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Havaiano Nativo ou Outro Ilhéu do Pacífico , Humanos , Austrália/epidemiologia , Hepatopatia Gordurosa não Alcoólica/etnologia , Hepatopatia Gordurosa não Alcoólica/terapia , Fígado Gorduroso/etnologia , Serviços de Saúde do Indígena/organização & administração , Povos Aborígenes Australianos e Ilhéus do Estreito de TorresRESUMO
Resident macrophages orchestrate homeostatic, inflammatory, and reparative activities. It is appreciated that different tissues instruct specialized macrophage functions. However, individual tissues contain heterogeneous subpopulations, and how these subpopulations are related is unclear. We asked whether common transcriptional and functional elements could reveal an underlying framework across tissues. Using single-cell RNA sequencing and random forest modeling, we observed that four genes could predict three macrophage subsets that were present in murine heart, liver, lung, kidney, and brain. Parabiotic and genetic fate mapping studies revealed that these core markers predicted three unique life cycles across 17 tissues. TLF+ (expressing TIMD4 and/or LYVE1 and/or FOLR2) macrophages were maintained through self-renewal with minimal monocyte input; CCR2+ (TIMD4−LYVE1−FOLR2−) macrophages were almost entirely replaced by monocytes, and MHC-IIhi macrophages (TIMD4−LYVE1−FOLR2−CCR2−), while receiving modest monocyte contribution, were not continually replaced. Rather, monocyte-derived macrophages contributed to the resident macrophage population until they reached a defined upper limit after which they did not outcompete pre-existing resident macrophages. Developmentally, TLF+ macrophages were first to emerge in the yolk sac and early fetal organs. Fate mapping studies in the mouse and human single-cell RNA sequencing indicated that TLF+ macrophages originated from both yolk sac and fetal monocyte precursors. Furthermore, TLF+ macrophages were the most transcriptionally conserved subset across mouse tissues and between mice and humans, despite organ- and species-specific transcriptional differences. Here, we define the existence of three murine macrophage subpopulations based on common life cycle properties and core gene signatures and provide a common starting point to understand tissue macrophage heterogeneity.
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Receptor 2 de Folato/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Macrófagos/imunologia , Proteínas de Membrana/imunologia , Receptores CCR2/imunologia , Proteínas de Transporte Vesicular/imunologia , Animais , Estágios do Ciclo de Vida/imunologia , Ativação de Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores CCR2/deficiênciaRESUMO
Hypertension affects one-third of the world's population, leading to cardiac dysfunction that is modulated by resident and recruited immune cells. Cardiomyocyte growth and increased cardiac mass are essential to withstand hypertensive stress; however, whether immune cells are involved in this compensatory cardioprotective process is unclear. In normotensive animals, single-cell transcriptomics of fate-mapped self-renewing cardiac resident macrophages (RMs) revealed transcriptionally diverse cell states with a core repertoire of reparative gene programs, including high expression of insulin-like growth factor-1 (Igf1). Hypertension drove selective in situ proliferation and transcriptional activation of some cardiac RM states, directly correlating with increased cardiomyocyte growth. During hypertension, inducible ablation of RMs or selective deletion of RM-derived Igf1 prevented adaptive cardiomyocyte growth, and cardiac mass failed to increase, which led to cardiac dysfunction. Single-cell transcriptomics identified a conserved IGF1-expressing macrophage subpopulation in human cardiomyopathy. Here we defined the absolute requirement of RM-produced IGF-1 in cardiac adaptation to hypertension.
