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1.
J Immunol ; 205(10): 2883-2892, 2020 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-33077644

RESUMO

CD98, which is required for the rapid proliferation of both normal and cancer cells, and MET, the hepatocyte growth factor receptor, are potential targets for therapeutic antitumor Abs. In this study, we report that the antiproliferative activity of a prototype anti-CD98 Ab, UM7F8, is due to Ab-induced membrane-associated ring CH (MARCH) E3 ubiquitin ligase-mediated ubiquitination and downregulation of cell surface CD98. MARCH1-mediated ubiquitination of CD98 is required for UM7F8's capacity to reduce CD98 surface expression and its capacity to inhibit the proliferation of murine T cells. Similarly, CD98 ubiquitination is required for UM7F8's capacity to block the colony-forming ability of murine leukemia-initiating cells. To test the potential generality of the paradigm that MARCH E3 ligases can mediate the antiproliferative response to antitumor Abs, we examined the potential effects of MARCH proteins on responses to emibetuzumab, an anti-MET Ab currently in clinical trials for various cancers. We report that MET surface expression is reduced by MARCH1, 4, or 8-mediated ubiquitination and that emibetuzumab-induced MET ubiquitination contributes to its capacity to downregulate MET and inhibit human tumor cell proliferation. Thus, MARCH E3 ligases can act as cofactors for antitumor Abs that target cell surface proteins, suggesting that the MARCH protein repertoire of cells is a determinant of their response to such Abs.


Assuntos
Antígenos de Neoplasias/metabolismo , Antineoplásicos Imunológicos/farmacologia , Cadeia Pesada da Proteína-1 Reguladora de Fusão/metabolismo , Neoplasias/tratamento farmacológico , Ubiquitina-Proteína Ligases/metabolismo , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Antineoplásicos Imunológicos/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Cadeia Pesada da Proteína-1 Reguladora de Fusão/antagonistas & inibidores , Cadeia Pesada da Proteína-1 Reguladora de Fusão/genética , Cadeia Pesada da Proteína-1 Reguladora de Fusão/imunologia , Técnicas de Inativação de Genes , Células HeLa , Humanos , Células Jurkat , Camundongos , Camundongos Knockout , Neoplasias/imunologia , Neoplasias/patologia , Proteólise , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/genética , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Ubiquitina-Proteína Ligases/genética , Ubiquitinação/imunologia
2.
J Immunol ; 200(12): 4012-4023, 2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29703862

RESUMO

Maintenance of the regulatory T (Treg) cell pool is essential for peripheral tolerance and prevention of autoimmunity. Integrins, heterodimeric transmembrane proteins consisting of α and ß subunits that mediate cell-to-cell and cell-to-extracellular matrix interactions, play an important role in facilitating Treg cell contact-mediated suppression. In this article, we show that integrin activation plays an essential, previously unappreciated role in maintaining murine Treg cell function. Treg cell-specific loss of talin, a ß integrin-binding protein, or expression of talin(L325R), a mutant that selectively abrogates integrin activation, resulted in lethal systemic autoimmunity. This dysfunction could be attributed, in part, to a global dysregulation of the Treg cell transcriptome. Activation of integrin α4ß1 led to increased suppressive capacity of the Treg cell pool, suggesting that modulating integrin activation on Treg cells may be a useful therapeutic strategy for autoimmune and inflammatory disorders. Taken together, these results reveal a critical role for integrin-mediated signals in controlling peripheral tolerance by virtue of maintaining Treg cell function.


Assuntos
Integrinas/imunologia , Tolerância Periférica/imunologia , Linfócitos T Reguladores/imunologia , Animais , Autoimunidade/imunologia , Inflamação/imunologia , Camundongos , Talina/imunologia , Transcriptoma/imunologia
3.
J Immunol ; 198(9): 3410-3415, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28348273

RESUMO

Rap1-interacting adaptor molecule (RIAM) is a Rap1 effector that mediates the recruitment of talin to integrins, thereby supporting their activation. In this study, we investigated the role of RIAM in an adoptive transfer model for type I diabetes and report that RIAM expression in T cells is necessary for diabetes development. Loss of RIAM did not prevent lymphocyte recruitment to draining lymph nodes 24 h after transfer, but it was required for Ag-driven proliferation and cytotoxic killing. RIAM is recruited to immune synapses along with talin and LFA-1, and loss of RIAM profoundly suppresses Ag-dependent conjugate formation in primary naive and effector T cells. These data identify the requirement of RIAM for formation of immunological synapses and in resulting T cell functions in autoimmunity. Moreover, because RIAM-null mice are healthy, fertile, and display no bleeding abnormalities, our results identify RIAM and its regulators as potential targets for therapies of T cell-mediated autoimmunity.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Células Apresentadoras de Antígenos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Antígeno-1 Associado à Função Linfocitária/metabolismo , Proteínas de Membrana/metabolismo , Linfócitos T/imunologia , Talina/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Transferência Adotiva , Animais , Proliferação de Células/genética , Células Cultivadas , Citotoxicidade Imunológica/genética , Humanos , Sinapses Imunológicas/imunologia , Proteínas de Membrana/genética , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T/transplante
4.
J Cell Sci ; 128(23): 4273-8, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-26493331

