RESUMO
IL-17A and IL-22 derived from Th17 cells play a significant role in mucosal immunity and inflammation. TGF-ß and IL-6 promote Th17 differentiation; however, these cytokines have multiple targets. The identification and screening of additional molecules that regulate IL-17A and IL-22 responses in certain inflammatory conditions is of great clinical significance. In this study, we show that CDDO-Im, a specific Nrf2 activator, promotes IL-17A and IL-22 responses in murine Th17 cells. In contrast, CDDO-Im inhibits IL-17A response in multiple sclerosis patient-derived PBMCs. However, Nrf2 specifically regulates IL-22 response in vivo. Nrf2 acts through the regulation of antioxidant response element (ARE) binding motifs in target genes to induce or repress transcription. Promoter analysis revealed that Il17a, Rorc, and Ahr genes have several ARE motifs. We showed that Nrf2 bound to ARE repressor (ARE-R2) of Rorc and inhibited Rorc-dependent IL-17A transactivation. The luciferase reporter assay data showed that CDDO-Im regulated Ahr promoter activity. Chromatin immunoprecipitation quantitative PCR data showed that Nrf2 bound to ARE of AhR. Finally, we confirmed that the CDDO-Im-mediated induction of IL-22 production in CD4+ T cells was abrogated in CD4-specific Ahr knockout mice (AhrCD4 ). CH-223191, a specific AhR antagonist, inhibits CDDO-Im-induced IL-22 production in CD4+ T cells, which further confirmed the AhR-dependent regulation. Collectively, our data showed that Nrf2 via AhR pathways regulated IL-22 response in CD4+ T cells.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Interleucinas/metabolismo , Esclerose Múltipla/imunologia , Fator 2 Relacionado a NF-E2/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Células Th17/imunologia , Animais , Compostos Azo/metabolismo , Regulação da Expressão Gênica , Humanos , Imidazóis/metabolismo , Interleucina-17/genética , Interleucina-17/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Knockout , Fator 2 Relacionado a NF-E2/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/metabolismo , Regiões Promotoras Genéticas/genética , Pirazóis/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Transdução de Sinais , Interleucina 22RESUMO
The female steroid hormone progesterone regulates ovulation and supports pregnancy, but also controls human sperm function within the female reproductive tract. Progesterone causes elevation of sperm intracellular Ca(2+) leading to sperm hyperactivation, acrosome reaction, and perhaps chemotaxis toward the egg. Although it has been suggested that progesterone-dependent Ca(2+) influx into human spermatozoa is primarily mediated by cationic channel of sperm (CatSper), the principal flagellar Ca(2+) channel of sperm, conclusive loss-of-function genetic evidence for activation of CatSper by progesterone has yet to be provided. Moreover, it is not clear whether the responsiveness of CatSper to progesterone is an innate property of human spermatozoa or is acquired as the result of exposure to the seminal plasma. Here, by recording ionic currents from spermatozoa of an infertile CatSper-deficient patient, we demonstrate that CatSper is indeed the principal Ca(2+) channel of human spermatozoa, and that it is strongly potentiated by progesterone. In addition, by recording CatSper currents from human epididymal and testicular spermatozoa, we show that CatSper sensitivity to progesterone arises early in sperm development and increases gradually to a peak when spermatozoa are ejaculated. These results unambiguously establish an important role of CatSper channel in human sperm nongenomic progesterone signaling and demonstrate that the molecular mechanism responsible for activation of CatSper by progesterone arises early in sperm development concurrently with the CatSper channel itself.
Assuntos
Canais de Cálcio/metabolismo , Infertilidade Masculina/fisiopatologia , Espermatozoides/química , Adulto , Canais de Cálcio/deficiência , Epididimo/metabolismo , Humanos , Masculino , Técnicas de Patch-Clamp , Progesterona/farmacologia , Espermatozoides/fisiologia , Testículo/metabolismoRESUMO
Neurologic manifestations of sarcoidosis are rare, and even rarer still are cases of isolated neurosarcoidosis. The clinical presentation of isolated neurosarcoidosis can be highly variable, and diagnosis is particularly challenging, the gold standard being tissue biopsy. We describe a patient with a history of atypical parkinsonian syndrome and chronic right frontal lobe infarct who developed weakness, imbalance, and gait disequilibrium in 2008, with magnetic resonance imaging at that time showing leptomeningeal and nodular enhancements in the bilateral frontal and parietal lobes. The patient had an extensive negative workup in 2010 but ultimately did not receive a definitive diagnosis with a tissue biopsy until 2020. The patient also notably failed a 3-month course of steroids after his biopsy due to a lack of symptomatic improvement. This case highlights the clinical variability and diagnostic difficulties of isolated neurosarcoidosis. We also highlight that our patient did not have any symptomatic improvement on steroids, which do typically provide some relief for patients.
