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2.
Clin Lab Med ; 39(4): 591-607, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31668272

RESUMO

Flow cytometry is an incredibly powerful diagnostic tool in the evaluation of primary and secondary immune deficiencies. Assay design and setup involves a methodological consideration of specimen collection, marker and fluorochrome selection, antibody titration, instrumentation, compensation, gating, reference range development, and cross validation. Commonly used analyses for lymphocytes are the lymphocyte subset, T-cell subset, B-cell and T-cell naive/memory, double-negative T-cell, and plasmablast panels. Flow cytometry has direct clinical applicability to the workup of severe forms of primary immune deficiency disorders and is used diagnostically and for therapeutic monitoring in the context of secondary immune deficiency disorders.

3.
Clin Lab Med ; 39(4): 669-683, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31668277

RESUMO

Immune-targeted therapeutics are being used in cancer. Immune "checkpoint inhibition" provides promise for prolonged disease-free patient survival. Use of immune checkpoint inhibitors in cancer has coincided with the onset of immune-related adverse events (irAEs). irAEs are caused by a break in host self-tolerance, which can be deadly. Acute management of irAEs is complicated by difficulty making a prompt clinical diagnosis. The goal is to maximize anticancer benefit while minimizing irAE risk. We currently lack diagnostic tools to assess pretreatment irAE risk and facilitate diagnosis. Current immunologic understanding of irAEs is discussed with an emphasis on how patients with congenital syndromes of T-cell activation may inform this understanding. The prospects of improving diagnostics for and treatment of irAEs are discussed.

4.
Clin Lab Med ; 39(4): 685-697, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31668278

RESUMO

Primary immunodeficiency diseases are a heterogeneous group of rare inherited disorders of innate or adaptive immune system function. Patients with primary immunodeficiencies typically present with recurrent and severe infections in infancy or young adulthood. More recently, the co-occurrence of autoimmune, benign lymphoproliferative, atopic, and malignant complications has been described. The diagnosis of a primary immunodeficiency disorder requires a thorough assessment of a patient's underlying immune system function. Historically, this has been accomplished at the time of symptomatic presentation by measuring immunoglobulins, complement components, protective antibody titers, or immune cell counts in the peripheral blood. Although these data can be used to critically assess the degree of immune dysregulation in the patient, this approach fall short in at least 2 regards. First, this assessment often occurs after the patient has suffered life-threatening infectious or autoinflammatory complications. Second, these data fail to uncover an underlying molecular cause of the patient's primary immune dysfunction, prohibiting the use of molecularly targeted therapeutic interventions. Within the last decade, the field of primary immunodeficiency diagnostics has been revolutionized by 2 major molecular advancements: (1) the onset of newborn screening in 2008, and (2) the onset of next-generation sequencing in 2010. In this article, the techniques of newborn screening and next-generation sequencing are reviewed and their respective impacts on the field of primary immunodeficiency disorders are discussed with a specific emphasis on severe combined immune deficiency and common variable immune deficiency.

5.
Sci Signal ; 12(604)2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31641080

RESUMO

Transitional B cells must actively undergo selection for self-tolerance before maturing into their resting follicular B cell successors. We found that metabolic quiescence was acquired at the follicular B cell stage in both humans and mice. In follicular B cells, the expression of genes involved in ribosome biogenesis, aerobic respiration, and mammalian target of rapamycin complex 1 (mTORC1) signaling was reduced when compared to that in transitional B cells. Functional metabolism studies, profiling of whole-cell metabolites, and analysis of cell surface proteins in human B cells suggested that this transition was also associated with increased extracellular adenosine salvage. Follicular B cells increased the abundance of the cell surface ectonucleotidase CD73, which coincided with adenosine 5'-monophosphate-activated protein kinase (AMPK) activation. Differentiation to the follicular B cell stage in vitro correlated with surface acquisition of CD73 on human transitional B cells and was augmented with the AMPK agonist, AICAR. Last, individuals with gain-of-function PIK3CD (PI3Kδ) mutations and increased pS6 activation exhibited a near absence of circulating follicular B cells. Together, our data suggest that mTORC1 attenuation may be necessary for human follicular B cell development. These data identify a distinct metabolic switch during human B cell development at the transitional to follicular stages, which is characterized by an induction of extracellular adenosine salvage, AMPK activation, and the acquisition of metabolic quiescence.

