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1.
Sci Adv ; 10(27): eado2365, 2024 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-38959302

RESUMEN

Pityriasis rubra pilaris (PRP) is a rare inflammatory skin disease with a poorly understood pathogenesis. Through a molecularly driven precision medicine approach and an extensive mechanistic pathway analysis in PRP skin samples, compared to psoriasis, atopic dermatitis, healed PRP, and healthy controls, we identified IL-1ß as a key mediator, orchestrating an NF-κB-mediated IL-1ß-CCL20 axis, including activation of CARD14 and NOD2. Treatment of three patients with the IL-1 antagonists anakinra and canakinumab resulted in rapid clinical improvement and reversal of the PRP-associated molecular signature with a 50% improvement in skin lesions after 2 to 3 weeks. This transcriptional signature was consistent with in vitro stimulation of keratinocytes with IL-1ß. With the central role of IL-1ß underscoring its potential as a therapeutic target, our findings propose a redefinition of PRP as an autoinflammatory keratinization disorder. Further clinical trials are needed to validate the efficacy of IL-1ß antagonists in PRP.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Proteína Antagonista del Receptor de Interleucina 1 , Interleucina-1beta , Queratinocitos , Pitiriasis Rubra Pilaris , Humanos , Pitiriasis Rubra Pilaris/tratamiento farmacológico , Pitiriasis Rubra Pilaris/patología , Pitiriasis Rubra Pilaris/genética , Interleucina-1beta/metabolismo , Interleucina-1beta/antagonistas & inhibidores , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Queratinocitos/metabolismo , Queratinocitos/efectos de los fármacos , Queratinocitos/patología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Masculino , FN-kappa B/metabolismo , Proteína Adaptadora de Señalización NOD2/metabolismo , Proteína Adaptadora de Señalización NOD2/genética , Proteína Adaptadora de Señalización NOD2/antagonistas & inhibidores , Femenino , Proteínas Adaptadoras de Señalización CARD/metabolismo , Proteínas Adaptadoras de Señalización CARD/genética , Piel/patología , Piel/metabolismo , Piel/efectos de los fármacos , Interleucina-1/antagonistas & inhibidores , Interleucina-1/metabolismo , Interleucina-1/genética , Persona de Mediana Edad , Guanilato Ciclasa/metabolismo , Guanilato Ciclasa/antagonistas & inhibidores , Guanilato Ciclasa/genética , Adulto , Transducción de Señal/efectos de los fármacos , Proteínas de la Membrana
3.
Front Immunol ; 14: 1286684, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38077350

RESUMEN

Objective: Immunosuppressive therapy for cardiac sarcoidosis (CS) still largely consists of corticosteroid monotherapy. However, high relapse rates after tapering and insufficient efficacy are significant problems. The objective of this study was to investigate the efficacy and safety of non-biological and biological disease-modifying anti-rheumatic drugs (nb/bDMARDs) considering control of myocardial inflammation assessed by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) of the heart. Methods: We conducted a retrospective analysis of treatment response to nb/bDMARDs of all CS patients seen in the sarcoidosis center of the University Hospital Zurich between January 2016 and December 2020. Results: We identified 50 patients with CS. Forty-five patients with at least one follow-up PET/CT scan were followed up for a mean of 20.5 ± 12.8 months. Most of the patients were treated with prednisone and concomitant nb/bDMARDs. At the first follow-up PET/CT scan after approximately 6.7 ± 3 months, only adalimumab showed a significant reduction in cardiac metabolic activity. Furthermore, comparing all serial follow-up PET/CT scans (143), tumor necrosis factor inhibitor (TNFi)-based therapies showed statistically significant better suppression of myocardial 18F-FDG uptake compared to other treatment regimens. On the last follow-up, most adalimumab-treated patients were inactive (n = 15, 48%) or remitting (n = 11, 35%), and only five patients (16%) were progressive. TNFi was safe even in patients with severely reduced left ventricular ejection fraction (LVEF), and a significant improvement in LVEF under TNFi treatment was observed. Conclusion: TNFi shows better control of myocardial inflammation compared to nbDMARDs and corticosteroid monotherapies in patients with CS. TNFi was efficient and safe even in patients with severely reduced LVEF.