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Background: Powassan is a positive-sense, single-stranded, enveloped RNA virus that is a tick-borne Flavivirus, transmitted by Ixodes species, with groundhogs being the usual mammalian host. The virus is endemic to North America, with peak transmission during the summer and fall. The incubation period is 7-34 days, followed by a prodrome of flu-like symptoms. Although most infected individuals are asymptomatic, the virus can penetrate the CNS to produce a viral encephalitis. The key to the diagnosis is a positive serology. Results: The patient is a 62-year-old male with a past history of a right putamen infarct, hepatitis C, hypertension, and substance abuse who presented due to acute onset altered mental status, dysarthria, and left-sided facial droop. He had several tick bites around the time of presentation in December. He was empirically treated for possible meningitis, as CSF revealed WBC 370 (80% mononuclear cells); RBC 10, protein 152 mg/dL, and glucose 59 mg/dL. An MRI scan of the brain showed a subacute left putamen stroke. MRAs of the head and neck were unremarkable. A Mayo Clinic Encephalopathy Panel was unremarkable; however, a New York State Arbovirus panel revealed Powassan IgM ELISA as well as Powassan Polyvalent microsphere immunofluorescence assay reactivity. His hospital course was complicated by critical illness myopathy and respiratory failure requiring tracheostomy. Conclusion: The Powassan virus is a known etiology for encephalitis in North America. Although the peak incidence of transmission is in the summer and fall, this does not exclude transmission during other seasons. Due to the increasing prevalence of Powassan virus in Lyme-endemic areas particularly in the Midwest and Northeast, United States, patients with an unexplained altered mental status in these regions should be screened for Powassan virus, regardless of the time of year.
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Relapsing-remitting multiple sclerosis (RRMS) is associated with persistent blood-brain barrier (BBB) dysfunction. The impact of this persistent dysfunction in both active and chronic MS lesions has yet to be investigated due to technological challenges associated with invasive assessment of BBB water transportation (e.g. 15O-PET). The purpose of this study was to test if persistent BBB dysfunction in RRMS manifests as lower BBB water exchange in chronic lesions using a recently developed noninvasive MRI paradigm. Patients with relapsing-remitting MS and healthy subjects were recruited for this prospective study. The novel Intrinsic Diffusivity Encoding of Arterial Labeled Spins (IDEALS) MRI method was used to map BBB water extraction fraction (Ew) and water permeability surface area product (PSw), as well as cerebral blood flow (CBF). Regional differences in BBB water exchange were evaluated between MS patients (normal appearing white matter [NAWM] and normal appearing gray matter [NAGM]) and healthy subjects (white matter [WM] and gray matter [GM]) and within MS subjects in non gadolinium-based contrast-agent (GBCA) enhancing chronic lesions, perilesional areas, and NAWM. Significantly lower PSw and Ew were observed in NAWM compared to WM (ΔPSw: -11.9 mL/100 g/min, p < .05; ΔEw: -4.3%, p < .01). Significantly lower Ew was observed in NAGM compared to GM (ΔEw: -12.1%, p < .01). Significantly lower PSw and CBF were observed in non-GBCA contrast enhancing lesions compared to NAWM (ΔPSw = -11.5 mL/100 g/min, p < .05; ΔCBF = -8.1 mL/100 g/min, p < .05). Ew was significantly higher in non-GBCA enhancing chronic MS lesions compared to NAWM (ΔEw = 1.6%, p < .05). The lower BBB water exchange in chronic MS lesions is consistent with previously reported observations and may demonstrate metabolic changes associated with MS.
Assuntos
Barreira Hematoencefálica/diagnóstico por imagem , Barreira Hematoencefálica/metabolismo , Imageamento por Ressonância Magnética , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/metabolismo , Água/metabolismo , Adulto , Transporte Biológico , Circulação Cerebrovascular , Doença Crônica , Feminino , Humanos , Pessoa de Meia-Idade , Esclerose Múltipla/fisiopatologia , PermeabilidadeRESUMO
Radiologically isolated syndrome (RIS) is the asymptomatic precursor to clinically isolated syndrome, relapsing-remitting multiple sclerosis (MS) or primary progressive MS. RIS is frequently diagnosed when an individual gets an MRI for an unrelated medical issue, such as headache or trauma. Treating RIS patients is controversial, but physicians may be inclined to offer prophylactic treatment for high-risk RIS patients. Identifying imaging and clinical features associated with high likelihood of early clinical conversion may prove helpful to identify a high-risk subset for potential MS therapy. The goal of this paper is to review current literatures to identify imaging and clinical features that predict early (within 5 years) conversion from RIS to MS.
Assuntos
Encéfalo/diagnóstico por imagem , Progressão da Doença , Imageamento por Ressonância Magnética , Esclerose Múltipla/diagnóstico por imagem , Medula Espinal/diagnóstico por imagem , Encéfalo/patologia , Humanos , Esclerose Múltipla/patologia , Medula Espinal/patologiaRESUMO
Objective. To describe a unique presentation of neurosarcoidosis. Background. Central nervous system involvement is rare in sarcoidosis. Sarcoidosis can be severe and can be mistaken for systemic lymphoma. Case Description. A 55-year-old right-handed white male with past medical history of obstructive sleep apnea, Raynaud's disease, and Hashimoto's thyroiditis was noted to have cognitive decline over a duration of few weeks and 20 lb weight loss. His neurologic exam (including cranial nerves) was normal except for five-minute recall. Head CT revealed a lacrimal gland mass, confirmed on brain MRI, which was suspicious for lymphoma on brain PET/MRI. Subsequent whole-body FDG PET/CT scan showed multiple enlarged lymph nodes. Bone marrow biopsy was negative. Serum and CSF ACE levels were within normal limits. Supraclavicular lymph node biopsy before steroids therapy was initiated and revealed multiple noncaseating granulomas, diagnostic of "sarcoidosis." He was treated with daily prednisone for two months, followed by weekly infliximab. Brain MRI two months after treatment with prednisone showed decrease in size of lacrimal lesion, and brain PET/MRI showed normal brain metabolism pattern after five months. Neurocognitive evaluation three months after diagnosis demonstrated improvements in memory abilities. Discussion. Both clinically and radiographically, neurosarcoidosis can mimic systemic lymphoma. Biopsy in these types of cases is necessary to establish the diagnosis.