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Adaptação Fisiológica/fisiologia , Hipertensão/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Macrófagos/metabolismo , Remodelação Ventricular/fisiologia , Animais , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Humanos , Hipertensão/complicações , Hipertensão/imunologia , Lactente , Masculino , Camundongos , Pessoa de Meia-Idade , Miocárdio/imunologia , Miocárdio/metabolismo , Miocárdio/patologiaRESUMO
RATIONALE: Bone marrow transplantation (BMT) is used frequently to study the role of hematopoietic cells in atherosclerosis, but aortic arch lesions are smaller in mice after BMT. OBJECTIVE: To identify the earliest stage of atherosclerosis inhibited by BMT and elucidate potential mechanisms. METHODS AND RESULTS: Ldlr-/- mice underwent total body γ-irradiation, bone marrow reconstitution, and 6-week recovery. Atherosclerosis was studied in the ascending aortic arch and compared with mice without BMT. In BMT mice, neutral lipid and myeloid cell topography were lower in lesions after feeding a cholesterol-rich diet for 3, 6, and 12 weeks. Lesion coalescence and height were suppressed dramatically in mice post-BMT, whereas lateral growth was inhibited minimally. Targeted radiation to the upper thorax alone reproduced the BMT phenotype. Classical monocyte recruitment, intimal myeloid cell proliferation, and apoptosis did not account for the post-BMT phenotype. Neutral lipid accumulation was reduced in 5-day lesions, thus we developed quantitative assays for LDL (low-density lipoprotein) accumulation and paracellular leakage using DiI-labeled human LDL and rhodamine B-labeled 70 kD dextran. LDL accumulation was dramatically higher in the intima of Ldlr-/- relative to Ldlr+/+ mice, and was inhibited by injection of HDL mimics, suggesting a regulated process. LDL, but not dextran, accumulation was lower in mice post-BMT both at baseline and in 5-day lesions. Since the transcript abundance of molecules implicated in LDL transcytosis was not significantly different in the post-BMT intima, transcriptomics from whole aortic arch intima, and at single-cell resolution, was performed to give insights into pathways modulated by BMT. CONCLUSIONS: Radiation exposure inhibits LDL entry into the aortic intima at baseline and the earliest stages of atherosclerosis. Single-cell transcriptomic analysis suggests that LDL uptake by endothelial cells is diverted to lysosomal degradation and reverse cholesterol transport pathways. This reduces intimal accumulation of lipid and impacts lesion initiation and growth.
Assuntos
Aterosclerose/metabolismo , Raios gama , Lipoproteínas LDL/metabolismo , Túnica Íntima/efeitos da radiação , Animais , Aorta/metabolismo , Aorta/efeitos da radiação , Camundongos , Camundongos Endogâmicos C57BL , Receptores de LDL/deficiência , Receptores de LDL/genética , Transcriptoma , Túnica Íntima/metabolismoRESUMO
High dimensional approaches that characterize single cells at unprecedented depth have helped uncover unappreciated heterogeneity, a better understanding of myeloid cell origins, developmental relationships and functions. These advancements are particularly important in cardiovascular disease, which remains the leading cause of death worldwide. Gradual, monocyte-dependent inflammatory processes, such as the development of atherosclerotic plaque within arterial vessels, contrasts with the robust acute response within the myocardium that occurs when a vessel is occluded. Monocytes and macrophages differentially contribute to tissue injury, repair and regeneration in these contexts, yet many questions remain about which myeloid cell types are involved in a coordinated, organ-level sterile inflammatory response. Single cell RNA sequencing, combined with functional analyses have demonstrated that at least three populations of resident cardiac macrophages exist, and after tissue injury, there is significant diversification of the tissue macrophage pool driven by recruited monocytes. While these studies have provided important insights, they raise many new questions and avenues for future exploration. For example, how do transcriptionally defined sub-populations of cardiac macrophages relate to each other? Are they different activation states along a pre-defined trajectory of macrophage differentiation or do local microenvironments drive newly recruited monocytes into distinct functions? The answers to these questions will require integration of high-dimensional approaches into biologically relevant in vivo experimental systems to ensure the predicted heterogeneity possess a functional outcome.
Assuntos
Doenças Cardiovasculares/imunologia , Macrófagos/imunologia , Monócitos/imunologia , Miocárdio/imunologia , Placa Aterosclerótica/imunologia , Análise de Célula Única , Animais , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Humanos , Macrófagos/patologia , Monócitos/patologia , Miocárdio/patologia , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologiaRESUMO
In the version of this article initially published, the equal contribution of the third author was omitted. The footnote links for that author should be "Sara Nejat1,11" and the correct statement is as follows: "11These authors contributed equally: Sarah A. Dick, Jillian A. Macklin, Sara Nejat." The error has been corrected in the HTML and PDF versions of the article.