Asunto(s)
Miocarditis , Sarcoidosis , Humanos , Fluorodesoxiglucosa F18 , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Estudios Retrospectivos , Radiofármacos , Volumen Sistólico , Adalimumab/uso terapéutico , Función Ventricular Izquierda , Sarcoidosis/diagnóstico por imagen , Sarcoidosis/tratamiento farmacológico , Sarcoidosis/complicaciones , Miocarditis/tratamiento farmacológico , Corticoesteroides/uso terapéutico , Inflamación/tratamiento farmacológico
4.
Trends Mol Med ; 28(7): 596-612, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35624009

RESUMEN

Autoimmune diseases are characterized by dysregulation and aberrant activation of cells in the immune system. Therefore, restoration of the immune balance represents a promising therapeutic target in autoimmune diseases. Interleukin-2 (IL-2) can promote the expansion and differentiation of different immune cell subsets dose-dependently. At high doses, IL-2 can promote the differentiation and expansion of effector and memory T cells, whereas at low doses, IL-2 can promote the differentiation, survival, and function of regulatory T (Treg) cells, a CD4+ T cell subset that is essential for the maintenance of immune homeostasis and immune tolerance. Therefore, IL-2 exerts immunostimulatory and immunosuppressive effects in autoimmune diseases. The immunoregulatory role of low-dose IL-2 has sparked excitement for the therapeutic exploration of modulating the IL-2-Treg axis in the context of autoimmune diseases. In this review, we discuss recent advances in the therapeutic potential of IL-2 or IL-2-derived molecules in the treatment of autoimmune diseases.


Asunto(s)
Enfermedades Autoinmunes , Interleucina-2 , Humanos , Tolerancia Inmunológica , Interleucina-2/farmacología , Interleucina-2/uso terapéutico , Subgrupos de Linfocitos T , Linfocitos T Reguladores
5.
Swiss Med Wkly ; 152: w30049, 2022 01 03.
Artículo en Inglés | MEDLINE | ID: mdl-35072393

RESUMEN

Sarcoidosis is a systemic inflammatory disease, characterised by granuloma formation upon an unknown trigger in genetically predisposed individuals. The inflammation is characterised by an activation of both the innate immune system, with macrophages differentiating into epitheloid cells and dendritic cells, and the adaptive immune system, particularly T helper (Th) 1 and Th17 cells. Since all organs can be affected to varying extents, clinical presentation is often diverse. Most commonly, the lungs, lymph nodes, skin and eyes are involved, whereas cardiac, renal and neurological manifestations are less common but associated with higher morbidity. Depending on the clinical symptoms, a detailed evaluation including thorough clinical examination, imaging and laboratory tests should explore all possible organ involvements. In some patients, fatigue manifests as a para-sarcoidosis symptom impacting quality of life, even if sarcoidosis is in remission. Some acute syndromic presentations, such as Löfgren's syndrome, have a good prognosis and are commonly self-limiting. If possible, a topical treatment, for example for cutaneous sarcoidosis or bronchial involvement, should be applied. Treatment of severe cases with persisting disease activity necessitates long-term immunosuppressive drugs, with glucocorticoids as the first-line option. Steroid-sparing and second-line drugs include methotrexate, azathioprine, mycophenolate mofetil and immunomodulators such hydroxychloroquine, with the latter being first-line therapy in cutaneous sarcoidosis. Tumour necrosis factor-alpha inhibitors (particularly adalimumab and infliximab) are used as third-line agents but are administered earlier in cases of persistent disease activity, severe organ-involvement or intolerance to conventional drugs. Treatment decisions should be based on a multidisciplinary approach, depending on organ involvement and treatment tolerability. Para-sarcoidosis manifestations, particularly fatigue, should also be carefully addressed, where the patient could also be enrolled in multidimensional rehabilitation programmes. With various organ involvement and different phenotypes, larger studies including real-world data from registries are necessary to evaluate different sarcoidosis endotypes and preferential treatment pathways.