RESUMO

CD98 heavy chain (SLC3A2) facilitates lymphocyte clonal expansion that enables adaptive immunity; however, increased expression of CD98 is also a feature of both lymphomas and leukemias and represents a potential therapeutic target in these diseases. CD98 is transcriptionally regulated and ectopic expression of the membrane-associated RING-CH (MARCH) E3 ubiquitin ligases MARCH1 or MARCH8 leads to ubiquitylation and lysosomal degradation of CD98. Here, we examined the potential role of ubiquitylation in regulating CD98 expression and cell proliferation. We report that blocking ubiquitylation by use of a catalytically inactive MARCH or by creating a ubiquitylation-resistant CD98 mutant, prevents MARCH-induced CD98 downregulation in HeLa cells. March1-null T cells display increased CD98 expression. Similarly, T cells expressing ubiquitylation-resistant CD98 manifest increased proliferation in vitro and clonal expansion in vivo. Thus, ubiquitylation and the resulting downregulation of CD98 can limit cell proliferation and clonal expansion.


Assuntos
Proliferação de Células/fisiologia , Cadeia Pesada da Proteína-1 Reguladora de Fusão/metabolismo , Lisossomos/metabolismo , Proteólise , Ubiquitinação/fisiologia , Animais , Cadeia Pesada da Proteína-1 Reguladora de Fusão/genética , Células HeLa , Humanos , Células Jurkat , Lisossomos/genética , Camundongos , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
5.
Blood ; 125(12): 1995-2004, 2015 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-25587038

RESUMO

The bidirectional signaling and hemostatic functions of platelet αIIbß3 are regulated by kindlin-3 through interactions with the ß3 cytoplasmic tail. Little is known about kindlin regulation of the related "vitronectin receptor," αVß3. These relationships were investigated in endothelial cells, which express αVß3 and kindlin-2 endogenously. "ß3ΔRGT" knock-in mice lack the 3 C-terminal ß3 tail residues, whereas in "ß3/ß1(EGK)" mice, RGT is replaced by the corresponding residues of ß1. The wild-type ß3 tail pulled down kindlin-2 and c-Src in vitro, whereas ß3ΔRGT bound neither protein and ß3/ß1(EGK) bound kindlin-2, but not c-Src. ß3ΔRGT endothelial cells, but not ß3/ß1(EGK) endothelial cells, exhibited migration and spreading defects on vitronectin and reduced sprouting in 3-dimensional fibrin. Short hairpin RNA silencing of kindlin-2, but not c-Src, blocked sprouting by ß3 wild-type endothelial cells. Moreover, defective sprouting by ß3ΔRGT endothelial cells could be rescued by conditional, forced interaction of αVß3ΔRGT with kindlin-2. Stimulation of ß3ΔRGT endothelial cells led to normal extracellular ligand binding to αVß3, pin-pointing their defect to one of outside-in αVß3 signaling. ß3ΔRGT mice, but not ß3/ß1(EGK) mice, exhibited defects in both developmental and tumor angiogenesis, responses that require endothelial cell function. Thus, the ß3/kindlin-2 interaction promotes outside-in αVß3 signaling selectively, with biological consequences in vivo.


