RESUMO
BACKGROUND: Plasmacytosis (ie, an expansion of plasma cell populations to much greater than the homeostatic level) occurs in the context of various immune disorders and plasma cell neoplasia. This condition is often associated with immunodeficiency that causes increased susceptibility to severe infections. Yet a causative link between plasmacytosis and immunodeficiency has not been established. OBJECTIVE: Because recent studies have identified plasma cells as a relevant source of the immunosuppressive cytokine IL-10, we sought to investigate the role of IL-10 during conditions of polyclonal and neoplastic plasmacytosis for the regulation of immunity and its effect on inflammation and immunodeficiency. METHODS: We used flow cytometry, IL-10 reporter (Vert-X) and B cell-specific IL-10 knockout mice, migration assays, and antibody-mediated IL-10 receptor blockade to study plasmacytosis-associated IL-10 expression and its effect on inflammation and Streptococcus pneumoniae infection in mice. ELISA was used to quantify IL-10 levels in patients with myeloma. RESULTS: IL-10 production was a common feature of normal and neoplastic plasma cells in mice, and IL-10 levels increased with myeloma progression in patients. IL-10 directly inhibited neutrophil migration toward the anaphylatoxin C5a and suppressed neutrophil-dependent inflammation in a murine model of autoimmune disease. MOPC.315.BM murine myeloma leads to an increased incidence of bacterial infection in the airways, which was reversed after IL-10 receptor blockade. CONCLUSION: We provide evidence that plasmacytosis-associated overexpression of IL-10 inhibits neutrophil migration and neutrophil-mediated inflammation but also promotes immunodeficiency.
Assuntos
Interleucina-10/imunologia , Plasmócitos/imunologia , Animais , Linhagem Celular Tumoral , Complemento C5a/imunologia , Humanos , Doenças do Sistema Imunitário/imunologia , Inflamação/imunologia , Interleucina-10/genética , Transtornos Leucocíticos/imunologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mieloma Múltiplo/imunologia , Neutrófilos/imunologia , Infecções Pneumocócicas/imunologiaRESUMO
Although well-designed prospective trials are generally lacking, intravenous immunoglobulins (IVIG) seem an effective adjuvant treatment for autoimmune bullous skin diseases. Here, efficacy of IVIG monotherapy was compared with corticosteroid treatment in mice with immunization-induced experimental epidermolysis bullosa acquisita (EBA), an autoimmune bullous skin disease characterized by autoantibodies against type VII collagen. We found that IVIG significantly ameliorated clinical disease severity and skin neutrophil infiltration compared with vehicle-treated mice, whereas methylprednisolone showed comparatively less pronounced effects. Efficacy of IVIG was accompanied by reduced levels of autoantibodies, a shift toward noncomplement-fixing autoantibodies, and lower complement deposition at the dermal-epidermal junction. In addition, peripheral Gr-1-positive cells of IVIG-treated animals showed reduced expression of the activating Fcγ receptor IV, which we recently described as a major mediator of tissue injury in experimental EBA. These data show that treatment with IVIG is superior to systemic corticosteroids in experimental EBA and that the effects of IVIG are pleiotropic involving modulation of both the adaptive and innate immune response, although the detailed mode of action of IVIG in this model remains in need of further elucidation.
Assuntos
Epidermólise Bolhosa Adquirida/tratamento farmacológico , Epidermólise Bolhosa Adquirida/metabolismo , Imunoglobulinas Intravenosas/uso terapêutico , Índice de Gravidade de Doença , Corticosteroides/uso terapêutico , Animais , Autoanticorpos/metabolismo , Colágeno Tipo VII/imunologia , Modelos Animais de Doenças , Camundongos , Camundongos Mutantes , Receptores de Superfície Celular/metabolismo , Receptores de IgG/metabolismo , Resultado do TratamentoRESUMO
Multiple myeloma is a bone marrow plasma cell tumor which is supported by the external growth factors APRIL and IL-6, among others. Recently, we identified eosinophils and megakaryocytes to be functional components of the micro-environmental niches of benign bone marrow plasma cells and to be important local sources of these cytokines. Here, we investigated whether eosinophils and megakaryocytes also support the growth of tumor plasma cells in the MOPC315.BM model for multiple myeloma. As it was shown for benign plasma cells and multiple myeloma cells, IL-6 and APRIL also supported MOPC315.BM cell growth in vitro, IL-5 had no effect. Depletion of eosinophils in vivo by IL-5 blockade led to a reduction of the early myeloma load. Consistent with this, myeloma growth in early stages was retarded in eosinophil-deficient ΔdblGATA-1 mice. Late myeloma stages were unaffected, possibly due to megakaryocytes compensating for the loss of eosinophils, since megakaryocytes were found to be in contact with myeloma cells in vivo and supported myeloma growth in vitro. We conclude that eosinophils and megakaryocytes in the niches for benign bone marrow plasma cells support the growth of malignant plasma cells. Further investigations are required to test whether perturbation of these niches represents a potential strategy for the treatment of multiple myeloma.
