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1.
JCI Insight ; 5(12)2020 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-32396533

RESUMO

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.

2.
Arthritis Care Res (Hoboken) ; 72(2): 233-242, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31502417

RESUMO

The Accelerating Medicines Partnership (AMP) Lupus Network was established as a partnership between the National Institutes of Health, pharmaceutical companies, nonprofit stakeholders, and lupus investigators across multiple academic centers to apply high-throughput technologies to the analysis of renal tissue, urine, and blood from patients with lupus nephritis (LN). The AMP network provides publicly accessible data to the community with the goal of generating new scientific hypotheses and improving diagnostic and therapeutic tools so as to improve disease outcomes. We present here a description of the structure of the AMP Lupus Network and a summary of the preliminary results from the phase 1 studies. The successful completion of phase 1 sets the stage for analysis of a large cohort of LN samples in phase 2 and provides a model for establishing similar discovery cohorts.


Assuntos
Centros Médicos Acadêmicos/organização & administração , Ensaios Clínicos Fase I como Assunto/métodos , Indústria Farmacêutica/organização & administração , Nefrite Lúpica/metabolismo , National Institutes of Health (U.S.)/organização & administração , Dados Preliminares , Parcerias Público-Privadas/organização & administração , Biomarcadores/metabolismo , Humanos , Nefrite Lúpica/epidemiologia , Nefrite Lúpica/genética , Análise de Sequência de RNA/métodos , Estados Unidos/epidemiologia
3.
Nat Rev Nephrol ; 16(4): 238-250, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31853010

RESUMO

The immune mechanisms that cause tissue injury in lupus nephritis have been challenging to define. The advent of high-dimensional cellular analyses, such as single-cell RNA sequencing, has enabled detailed characterization of the cell populations present in small biopsy samples of kidney tissue. In parallel, the development of methods that cryopreserve kidney biopsy specimens in a manner that preserves intact, viable cells, has enabled the uniform analysis of tissue samples collected at multiple sites and across many geographic areas and demographic cohorts with high-dimensional platforms. The application of these methods to kidney biopsy samples from patients with lupus nephritis has begun to define the phenotypes of both infiltrating and resident immune cells, as well as parenchymal cells, present in nephritic kidneys. The detection of similar immune cell populations in urine suggests that it might be possible to non-invasively monitor immune activation in kidneys. Once applied to large patient cohorts, these high-dimensional studies might enable patient stratification according to patterns of immune cell activation in the kidney or identify disease features that can be used as surrogate measures of efficacy in clinical trials. Applied broadly across multiple inflammatory kidney diseases, these studies promise to enormously expand our understanding of renal inflammation in the next decade.


Assuntos
Células Epiteliais/imunologia , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Sequenciamento Completo do Exoma/métodos , Biópsia por Agulha , Células Epiteliais/patologia , Feminino , Humanos , Imuno-Histoquímica , Nefrite Lúpica/genética , Masculino , Biologia Molecular/métodos , Sensibilidade e Especificidade , Análise de Sequência de RNA
4.
JCI Insight ; 4(20)2019 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-31536480

RESUMO

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by pathologic T cell-B cell interactions and autoantibody production. Defining the T cell populations that drive B cell responses in SLE may enable design of therapies that specifically target pathologic cell subsets. Here, we evaluated the phenotypes of CD4+ T cells in the circulation of 52 SLE patients drawn from multiple cohorts and identified a highly expanded PD-1hiCXCR5-CD4+ T cell population. Cytometric, transcriptomic, and functional assays demonstrated that PD-1hiCXCR5-CD4+ T cells from SLE patients are T peripheral helper (Tph) cells, a CXCR5- T cell population that stimulates B cell responses via IL-21. The frequency of Tph cells, but not T follicular helper (Tfh) cells, correlated with both clinical disease activity and the frequency of CD11c+ B cells in SLE patients. PD-1hiCD4+ T cells were found within lupus nephritis kidneys and correlated with B cell numbers in the kidney. Both IL-21 neutralization and CRISPR-mediated deletion of MAF abrogated the ability of Tph cells to induce memory B cell differentiation into plasmablasts in vitro. These findings identify Tph cells as a highly expanded T cell population in SLE and suggest a key role for Tph cells in stimulating pathologic B cell responses.


Assuntos
Linfócitos B/imunologia , Interleucinas/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Proteínas Proto-Oncogênicas c-maf/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Adulto , Idoso , Antígeno CD11c/metabolismo , Sistemas CRISPR-Cas/genética , Estudos de Casos e Controles , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/genética , Comunicação Celular/imunologia , Técnicas de Cultura de Células , Separação Celular , Células Cultivadas , Técnicas de Cocultura , Feminino , Citometria de Fluxo , Técnicas de Inativação de Genes , Humanos , Interleucinas/antagonistas & inibidores , Lúpus Eritematoso Sistêmico/sangue , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/genética , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/metabolismo , Proteínas Proto-Oncogênicas c-maf/genética , RNA-Seq , Receptores CXCR5/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo
6.
Nat Immunol ; 20(7): 902-914, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209404

RESUMO

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.