6.
J Allergy Clin Immunol Pract ; 7(6): 1970-1985.e4, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30877075

RESUMO

BACKGROUND: Although autoimmunity and hyperinflammation secondary to recombination activating gene (RAG) deficiency have been associated with delayed diagnosis and even death, our current understanding is limited primarily to small case series. OBJECTIVE: Understand the frequency, severity, and treatment responsiveness of autoimmunity and hyperinflammation in RAG deficiency. METHODS: In reviewing the literature and our own database, we identified 85 patients with RAG deficiency, reported between 2001 and 2016, and compiled the largest case series to date of 63 patients with prominent autoimmune and/or hyperinflammatory pathology. RESULTS: Diagnosis of RAG deficiency was delayed a median of 5 years from the first clinical signs of immune dysregulation. Most patients (55.6%) presented with more than 1 autoimmune or hyperinflammatory complication, with the most common etiologies being cytopenias (84.1%), granulomas (23.8%), and inflammatory skin disorders (19.0%). Infections, including live viral vaccinations, closely preceded the onset of autoimmunity in 28.6% of cases. Autoimmune cytopenias had early onset (median, 1.9, 2.1, and 2.6 years for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively) and were refractory to intravenous immunoglobulin, steroids, and rituximab in most cases (64.7%, 73.7%, and 71.4% for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively). Evans syndrome specifically was associated with lack of response to first-line therapy. Treatment-refractory autoimmunity/hyperinflammation prompted hematopoietic stem cell transplantation in 20 patients. CONCLUSIONS: Autoimmunity/hyperinflammation can be a presenting sign of RAG deficiency and should prompt further evaluation. Multilineage cytopenias are often refractory to immunosuppressive treatment and may require hematopoietic cell transplantation for definitive management.

9.
JAMA Netw Open ; 1(7): e184169, 2018 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-30646343

RESUMO

Importance: Rituximab is an anti-CD20 chimeric antibody used in a wide variety of clinical indications. There has not been widespread adoption of consistent immune monitoring before and after rituximab therapy. However, there is a subset of patients who develop prolonged, symptomatic hypogammaglobulinemia following rituximab, and monitoring before and after rituximab therapy could help to identify these patients and initiate measures to prevent excess morbidity and mortality. Objective: To determine the current levels of screening for hypogammaglobulinemia (specifically, low immunoglobulin G), infectious risks associated with hypogammaglobulinemia, and variables associated with an increased risk of mortality. Design, Setting, and Participants: A cohort study was conducted of 8633 patients receiving rituximab from January 1, 1997, to December 31, 2017, at a large, tertiary referral center (Partners HealthCare System). Exposures: Rituximab administration. Main Outcomes and Measures: The primary outcome measures were immunoglobulin measurements, infectious complications, and mortality. Cox regression analysis was used to examine the results of infectious complications on survival, adjusted for age, sex, and indication for rituximab use. Results: Of the 8633 patients who received rituximab in the large, academic, health care system, 4479 satisfied inclusion criteria, with a mean (SD) age of 59.8 (16.2) years; 2280 patients (50.9%) were women. Most patients (3824 [85.4%]) did not have immunoglobulin levels checked before rituximab therapy. Of those who had levels determined, hypogammaglobulinemia was noted in 313 (47.8%) patients before initiation of rituximab. Following rituximab administration, worsening hypogammaglobulinemia was noted. There was an increase in severe infections after rituximab use in the study cohort (from 17.2% to 21.7%; P < .001). In the survival analysis, increased mortality was associated with increasing age (hazard ratio [HR], 1.02; 95% CI, 1.01-1.02; P < .001), male sex (HR, 1.14; 95% CI, 1.02-1.28; P = .02), and severe infectious complications in the 6 months before (HR, 3.14; 95% CI, 2.77-3.55; P < .001) and after (HR, 4.97; 95% CI, 4.41-5.60; P < .001) the first rituximab infusion. A total of 201 patients (4.5%) received immunoglobulin replacement following rituximab, and among these patients, higher cumulative immunoglobulin replacement dose was associated with a reduced risk of serious infectious complications (HR, 0.98; 95% CI, 0.96-0.99; P = .002). Conclusions and Relevance: Many patients are not being screened or properly identified as having hypogammaglobulinemia both before and after rituximab administration. Monitoring of immunoglobulin levels both before and after rituximab therapy may allow for earlier identification of risk for developing significant infection and identify patients who may benefit from immunoglobulin replacement, which may in turn help to avoid excess morbidity and mortality.


