Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 8 de 8
Filtrar
1.
J Clin Invest ; 131(3)2021 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-33529166

RESUMEN

The coat protein I (COPI) complex mediates retrograde trafficking from the Golgi to the endoplasmic reticulum (ER). Five siblings with persistent bacterial and viral infections and defective humoral and cellular immunity had a homozygous p.K652E mutation in the γ1 subunit of COPI (γ1-COP). The mutation disrupts COPI binding to the KDEL receptor and impairs the retrieval of KDEL-bearing chaperones from the Golgi to the ER. Homozygous Copg1K652E mice had increased ER stress in activated T and B cells, poor antibody responses, and normal numbers of T cells that proliferated normally, but underwent increased apoptosis upon activation. Exposure of the mutants to pet store mice caused weight loss, lymphopenia, and defective T cell proliferation that recapitulated the findings in the patients. The ER stress-relieving agent tauroursodeoxycholic acid corrected the immune defects of the mutants and reversed the phenotype they acquired following exposure to pet store mice. This study establishes the role of γ1-COP in the ER retrieval of KDEL-bearing chaperones and thereby the importance of ER homeostasis in adaptive immunity.


Asunto(s)
Apoptosis/inmunología , Linfocitos B/inmunología , Estrés del Retículo Endoplásmico/inmunología , Activación de Linfocitos , Mutación Missense , Inmunodeficiencia Combinada Grave/inmunología , Linfocitos T/inmunología , Sustitución de Aminoácidos , Animales , Apoptosis/genética , Proteína Coatómero/genética , Retículo Endoplásmico/genética , Retículo Endoplásmico/inmunología , Estrés del Retículo Endoplásmico/genética , Aparato de Golgi/genética , Aparato de Golgi/inmunología , Humanos , Ratones , Ratones Mutantes , Receptores de Péptidos/genética , Receptores de Péptidos/inmunología , Inmunodeficiencia Combinada Grave/genética
3.
Blood ; 136(26): 2994-3003, 2020 12 24.
Artículo en Inglés | MEDLINE | ID: mdl-32870250

RESUMEN

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare primary immunodeficiency caused by gain-of-function mutations in the CXCR4 gene. We report the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of mavorixafor from a phase 2 open-label dose-escalation and extension study in 8 adult patients with genetically confirmed WHIM syndrome. Mavorixafor is an oral small molecule selective antagonist of the CXCR4 receptor that increases mobilization and trafficking of white blood cells from the bone marrow. Patients received escalating doses of mavorixafor, up to 400 mg once daily. Five patients continued on the extension study for up to 28.6 months. Mavorixafor was well tolerated with no treatment-related serious adverse events. At a median follow-up of 16.5 months, we observed dose-dependent increases in absolute neutrophil count (ANC) and absolute lymphocyte count (ALC). At doses ≥300 mg/d, ANC was maintained at >500 cells per microliter for a median of 12.6 hours, and ALC was maintained at >1000 cells per microliter for up to 16.9 hours. Continued follow-up on the extension study resulted in a yearly infection rate that decreased from 4.63 events (95% confidence interval, 3.3-6.3) in the 12 months prior to the trial to 2.27 events (95% confidence interval, 1.4-3.5) for patients on effective doses. We observed an average 75% reduction in the number of cutaneous warts. This study demonstrates that mavorixafor, 400 mg once daily, mobilizes neutrophil and lymphocytes in adult patients with WHIM syndrome and provides preliminary evidence of clinical benefit for patients on long-term therapy. The trial was registered at www.clinicaltrials.gov as #NCT03005327.


Asunto(s)
Aminoquinolinas/administración & dosificación , Bencimidazoles/administración & dosificación , Butilaminas/administración & dosificación , Enfermedades de Inmunodeficiencia Primaria/tratamiento farmacológico , Receptores CXCR4/antagonistas & inhibidores , Verrugas/tratamiento farmacológico , Administración Oral , Adolescente , Adulto , Aminoquinolinas/efectos adversos , Bencimidazoles/efectos adversos , Butilaminas/efectos adversos , Femenino , Humanos , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Neutrófilos , Enfermedades de Inmunodeficiencia Primaria/sangre , Enfermedades de Inmunodeficiencia Primaria/genética , Estudios Prospectivos , Receptores CXCR4/genética , Verrugas/sangre , Verrugas/genética
6.
J Exp Med ; 214(7): 2023-2040, 2017 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-28550161