Assuntos
Proteínas do Citoesqueleto/metabolismo , Integrina alfaVbeta3/metabolismo , Integrina beta3/metabolismo , Proteínas Musculares/metabolismo , Animais , Plaquetas/metabolismo , Transplante de Medula Óssea , Movimento Celular , Citoplasma/metabolismo , Células Endoteliais , Humanos , Melanoma Experimental , Proteínas de Membrana/metabolismo , Camundongos , Mutação , Proteínas de Neoplasias/metabolismo , Transplante de Neoplasias , Neovascularização Patológica , Ligação Proteica , Estrutura Terciária de Proteína , Interferência de RNA , Transdução de Sinais
6.
Arterioscler Thromb Vasc Biol ; 36(11): 2163-2166, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27687603

RESUMO

OBJECTIVE: CD98 regulates integrin signaling and is critical for tumor cell proliferation. It is also expressed on endothelial cells (EC), but its role in angiogenesis is unclear. APPROACH AND RESULTS: We used specific genetic targeting and antibody blockade approaches to examine the function of CD98 in EC proliferation, blood vessel growth, and tumor angiogenesis. It is upregulated on angiogenic ECs, and EC-specific deletion of CD98 in mice inhibited tumor growth, retinal angiogenesis, and EC proliferation. Reconstitution with CD98 mutants showed that integrin and CD98 interaction is necessary for EC survival and growth. Moreover, anti-CD98 treatment inhibited vessel formation and reversed EC-assisted tumor growth. CONCLUSIONS: Our findings demonstrate a requirement for CD98 in EC growth and suggest that CD98-specific reagents could have a dual anticancer effect: directly by inhibiting tumor cell proliferation and indirectly by preventing tumor angiogenesis.


Assuntos
Carcinoma Pulmonar de Lewis/metabolismo , Cadeia Pesada da Proteína-1 Reguladora de Fusão/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Melanoma Experimental/metabolismo , Neovascularização Patológica , Neovascularização Fisiológica , Neovascularização Retiniana/metabolismo , Inibidores da Angiogênese/farmacologia , Animais , Anticorpos/farmacologia , Carcinoma Pulmonar de Lewis/irrigação sanguínea , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/genética , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Cadeia Pesada da Proteína-1 Reguladora de Fusão/genética , Cadeia Pesada da Proteína-1 Reguladora de Fusão/imunologia , Genótipo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/imunologia , Células Endoteliais da Veia Umbilical Humana/transplante , Humanos , Integrinas/metabolismo , Masculino , Melanoma Experimental/irrigação sanguínea , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/genética , Camundongos Knockout , Neovascularização Fisiológica/efeitos dos fármacos , Fenótipo , Fosforilação , Neovascularização Retiniana/tratamento farmacológico , Neovascularização Retiniana/genética , Neovascularização Retiniana/patologia , Transdução de Sinais , Fatores de Tempo , Carga Tumoral , Fator A de Crescimento do Endotélio Vascular/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
7.
Int J Cancer ; 137(3): 710-20, 2015 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-25556716

RESUMO

CD98 is expressed on several tissue types and specifically upregulated on fast-cycling cells undergoing clonal expansion. Various solid (e.g., nonsmall cell lung carcinoma) as well as hematological malignancies (e.g., acute myeloid leukemia) overexpress CD98. We have identified a CD98-specific mouse monoclonal antibody that exhibits potent preclinical antitumor activity against established lymphoma tumor xenografts. Additionally, the humanized antibody designated IGN523 demonstrated robust tumor growth inhibition in leukemic cell-line derived xenograft models and was as efficacious as standard of care carboplatin in patient-derived nonsmall lung cancer xenografts. In vitro studies revealed that IGN523 elicited strong ADCC activity, induced lysosomal membrane permeabilization and inhibited essential amino acid transport function, ultimately resulting in caspase-3 and -7-mediated apoptosis of tumor cells. IGN523 is currently being evaluated in a Phase I clinical trial for acute myeloid leukemia (NCT02040506). Furthermore, preclinical data support the therapeutic potential of IGN523 in solid tumors.


Assuntos
Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Proteína-1 Reguladora de Fusão/antagonistas & inibidores , Aminoácidos/metabolismo , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/farmacologia , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Antineoplásicos/administração & dosagem , Transporte Biológico , Caspases/metabolismo , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Proteínas do Sistema Complemento/imunologia , Citotoxicidade Imunológica , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Lisossomos/metabolismo , Camundongos , Modelos Biológicos , Ligação Proteica , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
J Cell Sci ; 125(Pt 6): 1373-82, 2012 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-22499670

