblasts consecutively activated CD4+ T cells upon receptor crosslinking via superantigens. HLA-DR+CD90+ synovial fibroblasts also activated CD4+ T cells in the absence of superantigens, an effect that was initiated by NK cell-derived IFNγ and that was 4 times stronger in patients with RA compared to patients with osteoarthritis. Finally, JAK inhibition in synovial fibroblasts prevented HLA-DR induction and blocked proinflammatory signals to T cells. CONCLUSION: The HLA-DR+CD90+ phenotype represents an activation state of synovial fibroblasts during the process of inflammation in RA that can be induced by IFNγ, likely generated from infiltrating leukocytes such as activated NK cells. The induction of these proinflammatory, interleukin-6-producing, and likely antigen-presenting synovial fibroblasts can be targeted by JAK inhibition.


Assuntos
Artrite Reumatoide/metabolismo , Fibroblastos/efeitos dos fármacos , Antígenos HLA-DR/metabolismo , Interferon gama/farmacologia , Líquido Sinovial/metabolismo , Membrana Sinovial/metabolismo , Antígenos Thy-1/metabolismo , Artrite Reumatoide/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/patologia
12.
Arthritis Rheumatol ; 74(5): 829-839, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-34783463

RESUMO

OBJECTIVE: Current lupus nephritis (LN) treatments are effective in only 30% of patients, emphasizing the need for novel therapeutic strategies. We undertook this study to develop mechanistic hypotheses and explore novel biomarkers by analyzing the longitudinal urinary proteomic profiles in LN patients undergoing treatment. METHODS: We quantified 1,000 urinary proteins in 30 patients with LN at the time of the diagnostic renal biopsy and after 3, 6, and 12 months. The proteins and molecular pathways detected in the urine proteome were then analyzed with respect to baseline clinical features and longitudinal trajectories. The intrarenal expression of candidate biomarkers was evaluated using single-cell transcriptomics of renal biopsy sections from LN patients. RESULTS: Our analysis revealed multiple biologic pathways, including chemotaxis, neutrophil activation, platelet degranulation, and extracellular matrix organization, which could be noninvasively quantified and monitored in the urine. We identified 237 urinary biomarkers associated with LN, as compared to controls without systemic lupus erythematosus. Interleukin-16 (IL-16), CD163, and transforming growth factor ß mirrored intrarenal nephritis activity. Response to treatment was paralleled by a reduction in urinary IL-16, a CD4 ligand with proinflammatory and chemotactic properties. Single-cell RNA sequencing independently demonstrated that IL16 is the second most expressed cytokine by most infiltrating immune cells in LN kidneys. IL-16-producing cells were found at key sites of kidney injury. CONCLUSION: Urine proteomics may profoundly change the diagnosis and management of LN by noninvasively monitoring active intrarenal biologic pathways. These findings implicate IL-16 in LN pathogenesis, designating it as a potentially treatable target and biomarker.


Assuntos
Produtos Biológicos , Nefrite Lúpica , Biomarcadores/metabolismo , Feminino , Humanos , Interleucina-16/genética , Interleucina-16/metabolismo , Rim/patologia , Nefrite Lúpica/patologia , Masculino , Proteômica/métodos , Transcriptoma
13.
Methods Mol Biol ; 2380: 59-76, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34802122

RESUMO

T peripheral helper (Tph) cells represent a T cell population that stimulates B cell responses within peripheral tissues. Like T follicular helper (Tfh) cells, PD-1hi CXCR5- CD4+ Tph cells produce IL-21 and CXCL13, yet these cells differ from Tfh cells in expression of both transcription factors and chemokine receptors. Originally identified in rheumatoid arthritis synovium, Tph cells are expanded in multiple autoimmune diseases. Tph cells can be identified and distinguished from Tfh cells by both flow cytometry and mass cytometry. Here, we describe detailed methods to identify Tph cells and characterize associated phenotypic features and functions. These protocols and additional notes provide a guide to identify and explore the roles of Tph cells in various human diseases.