Asunto(s)
Sarcoidosis Pulmonar , Sarcoidosis , Azatioprina/uso terapéutico , Humanos , Inmunosupresores/uso terapéutico , Calidad de Vida , Sarcoidosis/diagnóstico , Sarcoidosis/tratamiento farmacológico , Sarcoidosis Pulmonar/tratamiento farmacológico
7.
Nat Rev Rheumatol ; 17(12): 749-766, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34728817

RESUMEN

Failure of regulatory T (Treg) cells to properly control immune responses leads invariably to autoimmunity and organ damage. Decreased numbers or impaired function of Treg cells, especially in the context of inflammation, has been documented in many human autoimmune diseases. Restoration of Treg cell fitness and/or expansion of their numbers using low-dose natural IL-2, the main cytokine driving Treg cell survival and function, has demonstrated clinical efficacy in early clinical trials. Genetically modified IL-2 with an extended half-life and increased selectivity for Treg cells is now in clinical development. Administration of IL-2 combined with therapies targeting other pathways involved in the expression of autoimmune diseases should further enhance its therapeutic potential. Ongoing clinical efforts that capitalize on the early clinical success of IL-2 treatment should bring the use of this cytokine to the forefront of biological treatments for autoimmune diseases.


Asunto(s)
Interleucina-2 , Enfermedades Reumáticas , Linfocitos T Reguladores , Humanos , Interleucina-2/uso terapéutico , Enfermedades Reumáticas/terapia
8.
Nat Rev Rheumatol ; 17(5): 253-254, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33633360
9.
Dermatology ; 237(2): 166-178, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33406520

RESUMEN

Topical treatment is crucial for the successful management of plaque psoriasis. Topicals are used either as a stand-alone therapy for mild psoriasis or else in combination with UV or systemic treatment for moderate-to-severe disease. For the choice of a suitable topical treatment, the formulation matters and not just the active substances. This expert opinion paper was developed via a non-structured consensus process by Swiss dermatologists in hospitals and private practices to illustrate the current treatment options to general practitioners and dermatologists in Switzerland. Defining treatment goals together with the patient is crucial and increases treatment adherence. Patients' personal preferences and pre-existing experiences should be considered and their satisfaction with treatment and outcome regularly assessed. During the induction phase of "classical" mild-to-moderate psoriasis, the fixed combination of topical calcipotriol (Cal) 50 µg/g and betamethasone dipropionate (BD) 0.5 mg/g once daily is frequently used for 4-8 weeks. During the maintenance phase, a twice weekly (proactive) management has proved to reduce the risk of relapse. Of the fixed combinations, Cal/BD aerosol foam is the most effective formulation. However, the individual choice of formulation should be based on a patient's preference and the location of the psoriatic plaques. Tailored recommendations are given for the topical management of specific areas (scalp, facial, intertriginous/genital, or palmoplantar lesions), certain symptoms (hyperkeratotic or hyperinflammatory forms) as well as during pregnancy or a period of breastfeeding. As concomitant basic therapy, several emollients are recommended. If topical treatment alone does not appear to be sufficient, the regimen should be escalated according to the Swiss S1-guideline for the systemic treatment of psoriasis.


Asunto(s)
Corticoesteroides/administración & dosificación , Antiinflamatorios/administración & dosificación , Fármacos Dermatológicos/administración & dosificación , Guías de Práctica Clínica como Asunto , Psoriasis/tratamiento farmacológico , Administración Cutánea , Lactancia Materna , Combinación de Medicamentos , Cara , Femenino , Humanos , Quimioterapia de Inducción/normas , Quimioterapia de Mantención/normas , Masculino , Planificación de Atención al Paciente , Prioridad del Paciente , Embarazo , Cuero Cabelludo , Suiza
10.
Curr Opin Rheumatol ; 33(2): 181-189, 2021 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-33332887

RESUMEN

PURPOSE OF REVIEW: This review gives an overview of the recently published clinical trials in systemic lupus erythematosus (SLE). RECENT FINDINGS: Our continuously improving understanding of the cellular and molecular mechanisms, which are involved in the pathogenesis of SLE, has inspired the performance of multiple clinical trials in an attempt to modify recognized targets. Here, we summarize results obtained from recent trials, which used monoclonal antibodies blocking cytokines, blockers of costimulatory molecules or deleting immune cells, small drug inhibitors of kinases and replenishment of cytokines. SUMMARY: The therapeutic options for patients with SLE grow continuously and in parallel it raises the need for pathogenetic mechanism-based precision medicine so that we may select the right treatment for the right patient.


