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1.
J Biol Chem ; 291(32): 16840-8, 2016 08 05.
Artículo en Inglés | MEDLINE | ID: mdl-27231345

RESUMEN

Interleukin-16 (IL-16) is reported to be a chemoattractant cytokine and modulator of T-cell activation, and has been proposed as a ligand for the co-receptor CD4. The secreted active form of IL-16 has been detected at sites of TH1-mediated inflammation, such as those seen in autoimmune diseases, ischemic reperfusion injury (IRI), and tissue transplant rejection. Neutralization of IL-16 recruitment to its receptor, using an anti-IL16 antibody, has been shown to significantly attenuate inflammation and disease pathology in IRI, as well as in some autoimmune diseases. The 14.1 antibody is a monoclonal anti-IL-16 antibody, which when incubated with CD4(+) cells is reported to cause a reduction in the TH1-type inflammatory response. Secreted IL-16 contains a characteristic PDZ domain. PDZ domains are typically characterized by a defined globular structure, along with a peptide-binding site located in a groove between the αB and ßB structural elements and a highly conserved carboxylate-binding loop. In contrast to other reported PDZ domains, the solution structure previously reported for IL-16 reveals a tryptophan residue obscuring the recognition groove. We have solved the structure of the 14.1Fab fragment in complex with IL-16, revealing that binding of the antibody requires a conformational change in the IL-16 PDZ domain. This involves the rotation of the αB-helix, accompanied movement of the peptide groove obscuring tryptophan residue, and consequent opening up of the binding site for interaction. Our study reveals a surprising mechanism of action for the antibody and identifies new opportunities for the development of IL-16-targeted therapeutics, including small molecules that mimic the interaction of the antibody.


Asunto(s)
Anticuerpos Monoclonales/química , Sitios de Unión de Anticuerpos , Fragmentos Fab de Inmunoglobulinas/química , Interleucina-16/química , Cristalografía por Rayos X , Humanos , Dominios Proteicos , Estructura Secundaria de Proteína
2.
Acta Neuropathol ; 134(1): 15-34, 2017 07.
Artículo en Inglés | MEDLINE | ID: mdl-28386765

RESUMEN

Cortical demyelination is a widely recognized hallmark of multiple sclerosis (MS) and correlate of disease progression and cognitive decline. The pathomechanisms initiating and driving gray matter damage are only incompletely understood. Here, we determined the infiltrating leukocyte subpopulations in 26 cortical demyelinated lesions of biopsied MS patients and assessed their contribution to cortical lesion formation in a newly developed mouse model. We find that conformation-specific anti-myelin antibodies contribute to cortical demyelination even in the absence of the classical complement pathway. T cells and natural killer cells are relevant for intracortical type 2 but dispensable for subpial type 3 lesions, whereas CCR2+ monocytes are required for both. Depleting CCR2+ monocytes in marmoset monkeys with experimental autoimmune encephalomyelitis using a novel humanized CCR2 targeting antibody translates into significantly less cortical demyelination and disease severity. We conclude that biologics depleting CCR2+ monocytes might be attractive candidates for preventing cortical lesion formation and ameliorating disease progression in MS.


Asunto(s)
Corteza Cerebral/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Monocitos/inmunología , Esclerosis Múltiple/inmunología , Adulto , Animales , Callithrix , Corteza Cerebral/patología , Estudios de Cohortes , Encefalomielitis Autoinmune Experimental/patología , Femenino , Humanos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/patología , Masculino , Meninges/inmunología , Meninges/patología , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , Monocitos/patología , Esclerosis Múltiple/patología , Distribución Aleatoria , Receptores CCR2/metabolismo , Linfocitos T/inmunología , Linfocitos T/patología
3.
Infect Immun ; 77(12): 5659-67, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19805526

RESUMEN

Antigen-specific antibodies (Abs) to the 19-kDa carboxy-terminal region of Plasmodium falciparum merozoite surface protein 1 (MSP1(19)) play an important role in protective immunity to malaria. Mouse monoclonal Abs (MAbs) 12.10 and 12.8 recognizing MSP1(19) can inhibit red cell invasion by interfering with MSP1 processing on the merozoite surface. We show here that this ability is dependent on the intact Ab since Fab and F(ab')(2) fragments derived from MAb 12.10, although capable of binding MSP1 with high affinity and competing with the intact antibody for binding to MSP1, were unable to inhibit erythrocyte invasion or MSP1 processing. The DNA sequences of the variable (V) regions of both MAbs 12.8 and 12.10 were obtained, and partial amino acid sequences of the same regions were confirmed by mass spectrometry. Human chimeric Abs constructed by using these sequences, which combine the original mouse V regions with human gamma1 and gamma3 constant regions, retain the ability to bind to both parasites and recombinant MSP1(19), and both chimeric human immunoglobulin G1s (IgG1s) were at least as good at inhibiting erythrocyte invasion as the parental murine MAbs 12.8 and 12.10. Furthermore, the human chimeric Abs of the IgG1 class (but not the corresponding human IgG3), induced significant NADPH-mediated oxidative bursts and degranulation from human neutrophils. These chimeric human Abs will enable investigators to examine the role of human Fcgamma receptors in immunity to malaria using a transgenic parasite and mouse model and may prove useful in humans for neutralizing parasites as an adjunct to antimalarial drug therapy.


Asunto(s)
Anticuerpos Antiprotozoarios/inmunología , Eritrocitos/parasitología , Inmunoglobulina G/inmunología , Proteína 1 de Superficie de Merozoito/antagonistas & inhibidores , Plasmodium falciparum/inmunología , Secuencia de Aminoácidos , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/metabolismo , Anticuerpos Antiprotozoarios/metabolismo , Secuencia de Bases , Humanos , Fragmentos Fab de Inmunoglobulinas/metabolismo , Proteína 1 de Superficie de Merozoito/inmunología , Proteína 1 de Superficie de Merozoito/metabolismo , Ratones , Datos de Secuencia Molecular , Neutrófilos/inmunología , Unión Proteica , ARN , Estallido Respiratorio
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