Assuntos
Linfócitos T Auxiliares-Indutores , Artrite Reumatoide , Linfócitos B , Humanos , Interleucinas , Receptores CXCR5 , Membrana Sinovial
14.
Cell Rep ; 37(4): 109902, 2021 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-34706228

RESUMO

Rheumatoid arthritis is a systemic autoimmune disease, but disease flares typically affect only a subset of joints, distributed in a distinctive pattern for each patient. Pursuing this intriguing pattern, we show that arthritis recurrence is mediated by long-lived synovial resident memory T cells (TRM). In three murine models, CD8+ cells bearing TRM markers remain in previously inflamed joints during remission. These cells are bona fide TRM, exhibiting a failure to migrate between joints, preferential uptake of fatty acids, and long-term residency. Disease flares result from TRM activation by antigen, leading to CCL5-mediated recruitment of circulating effector cells. Correspondingly, TRM depletion ameliorates recurrence in a site-specific manner. Human rheumatoid arthritis joint tissues contain a comparable CD8+-predominant TRM population, which is most evident in late-stage leukocyte-poor synovium, exhibiting limited T cell receptor diversity and a pro-inflammatory transcriptomic signature. Together, these findings establish synovial TRM as a targetable mediator of disease chronicity in autoimmune arthritis.


Assuntos
Artrite Reumatoide/imunologia , Linfócitos T CD8-Positivos/imunologia , Membrana Sinovial/imunologia , Transcriptoma/imunologia , Animais , Artrite Reumatoide/patologia , Linfócitos T CD8-Positivos/patologia , Humanos , Camundongos , Camundongos Knockout , Membrana Sinovial/patologia
15.
J Clin Invest ; 131(18)2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34343136

RESUMO

IL-1ß is a proinflammatory mediator with roles in innate and adaptive immunity. Here we show that IL-1ß contributes to autoimmune arthritis by inducing osteoclastogenic capacity in Tregs. Using mice with joint inflammation arising through deficiency of the IL-1 receptor antagonist (Il1rn-/-), we observed that IL-1ß blockade attenuated disease more effectively in early arthritis than in established arthritis, especially with respect to bone erosion. Protection was accompanied by a reduction in synovial CD4+Foxp3+ Tregs that displayed preserved suppressive capacity and aerobic metabolism but aberrant expression of RANKL and a striking capacity to drive RANKL-dependent osteoclast differentiation. Both Il1rn-/- Tregs and wild-type Tregs differentiated with IL-1ß accelerated bone erosion upon adoptive transfer. Human Tregs exhibited analogous differentiation, and corresponding RANKLhiFoxp3+ T cells could be identified in rheumatoid arthritis synovial tissue. Together, these findings identify IL-1ß-induced osteoclastogenic Tregs as a contributor to bone erosion in arthritis.


Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Interleucina-1beta/imunologia , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Artrite Experimental/etiologia , Artrite Experimental/patologia , Artrite Reumatoide/etiologia , Artrite Reumatoide/patologia , Diferenciação Celular/imunologia , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/deficiência , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Osteoclastos/imunologia , Osteoclastos/patologia , Osteogênese/imunologia , Ligante RANK/imunologia , Linfócitos T Reguladores/metabolismo
16.
Lupus Sci Med ; 8(1)2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34389634

RESUMO

OBJECTIVES: In lupus nephritis the pathological diagnosis from tissue retrieved during kidney biopsy drives treatment and management. Despite recent approval of new drugs, complete remission rates remain well under aspirational levels, necessitating identification of new therapeutic targets by greater dissection of the pathways to tissue inflammation and injury. This study assessed the safety of kidney biopsies in patients with SLE enrolled in the Accelerating Medicines Partnership, a consortium formed to molecularly deconstruct nephritis. METHODS: 475 patients with SLE across 15 clinical sites in the USA consented to obtain tissue for research purposes during a clinically indicated kidney biopsy. Adverse events (AEs) were documented for 30 days following the procedure and were determined to be related or unrelated by all site investigators. Serious AEs were defined according to the National Institutes of Health reporting guidelines. RESULTS: 34 patients (7.2%) experienced a procedure-related AE: 30 with haematoma, 2 with jets, 1 with pain and 1 with an arteriovenous fistula. Eighteen (3.8%) experienced a serious AE requiring hospitalisation; four patients (0.8%) required a blood transfusion related to the kidney biopsy. At one site where the number of cores retrieved during the biopsy was recorded, the mean was 3.4 for those who experienced a related AE (n=9) and 3.07 for those who did not experience any AE (n=140). All related AEs resolved. CONCLUSIONS: Procurement of research tissue should be considered feasible, accompanied by a complication risk likely no greater than that incurred for standard clinical purposes. In the quest for targeted treatments personalised based on molecular findings, enhanced diagnostics beyond histology will likely be required.