Assuntos
Agamaglobulinemia/complicações , Causas de Morte , Imunoglobulina G/sangue , Infecção/etiologia , Programas de Rastreamento , Rituximab/efeitos adversos , Adulto , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/mortalidade , Idoso , Animais , Estudos de Coortes , Monitoramento de Medicamentos , Feminino , Humanos , Infecção/sangue , Masculino , Camundongos , Pessoa de Meia-Idade , Prevalência , Modelos de Riscos Proporcionais , Fatores de Risco , Índice de Gravidade de Doença
11.
Eur J Immunol ; 47(11): 1959-1969, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28718914

RESUMO

Recent studies identified an emerging role of group 2 and 3 innate lymphoid cells (ILCs) as key players in the generation of T-dependent and T-independent antibody production. In this retrospective case-control study, CD117+ ILCs (including the majority of ILC2 and ILC3) were reduced in patients with common variable immunodeficiency (CVID). The reduction in CD117+ ILCs was distinctive to CVID and could not be observed in patients with X-linked agammaglobulinemia. Patients with a more pronounced reduction in CD117+ ILC numbers showed significantly lower numbers of peripheral MZ-like B cells and an increased prevalence of chronic, non-infectious enteropathy. Subsequent phenotyping of ILC subsets in CVID revealed that the reduction in CD117+ ILC numbers is due to a reduction in ILC2 numbers. In vitro expansion of CVID ILC2 in response to IL-2, IL-7, IL-25 and IL-33 was impaired. Furthermore, upregulation of MHCII and IL-2RA in response to IL-2, IL-7, IL-25 and IL-33 was impaired in CVID ILC2. Thus, our results indicate a dysregulation of ILC subsets with a reduction in ILC2 numbers in CVID, however, further studies are needed to explore whether ILC abnormalities are a primary finding or secondary to disease complications encountered in CVID.


Assuntos
Imunodeficiência de Variável Comum/imunologia , Subpopulações de Linfócitos/imunologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-kit/imunologia , Estudos Retrospectivos
12.
A A Case Rep ; 9(3): 84-86, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28448320

RESUMO

Difficult airway management in the gravid patient is a well-described phenomenon. We present a case of emergent cesarean delivery complicated by a "cannot intubate, cannot ventilate" scenario that was later determined to be secondary to an allergic, IgE-mediated reaction to epidurally administered local anesthetic.


