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1.
J Immunol ; 189(6): 2735-45, 2012 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-22891284

RESUMEN

Plasmacytoid dendritic cells (pDC) are rare cells found in peripheral blood and lymphoid tissues. pDC are considered to be "professional" type I IFN-producing cells and produce 10- to 100-fold more IFN-α than other cell types in response to enveloped viruses or synthetic TLR7 and TLR9 agonists. In this study, purified pDC were found to express high levels of IFN-λ receptor mRNA, as well as cell-surface IFN-λ receptor. We have developed intracellular flow cytometry assays using Abs to IFN-λ1/3 or -λ2 to assess the expression of IFN-λ proteins by pDC. We observed that a subset of human pDC expresses only intracellular IFN-α, whereas another subset produces both IFN-α and IFN-λ after stimulation with virus or the TLR9 agonist, CpG A; the cells that coexpressed IFN-α and IFN-λ were the cells with the highest levels of IFN-α expression. Ab cross-linking of CD4 or CD303 molecules on pDC inhibited both HSV-induced IFN-λ and IFN-α production. Like the production of IFN-α, the HSV-induced IFN-λ production in pDC was mediated through TLR9 and independent of virus replication. Exogenous IFN-λ treatment of pDC resulted in increased virus-induced expression of both IFN-α and IFN-λ. In addition, both exogenous IFN-λ and -α inhibited dexamethasone-induced apoptosis of pDC. We conclude that pDC are major producers of IFN-λ1 and -λ2 in response to viral stimulation and also express functional receptors for this cytokine. Thus, IFN-λ can serve as an autocrine signal to strengthen the antiviral response of pDC by increasing IFN-α and IFN-λ production, resulting in prolonged pDC survival.


Asunto(s)
Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Interleucinas/biosíntesis , Interleucinas/fisiología , Células Cultivadas , Células Dendríticas/virología , Células HEK293 , Células Hep G2 , Herpesvirus Humano 1/inmunología , Humanos , Virus de la Influenza A/inmunología , Interferones , Interleucinas/genética , Receptores de Citocinas/metabolismo , Virus Sendai/inmunología
2.
MAbs ; 4(1): 69-83, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22327431

RESUMEN

Interleukin-21 (IL-21) is a type I four-helical bundle cytokine that exerts a variety of significant effects on many hematopoietic cells, including T and B lymphocytes and natural killer cells. IL-21 is produced predominantly by CD4+ T cells and natural killer T cells and, when aberrantly overexpressed, appears to play important roles in a wide variety of autoimmune disorders. To generate potential therapeutic reagents capable of inhibiting IL-21 for clinical use, we immunized human immunoglobulin transgenic mice with IL-21 and then identified and cloned a panel of human anti-human IL-21 binding monoclonal antibodies. IL-21 neutralizing and IL-21-binding, non-neutralizing antibodies were assigned to distinct epitope "bins" based on surface plasmon resonance competition studies. The most potent neutralizing antibodies had extremely high (sub pM) affinity for IL-21 and were able to block IL-21 activity in various biological assays using either an IL-21R-transfected pre-B-cell line or primary human B cells, and their neutralizing activity was, in some cases, superior to that of a soluble form of the high affinity heterodimeric IL-21 receptor. Characterization of this panel of IL-21 antibodies provided the basis for the selection of a therapeutic candidate antibody capable of inhibiting IL-21 activity for the treatment of autoimmune and inflammatory diseases.


Asunto(s)
Anticuerpos Monoclonales/biosíntesis , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/biosíntesis , Anticuerpos Neutralizantes/inmunología , Interleucinas/inmunología , Secuencia de Aminoácidos , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Neutralizantes/farmacología , Anticuerpos Neutralizantes/uso terapéutico , Autoinmunidad , Linfocitos B/inmunología , Células CHO , Línea Celular , Cricetinae , Epítopos/inmunología , Humanos , Interleucinas/administración & dosificación , Interleucinas/química , Interleucinas/genética , Células Asesinas Naturales/inmunología , Ratones , Ratones Transgénicos , Células Precursoras de Linfocitos B/inmunología , Conejos , Ratas , Receptores de Interleucina-21/genética , Receptores de Interleucina-21/inmunología , Linfocitos T/inmunología
3.
Nat Immunol ; 4(1): 63-8, 2003 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-12469119

RESUMEN

Cytokines play a critical role in modulating the innate and adaptive immune systems. Here, we have identified from the human genomic sequence a family of three cytokines, designated interleukin 28A (IL-28A), IL-28B and IL-29, that are distantly related to type I interferons (IFNs) and the IL-10 family. We found that like type I IFNs, IL-28 and IL-29 were induced by viral infection and showed antiviral activity. However, IL-28 and IL-29 interacted with a heterodimeric class II cytokine receptor that consisted of IL-10 receptor beta (IL-10Rbeta) and an orphan class II receptor chain, designated IL-28Ralpha. This newly described cytokine family may serve as an alternative to type I IFNs in providing immunity to viral infection.


Asunto(s)
Interleucinas/genética , Interleucinas/metabolismo , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo , Secuencia de Aminoácidos , Animales , Células COS , Clonación Molecular , Citocinas , Expresión Génica , Humanos , Técnicas In Vitro , Interferones , Datos de Secuencia Molecular , Subunidades de Proteína , ARN/genética , ARN/metabolismo , Receptores de Citocinas/química , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Homología de Secuencia de Aminoácido , Transducción de Señal , Virosis/inmunología
4.
Neuromuscul Disord ; 12(2): 141-50, 2002 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-11738356

RESUMEN

IL-17B is a recently identified homolog of IL-17. Northern analysis revealed that IL-17B mRNA is expressed at very high levels in spinal cord and at much lower and more variable levels in trachea, prostate, lung, small intestine, testes, adrenal, and pancreas. In developing mouse embryos IL-17B expression was first detected at day 11 and appeared to peak at day 15. In situ analysis of mouse spinal cord, dorsal root ganglia, and brain demonstrated that IL-17B mRNA is primarily expressed by the neurons. Immunohistochemical analysis of human spinal cord, dorsal root ganglia, cerebral cortex, cerebellum, and hippocampus demonstrated that IL-17B protein is primarily localized to the neuronal cell bodies and axons. Radiation hybrid mapping localized the IL-17B gene to a region on human chromosome 5q that is associated with a rare autosomal recessive form of Charcot-Marie-Tooth demyelinating disease. However, no changes were found in the coding regions, splice junctions, intron 1, or the 5' and 3' untranslated regions of IL-17B genes of patients affected with this disease.


Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Mapeo Cromosómico , Cromosomas Humanos Par 5 , Interleucina-17/genética , Neuronas/inmunología , Neuronas/fisiología , Secuencia de Aminoácidos , Animales , Encéfalo/inmunología , Línea Celular , Enfermedad de Charcot-Marie-Tooth/inmunología , Cricetinae , Desarrollo Embrionario y Fetal , Etiquetas de Secuencia Expresada , Regulación del Desarrollo de la Expresión Génica/fisiología , Biblioteca de Genes , Humanos , Interleucina-17/fisiología , Masculino , Ratones , Ratones Endogámicos BALB C , Datos de Secuencia Molecular , Especificidad de Órganos , Próstata/metabolismo , ARN Mensajero/genética , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Médula Espinal/inmunología , Tráquea/metabolismo , Transcripción Genética
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