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BACKGROUND: For psoriatic patients who need to receive nonlive or live vaccines, evidence-based recommendations are needed regarding whether to pause or continue systemic therapies for psoriasis and/or psoriatic arthritis. OBJECTIVE: To evaluate literature regarding vaccine efficacy and safety and to generate consensus-based recommendations for adults receiving systemic therapies for psoriasis and/or psoriatic arthritis receiving nonlive or live vaccines. METHODS: Using a modified Delphi process, 22 consensus statements were developed by the National Psoriasis Foundation Medical Board and COVID-19 Task Force, and infectious disease experts. RESULTS: Key recommendations include continuing most oral and biologic therapies without modification for patients receiving nonlive vaccines; consider interruption of methotrexate for nonlive vaccines. For patients receiving live vaccines, discontinue most oral and biologic medications before and after administration of live vaccine. Specific recommendations include discontinuing most biologic therapies, except for abatacept, for 2-3 half-lives before live vaccine administration and deferring next dose 2-4 weeks after live vaccination. LIMITATIONS: Studies regarding infection rates after vaccination are lacking. CONCLUSION: Interruption of antipsoriatic oral and biologic therapies is generally not necessary for patients receiving nonlive vaccines. Temporary interruption of oral and biologic therapies before and after administration of live vaccines is recommended in most cases.
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Artrite Psoriásica , Produtos Biológicos , Consenso , Técnica Delphi , Psoríase , Humanos , Psoríase/tratamento farmacológico , Artrite Psoriásica/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Produtos Biológicos/administração & dosagem , Administração Oral , Vacinação/normas , Adulto , COVID-19/prevenção & controle , Vacinas contra COVID-19/administração & dosagem , SARS-CoV-2 , Metotrexato/uso terapêutico , Metotrexato/administração & dosagem , Fármacos Dermatológicos/administração & dosagem , Fármacos Dermatológicos/uso terapêuticoRESUMO
Muscle-specific tyrosine kinase myasthenia gravis (MuSK MG) is an autoimmune disease that causes life-threatening muscle weakness due to anti-MuSK autoantibodies that disrupt neuromuscular junction signaling. To avoid chronic immunosuppression from current therapies, we engineered T cells to express a MuSK chimeric autoantibody receptor with CD137-CD3ζ signaling domains (MuSK-CAART) for precision targeting of B cells expressing anti-MuSK autoantibodies. MuSK-CAART demonstrated similar efficacy as anti-CD19 chimeric antigen receptor T cells for depletion of anti-MuSK B cells and retained cytolytic activity in the presence of soluble anti-MuSK antibodies. In an experimental autoimmune MG mouse model, MuSK-CAART reduced anti-MuSK IgG without decreasing B cells or total IgG levels, reflecting MuSK-specific B cell depletion. Specific off-target interactions of MuSK-CAART were not identified in vivo, in primary human cell screens or by high-throughput human membrane proteome array. These data contributed to an investigational new drug application and phase 1 clinical study design for MuSK-CAART for the treatment of MuSK autoantibody-positive MG.
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Miastenia Gravis Autoimune Experimental , Receptores Colinérgicos , Humanos , Camundongos , Animais , Receptores Colinérgicos/uso terapêutico , Autoantígenos/uso terapêutico , Miastenia Gravis Autoimune Experimental/tratamento farmacológico , Linfócitos T , Autoanticorpos/uso terapêutico , Imunoglobulina G , Proteínas Tirosina Quinases/uso terapêutico , MúsculosRESUMO
BACKGROUND: Programmed cell death protein (PD-1) and programmed death-ligand 1 (PD-L1) inhibition checkpoint blockade leads to various cutaneous adverse reactions, including bullous pemphigoid and lichen-planus-like reactions. However, lichen planus pemphigoides (LPP), manifesting histopathologic features of both lichen planus and bullous pemphigoid, has more rarely been associated with immunotherapy. METHODS: The clinical and histopathologic findings of three patients were examined, and a review of cases of LPP and bullous lichen planus secondary to PD-1 inhibitor therapy was performed. RESULTS: Three patients (two with advanced non-small-cell lung adenocarcinoma and the third with metastatic breast cancer) presented with both lichenoid eruptions and bullae. Biopsy of the lesions revealed lichenoid tissue reactions in all three patients. Together with the histopathologic findings, direct immunofluorescence (DIF) showing linear C3 and IgG deposition and positive enzyme-linked immunosorbent assay (ELISA) showing BP180 positivity supported a diagnosis of LPP in two patients. The third patient in our series also showed confirmatory ELISA testing supporting LPP. CONCLUSIONS: Lichen planus pemphigoides is a distinct cutaneous toxicity to checkpoint inhibitor therapy illustrates a possible pathogenic mechanism and the importance of dermatopathology recognition to render an accurate diagnosis.