Assuntos
Manuseio das Vias Aéreas/métodos , Anestésicos Locais/efeitos adversos , Cesárea , Hipersensibilidade a Drogas/complicações , Lidocaína/efeitos adversos , Adulto , Anafilaxia/induzido quimicamente , Angioedema/induzido quimicamente , Cesárea/efeitos adversos , Feminino , Humanos , Gravidez
13.
Front Immunol ; 8: 1740, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29375540

RESUMO

Common variable immunodeficiency (CVID) is increasingly recognized for its association with autoimmune and inflammatory complications. Despite recent advances in immunophenotypic and genetic discovery, clinical care of CVID remains limited by our inability to accurately model risk for non-infectious disease development. Herein, we demonstrate the utility of unbiased network clustering as a novel method to analyze inter-relationships between non-infectious disease outcomes in CVID using databases at the United States Immunodeficiency Network (USIDNET), the centralized immunodeficiency registry of the United States, and Partners, a tertiary care network in Boston, MA, USA, with a shared electronic medical record amenable to natural language processing. Immunophenotypes were comparable in terms of native antibody deficiencies, low titer response to pneumococcus, and B cell maturation arrest. However, recorded non-infectious disease outcomes were more substantial in the Partners cohort across the spectrum of lymphoproliferation, cytopenias, autoimmunity, atopy, and malignancy. Using unbiased network clustering to analyze 34 non-infectious disease outcomes in the Partners cohort, we further identified unique patterns of lymphoproliferative (two clusters), autoimmune (two clusters), and atopic (one cluster) disease that were defined as CVID non-infectious endotypes according to discrete and non-overlapping immunophenotypes. Markers were both previously described {high serum IgE in the atopic cluster [odds ratio (OR) 6.5] and low class-switched memory B cells in the total lymphoproliferative cluster (OR 9.2)} and novel [low serum C3 in the total lymphoproliferative cluster (OR 5.1)]. Mortality risk in the Partners cohort was significantly associated with individual non-infectious disease outcomes as well as lymphoproliferative cluster 2, specifically (OR 5.9). In contrast, unbiased network clustering failed to associate known comorbidities in the adult USIDNET cohort. Together, these data suggest that unbiased network clustering can be used in CVID to redefine non-infectious disease inter-relationships; however, applicability may be limited to datasets well annotated through mechanisms such as natural language processing. The lymphoproliferative, autoimmune, and atopic Partners CVID endotypes herein described can be used moving forward to streamline genetic and biomarker discovery and to facilitate early screening and intervention in CVID patients at highest risk for autoimmune and inflammatory progression.

14.
J Allergy Clin Immunol Pract ; 4(6): 1089-1100, 2016 Nov - Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27836058

RESUMO

A broad spectrum of autoimmunity is now well described in patients with primary immunodeficiencies (PIDs). Management of autoimmune disease in the background of PID is particularly challenging given the seemingly discordant goals of immune support and immune suppression. Our growing ability to define the molecular underpinnings of immune dysregulation has facilitated novel targeted therapeutics. This review focuses on mechanism-based treatment strategies for the most common autoimmune and inflammatory complications of PID including autoimmune cytopenias, rheumatologic disease, and gastrointestinal disease. We aim to provide guidance regarding the rational use of these agents in the complex PID patient population.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Gastroenteropatias/tratamento farmacológico , Síndromes de Imunodeficiência/tratamento farmacológico , Animais , Doenças Autoimunes/etiologia , Doenças Autoimunes/imunologia , Autoimunidade , Gastroenteropatias/etiologia , Gastroenteropatias/imunologia , Humanos , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/imunologia
15.
Case Reports Immunol ; 2014: 910215, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25379312

RESUMO

Humoral immune deficiencies have been associated with noninfectious disease complications including autoimmune cytopenias and pulmonary disease. Herein we present a patient who underwent splenectomy for autoimmune cytopenias and subsequently was diagnosed with humoral immune deficiency in the context of recurrent infections. Immunoglobulin analysis prior to initiation of intravenous immunoglobulin (IVIG) therapy was notable for low age-matched serum levels of IgA (11 mg/dL), IgG2 (14 mg/L), and IgG4 (5 mg/L) with a preserved total level of IgG. Flow cytometry was remarkable for B cell maturation arrest at the IgM+/IgD+ stage. Selective screening for known primary immune deficiency-causing genetic defects was negative. The disease course was uniquely complicated by the development of pulmonary arteriovenous malformations (AVMs), ultimately requiring bilateral lung transplantation in 2012. This is a patient with humoral immune deficiency that became apparent only after splenectomy, which argues for routine immunologic evaluation prior to vaccination and splenectomy. Lung transplantation is a rare therapeutic endpoint and to our knowledge has never before been described in a patient with humoral immune deficiency for the indication of pulmonary AVMs.