RESUMEN

The CXCL12/CXCR4 signaling exerts a dominant role in promoting hematopoietic stem and progenitor cell (HSPC) retention and quiescence in bone marrow. Gain-of-function CXCR4 mutations that affect homologous desensitization of the receptor have been reported in the WHIM Syndrome (WS), a rare immunodeficiency characterized by lymphopenia. The mechanisms underpinning this remain obscure. Using a mouse model with a naturally occurring WS-linked gain-of-function Cxcr4 mutation, we explored the possibility that the lymphopenia in WS arises from defects at the HSPC level. We reported that Cxcr4 desensitization is required for quiescence/cycling balance of murine short-term hematopoietic stem cells and their differentiation into multipotent and downstream lymphoid-biased progenitors. Alteration in Cxcr4 desensitization resulted in decrease of circulating HSPCs in five patients with WS. This was also evidenced in WS mice and mirrored by accumulation of HSPCs in the spleen, where we observed enhanced extramedullary hematopoiesis. Therefore, efficient Cxcr4 desensitization is critical for lymphoid differentiation of HSPCs, and its impairment is a key mechanism underpinning the lymphopenia observed in mice and likely in WS patients.


Asunto(s)
Diferenciación Celular/genética , Células Madre Hematopoyéticas/metabolismo , Linfocitos/metabolismo , Receptores CXCR4/genética , Adulto , Animales , Células de la Médula Ósea/metabolismo , Trasplante de Médula Ósea/métodos , Supervivencia Celular/genética , Niño , Citometría de Flujo , Expresión Génica , Humanos , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/metabolismo , Recuento de Linfocitos , Ratones Transgénicos , Mutación , Enfermedades de Inmunodeficiencia Primaria , Receptores CXCR4/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/genética , Bazo/citología , Bazo/metabolismo , Verrugas/genética , Verrugas/metabolismo
8.
Orphanet J Rare Dis ; 7: 71, 2012 Sep 25.
Artículo en Inglés | MEDLINE | ID: mdl-23009155

RESUMEN

BACKGROUND: WHIM syndrome (WS), a rare congenital neutropenia due to mutations of the CXCR4 chemokine receptor, is associated with Human Papillomavirus (HPV)-induced Warts, Hypogammaglobulinemia, bacterial Infections and Myelokathexis. The long term follow up of eight patients highlights the clinical heterogeneity of this disease as well as the main therapeutic approaches and remaining challenges in the light of the recent development of new CXCR4 inhibitors. OBJECTIVE: This study aims to describe the natural history of WS based on a French cohort of 8 patients. METHODS: We have reviewed the clinical, biological and immunological features of patients with WS enrolled into the French Severe Chronic Neutropenia Registry. RESULTS: We identified four pedigrees with WS comprised of eight patients and one foetus. Estimated incidence for WS was of 0.23 per million births. Median age at the last visit was 29 years. Three pedigrees encompassing seven patients and the fetus displayed autosomal dominant heterozygous mutations of the CXCR4 gene, while one patient presented a wild-type CXCR4 gene. Two subjects exhibited congenital conotruncal heart malformations. In addition to neutropenia and myelokathexis, all patients presented deep monocytopenia and lymphopenia. Seven patients presented repeated bacterial Ears Nose Throat as well as severe bacterial infections that were curable with antibiotics. Four patients with late onset prophylaxis developed chronic obstructive pulmonary disease (COPD). Two patients reported atypical mycobacteria infections which in one case may have been responsible for one patient's death due to liver failure at the age of 40.6 years. HPV-related disease manifested in five subjects and progressed as invasive vulvar carcinoma with a fatal course in one patient at the age of 39.5 years. In addition, two patients developed T cell lymphoma skin cancer and basal cell carcinoma at the age of 38 and 65 years. CONCLUSIONS: Continuous prophylactic anti-infective measures, when started in early childhood, seem to effectively prevent further bacterial infections and the consequent development of COPD. Long-term follow up is needed to evaluate the effect of early anti-HPV targeted prophylaxis on the development of skin and genital warts.


Asunto(s)
Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/patología , Verrugas/genética , Verrugas/patología , Adolescente , Adulto , Antibacterianos/uso terapéutico , Infecciones Bacterianas/etiología , Infecciones Bacterianas/prevención & control , Niño , Preescolar , Femenino , Humanos , Síndromes de Inmunodeficiencia/complicaciones , Lactante , Masculino , Linaje , Enfermedades de Inmunodeficiencia Primaria , Receptores CXCR4/genética , Sistema de Registros , Verrugas/complicaciones , Adulto Joven
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...