RESUMO

Adaptive immunity, a vertebrate specialization, adds memory and exquisite specificity to the basic innate immune responses present in invertebrates while conserving metabolic resources. In adaptive immunity, antigenic challenge requires extremely rapid proliferation of rare antigen-specific lymphocytes to produce large, clonally expanded effector populations that neutralize pathogens. Rapid proliferation and resulting clonal expansion are dependent on CD98, a protein whose well-conserved orthologs appear restricted to vertebrates. Thus, CD98 supports lymphocyte clonal expansion to enable protective adaptive immunity, an advantage that could account for the presence of CD98 in vertebrates. CD98 supports lymphocyte clonal expansion by amplifying integrin signals that enable proliferation and prevent apoptosis. These integrin-dependent signals can also provoke cancer development and invasion, anchorage-independence and the rapid proliferation of tumor cells. CD98 is highly expressed in many cancers and contributes to formation of tumors in experimental models. Strikingly, vertebrates, which possess highly conserved CD98 proteins, CD98-binding integrins and adaptive immunity, also display propensity towards invasive and metastatic tumors. In this Commentary, we review the roles of CD98 in lymphocyte biology and cancer. We suggest that the CD98 amplification of integrin signaling in adaptive immunity provides survival benefits to vertebrates, which, in turn, bear the price of increased susceptibility to cancer.


Assuntos
Imunidade Adaptativa/fisiologia , Proteína-1 Reguladora de Fusão/fisiologia , Neoplasias/imunologia , Neoplasias/metabolismo , Animais , Proliferação de Células , Células Clonais , Humanos , Integrinas/fisiologia
9.
Immunol Rev ; 223: 236-51, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18613840

RESUMO

SUMMARY: Integrins are adhesion receptors important for hematopoiesis, leukocyte trafficking, and formation of immunological synapses; hence, they may provide targets for therapeutic intervention in leukocyte-driven pathologies. Blocking integrin-ligand binding is one strategy for inhibiting integrins; however, a complete loss of integrin function can lead to mechanism-based toxicities. Because integrin alpha and beta subunits interact with a variety of other proteins to receive and transmit cellular signals, targeting these integrin-associated proteins may utilize alternative sites for intervention that lead to therapies with fewer side effects. This review summarizes integrin-associated proteins in leukocytes and focuses on four of these proteins with perceived therapeutic potential. Specific mutations in the alpha4 integrin cytoplasmic tail block or enforce binding to paxillin and thus modulate integrin signaling required for efficient cell migration. Similarly, the association of RAPL(NORE1B) with beta2 integrins may participate in adhesive and migratory events in leukocytes. The beta integrin cytoplasmic tail-binding protein talin is critical for increasing the affinity of integrins (activation), and blockade of talin binding can prevent leukocyte arrest on the endothelium. Finally, the membrane protein CD98 mediates beta1 and beta3 integrin signaling and may be involved in leukocyte functions. Identification of biologically important interactions of integrins and signaling proteins can thus pave the way to new strategies for manipulating leukocyte functions.


Assuntos
Adesão Celular/imunologia , Integrinas/imunologia , Proteínas Monoméricas de Ligação ao GTP/imunologia , Paxilina/imunologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Proteínas Reguladoras de Apoptose , Adesão Celular/genética , Movimento Celular/imunologia , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Proteína-1 Reguladora de Fusão/imunologia , Proteína-1 Reguladora de Fusão/metabolismo , Humanos , Integrinas/química , Integrinas/genética , Integrinas/metabolismo , Leucócitos/citologia , Leucócitos/enzimologia , Leucócitos/metabolismo , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Paxilina/metabolismo , Ligação Proteica , Talina/imunologia , Talina/metabolismo , Trombose/imunologia
10.
Diabetes ; 65(11): 3505-3515, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27495221

RESUMO

Diabetes is associated with a deficit of circulating endothelial progenitor cells (EPCs), which has been attributed to their defective mobilization from the bone marrow. The basis for this mobilization defect is not completely understood, and we sought to determine if hyperglycemic conditions enhanced EPC adhesion. We found that culturing EPCs in high glucose media increased adhesion to bone marrow stromal cells. This enhanced adhesion was associated with decreased expression of protein kinase A regulatory subunit 1ß (PRKAR1ß), activation of protein kinase A (PKA), and phosphorylation of α4-integrin on serine 988. This potentiated adhesion was reversed by treatment with a PKA inhibitor, overexpression of PRKAR1ß, or expression of a phosphorylation-defective α4-integrin variant (α4[S988A]). Using a model of type 1 diabetes, we showed that α4(S988A)-expressing mice have more circulating EPCs than their wild-type counterparts. Moreover, diabetic α4(S988A) mice demonstrate enhanced revascularization after hind limb ischemia. Thus, we have identified a novel signaling mechanism activating PKA in diabetes (downregulation of an inhibitory regulatory subunit) that leads to deficits of circulating EPCs and impaired vascular repair, which could be reversed by α4-integrin mutation.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Células Progenitoras Endoteliais/metabolismo , Integrina alfa4beta1/metabolismo , Animais , Adesão Celular/genética , Adesão Celular/fisiologia , Células Cultivadas , Proteínas Quinases Dependentes de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Diabetes Mellitus Experimental/genética , Membro Posterior/patologia , Integrina alfa4beta1/genética , Isquemia/metabolismo , Masculino , Camundongos , Mutação/genética , Fosforilação , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
11.
Cancer Cell ; 30(5): 792-805, 2016 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-27908736