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Macrophages promote both injury and repair after myocardial infarction, but discriminating functions within mixed populations remains challenging. Here we used fate mapping, parabiosis and single-cell transcriptomics to demonstrate that at steady state, TIMD4+LYVE1+MHC-IIloCCR2- resident cardiac macrophages self-renew with negligible blood monocyte input. Monocytes partially replaced resident TIMD4-LYVE1-MHC-IIhiCCR2- macrophages and fully replaced TIMD4-LYVE1-MHC-IIhiCCR2+ macrophages, revealing a hierarchy of monocyte contribution to functionally distinct macrophage subsets. Ischemic injury reduced TIMD4+ and TIMD4- resident macrophage abundance, whereas CCR2+ monocyte-derived macrophages adopted multiple cell fates within infarcted tissue, including those nearly indistinguishable from resident macrophages. Recruited macrophages did not express TIMD4, highlighting the ability of TIMD4 to track a subset of resident macrophages in the absence of fate mapping. Despite this similarity, inducible depletion of resident macrophages using a Cx3cr1-based system led to impaired cardiac function and promoted adverse remodeling primarily within the peri-infarct zone, revealing a nonredundant, cardioprotective role of resident cardiac macrophages.
Assuntos
Macrófagos/fisiologia , Infarto do Miocárdio/imunologia , Miocárdio/patologia , Animais , Receptor 1 de Quimiocina CX3C/metabolismo , Diferenciação Celular , Linhagem da Célula , Autorrenovação Celular , Perfilação da Expressão Gênica , Antígenos de Histocompatibilidade Classe II/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Parabiose , Receptores CCR2/genética , Receptores CCR2/metabolismo , Análise de Célula Única , Remodelação Ventricular , Proteínas de Transporte Vesicular/metabolismoAssuntos
Diabetes Mellitus Tipo 2/psicologia , Gerenciamento Clínico , Família/psicologia , Estilo de Vida Saudável , Hispânico ou Latino/psicologia , Adulto , Assistência à Saúde Culturalmente Competente , Diabetes Mellitus Tipo 2/terapia , Feminino , Grupos Focais , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Muscle-enriched lamin-interacting protein (Mlip) is an alternatively spliced gene whose splicing specificity is dictated by tissue type. MLIP is most abundantly expressed in brain, cardiac, and skeletal muscle. In the present study, we systematically mapped the transcriptional start and stop sites of murine Mlip Rapid amplification of cDNA ends (RACE) of Mlip transcripts from the brain, heart, and skeletal muscle revealed two transcriptional start sites (TSSs), exon 1a and exon 1b, and only one transcriptional termination site. RT-PCR analysis of the usage of the two identified TSSs revealed that the heart utilizes only exon 1a for MLIP expression, whereas the brain exclusively uses exon 1b TSS. Loss of Mlip exon 1a in mice resulted in a 7-fold increase in the prevalence of centralized nuclei in muscle fibers with the Mlip exon1a-deficient satellite cells on single fibers exhibiting a significant delay in commitment to a MYOD-positive phenotype. Furthermore, we demonstrate that the A-type lamin-binding domain in MLIP is encoded in exon 1a, indicating that MLIP isoforms generated with exon 1b TSS lack the A-type lamin-binding domain. Collectively these findings suggest that Mlip tissue-specific expression and alternative splicing play a critical role in determining MLIP's functions in mice.
Assuntos
Processamento Alternativo/genética , Proteínas de Transporte/genética , Regulação da Expressão Gênica/genética , Proteínas Nucleares/genética , Sítio de Iniciação de Transcrição , Sequência de Aminoácidos , Proteínas de Transporte/química , Proteínas de Transporte/metabolismo , Linhagem Celular , Proteínas Correpressoras , Éxons/genética , Humanos , Íntrons/genética , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Especificidade de Órgãos , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismoRESUMO
Innate and adaptive immune cells modulate heart failure pathogenesis during viral myocarditis, yet their identities and functions remain poorly defined. We utilized a combination of genetic fate mapping, parabiotic, transcriptional, and functional analyses and demonstrated that the heart contained two major conventional dendritic cell (cDC) subsets, CD103+ and CD11b+, which differentially relied on local proliferation and precursor recruitment to maintain their tissue residency. Following viral infection of the myocardium, cDCs accumulated in the heart coincident with monocyte infiltration and loss of resident reparative embryonic-derived cardiac macrophages. cDC depletion abrogated antigen-specific CD8+ T cell proliferative expansion, transforming subclinical cardiac injury to overt heart failure. These effects were mediated by CD103+ cDCs, which are dependent on the transcription factor BATF3 for their development. Collectively, our findings identified resident cardiac cDC subsets, defined their origins, and revealed an essential role for CD103+ cDCs in antigen-specific T cell responses during subclinical viral myocarditis.