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Carcinoma Pulmonar de Células não Pequenas , Líquen Plano , Neoplasias Pulmonares , Penfigoide Bolhoso , Proteínas Reguladoras de Apoptose/uso terapêutico , Antígeno B7-H1 , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Imunoglobulina G , Líquen Plano/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Penfigoide Bolhoso/diagnóstico , Receptor de Morte Celular Programada 1RESUMO
Pemphigus and pemphigoid are paradigms for understanding the mechanisms of antibody-mediated autoimmune disease in humans. In pemphigus, IgG4-predominant autoantibodies cause intraepidermal blistering by direct interference with desmoglein interactions and subsequent disruption of desmosomes and signaling pathways. In pemphigoid, IgG1, IgG4, and IgE autoantibodies against basement membrane zone antigens directly interfere with hemidesmosomal adhesion, activating complement and Fc receptorâmediated effector pathways. Unraveling disease mechanisms in pemphigus and pemphigoid has identified numerous opportunities for clinical trials, which hold promise to identify safer and more effective therapies for these potentially life-threatening diseases.
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Doenças Autoimunes , Penfigoide Bolhoso , Pênfigo , Autoanticorpos , Humanos , Imunoglobulina G , Penfigoide Bolhoso/tratamento farmacológico , Pênfigo/tratamento farmacológicoRESUMO
Follicular T helper cells (Tfh) are a specialized subset of CD4 effector T cells that are crucial for germinal center (GC) reactions and for selecting B cells to undergo affinity maturation. Despite this central role for humoral immunity, only few data exist about their clonal distribution when multiple lymphoid organs are exposed to the same antigen (Ag) as it is the case in autoimmunity. Here, we used an autoantibody-mediated disease model of the skin and injected one auto-Ag into the two footpads of the same mouse and analyzed the T cell receptor (TCR)ß sequences of Tfh located in GCs of both contralateral draining lymph nodes. We found that over 90% of the dominant GC-Tfh clonotypes were shared in both lymph nodes but only transiently. The initially dominant Tfh clonotypes especially declined after establishment of chronic disease while GC reaction and autoimmune disease continued. Our data demonstrates a dynamic behavior of Tfh clonotypes under autoimmune conditions and emphasizes the importance of the time point for distinguishing auto-Ag-specific Tfh clonotypes from potential bystander activated ones.