16.
PLoS One ; 8(3): e58813, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23505563

RESUMO

Despite the crucial role of innate immunity in preventing or controlling pathogen-induced damage in most, if not all, cell types, very little is known about the activity of this essential defense system in central nervous system neurons, especially in humans. In this report we use both an established neuronal cell line model and an embryonic stem cell-based system to examine human neuronal innate immunity and responses to neurotropic alphavirus infection in cultured cells. We demonstrate that neuronal differentiation is associated with increased expression of crucial type I interferon signaling pathway components, including interferon regulatory factor-9 and an interferon receptor heterodimer subunit, which results in enhanced interferon stimulation and subsequent heightened antiviral activity and cytoprotective responses against neurotropic alphaviruses such as western equine encephalitis virus. These results identify important differentiation-dependent changes in innate immune system function that control cell-autonomous neuronal responses. Furthermore, this work demonstrates the utility of human embryonic stem cell-derived cultures as a platform to study the interactions between innate immunity, virus infection, and pathogenesis in central nervous system neurons.


Assuntos
Diferenciação Celular , Interferon Tipo I/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Transdução de Sinais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Linhagem Celular , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Expressão Gênica , Ordem dos Genes , Humanos , Imunidade Inata , Interferon Tipo I/imunologia , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Neurônios/imunologia , RNA Mensageiro/genética , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/metabolismo , Fator de Transcrição STAT2/genética , Fator de Transcrição STAT2/metabolismo
17.
J Virol ; 87(3): 1821-33, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23192868

RESUMO

Cell-intrinsic innate immune responses mediated by the transcription factor interferon regulatory factor 3 (IRF-3) are often vital for early pathogen control, and effective responses in neurons may be crucial to prevent the irreversible loss of these critical central nervous system cells after infection with neurotropic pathogens. To investigate this hypothesis, we used targeted molecular and genetic approaches with cultured neurons to study cell-intrinsic host defense pathways primarily using the neurotropic alphavirus western equine encephalitis virus (WEEV). We found that WEEV activated IRF-3-mediated neuronal innate immune pathways in a replication-dependent manner, and abrogation of IRF-3 function enhanced virus-mediated injury by WEEV and the unrelated flavivirus St. Louis encephalitis virus. Furthermore, IRF-3-dependent neuronal protection from virus-mediated cytopathology occurred independently of autocrine or paracrine type I interferon activity. Despite being partially controlled by IRF-3-dependent signals, WEEV also disrupted antiviral responses by inhibiting pattern recognition receptor pathways. This antagonist activity was mapped to the WEEV capsid gene, which disrupted signal transduction downstream of IRF-3 activation and was independent of capsid-mediated inhibition of host macromolecular synthesis. Overall, these results indicate that innate immune pathways have important cytoprotective activity in neurons and contribute to limiting injury associated with infection by neurotropic arboviruses.