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Antígenos CD/análise , Infecções por Cardiovirus/complicações , Células Dendríticas/imunologia , Vírus da Encefalomiocardite , Insuficiência Cardíaca/prevenção & controle , Cadeias alfa de Integrinas/análise , Miocardite/complicações , Animais , Antígeno CD11b/análise , Linfócitos T CD8-Positivos/imunologia , Infecções por Cardiovirus/imunologia , Movimento Celular , Feminino , Hematopoese , Memória Imunológica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miocardite/imunologia , Receptores CCR2/fisiologiaRESUMO
Hispanics in the United States experience significant health disparities. Using focus groups conducted in Spanish, we explored the perspectives of 172 Hispanic adults regarding their healthcare experiences. Many participants were women (64.5%) and primarily from Mexico (80%). Four major qualitative themes emerged: (a) provide us with information, (b) want attentive and respectful relationships, (c) want better care, and (d) perceived discrimination. Suboptimal patient-provider interactions were described. Research is needed to explore interventions that address these issues. Incorporating person-centered care principles and practices such as clear and understandable communication, culturally competent care, and customer service skills may benefit provider interactions with Hispanics.
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Atitude Frente a Saúde/etnologia , Diabetes Mellitus Tipo 2/terapia , Hispânico ou Latino , Diabetes Mellitus Tipo 2/etnologia , Família , Feminino , Grupos Focais , Disparidades em Assistência à Saúde , Hispânico ou Latino/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Pesquisa Qualitativa , Qualidade da Assistência à Saúde , Racismo/psicologiaRESUMO
As a greater proportion of patients survive their initial cardiac insult, medical systems worldwide are being faced with an ever-growing need to understand the mechanisms behind the pathogenesis of chronic heart failure (HF). There is a wealth of information about the role of inflammatory cells and pathways during acute injury and the reparative processes that are subsequently activated. We discuss the different causes that lead to chronic HF development and how the sum of initial inflammatory and reparative responses only sets the trajectory for disease progression. Unfortunately, comparatively little is known about the contribution of the immune system once the trajectory has been set, and chronic HF has been established-which clinically represents the majority of patients. It is known that chronic HF is associated with circulating inflammatory cytokines that can predict clinical outcomes, yet the causative role inflammation plays in disease progression is not well defined, and the majority of clinical trials that target aspects of inflammation in patients with chronic HF have largely been negative. This review will present what is currently known about inflammation in chronic HF in both humans and animal models as a means to highlight the gap in our knowledge base that requires further examination.
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Anti-Inflamatórios/uso terapêutico , Fármacos Cardiovasculares/uso terapêutico , Insuficiência Cardíaca/metabolismo , Animais , Ensaios Clínicos como Assunto , Citocinas/metabolismo , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/etiologia , HumanosRESUMO
The conventional CaCl2-H2O phase diagram is often used to describe how calcium chloride behaves when it is used on a concrete pavement undergoing freeze-thaw damage. However, the chemistry of the concrete can alter the appropriateness of using the CaCl2-H2O phase diagram. This study shows that the Ca(OH)2 present in a hydrated portland cement can interact with CaCl2 solution creating a behavior that is similar to that observed in isoplethal sections of a ternary phase diagram for a Ca(OH)2-CaCl2-H2O system. As such, it is suggested that such isoplethal sections provide a reasonable model that can be used to describe the behavior of concrete exposed to CaCl2 solution as the temperature changes. Specifically, the Ca(OH)2 can react with CaCl2 and H2O resulting in the formation of calcium oxychloride. The formation of the calcium oxychloride is expansive and can produce damage in concrete at temperatures above freezing. Its formation can also cause a significant decrease in fluid ingress into concrete. For solutions with CaCl2 concentrations greater than about 11.3 % (by mass), it is found that calcium oxychloride forms rapidly and is stable at room temperature (23 °C).
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Compensatory growth and regeneration of skeletal muscle is dependent on the resident stem cell population, satellite cells (SCs). Self-renewal and maintenance of the SC niche is coordinated by the paired-box transcription factor Pax7, and yet continued expression of this protein inhibits the myoblast differentiation program. As such, the reduction or removal of Pax7 may denote a key prerequisite for SCs to abandon self-renewal and acquire differentiation competence. Here, we identify caspase 3 cleavage inactivation of Pax7 as a crucial step for terminating the self-renewal process. Inhibition of caspase 3 results in elevated Pax7 protein and SC self-renewal, whereas caspase activation leads to Pax7 cleavage and initiation of the myogenic differentiation program. Moreover, in vivo inhibition of caspase 3 activity leads to a profound disruption in skeletal muscle regeneration with an accumulation of SCs within the niche. We have also noted that casein kinase 2 (CK2)-directed phosphorylation of Pax7 attenuates caspase-directed cleavage. Together, these results demonstrate that SC fate is dependent on opposing posttranslational modifications of the Pax7 protein.