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Autoanticorpos/imunologia , Autoimunidade/imunologia , Centro Germinativo/imunologia , Linfonodos/imunologia , Células T Auxiliares Foliculares/imunologia , Animais , Antígenos/administração & dosagem , Antígenos/imunologia , Linfócitos B/imunologia , Feminino , Imunidade Humoral , Imunização , Linfonodos/citologia , Camundongos , Camundongos Endogâmicos C57BLRESUMO
OBJECTIVE: To update guidance regarding the management of psoriatic disease during the COVID-19 pandemic. STUDY DESIGN: The task force (TF) includes 18 physician voting members with expertise in dermatology, rheumatology, epidemiology, infectious diseases, and critical care. The TF was supplemented by nonvoting members, which included fellows and National Psoriasis Foundation staff. Clinical questions relevant to the psoriatic disease community were informed by inquiries received by the National Psoriasis Foundation. A Delphi process was conducted. RESULTS: The TF updated evidence for the original 22 statements and added 5 new recommendations. The average of the votes was within the category of agreement for all statements, 13 with high consensus and 14 with moderate consensus. LIMITATIONS: The evidence behind many guidance statements is variable in quality and/or quantity. CONCLUSIONS: These statements provide guidance for the treatment of patients with psoriatic disease on topics including how the disease and its treatments affect COVID-19 risk, how medical care can be optimized during the pandemic, what patients should do to lower their risk of getting infected with severe acute respiratory syndrome coronavirus 2 (including novel vaccination), and what they should do if they develop COVID-19. The guidance is a living document that is continuously updated by the TF as data emerge.
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Vacinas contra COVID-19 , COVID-19/prevenção & controle , Psoríase/tratamento farmacológico , Produtos Biológicos/uso terapêutico , COVID-19/complicações , COVID-19/epidemiologia , Tomada de Decisão Compartilhada , Medicina Baseada em Evidências , Humanos , Fatores Imunológicos/uso terapêutico , Pandemias , Psoríase/complicações , Fatores de Risco , Estados Unidos/epidemiologia , Tratamento Farmacológico da COVID-19RESUMO
OBJECTIVE: To provide guidance about management of psoriatic disease during the coronavirus disease 2019 (COVID-19) pandemic. STUDY DESIGN: A task force (TF) of 18 physician voting members with expertise in dermatology, rheumatology, epidemiology, infectious diseases, and critical care was convened. The TF was supplemented by nonvoting members, which included fellows and National Psoriasis Foundation (NPF) staff. Clinical questions relevant to the psoriatic disease community were informed by questions received by the NPF. A Delphi process was conducted. RESULTS: The TF approved 22 guidance statements. The average of the votes was within the category of agreement for all statements. All guidance statements proposed were recommended, 9 with high consensus and 13 with moderate consensus. LIMITATIONS: The evidence behind many guidance statements is limited in quality. CONCLUSION: These statements provide guidance for the management of patients with psoriatic disease on topics ranging from how the disease and its treatments impact COVID-19 risk and outcome, how medical care can be optimized during the pandemic, what patients should do to lower their risk of getting infected with severe acute respiratory syndrome coronavirus 2 and what they should do if they develop COVID-19. The guidance is intended to be a living document that will be updated by the TF as data emerge.
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Infecções por Coronavirus/epidemiologia , Imunossupressores/efeitos adversos , Organizações sem Fins Lucrativos/normas , Pneumonia Viral/epidemiologia , Psoríase/tratamento farmacológico , Comitês Consultivos/normas , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , COVID-19 , Consenso , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/virologia , Cuidados Críticos/normas , Técnica Delphi , Dermatologia/normas , Epidemiologia/normas , Humanos , Infectologia/normas , Organizações sem Fins Lucrativos/organização & administração , Pandemias/prevenção & controle , Pneumonia Viral/imunologia , Pneumonia Viral/prevenção & controle , Pneumonia Viral/virologia , Psoríase/complicações , Psoríase/imunologia , Reumatologia/normas , SARS-CoV-2 , Estados Unidos/epidemiologiaRESUMO
Desmoglein 3 chimeric autoantibody receptor T cells (DSG3-CAART) expressing the pemphigus vulgaris (PV) autoantigen DSG3 fused to CD137-CD3ζ signaling domains, represent a precision cellular immunotherapy approach for antigen-specific B cell depletion. Here, we present definitive preclinical studies enabling a first-in-human trial of DSG3-CAART for mucosal PV. DSG3-CAART specifically lysed human anti-DSG3 B cells from PV patients and demonstrated activity consistent with a threshold dose in vivo, resulting in decreased target cell burden, decreased serum and tissue-bound autoantibodies, and increased DSG3-CAART engraftment. In a PV active immune model with physiologic anti-DSG3 IgG levels, DSG3-CAART inhibited antibody responses against pathogenic DSG3 epitopes and autoantibody binding to epithelial tissues, leading to clinical and histologic resolution of blisters. DSG3 autoantibodies stimulated DSG3-CAART IFN-γ secretion and homotypic clustering, consistent with an activated phenotype. Toxicology screens using primary human cells and high-throughput membrane proteome arrays did not identify off-target cytotoxic interactions. These preclinical data guided the trial design for DSG3-CAART and may help inform CAART preclinical development for other antibody-mediated diseases.
