RESUMO
CXCR3, an X-linked gene, is subject to X chromosome inactivation (XCI), but it is unclear whether CXCR3 escapes XCI in immune cells. We determined whether CXCR3 escapes XCI in vivo, evaluated the contribution of allelic CXCR3 expression to the phenotypic properties of T cells during experimental infection with Leishmania, and examined the potential implications to sex differences in immune responses. We used a bicistronic CXCR3 dual-reporter mouse, with each CXCR3 allele linked to a green or red fluorescent reporter without affecting endogenous CXCR3 expression. Our results show that CXCR3 escapes XCI, biallelic CXCR3-expressing T cells produce more CXCR3 protein than monoallelic CXCR3-expressing cells, and biallelic CXCR3-expressing T cells produce more IFN-γ, IL-2, and CD69 compared with T cells that express CXCR3 from one allele during Leishmania mexicana infection. These results demonstrate that XCI escape by CXCR3 potentially contributes to the sex-associated bias observed during infection.
Assuntos
Receptores CXCR3/imunologia , Caracteres Sexuais , Subpopulações de Linfócitos T/imunologia , Células Th1/imunologia , Inativação do Cromossomo X/imunologia , Animais , Feminino , Infecções/imunologia , Masculino , Camundongos , Camundongos Mutantes , Receptores CXCR3/genéticaRESUMO
Cutaneous leishmaniasis, caused mainly by Leishmania major, an obligate intracellular parasite, is a disfiguring disease characterized by large skin lesions and is transmitted by a sand fly vector. We previously showed that the chemokine receptor CXCR3 plays a critical role in mediating resistance to cutaneous leishmaniasis caused by Leishmania major. Furthermore, T cells from L. major-susceptible BALB/c but not L. major-resistant C57BL/6 mice fail to efficiently upregulate CXCR3 upon activation. We therefore examined whether transgenic expression of CXCR3 on T cells would enhance resistance to L. major infection in susceptible BALB/c mice. We generated BALB/c and C57BL/6 transgenic mice, which constitutively overexpressed CXCR3 under a CD2 promoter, and then examined the outcomes with L. major infection. Contrary to our hypothesis, transgenic expression of CXCR3 (CXCR3(Tg)) on T cells of BALB/c mice resulted in increased lesion sizes and parasite burdens compared to wild-type (WT) littermates after L. major infection. Restimulated lymph node cells from L. major-infected BALB/c-CXCR3(Tg) mice produced more interleukin-4 (IL-4) and IL-10 and less gamma interferon (IFN-γ). Cells in draining lymph nodes from BALB/c-CXCR3(Tg) mice showed enhanced Th2 and reduced Th1 cell accumulation associated with increased neutrophils and inflammatory monocytes. However, monocytes displayed an immature phenotype which correlated with increased parasite burdens. Interestingly, transgenic expression of CXCR3 on T cells did not impact the outcome of L. major infection in C57BL/6 mice, which mounted a predominantly Th1 response and spontaneously resolved their infection similar to WT littermates. Our findings demonstrate that transgenic expression of CXCR3 on T cells increases susceptibility of BALB/c mice to L. major.
Assuntos
Suscetibilidade a Doenças , Expressão Gênica , Leishmania major/imunologia , Leishmaniose Cutânea/imunologia , Monócitos/imunologia , Receptores CXCR3/metabolismo , Células Th2/imunologia , Animais , Modelos Animais de Doenças , Feminino , Leishmaniose Cutânea/patologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Carga Parasitária , Receptores CXCR3/genética , Pele/parasitologia , Pele/patologiaRESUMO
Alemtuzumab is an anti-CD52 monoclonal antibody used to treat relapsing-remitting multiple sclerosis following failure of second-line medications. It is administered intravenously in 2 treatment sequences 1 year apart. This drug is frequently associated with mild infusion reactions within days of administration, increased infection risk, and long term adverse events from secondary autoimmunity. Alemtuzumab-induced serious immune-mediated thrombocytopenia (ITP) is well-reported and occurred in 1.0-2.2% of participants in initial phase 2 and 3 trials for multiple sclerosis. Significant neutropenia, however, is rare and was only observed in 0.1% of study participants. Delayed neutropenia and/or ITP is thought to occur from secondary autoimmunity. Few case reports have described severe neutropenia occurring beyond 2 months of last alemtuzumab dose. We present an unusual case of delayed combined neutropenia and thrombocytopenia that occurred 15 months after the second infusion of alemtuzumab. The patient was asymptomatic and presented following discovery of neutropenia and thrombocytopenia during routine laboratory studies. The patient responded to steroids initially and was discharged, although outpatient cell counts subsequently revealed recurrent neutropenia and ITP. The adverse drug reaction probability (Naranjo) scale was completed and showed probable likelihood that the adverse event was alemtuzumab-related. Long term screening for delayed hematologic abnormalities, at least 4 years after initial dose, is necessary when using alemtuzumab. Greater research is needed to understand the mechanism of drug-associated neutropenia.
Assuntos
Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Neutropenia , Trombocitopenia , Humanos , Alemtuzumab/efeitos adversos , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla/induzido quimicamente , Esclerose Múltipla/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos , Neutropenia/induzido quimicamente , Neutropenia/diagnóstico , Neutropenia/tratamento farmacológico , Trombocitopenia/induzido quimicamente , Trombocitopenia/diagnósticoRESUMO
BACKGROUND: Cardiotoxicity is a limitation of several cancer therapies and early recognition improves outcomes. Symptom-tracking mobile health (mHealth) apps are feasible and beneficial, but key elements for mHealth symptom-tracking to indicate early signs of cardiotoxicity are unknown. OBJECTIVE: We explored considerations for the design of, and implementation into a large academic medical center, an mHealth symptom-tracking tool for early recognition of cardiotoxicity in patients with cancer after cancer therapy initiation. METHODS: We conducted semistructured interviews of >50% of the providers (oncologists, cardio-oncologists, and radiation oncologists) who manage cancer treatment-related cardiotoxicity in the participating institution (n=11), and either interviews or co-design or both with 6 patients. Data were coded and analyzed using thematic analysis. RESULTS: Providers indicated that there was no existing process to enable early recognition of cardiotoxicity and felt the app could reduce delays in diagnosis and lead to better patient outcomes. Signs and symptoms providers recommended for tracking included chest pain or tightness, shortness of breath, heart racing or palpitations, syncope, lightheadedness, edema, and excessive fatigue. Implementation barriers included determining who would receive symptom reports, ensuring all members of the patient's care team (eg, oncologist, cardiologist, and primary care) were informed of the symptom reports and could collaborate on care plans, and how to best integrate the app data into the electronic health record. Patients (n=6, 100%) agreed that the app would be useful for enhanced symptom capture and education and indicated willingness to use it. CONCLUSIONS: Providers and patients agree that a patient-facing, cancer treatment-related cardiotoxicity symptom-tracking mHealth app would be beneficial. Additional studies evaluating the role of mHealth as a potential strategy for targeted early cardioprotective therapy initiation are needed.