Assuntos
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
7.
Cancer Immunol Immunother ; 68(3): 421-432, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30564891

RESUMO

Targeting immune checkpoint pathways, such as programmed death ligand-1 (PD-L1, also known as CD274 or B7-H1) or its receptor programmed cell death-1 (PD-1) has shown improved survival for patients with numerous types of cancers, not limited to lung cancer, melanoma, renal cell carcinoma, and Hodgkin lymphoma. PD-L1 is a co-inhibitory molecule whose expression on the surface of tumor cells is associated with worse prognosis in many tumors. Here we describe a splice variant (secPD-L1) that does not splice into the transmembrane domain, but instead produces a secreted form of PD-L1 that has a unique 18 amino acid tail containing a cysteine that allows it to homodimerize and more effectively inhibit lymphocyte function than monomeric soluble PD-L1. We show that recombinant secPD-L1 can dimerize and inhibit T-cell proliferation and IFN-gamma production in vitro. The secPD-L1 variant is expressed by malignant cells in vitro that also express high levels of full-length PD-L1. Transcriptomic analysis of gene expression across The Cancer Genome Atlas found the strongest association of secPD-L1 with full-length PD-L1, but also with subsets of immunologic genes, such as in myeloid-derived suppressor cells. Moreover, the splice variant is also expressed in normal tissues and within normal peripheral blood cells it is preferentially expressed in activated myeloid cells. This is the first report of a form of secreted PD-L1 that homodimerizes and is functionally active. SecPD-L1 may function as a paracrine negative immune regulator within the tumor, since secPD-L1 does not require a cell-to-cell interaction to mediate its inhibitory effect.


Assuntos
Antígeno B7-H1/genética , Imunossupressores/farmacologia , Multimerização Proteica , Processamento de RNA , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/química , Antígeno B7-H1/farmacologia , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica , Humanos , Células Supressoras Mieloides/fisiologia , Placenta/metabolismo , Gravidez , Microambiente Tumoral
8.
Cell Metab ; 25(3): 727-738, 2017 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-28190773

RESUMO

Type 1 diabetes (T1D) is a chronic autoimmune disease that involves immune-mediated destruction of ß cells. How ß cells respond to immune attack is unknown. We identified a population of ß cells during the progression of T1D in non-obese diabetic (NOD) mice that survives immune attack. This population develops from normal ß cells confronted with islet infiltrates. Pathways involving cell movement, growth and proliferation, immune responses, and cell death and survival are activated in these cells. There is reduced expression of ß cell identity genes and diabetes antigens and increased immune inhibitory markers and stemness genes. This new subpopulation is resistant to killing when diabetes is precipitated with cyclophosphamide. Human ß cells show similar changes when cultured with immune cells. These changes may account for the chronicity of the disease and the long-term survival of ß cells in some patients.


Assuntos
Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Progressão da Doença , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/patologia , Animais , Anticorpos Monoclonais/farmacologia , Complexo CD3/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Células Cultivadas , Feminino , Humanos , Imunoterapia , Células Secretoras de Insulina/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Linfócitos/patologia , Camundongos Endogâmicos NOD , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de RNA , Transcrição Genética/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Transcriptoma/genética
9.
Semin Immunol ; 25(3): 193-200, 2013 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-23375135

RESUMO

Systems immunology is an emerging paradigm that aims at a more systematic and quantitative understanding of the immune system. Two major approaches have been utilized to date in this field: unbiased data-driven modeling to comprehensively identify molecular and cellular components of a system and their interactions; and hypothesis-based quantitative modeling to understand the operating principles of a system by extracting a minimal set of variables and rules underlying them. In this review, we describe applications of the two approaches to the study of viral infections and autoimmune diseases in humans, and discuss possible ways by which these two approaches can synergize when applied to human immunology.


Assuntos
Alergia e Imunologia , Doenças Autoimunes/imunologia , Sistema Imunitário , Biologia de Sistemas , Viroses/imunologia , Medicina Baseada em Evidências , Humanos , Modelos Biológicos
10.
PLoS One ; 4(12): e8447, 2009 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-20041142

RESUMO

BACKGROUND: Regulatory T cells (Tregs) were shown to be central in maintaining immunological homeostasis and preventing the development of autoimmune diseases. Several subsets of Tregs have been identified to date; however, the dynamics of the interactions between these subsets, and their implications on their regulatory functions are yet to be elucidated. METHODOLOGY/PRINCIPAL FINDINGS: We employed a combination of mathematical modeling and frequent in vivo measurements of several T cell subsets. Healthy BALB/c mice received a single injection of either hCDR1--a tolerogenic peptide previously shown to induce Tregs, a control peptide or vehicle alone, and were monitored for 16 days. During this period, splenocytes from the treated mice were analyzed for the levels of CD4, CD25, CD8, CD28 and Foxp3. The collected data were then fitted to mathematical models, in order to test competing hypotheses regarding the interactions between the followed T cell subsets. In all 3 treatment groups, a significant, lasting, non-random perturbation of the immune system could be observed. Our analysis predicted the emergence of functional CD4 Tregs based on inverse oscillations of the latter and CD4(+)CD25(-) cells. Furthermore, CD4 Tregs seemed to require a sufficiently high level of CD8 Tregs in order to become functional, while conversion was unlikely to be their major source. Our results indicated in addition that Foxp3 is not a sufficient marker for regulatory activity. CONCLUSIONS/SIGNIFICANCE: In this work, we unraveled the dynamics of the interplay between CD4, CD8 Tregs and effector T cells, using, for the first time, a mathematical-mechanistic perspective in the analysis of Treg kinetics. Furthermore, the results obtained from this interdisciplinary approach supported the notion that CD4 Tregs need to interact with CD8 Tregs in order to become functional. Finally, we generated predictions regarding the time-dependent function of Tregs, which can be further tested empirically in future work.


Assuntos
Antígenos CD4/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Comunicação Celular , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Animais , Antígenos CD28/metabolismo , Antígenos CD8/metabolismo , Feminino , Citometria de Fluxo , Fatores de Transcrição Forkhead/metabolismo , Cinética , Subpopulações de Linfócitos/citologia , Subpopulações de Linfócitos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Modelos Imunológicos , Baço/citologia
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