RESUMO

Acute myelogenous leukemia (AML) is an aggressive disease associated with drug resistance and relapse. To improve therapeutic strategies, it is critical to better understand the mechanisms that underlie AML progression. Here we show that the integrin binding glycoprotein CD98 plays a central role in AML. CD98 promotes AML propagation and lethality by driving engagement of leukemia cells with their microenvironment and maintaining leukemic stem cells. Further, delivery of a humanized anti-CD98 antibody blocks growth of patient-derived AML, highlighting the importance of this pathway in human disease. These findings indicate that microenvironmental interactions are key regulators of AML and that disrupting these signals with targeted inhibitors such as CD98 antibodies may be a valuable therapeutic approach for adults and children with this disease.


Assuntos
Anticorpos/administração & dosagem , Proteína-1 Reguladora de Fusão/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Células-Tronco Neoplásicas/patologia , Animais , Anticorpos/farmacologia , Adesão Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteína-1 Reguladora de Fusão/antagonistas & inibidores , Técnicas de Inativação de Genes , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Camundongos , Transplante de Neoplasias
12.
Cancer Immunol Res ; 3(6): 661-7, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25600437

RESUMO

Inefficient T-cell homing to tissues limits adoptive T-cell immunotherapy of solid tumors. αLß2 and α4ß1 integrins mediate trafficking of T cells into tissues via engagement of ICAM-1 and VCAM-1, respectively. Inhibiting protein kinase A (PKA)-mediated phosphorylation of α4 integrin in cells results in an increase in αLß2-mediated migration on mixed ICAM-1-VCAM-1 substrates in vitro, a phenomenon termed "integrin trans-regulation." Here, we created an α4(S988A)-bearing mouse, which precludes PKA-mediated α4 phosphorylation, to examine the effect of integrin trans-regulation in vivo. The α4(S988A) mouse exhibited a dramatic and selective increase in migration of lymphocytes, but not myeloid cells, to sites of inflammation. Importantly, we found that the α4(S988A) mice exhibited a marked increase in T-cell entry into and reduced growth of B16 melanomas, consistent with antitumor roles of infiltrating T cells and progrowth functions of tumor-associated macrophages. Thus, increased α4 trans-regulation of αLß2 integrin function biases leukocyte emigration toward lymphocytes relative to myeloid cells and enhances tumor immunity.


Assuntos
Integrinas/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Animais , Quimiotaxia de Leucócito/imunologia , Modelos Animais de Doenças , Humanos , Integrina alfa4/genética , Integrina alfa4/metabolismo , Integrinas/genética , Antígeno-1 Associado à Função Linfocitária/genética , Antígeno-1 Associado à Função Linfocitária/metabolismo , Camundongos , Camundongos Transgênicos , Mutação , Neoplasias/genética , Neoplasias/patologia , Ligação Proteica , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Carga Tumoral
13.
J Neuroimmunol ; 274(1-2): 230-3, 2014 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-25002078

RESUMO

Current B cell-directed therapies for multiple sclerosis impact multiple B cell functions. CD98hc enables B cell clonal expansion and antibody production. I probed the relative importance of autoantibody secretion vs. other B cell functions in MS and targeted CD98hc as a possible therapeutic strategy. I report that the loss of CD98hc function in B cells largely prevents autoantibody production while preserving antigen-presenting and T cell-directing capacities. Mice lacking CD98hc in B cells are protected from EAE; importantly this is overcome with autoantibody-containing plasma. Thus CD98hc blockade is a possible avenue to treat MS by inhibiting clonal expansion and autoantibody.


Assuntos
Autoanticorpos/imunologia , Linfócitos B/imunologia , Encefalomielite Autoimune Experimental/imunologia , Proteína-1 Reguladora de Fusão/imunologia , Esclerose Múltipla/imunologia , Animais , Autoanticorpos/sangue , Linfócitos B/citologia , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/tratamento farmacológico , Humanos , Camundongos , Camundongos Mutantes , Esclerose Múltipla/tratamento farmacológico , Glicoproteína Mielina-Oligodendrócito/imunologia , Glicoproteína Mielina-Oligodendrócito/farmacologia , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/farmacologia
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