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Caspase 3/metabolismo , Músculo Esquelético/metabolismo , Fator de Transcrição PAX7/metabolismo , Células Satélites de Músculo Esquelético/citologia , Sequência de Aminoácidos , Animais , Sítios de Ligação , Caseína Quinases/metabolismo , Diferenciação Celular , Linhagem da Célula , Células Cultivadas , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Fosforilação , Proteínas Recombinantes/metabolismo , Regeneração , Homologia de Sequência de Aminoácidos , Células-Tronco/citologiaRESUMO
BACKGROUND: Adult skeletal muscle regeneration is a highly orchestrated process involving the activation and proliferation of satellite cells, an adult skeletal muscle stem cell. Activated satellite cells generate a transient amplifying progenitor pool of myoblasts that commit to differentiation and fuse into multinucleated myotubes. During regeneration, canonical Wnt signalling is activated and has been implicated in regulating myogenic lineage progression and terminal differentiation. METHODS: Here, we have undertaken a gene expression analysis of committed satellite cell-derived myoblasts to examine their ability to respond to canonical Wnt/ß-catenin signalling. RESULTS: We found that activation of canonical Wnt signalling induces follistatin expression in myoblasts and promotes myoblast fusion in a follistatin-dependent manner. In growth conditions, canonical Wnt/ß-catenin signalling prime myoblasts for myogenic differentiation by stimulating myogenin and follistatin expression. We further found that myogenin binds elements in the follistatin promoter and thus acts downstream of myogenin during differentiation. Finally, ectopic activation of canonical Wnt signalling in vivo promoted premature differentiation during muscle regeneration following acute injury. CONCLUSIONS: Together, these data reveal a novel mechanism by which myogenin mediates the canonical Wnt/ß-catenin-dependent activation of follistatin and induction of the myogenic differentiation process.
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Cardiomyocyte hypertrophy is the cellular response that mediates pathologic enlargement of the heart. This maladaptation is also characterized by cell behaviors that are typically associated with apoptosis, including cytoskeletal reorganization and disassembly, altered nuclear morphology, and enhanced protein synthesis/translation. Here, we investigated the requirement of apoptotic caspase pathways in mediating cardiomyocyte hypertrophy. Cardiomyocytes treated with hypertrophy agonists displayed rapid and transient activation of the intrinsic-mediated cell death pathway, characterized by elevated levels of caspase 9, followed by caspase 3 protease activity. Disruption of the intrinsic cell death pathway at multiple junctures led to a significant inhibition of cardiomyocyte hypertrophy during agonist stimulation, with a corresponding reduction in the expression of known hypertrophic markers (atrial natriuretic peptide) and transcription factor activity [myocyte enhancer factor-2, nuclear factor kappa B (NF-κB)]. Similarly, in vivo attenuation of caspase activity via adenoviral expression of the biologic effector caspase inhibitor p35 blunted cardiomyocyte hypertrophy in response to agonist stimulation. Treatment of cardiomyocytes with procaspase 3 activating compound 1, a small-molecule activator of caspase 3, resulted in a robust induction of the hypertrophy response in the absence of any agonist stimulation. These results suggest that caspase-dependent signaling is necessary and sufficient to promote cardiomyocyte hypertrophy. These results also confirm that cell death signal pathways behave as active remodeling agents in cardiomyocytes, independent of inducing an apoptosis response.
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Cardiomegalia/enzimologia , Caspase 3/metabolismo , Caspase 9/metabolismo , Miócitos Cardíacos/enzimologia , Angiotensina II/farmacologia , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Broncodilatadores/farmacologia , Cardiomegalia/patologia , Células Cultivadas , Inibidores de Cisteína Proteinase/farmacologia , Endotelina-1/farmacologia , Ativação Enzimática/efeitos dos fármacos , Imunofluorescência , Hipertrofia , Técnicas In Vitro , Isoproterenol/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Miocárdio/enzimologia , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Oligopeptídeos/farmacologia , Fenilefrina/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Vasoconstritores/farmacologiaRESUMO
Programmed cell death (PCD) or apoptosis is a broadly conserved phenomenon in metazoans, whereby activation of canonical signal pathways induces an ordered dismantling and death of a cell. Paradoxically, the constituent proteins and pathways of PCD (most notably the metacaspase/caspase protease mediated signal pathways) have been demonstrated to retain non-death functions across all phyla including yeast, nematodes, drosophila, and mammals. The ancient conservation of both death and non-death functions of PCD proteins raises an interesting evolutionary conundrum: was the primordial intent of these factors to induce cell death or to regulate other cellular adaptations? Here, we propose the hypothesis that apoptotic behavior of PCD proteins evolved or were co-opted from core non-death functions.