Assuntos
Arbovirus/imunologia , Proteínas do Capsídeo/metabolismo , Vírus da Encefalite Equina do Oeste/imunologia , Vírus da Encefalite Equina do Oeste/patogenicidade , Fator Regulador 3 de Interferon/imunologia , Neurônios/virologia , Animais , Linhagem Celular , Efeito Citopatogênico Viral/imunologia , Vírus da Encefalite de St. Louis/crescimento & desenvolvimento , Vírus da Encefalite Equina do Oeste/crescimento & desenvolvimento , Humanos , Camundongos , Camundongos Endogâmicos C57BL
18.
J Immunol ; 184(12): 7010-21, 2010 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-20483728

RESUMO

Innate immune pathways are early defense responses important for the immediate control and eventual clearance of many pathogens, where signaling is initiated via pattern recognition receptor (PRR)-mediated events that occur in a ligand- and cell-type specific manner. Within CNS neurons, innate immune pathways are likely crucial to control pathogens that target these essential yet virtually irreplaceable cells. However, relatively little is known about the induction and regulation of neuronal PRR signaling. In this report, we used human neuronal cell lines and primary rat neuronal cultures to examine PRR expression and function. We found that several innate immune receptor ligands, including Sendai virus, the dsRNA mimetic polyinosinic-polycytidylic acid, and LPS all activated differentiation-dependent neuronal innate immune pathways. Functional genetic analyses revealed that IFN regulatory factor 3-mediated pathways that resulted in IFN-beta transcriptional upregulation were activated in cultured human neuronal cells by the PRRs TLR3, MDA5, or RIG-I in a ligand-specific manner. Furthermore, genome-wide transcriptional array and targeted genetic and pharmacologic analyses identified PI3K signaling as crucial for the induction of innate immune pathways in neurons. These results indicate that human neuronal cells possess specific and functional PRR pathways essential for the effective induction of innate immune responses, and suggest that neurons can play an active role in defense against neurotropic pathogens.


Assuntos
Imunidade Inata , Neurônios/imunologia , Fosfatidilinositol 3-Quinases/imunologia , Transdução de Sinais/imunologia , Receptores Toll-Like/imunologia , Animais , Linhagem Celular , Citoplasma/imunologia , Citoplasma/metabolismo , Imunofluorescência , Humanos , Immunoblotting , Neurônios/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Fosfatidilinositol 3-Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa
19.
Am J Physiol Cell Physiol ; 289(4): C794-801, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15888549

RESUMO

Nuclear factor-kappaB (NF-kappaB) is a transcription factor with important roles in regulating innate immune and inflammatory responses. NF-kappaB is activated through the phosphorylation of its inhibitor, IkappaB, by the IkappaB kinase (IKK) complex. Physical exercise elicits changes in skeletal muscle gene expression, yet signaling cascades and transcription factors involved remain largely unknown. To determine whether NF-kappaB signaling is regulated by exercise in vivo, rats were run on a motorized treadmill for 5-60 min. Exercise resulted in up to twofold increases in IKKalpha/beta phosphorylation in the soleus and red gastrocnemius muscles throughout the time course studied. In red gastrocnemius muscles, NF-kappaB activity increased 50% 1-3 h after 60 min of treadmill exercise, returning to baseline by 5 h. Contraction of isolated extensor digitorum longus muscles in vitro increased IKKalpha/beta phosphorylation sevenfold and this was accompanied by a parallel increase in IkappaBalpha phosphorylation. Additional kinases that are activated by exercise include p38, extracellular-signal regulated protein kinase (ERK), and AMP-activated protein kinase (AMPK). Inhibitors of p38 (SB-203580) and ERK (U-0126) blunted contraction-mediated IKK phosphorylation by 39 +/- 4% (P = 0.06) and 35 +/- 10% (P = 0.09), respectively, and in combination by 76 +/- 5% (P < 0.05), suggesting that these kinases might influence the activation of IKK and NF-kappaB during exercise. In contrast, 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside, an activator of AMPK, had no effect on either IKK or NF-kappaB activity. In conclusion, acute submaximal exercise transiently stimulates NF-kappaB signaling in skeletal muscle. This activation is a local event because it can occur in the absence of exercise-derived systemic factors.


Assuntos
Contração Muscular/fisiologia , Músculo Esquelético/metabolismo , NF-kappa B/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Ativação Enzimática , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Quinase I-kappa B , Masculino , Esforço Físico/fisiologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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