Assuntos
Fístula Arteriovenosa , Nefrite Lúpica , Biópsia , Hematoma , Humanos , Rim , Nefrite Lúpica/tratamento farmacológico , Estados Unidos
17.
ACR Open Rheumatol ; 3(9): 601-613, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34255929

RESUMO

High-dimensional analyses of tissue samples from patients with rheumatic diseases are providing increasingly detailed descriptions of the immune cell populations that infiltrate tissues in different rheumatic diseases. Here we review key observations emerging from high-dimensional analyses of T cells within tissues in different rheumatic diseases, highlighting common themes across diseases as well as distinguishing features. Single-cell RNA sequencing analyses capture several dimensions of T-cell states, yet surprisingly, these analyses generally have not demonstrated distinct clusters of paradigmatic T-cell effector subsets, such as T helper (Th) 1, Th2, and Th17 cells. Rather, global transcriptomics robustly identify both proliferating T cells and regulatory T cells and have also helped to reveal new effector subsets in inflamed tissues, including T peripheral helper cells and granzyme K+ T cells. Further characterization of the T-cell populations that accumulate within target tissues should enable more precise targeting of biologic therapies and accelerate development of more specific biomarkers to track activity of relevant immune pathways in patients with rheumatic diseases.

18.
Rheum Dis Clin North Am ; 47(3): 335-350, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34215367

RESUMO

The Accelerating Medicines Partnership (AMP) SLE Network united resources from academic centers, government, nonprofit, and industry to accelerate discovery in lupus nephritis (LN). The AMP SLE Network developed a set of protocols for high-throughput analyses to systematically study kidney tissue, urine, and blood in LN. This article summarizes approaches and results from phase 1 of AMP SLE Network effort, including single cell RNA-seq analysis of LN kidney biopsies, cellular and proteomic studies of LN urine, and mass cytometry immunophenotyping of blood cells. This work provides a framework to guide studies of the clinical implications of active cellular/molecular pathways in LN.


Assuntos
Nefrite Lúpica , Biomarcadores , Biópsia , Humanos , Nefrite Lúpica/tratamento farmacológico , Proteômica , Biologia de Sistemas
20.
Front Immunol ; 12: 623716, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33717128

RESUMO

Giant cell arteritis (GCA) is a granulomatous systemic vasculitis of large- and medium-sized arteries that affects the elderly. In recent years, advances in diagnostic imaging have revealed a greater degree of large vessel involvement than previously recognized, distinguishing classical cranial- from large vessel (LV)- GCA. GCA often co-occurs with the poorly understood inflammatory arthritis/bursitis condition polymyalgia rheumatica (PMR) and has overlapping features with other non-infectious granulomatous vasculitides that affect the aorta, namely Takayasu Arteritis (TAK) and the more recently described clinically isolated aortitis (CIA). Here, we review the literature focused on the immunopathology of GCA on the background of the three settings in which comparisons are informative: LV and cranial variants of GCA; PMR and GCA; the three granulomatous vasculitides (GCA, TAK, and CIA). We discuss overlapping and unique features between these conditions across clinical presentation, epidemiology, imaging, and conventional histology. We propose a model of GCA where abnormally activated circulating cells, especially monocytes and CD4+ T cells, enter arteries after an unknown stimulus and cooperate to destroy it and review the evidence for how this mechanistically occurs in active disease and improves with treatment.


Assuntos
Aorta/patologia , Arterite de Células Gigantes/patologia , Arterite de Takayasu/patologia , Artérias Temporais/patologia , Animais , Aorta/imunologia , Aorta/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Arterite de Células Gigantes/epidemiologia , Arterite de Células Gigantes/imunologia , Arterite de Células Gigantes/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Arterite de Takayasu/epidemiologia , Arterite de Takayasu/imunologia , Arterite de Takayasu/metabolismo , Artérias Temporais/imunologia , Artérias Temporais/metabolismo
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