Asunto(s)
Lupus Eritematoso Sistémico , Anticuerpos Monoclonales/uso terapéutico , Citocinas , Humanos , Lupus Eritematoso Sistémico/tratamiento farmacológico
11.
Clin Immunol ; 222: 108574, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32805452

RESUMEN

Eosinophilic Granulomatosis with Polyangiitis (EGPA) is an ANCA-associated small-vessels vasculitis characterized by hypereosinophilia and eosinophilic asthma. EGPA with life-threatening organ involvement, particularly cardiac and central nervous system (CNS), is a medical emergency requiring immediate immunosuppression. We describe a 58-year-old patient with a history of chronic rhinosinusitis and eosinophilic asthma, who presented with fever, hypereosinophilia and systemic inflammation. Diagnostic workup identified a cardiac mass, CNS vasculitis, CNS embolization and Staphylococcus aureus in blood cultures. Due to rapid normalization of blood cultures, the intracardiac mass was not considered as primarily infective. Active EGPA with cardiac and CNS involvement complicated by a secondary S. aureus sepsis was diagnosed. In order to not negatively impact antibacterial immunity in active EGPA, antibiotic therapy was combined with Benralizumab, which was well tolerated and EGPA resolved rapidly. Benralizumab could serve as a therapeutic option for eosinophil-mediated pathologies in severely ill patients where immunosuppressives are initially contraindicated.


Asunto(s)
Antiasmáticos/uso terapéutico , Antibacterianos/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Síndrome de Churg-Strauss/tratamiento farmacológico , Granulomatosis con Poliangitis/tratamiento farmacológico , Infecciones Estafilocócicas/tratamiento farmacológico , Sistema Nervioso Central/patología , Humanos , Masculino , Persona de Mediana Edad , Miocardio/patología , Sepsis/tratamiento farmacológico , Sepsis/microbiología , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/aislamiento & purificación
12.
Dermatology ; 236(6): 529-539, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31958790

RESUMEN

BACKGROUND: Patients with mastocytosis often suffer from a variety of symptoms caused by mast cell mediators where treatments remain difficult, showing various success rates. Omalizumab, a monoclonal anti-IgE antibody, has been postulated to have a positive impact on mastocytosis-associated symptoms such as flush, vertigo, gastrointestinal problems, or anaphylaxis. OBJECTIVE: To investigate the efficacy and safety of omalizumab in systemic mastocytosis. METHODS: Patients with histologically proven mastocytosis were investigated in a multicenter prospective double-blind placebo-controlled trial to receive either omalizumab or placebo, dosed according to IgE and body weight. The primary endpoint was change in the AFIRMM activity score after 6 months of treatment. Different laboratory parameters were analyzed. RESULTS: Sixteen patients were analyzed: 7 to omalizumab and 9 to placebo (mean age 47.7 ± 13.8 vs. 45.4 ± 8.8 years; 66.6 vs. 85.7% were female; mean disease duration 10.0 ± 5.1 vs. 4.5 ± 2.9 years, respectively). After 6 months the median AFIRMM score decreased 50% from 52.0 to 26.0 in the omalizumab group versus 104.0-102.0 in the placebo group (p = 0.286); however, the difference was not significant (p = 0.941). Secondary endpoints, including the number of allergic reactions, changes in major complaints, wheal-and-flare reaction due to mechanical irritation (Darier's sign), and frequency of the use of mastocytosis-specific drugs improved in the omalizumab group, but not significantly. Adverse events like urticaria, bronchospasm, and anaphylactic shock showed no significant difference between the groups. No severe adverse events occurred. FcεRI (Fc-epsilon receptor) expression on basophils decreased after receiving omalizumab versus placebo. CONCLUSION: Omalizumab was safe and showed a tendency to improve mastocytosis-related symptoms, in particular diarrhea, dizziness, flush, and anaphylactic reactions, including the AFIRMM score and secondary endpoints; however, the difference was not significant. Due to the small study size and difference at baseline between the study groups, further studies are required to confirm our findings.


