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1.
J Immunol ; 188(7): 3199-207, 2012 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-22393152

RESUMO

CD23, the low-affinity receptor for IgE, exists in membrane and soluble forms. Soluble CD23 (sCD23) fragments are released from membrane (m)CD23 by the endogenous metalloprotease a disintegrin and metalloprotease 10. When purified tonsil B cells are incubated with IL-4 and anti-CD40 to induce class switching to IgE in vitro, mCD23 is upregulated, and sCD23 accumulates in the medium prior to IgE synthesis. We have uncoupled the effects of mCD23 cleavage and accumulation of sCD23 on IgE synthesis in this system. We show that small interfering RNA inhibition of CD23 synthesis or inhibition of mCD23 cleavage by an a disintegrin and metalloprotease 10 inhibitor, GI254023X, suppresses IL-4 and anti-CD40-stimulated IgE synthesis. Addition of a recombinant trimeric sCD23 enhances IgE synthesis in this system. This occurs even when endogenous mCD23 is protected from cleavage by GI254023X, indicating that IgE synthesis is positively controlled by sCD23. We show that recombinant trimeric sCD23 binds to cells coexpressing mIgE and mCD21 and caps these proteins on the B cell membrane. Upregulation of IgE by sCD23 occurs after class-switch recombination, and its effects are isotype-specific. These results suggest that mIgE and mCD21 cooperate in the sCD23-mediated positive regulation of IgE synthesis on cells committed to IgE synthesis. Feedback regulation may occur when the concentration of secreted IgE becomes great enough to allow binding to mCD23, thus preventing further release of sCD23. We interpret these results with the aid of a model for the upregulation of IgE by sCD23.


Assuntos
Linfócitos B/imunologia , Regulação da Expressão Gênica/imunologia , Genes de Imunoglobulinas , Imunoglobulina E/biossíntese , Receptores de IgE/imunologia , Proteínas ADAM/antagonistas & inibidores , Proteína ADAM10 , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Linfócitos B/metabolismo , Dipeptídeos/farmacologia , Retroalimentação Fisiológica , Homeostase , Humanos , Ácidos Hidroxâmicos/farmacologia , Switching de Imunoglobulina , Capeamento Imunológico , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/fisiologia , Inibidores de Proteases/farmacologia , Ligação Proteica , Interferência de RNA , RNA Interferente Pequeno/farmacologia , Receptores de Complemento 3d/imunologia , Receptores de IgE/genética , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/farmacologia , Solubilidade , Regulação para Cima
2.
J Biol Chem ; 282(33): 24083-91, 2007 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-17576766

RESUMO

The low affinity IgE receptor, CD23, is implicated in IgE regulation and the pathogenesis of allergic disease. CD23 is a type II integral membrane protein, comprising a lectin "head," N-terminal "stalk," and C-terminal "tail" in the extracellular sequence. Endogenous proteases cleave CD23 in the stalk and the tail to release soluble fragments that either stimulate or inhibit IgE synthesis in human B cells. The molecular basis of these paradoxical activities is not understood. We have characterized three fragments of CD23, monomeric derCD23, monomeric exCD23, and oligomeric lzCD23. We show that the monomers inhibit and the oligomer stimulates IgE synthesis in human B cells after heavy chain switching to IgE. CD23 fragments could be targets for therapeutic intervention in allergic disease.


Assuntos
Linfócitos B/imunologia , Imunoglobulina E/biossíntese , Receptores de IgE/imunologia , Linfócitos B/metabolismo , Dimerização , Humanos , Hipersensibilidade , Fragmentos de Peptídeos , Receptores de IgE/metabolismo , Solubilidade
3.
J Immunol ; 174(4): 1938-46, 2005 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-15699121

RESUMO

Multiple sclerosis (MS) is thought to involve CD4 T cell recognition of self myelin, many studies focusing on a pathogenic role for anti-myelin, HLA-DR15-restricted T cells. In experimental allergic encephalomyelitis, it is known which epitopes trigger disease and that disease is associated with determinant spread of T cell reactivity. Characterization of these events in human MS is critical for the development of peptide immunotherapies, but it has been difficult to define the role of determinant spread or define which epitopes might be involved. In this study, we report humanized transgenic mice, strongly expressing HLA-DR15 with an MS-derived TCR; even on a RAG-2 wild-type background, mice spontaneously develop paralysis. Disease, involving demyelination and axonal degeneration, correlates with inter- and intramolecular spread of the T cell response to HLA-DR15-restricted epitopes of myelin basic protein, myelin oligodendrocyte glycoprotein, and alphaB-crystallin. Spread is reproducible and progressive, with two of the epitopes commonly described in responses of HLA-DR15 patients. The fact that this pattern is reiterated as a consequence of CNS tissue damage in mice demonstrates the value of the transgenic model in supplying an in vivo disease context for the human responses. This model, encompassing pathologically relevant, spontaneous disease with the presentation of myelin epitopes in the context of HLA-DR15, should offer new insights and predictions about T cell responses during MS as well as a more stringent test bed for immunotherapies.


Assuntos
Antígenos HLA-DR/genética , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Animais , Apresentação de Antígeno/genética , Apresentação de Antígeno/imunologia , Movimento Celular/genética , Movimento Celular/imunologia , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/patologia , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Progressão da Doença , Epitopos de Linfócito T/imunologia , Epitopos de Linfócito T/metabolismo , Antígenos HLA-DR/biossíntese , Antígenos HLA-DR/fisiologia , Subtipos Sorológicos de HLA-DR , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Esclerose Múltipla/patologia , Proteína Básica da Mielina/imunologia , Proteína Básica da Mielina/metabolismo , Paralisia/genética , Paralisia/imunologia , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , Receptores de Antígenos de Linfócitos T alfa-beta/biossíntese , Receptores de Antígenos de Linfócitos T alfa-beta/fisiologia , Subpopulações de Linfócitos T/patologia
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