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Transferência Adotiva , Linfócitos B/imunologia , Depleção Linfocítica , Pênfigo/terapia , Medicina de Precisão , Adulto , Animais , Autoanticorpos/imunologia , Linfócitos B/patologia , Desmogleína 3/genética , Desmogleína 3/imunologia , Modelos Animais de Doenças , Feminino , Humanos , Interferon gama/imunologia , Isoantígenos/genética , Isoantígenos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pênfigo/genética , Pênfigo/imunologia , Pênfigo/patologiaRESUMO
Current therapies for autoimmunity cause significant morbidity and mortality. Adoptive immunotherapy using genetically engineered T cells has led to durable remissions of B cell leukemias and lymphomas, raising the question of whether the approach can be modified to target autoreactive B and T cells to induce durable remissions of autoimmunity. Here we review antigen-specific approaches to modify immune cells to treat autoimmune disease. We focus on recent studies that aim to eliminate or suppress autoimmunity by targeting the disease-causing B or T cells through their B cell receptor or T cell receptor specificities.
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Doenças Autoimunes/etiologia , Doenças Autoimunes/terapia , Autoimunidade , Engenharia Genética , Imunoterapia , Animais , Autoantígenos/imunologia , Doenças Autoimunes/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Ensaios Clínicos como Assunto , Epitopos/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Pesquisa Translacional BiomédicaRESUMO
Lineage analysis of autoreactive B cells can reveal the origins of autoimmunity. In the autoimmune disease pemphigus vulgaris (PV), desmoglein 3 (DSG3) and DSG1 autoantibodies are predominantly of the IgG4 subclass and less frequently of IgG1 and IgA subclasses, prompting us to investigate whether anti-DSG IgG4 B cells share lineages with IgG1, IgA1, and IgA2. Combining subclass-specific B cell deep sequencing with high-throughput antibody screening, we identified 80 DSG-reactive lineages from 4 PV patients. Most anti-DSG IgG4 B cells lacked clonal relationships to other subclasses and preferentially targeted DSG adhesion domains, whereas anti-DSG IgA frequently evolved from or to other subclasses and recognized a broader range of epitopes. Our findings suggest that anti-DSG IgG4 B cells predominantly evolve independently or diverge early from other subclasses and that IgA is most often not the origin of IgG autoreactivity in PV. These data provide insight into how autoreactivity diversifies across B cell subclasses.
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Linfócitos B/imunologia , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Pênfigo/imunologia , HumanosRESUMO
This corrects the article DOI: 10.1038/nrdp.2018.13.