Asunto(s)
Antialérgicos/uso terapéutico , Mastocitosis Sistémica/tratamiento farmacológico , Omalizumab/uso terapéutico , Adulto , Método Doble Ciego , Femenino , Humanos , Masculino , Mastocitosis/tratamiento farmacológico , Persona de Mediana Edad , Estudios Prospectivos
13.
J Infect Dis ; 221(8): 1295-1303, 2020 03 28.
Artículo en Inglés | MEDLINE | ID: mdl-31268141

RESUMEN

BACKGROUND: Herpes zoster ophthalmicus occurs primarily in elderly or immunocompromised individuals after reactivation of varicella zoster virus (VZV). Recurrences of zoster ophthalmicus are uncommon because the reactivation efficiently boosts anti-VZV immunity. A 28-year-old female presented to our clinic with a history of multiple recurrences of zoster ophthalmicus. METHODS: Whole-exome sequencing (WES), analyses of VZV T-cell immunity, and pathogen recognition receptor function in primary antigen-presenting cells (APCs) and fibroblasts were performed. RESULTS: Normal VZV-specific T-cell immunity and antibody response were detected. Whole-exome sequencing identified a heterozygous nonsynonymous variant (c.2324C > T) in the Toll-like receptor 3 (TLR3) gene resulting in formation of a premature stop-codon. This alteration could potentially undermine TLR3 signaling in a dominant-negative fashion. Therefore, we investigated TLR3 signaling responses in APCs and fibroblasts from the patient. The APCs responded efficiently to stimulation with TLR3 ligands, whereas the responses from the fibroblasts were compromised. CONCLUSIONS: We report a novel TLR3 variant associated with recurrent zoster ophthalmicus. Toll-like receptor 3 responses that were unaffected in APCs but diminished in fibroblasts are in line with previous reports linking TLR3 deficiency with herpes simplex virus encephalitis. Mechanisms involving compromised viral sensing in infected cells may thus be central to the described immunodeficiency.


Asunto(s)
Herpes Zóster Oftálmico/virología , Herpesvirus Humano 3/patogenicidad , Mutación/genética , Receptor Toll-Like 3/genética , Adulto , Encefalitis por Herpes Simple/genética , Encefalitis por Herpes Simple/virología , Femenino , Fibroblastos/virología , Herpes Zóster/genética , Herpes Zóster/virología , Herpes Zóster Oftálmico/genética , Humanos , Huésped Inmunocomprometido/genética
14.
J Invest Dermatol ; 140(5): 1003-1014.e8, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-31678057

RESUMEN

Methotrexate (MTX) is an antiproliferative drug used for treating inflammatory diseases, including psoriasis. Nevertheless, its use in localized therapy is hindered because of poor transdermal penetration. We show that MTX coupled with gold nanoparticles (GNPs) demonstrates superior antiinflammatory efficacy than MTX alone in an imiquimod-induced mouse model, significantly reducing γδ T cells, CD4+ T cells, and neutrophils. Furthermore, it was well tolerated upon systemic and topical administration. In an AGR129 human xenograft mouse model, two-week topical treatment with MTX-GNPs inhibited skin hyperplasia significantly better than topical calcipotriol-betamethasone and led to profound tissue remodeling, involving the upregulation of extracellular matrix reorganization and the downregulation of cornification and keratinization processes. The number of resident T cells in the grafts, as well as interleukin-17 production, drastically decreased upon MTX-GNP treatment. While both MTX and MTX-GNPs directly prevented the proliferation and induced apoptosis of T cells, the suppression of cytokine production was a shared mechanism of GNP and MTX-GNPs. In conclusion, MTX-GNPs influence immune and stromal components of the skin, leading to the potent inhibition of pathogenesis in preclinical psoriasis. MTX-GNPs surpass the efficacy of conventional MTX and standard of care, emerging as a non-steroidal, topical alternative for psoriasis treatment.


Asunto(s)
Antiinflamatorios/uso terapéutico , Metotrexato/uso terapéutico , Nanopartículas/uso terapéutico , Psoriasis/tratamiento farmacológico , Piel/patología , Administración Tópica , Animales , Antiinflamatorios/química , Apoptosis , Proliferación Celular , Células Cultivadas , Modelos Animales de Enfermedad , Femenino , Oro/química , Humanos , Imiquimod , Inmunidad , Metotrexato/química , Ratones , Ratones Endogámicos C57BL , Nanopartículas/química , Células Th17 , Ensayos Antitumor por Modelo de Xenoinjerto
16.
J Am Soc Nephrol ; 30(11): 2262-2274, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31653784