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Adaptação Fisiológica/fisiologia , Proteínas Reguladoras de Apoptose/fisiologia , Apoptose/fisiologia , Animais , Proteínas Reguladoras de Apoptose/genética , Caspases/metabolismo , Diferenciação Celular , Eucariotos/citologia , Eucariotos/metabolismo , Evolução Molecular , Fosfatidilserinas/metabolismo , Transdução de SinaisRESUMO
Expression of the cell surface sialomucin CD34 is common to many adult stem cell types, including muscle satellite cells. However, no clear stem cell or regeneration-related phenotype has ever been reported in mice lacking CD34, and its function on these cells remains poorly understood. Here, we assess the functional role of CD34 on satellite cell-mediated muscle regeneration. We show that Cd34(-/-) mice, which have no obvious developmental phenotype, display a defect in muscle regeneration when challenged with either acute or chronic muscle injury. This regenerative defect is caused by impaired entry into proliferation and delayed myogenic progression. Consistent with the reported antiadhesive function of CD34, knockout satellite cells also show decreased motility along their host myofiber. Altogether, our results identify a role for CD34 in the poorly understood early steps of satellite cell activation and provide the first evidence that beyond being a stem cell marker, CD34 may play an important function in modulating stem cell activity.
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Antígenos CD34/metabolismo , Movimento Celular , Proliferação de Células , Músculo Esquelético/fisiologia , Regeneração , Células Satélites de Músculo Esquelético/citologia , Animais , Antígenos CD34/genética , Venenos Elapídicos/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Confocal , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/lesões , Mutação Puntual , Células Satélites de Músculo Esquelético/fisiologia , Imagem com Lapso de TempoRESUMO
A major obstacle in performing multicenter controlled trials for pemphigus is the lack of a validated disease activity scoring system. Here, we assess the reliability and convergent validity of the PDAI (pemphigus disease area index). A group of 10 dermatologists scored 15 patients with pemphigus to estimate the inter- and intra-rater reliability of the PDAI and the recently described ABSIS (autoimmune bullous skin disorder intensity score) instrument. To assess convergent validity, these tools were also correlated with the Physician's Global Assessment (PGA). Reliability studies demonstrated an intra-class correlation coefficient (ICC) for inter-rater reliability of 0.76 (95% confirdence interval (CI)=0.61-0.91) for the PDAI and 0.77 (0.63-0.91) for the ABSIS. The tools differed most in reliability of assessing skin activity, with an ICC of 0.39 (0.17-0.60) for the ABSIS and 0.86 (0.76-0.95) for the PDAI. Intra-rater test-retest reliability demonstrated an ICC of 0.98 (0.96-1.0) for the PDAI and 0.80 (0.65-0.96) for the ABSIS. The PDAI also correlated more closely with the PGA. We conclude that the PDAI is more reproducible and correlates better with physician impression of extent. Subset analysis suggests that for this population of mild-to-moderate disease activity, the PDAI captures more variability in cutaneous disease than the ABSIS.
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Avaliação de Resultados em Cuidados de Saúde/normas , Pênfigo/classificação , Pênfigo/patologia , Índice de Gravidade de Doença , Humanos , Variações Dependentes do Observador , Medição da Dor , Pênfigo/tratamento farmacológico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Pele/patologiaRESUMO
Our scientific knowledge of pemphigus has dramatically progressed in recent years. However, despite the availability of various therapeutic options for the treatment of inflammatory diseases, only a few multicenter controlled trials have helped to define effective therapies in pemphigus. A major obstacle in comparing therapeutic outcomes between centers is the lack of generally accepted definitions and measurements for the clinical evaluation of patients with pemphigus. Common terms and end points of pemphigus are needed so that experts in the field can accurately measure and assess disease extent, activity, severity, and therapeutic response, and thus facilitate and advance clinical trials. This consensus statement from the International Pemphigus Committee represents 2 years of collaborative efforts to attain mutually acceptable common definitions for pemphigus. These should assist in development of consistent reporting of outcomes in future studies.