RESUMO
HIV is adept at avoiding naturally generated T cell responses; therefore, there is a need to develop HIV-specific T cells with greater potency for use in HIV cure strategies. Starting with a CD4-based chimeric antigen receptor (CAR) that was previously used without toxicity in clinical trials, we optimized the vector backbone, promoter, HIV targeting moiety, and transmembrane and signaling domains to determine which components augmented the ability of T cells to control HIV replication. This re-engineered CAR was at least 50-fold more potent in vitro at controlling HIV replication than the original CD4 CAR, or a TCR-based approach, and substantially better than broadly neutralizing antibody-based CARs. A humanized mouse model of HIV infection demonstrated that T cells expressing optimized CARs were superior at expanding in response to antigen, protecting CD4 T cells from infection, and reducing viral loads compared to T cells expressing the original, clinical trial CAR. Moreover, in a humanized mouse model of HIV treatment, CD4 CAR T cells containing the 4-1BB costimulatory domain controlled HIV spread after ART removal better than analogous CAR T cells containing the CD28 costimulatory domain. Together, these data indicate that potent HIV-specific T cells can be generated using improved CAR design and that CAR T cells could be important components of an HIV cure strategy.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/terapia , Infecções por HIV/virologia , HIV-1/fisiologia , Recoverina/imunologia , Replicação Viral , Anticorpos Neutralizantes/imunologia , Infecções por HIV/imunologia , Humanos , Transdução de Sinais/fisiologiaRESUMO
Pemphigus vulgaris (PV) is an epithelial blistering disease caused by autoantibodies to the desmosomal cadherin desmoglein 3 (DSG3). Glucocorticoids improve disease within days by increasing DSG3 gene transcription, although the mechanism for this observation remains unknown. Here, we show that DSG3 transcription in keratinocytes is regulated by Stat3. Treatment of primary human keratinocytes (PHKs) with hydrocortisone or rapamycin, but not the p38 MAPK inhibitor SB202190, significantly increases DSG3 mRNA and protein expression and correspondingly reduces phospho-S727 Stat3. Stat3 inhibition or shRNA-knockdown also significantly increases DSG3 mRNA and protein levels. Hydrocortisone- or rapamycin-treated PHKs demonstrate increased number and length of desmosomes by electron microscopy and are resistant to PV IgG-induced loss of cell adhesion, whereas constitutive activation of Stat3 in PHKs abrogates DSG3 upregulation and inhibits hydrocortisone and rapamycin's therapeutic effects. Topical hydrocortisone, rapamycin, or Stat3 inhibitor XVIII prevents autoantibody-induced blistering in the PV passive transfer mouse model, correlating with increased epidermal DSG3 expression and decreased phospho-S727 Stat3. Our data indicate that glucocorticoids and rapamycin upregulate DSG3 transcription through inhibition of Stat3. These studies explain how glucocorticoids rapidly improve pemphigus and may also offer novel insights into the physiologic and pathophysiologic regulation of desmosomal cadherin expression in normal epidermis and epithelial carcinomas.
RESUMO
Pemphigus is a group of IgG-mediated autoimmune diseases of stratified squamous epithelia, such as the skin and oral mucosa, in which acantholysis (the loss of cell adhesion) causes blisters and erosions. Pemphigus has three major subtypes: pemphigus vulgaris, pemphigus foliaceus and paraneoplastic pemphigus. IgG autoantibodies are characteristically raised against desmoglein 1 and desmoglein 3, which are cell-cell adhesion molecules found in desmosomes. The sites of blister formation can be physiologically explained by the anti-desmoglein autoantibody profile and tissue-specific expression pattern of desmoglein isoforms. The pathophysiological roles of T cells and B cells have been characterized in mouse models of pemphigus and patients, revealing insights into the mechanisms of autoimmunity. Diagnosis is based on clinical manifestations and confirmed with histological and immunochemical testing. The current first-line treatment is systemic corticosteroids and adjuvant therapies, including immunosuppressive agents, intravenous immunoglobulin and plasmapheresis. Rituximab, a monoclonal antibody against CD20+ B cells, is a promising therapeutic option that may soon become first-line therapy. Pemphigus is one of the best-characterized human autoimmune diseases and provides an ideal paradigm for both basic and clinical research, especially towards the development of antigen-specific immune suppression treatments for autoimmune diseases.