RESUMEN

BACKGROUND: Patients on organ transplant waiting lists are evaluated for preexisting alloimmunity to minimize episodes of acute and chronic rejection by regularly monitoring for changes in alloimmune status. There are few studies on how alloimmunity changes over time in patients on kidney allograft waiting lists, and an apparent lack of research-based evidence supporting currently used monitoring intervals. METHODS: To investigate the dynamics of alloimmune responses directed at HLA antigens, we retrospectively evaluated data on anti-HLA antibodies measured by the single-antigen bead assay from 627 waitlisted patients who subsequently received a kidney transplant at University Hospital Zurich, Switzerland, between 2008 and 2017. Our analysis focused on a filtered dataset comprising 467 patients who had at least two assay measurements. RESULTS: Within the filtered dataset, we analyzed potential changes in mean fluorescence intensity values (reflecting bound anti-HLA antibodies) between consecutive measurements for individual patients in relation to the time interval between measurements. Using multiple approaches, we found no correlation between these two factors. However, when we stratified the dataset on the basis of documented previous immunizing events (transplant, pregnancy, or transfusion), we found significant differences in the magnitude of change in alloimmune status, especially among patients with a previous transplant versus patients without such a history. Further efforts to cluster patients according to statistical properties related to alloimmune status kinetics were unsuccessful, indicating considerable complexity in individual variability. CONCLUSIONS: Alloimmune kinetics in patients on a kidney transplant waiting list do not appear to be related to the interval between measurements, but are instead associated with alloimmunization history. This suggests that an individualized strategy for alloimmune status monitoring may be preferable to currently used intervals.


Asunto(s)
Antígenos HLA/inmunología , Isoanticuerpos/análisis , Trasplante de Riñón , Listas de Espera , Femenino , Humanos , Cinética , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Tiempo
17.
J Allergy Clin Immunol ; 144(1): 267-279.e4, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30768990

RESUMEN

BACKGROUND: Type 2 immunity serves to resist parasitic helminths, venoms, and toxins, but the role and regulation of neutrophils during type 2 immune responses are controversial. Helminth models suggested a contribution of neutrophils to type 2 immunity, whereas neutrophils are associated with increased disease severity during type 2 inflammatory disorders, such as asthma. OBJECTIVE: We sought to evaluate the effect of the prototypic type 2 cytokines IL-4 and IL-13 on human neutrophils. METHODS: Human neutrophils from peripheral blood were assessed without or with IL-4 or IL-13 for (1) expression of IL-4 receptor subunits, (2) neutrophil extracellular trap (NET) formation, (3) migration toward CXCL8 in vitro and in humanized mice, and (4) CXCR1, CXCR2, and CXCR4 expression, as well as (5) in nonallergic versus allergic subjects. RESULTS: Human neutrophils expressed both types of IL-4 receptors, and their stimulation through IL-4 or IL-13 diminished their ability to form NETs and migrate toward CXCL8 in vitro. Likewise, in vivo chemotaxis in NOD-scid-Il2rg-/- mice was reduced in IL-4-stimulated human neutrophils compared with control values. These effects were accompanied by downregulation of the CXCL8-binding chemokine receptors CXCR1 and CXCR2 on human neutrophils on IL-4 or IL-13 stimulation in vitro. Ex vivo analysis of neutrophils from allergic patients or exposure of neutrophils from nonallergic subjects to allergic donor serum in vitro impaired their NET formation and migration toward CXCL8, thereby mirroring IL-4/IL-13-stimulated neutrophils. CONCLUSION: IL-4 receptor signaling in human neutrophils affects several neutrophil effector functions, which bears important implications for immunity in type 2 inflammatory disorders.


Asunto(s)
Movimiento Celular/fisiología , Interleucina-13/fisiología , Interleucina-4/fisiología , Neutrófilos/fisiología , Animales , Trampas Extracelulares/fisiología , Humanos , Ratones Noqueados , Receptores de Interleucina-4/genética
18.
Clin Immunol ; 200: 16-18, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30630113

RESUMEN

Severe combined immunodeficiency (SCID) can be caused by deleterious mutations in DCLRE1C, leading to deficient non-homologous end joining by compromising the function of the Artemis protein. This impairs the process of V(D)J recombination of the T- and B-cell receptors and typically results in radiosensitive T-, B-, NK+ SCID presenting during the first months of life. We present a case of a 3-year-old girl with two novel compound heterozygous variants in DCLRE1C (c.58G>C and c.374A>C) that were associated with marked reduced numbers of peripheral T- and B-cells and undetectable total serum IgG. Despite the severe laboratory phenotype, the patient had a normal development, albeit failure to thrive (-2.5 to -3 SD), during her first years of life including day-care attendance at preschool for 1.5 years. After being diagnosed with pneumonia the clinical picture of SCID was recognized and the girl successfully underwent hematopoietic stem-cell transplantation.