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Pênfigo/diagnóstico , Pênfigo/terapia , Corticosteroides/uso terapêutico , Animais , Autoanticorpos/metabolismo , Desmogleína 1/imunologia , Desmogleína 3/imunologia , Modelos Animais de Doenças , Humanos , Imunoglobulina G/metabolismo , Imunoglobulinas Intravenosas/efeitos dos fármacos , Camundongos , Pênfigo/classificação , Pênfigo/imunologia , Plasmaferese , Resultado do TratamentoRESUMO
Despite the rising incidence of autoimmunity, therapeutic options for patients with autoimmune disease still rely on decades-old immunosuppressive strategies that risk severe and potentially fatal complications. Thus, novel therapeutic approaches for autoimmune diseases are greatly needed in order to minimize treatment-related toxicity. Such strategies would ideally target only the autoreactive immune components to preserve beneficial immunity. Here, we review how several decades of basic, translational, and clinical research on the immunology of pemphigus vulgaris (PV), an autoantibody-mediated skin disease, have enabled the development of targeted immunotherapeutic strategies. We discuss research to elucidate the pathophysiology of PV and how the knowledge afforded by these studies has led to the preclinical and clinical testing of targeted approaches to neutralize autoantibodies, to induce antigen-specific tolerance, and to specifically eliminate autoreactive B cells in PV.
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Pênfigo/terapia , Antígenos/imunologia , Autoanticorpos/imunologia , Linfócitos B/imunologia , Humanos , Tolerância Imunológica , Depleção Linfocítica , Pênfigo/imunologiaRESUMO
In autoantibody-mediated diseases such as pemphigus, serum antibodies lead to disease. Genetic analysis of B cells has allowed characterization of antibody repertoires in such diseases but would be complemented by proteomic analysis of serum autoantibodies. Here, we show using proteomic analysis that the serum autoantibody repertoire in pemphigus is much more polyclonal than that found by genetic studies of B cells. In addition, many B cells encode pemphigus autoantibodies that are not secreted into the serum. Heavy chain variable gene usage of serum autoantibodies is not shared among patients, implying targeting of the coded proteins will not be a useful therapeutic strategy. Analysis of autoantibodies in individual patients over several years indicates that many antibody clones persist but the proportion of each changes. These studies indicate a dynamic and diverse autoantibody response not revealed by genetic studies and explain why similar overall autoantibody titers may give variable disease activity.
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Autoanticorpos/imunologia , Linfócitos B/imunologia , Pênfigo/genética , Pênfigo/imunologia , Proteômica/métodos , Sequência de Aminoácidos , Técnicas de Visualização da Superfície Celular , Cromatografia Líquida , Células Clonais , Regiões Determinantes de Complementaridade/genética , Desmogleínas/metabolismo , Humanos , Mutação/genética , Pênfigo/sangue , Anticorpos de Cadeia Única/química , Anticorpos de Cadeia Única/metabolismo , Espectrometria de Massas em TandemRESUMO
Shared VH1-46 gene usage has been described in B cells reacting to desmoglein 3 (Dsg3) in the autoimmune disease pemphigus vulgaris (PV), as well as B cells responding to rotavirus capsid protein VP6. In both diseases, VH1-46 B cells bearing few to no somatic mutations can recognize the disease Ag. This intriguing connection between an autoimmune response to self-antigen and an immune response to foreign Ag prompted us to investigate whether VH1-46 B cells may be predisposed to Dsg3-VP6 cross-reactivity. Focused testing of VH1-46 mAbs previously isolated from PV and rotavirus-exposed individuals indicates that cross-reactivity is rare, found in only one of seven VH1-46 IgG clonotypes. High-throughput screening of IgG B cell repertoires from two PV patients identified no additional cross-reactive clonotypes. Screening of IgM B cell repertoires from one non-PV and three PV patients identified specific cross-reactive Abs in one PV patient, but notably all six cross-reactive clonotypes used VH1-46. Site-directed mutagenesis studies indicate that amino acid residues predisposing VH1-46 Abs to Dsg3 reactivity reside in CDR2. However, somatic mutations only rarely promote Dsg3-VP6 cross-reactivity; most mutations abolish VP6 and/or Dsg3 reactivity. Nevertheless, functional testing identified two cross-reactive VH1-46 Abs that both disrupt keratinocyte adhesion and inhibit rotavirus replication, indicating the potential for VH1-46 Abs to have both pathologic autoimmune and protective immune functions. Taken together, these studies suggest that certain VH1-46 B cell populations may be predisposed to Dsg3-VP6 cross-reactivity, but multiple mechanisms prevent the onset of autoimmunity after rotavirus exposure.