Asunto(s)
Agammaglobulinemia/genética , Proteínas de Unión al ADN/genética , Endonucleasas/genética , Inmunodeficiencia Combinada Grave/genética , Agammaglobulinemia/complicaciones , Agammaglobulinemia/inmunología , Preescolar , Femenino , Heterocigoto , Humanos , Mutación , Neumonía por Pneumocystis/diagnóstico , Neumonía por Pneumocystis/etiología , Inmunodeficiencia Combinada Grave/complicaciones , Inmunodeficiencia Combinada Grave/diagnóstico , Inmunodeficiencia Combinada Grave/inmunología
19.
J Pediatr Hematol Oncol ; 41(2): 155-157, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-29620681

RESUMEN

Thrombocytopenia presenting during early childhood is most commonly diagnosed as immune/idiopathic thrombocytopenic purpura (ITP), where the antibody-mediated destruction of thrombocytes is often transient. If treatment is indicated, the majority of patients respond to immune-modulation by intravenous immunoglobulin G infusion or systemic corticosteroids. Differential diagnoses to childhood ITP includes thrombocytopenia due to infections, drugs, rheumatologic conditions, immune dysregulation, and inherited bone marrow failures, for example, congenital amegakaryocytic thrombocytopenia. Isolated thrombocytopenia in an otherwise healthy appearing child that recurs after therapy and/or persists suggest a differential diagnosis rather than ITP. We present a case of symptomatic thrombocytopenia in a 2-year-old girl associated with adenosine deaminase deficiency.


Asunto(s)
Adenosina Desaminasa/deficiencia , Corticoesteroides/administración & dosificación , Agammaglobulinemia , Inmunoglobulinas Intravenosas/administración & dosificación , Péptidos y Proteínas de Señalización Intercelular/deficiencia , Púrpura Trombocitopénica Idiopática , Inmunodeficiencia Combinada Grave , Agammaglobulinemia/diagnóstico , Agammaglobulinemia/tratamiento farmacológico , Preescolar , Diagnóstico Diferencial , Femenino , Humanos , Púrpura Trombocitopénica Idiopática/diagnóstico , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Inmunodeficiencia Combinada Grave/diagnóstico , Inmunodeficiencia Combinada Grave/tratamiento farmacológico
20.
Allergy ; 74(3): 432-448, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30353939

RESUMEN

Chronic airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), together with their comorbidities, bear a significant burden on public health. Increased appreciation of molecular networks underlying inflammatory airway disease needs to be translated into new therapies for distinct phenotypes not controlled by current treatment regimens. On the other hand, development of new safe and effective therapies for such respiratory diseases is an arduous and expensive process. Antibody-based (biological) therapies are successful in treating certain respiratory conditions not controlled by standard therapies such as severe allergic and refractory eosinophilic severe asthma, while in other inflammatory respiratory diseases, such as COPD, biologicals are having a more limited impact. Small molecule drug (SMD)-based therapies represent an active field in pharmaceutical research and development. SMDs expand biologicals' therapeutic targets by reaching the intracellular compartment by delivery as either an oral or topically based formulation, offering both convenience and lower costs. Aim of this review was to compare and contrast the distinct pharmacological properties and clinical applications of SMDs- and antibody-based treatment strategies, their limitations and challenges, in order to highlight how they should be integrated for their optimal utilization and to fill the critical gaps in current treatment for these chronic inflammatory respiratory diseases.


Asunto(s)
Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Enfermedades Respiratorias/tratamiento farmacológico , Asma/diagnóstico , Asma/tratamiento farmacológico , Asma/etiología , Biomarcadores , Enfermedad Crónica , Diagnóstico Diferencial , Manejo de la Enfermedad , Humanos , Terapia Molecular Dirigida , Fenotipo , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/etiología , Enfermedades Respiratorias/diagnóstico , Enfermedades Respiratorias/etiología , Resultado del Tratamiento
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