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Antígenos Virais/imunologia , Autoantígenos/imunologia , Proteínas do Capsídeo/imunologia , Desmogleína 3/imunologia , Fosfatases de Especificidade Dupla/imunologia , Reações Cruzadas , Ensaio de Imunoadsorção Enzimática , Ensaios de Triagem em Larga Escala , Humanos , Microscopia de Fluorescência , Pênfigo/imunologia , Reação em Cadeia da Polimerase , Infecções por Rotavirus/imunologiaRESUMO
Ideally, therapy for autoimmune diseases should eliminate pathogenic autoimmune cells while sparing protective immunity, but feasible strategies for such an approach have been elusive. Here, we show that in the antibody-mediated autoimmune disease pemphigus vulgaris (PV), autoantigen-based chimeric immunoreceptors can direct T cells to kill autoreactive B lymphocytes through the specificity of the B cell receptor (BCR). We engineered human T cells to express a chimeric autoantibody receptor (CAAR), consisting of the PV autoantigen, desmoglein (Dsg) 3, fused to CD137-CD3ζ signaling domains. Dsg3 CAAR-T cells exhibit specific cytotoxicity against cells expressing anti-Dsg3 BCRs in vitro and expand, persist, and specifically eliminate Dsg3-specific B cells in vivo. CAAR-T cells may provide an effective and universal strategy for specific targeting of autoreactive B cells in antibody-mediated autoimmune disease.
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Autoanticorpos/imunologia , Desmogleína 3/imunologia , Terapia de Imunossupressão/métodos , Pênfigo/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Proteínas Recombinantes de Fusão/imunologia , Linfócitos T/imunologia , Animais , Autoanticorpos/sangue , Autoimunidade , Linfócitos B/imunologia , Complexo CD3/química , Complexo CD3/imunologia , Engenharia Celular , Citotoxicidade Imunológica , Modelos Animais de Doenças , Humanos , Memória Imunológica , Camundongos , Pênfigo/imunologia , Estrutura Terciária de Proteína , Receptores de Antígenos de Linfócitos T/genética , Proteínas Recombinantes de Fusão/genética , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/química , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologiaRESUMO
Pemphigus vulgaris (PV) is characterized by IgG1 and IgG4 autoantibodies to desmoglein (Dsg) 3, causing suprabasal blistering of skin and mucous membranes. IgG4 is the dominant autoantibody subclass in PV and correlates with disease activity, whereas IgG1 can be associated with remittent disease. It is unknown if switching the same variable region between IgG4 and IgG1 directly impacts pathogenicity. Here, we tested whether three pathogenic PV monoclonal antibodies (mAbs) from three different patients demonstrate differences in antigen affinity, epitope specificity, or pathogenicity when expressed as IgG1 or IgG4. F706 anti-Dsg3 IgG4 and F779 anti-Dsg3 IgG1, previously isolated as heterohybridomas, and Px43, a monovalent anti-Dsg3/Dsg1 IgG antibody isolated by phage display, were subcloned to obtain paired sets of IgG1 and IgG4 mAbs. Using ELISA and cell surface staining assays, F706 and F779 demonstrated similar antigen binding affinities of IgG1 and IgG4, whereas Px43 showed 3- to 8-fold higher affinity of IgG4 versus IgG1 by ELISA, but identical binding affinities to human skin, perhaps due to targeting of a quaternary epitope best displayed in tissues. All 3 mAb pairs targeted the same extracellular cadherin (EC) domain on Dsg3, caused Dsg3 internalization in primary human keratinocytes, and caused suprabasal blisters in human skin at comparable doses. We conclude that switching IgG1 and IgG4 subclasses of pathogenic PV mAbs does not directly affect their antigen binding or pathogenic properties.