Assuntos
Medula Óssea/patologia , Proliferação de Células , Eosinófilos/citologia , Megacariócitos/citologia , Mieloma Múltiplo/patologia , Animais , Técnicas de Cocultura , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Heat shock protein 90 (Hsp90) inhibition blocks T-cell-linked inflammatory disease pathways and exhibits therapeutic activity in autoimmune disease mouse models, including the blistering disease epidermolysis bullosa acquisita. Although we previously showed that preformed autoreactive plasma cells do not seem to be directly affected by anti-Hsp90 treatment, immunomodulatory effects of Hsp90 inhibition on (auto-)antibody responses are not yet fully understood. In this study, the Hsp90 blocker 17-DMAG inhibited proliferation of activated total B cells and their IgG secretion in cultures of human peripheral B cells from healthy subjects, but IgG production was no longer affected when these activated B cells were allowed to differentiate prior to a deferred application of the inhibitor. 17-DMAG treatment was associated with induction of nuclear and cytoplasmic heat shock factor 1 and Hsp70 in stimulated human B cells, respectively. Type VII collagen (epidermolysis bullosa acquisita)-immunized mice early treated with 17-DMAG had reduced total B cells in spleens, a relative increase in splenic regulatory B cell fractions, higher serum IL-10 concentrations, and lower levels of circulating autoantibodies (paralleled by less pronounced disease induction) compared with vehicle-treated immunized mice. Autoantibody production was blunted in isolated and autoantigen-restimulated lymph node cells from immunized mice by either 17-DMAG or purified autologous splenic regulatory B cells. Thus, in addition to the previously described T cell inhibitory effects of Hsp90 blockade, this treatment potently modulates humoral immune responses at the B cell level, further supporting the introduction of Hsp90 inhibitors into the clinical setting for treatment of autoantibody-mediated disorders.
Assuntos
Linfócitos B/efeitos dos fármacos , Benzoquinonas/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/efeitos dos fármacos , Imunidade Humoral/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Lactamas Macrocíclicas/farmacologia , Adulto , Animais , Autoanticorpos/metabolismo , Linfócitos B/metabolismo , Linfócitos B/patologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Colágeno Tipo VII/metabolismo , Proteínas de Ligação a DNA/metabolismo , Feminino , Proteínas de Choque Térmico HSP70/metabolismo , Fatores de Transcrição de Choque Térmico , Humanos , Imunidade Humoral/fisiologia , Imunoglobulina G/metabolismo , Técnicas In Vitro , Interleucina-10/metabolismo , Masculino , Camundongos , Camundongos Mutantes , Modelos Animais , Fatores de Transcrição/metabolismoRESUMO
Plasma cells are terminally differentiated B cells that secrete antibodies, important for immune protection, but also contribute to any allergic and autoimmune disease. There is increasing evidence that plasma cell populations exhibit a considerable degree of heterogeneity with respect to their immunophenotype, migration behavior, lifetime, and susceptibility to immunosuppressive drugs. Pathogenic long-lived plasma cells are refractory to existing therapies. In contrast, short-lived plasma cells can be depleted by steroids and cytostatic drugs. Therefore, long-lived plasma cells are responsible for therapy-resistant autoantibodies and resemble a challenge for the therapy of antibody-mediated autoimmune diseases. Both lifetime and therapy resistance of plasma cells are supported by factors produced within their microenviromental niches. Current results suggest that plasma cell differentiation and survival factors such as IL-6 also signal via mammalian miRNAs within the plasma cell to modulate downstream transcription factors. Recent evidence also suggests that plasma cells and/or their immediate precursors (plasmablasts) can produce important cytokines and act as antigen-presenting cells, exhibiting so far underestimated roles in immune regulation and bone homeostasis. Here, we provide an overview on plasma cell biology and discuss exciting, experimental, and potential therapeutic approaches to eliminate pathogenic plasma cells.
Assuntos
Doenças do Sistema Imunitário/imunologia , Plasmócitos/imunologia , Animais , Osso e Ossos/imunologia , Osso e Ossos/metabolismo , Movimento Celular/imunologia , Sobrevivência Celular , Microambiente Celular/imunologia , Homeostase , Humanos , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/metabolismo , Doenças do Sistema Imunitário/terapia , Imunidade , MicroRNAs/genética , Mucosa/citologia , Mucosa/imunologia , Especificidade de Órgãos/imunologia , Fenótipo , Plasmócitos/metabolismoRESUMO
In autoimmune bullous dermatoses (AIBD), autoantibodies induce blisters on skin or mucous membranes, or both. Mechanisms of continued autoantibody production and blistering have been well characterized using AIBD animal models. Mechanisms leading to the initial autoantibody production, however, have not been investigated in detail. Epidermolysis bullosa acquisita (EBA) is an AIBD associated with autoantibodies to type VII collagen (COL7). The majority of EBA patients' sera recognize the noncollagenous domain 1, including the von Willebrand factor A-like domain 2 (vWFA2). In experimental EBA induced by immunization with GST-COL7, disease manifestation depended on the genetic background, a Th1 polarization, and the GST-tag. In this model, nude mice neither produced autoantibodies nor blisters. It has remained uncertain which APC and T cell subsets are required for EBA induction. We established a novel EBA model by immunization with vWFA2 fused to intein (lacking the GST-tag). All tested mouse strains developed autoantibodies, but blisters were exclusively observed in mice carrying H2s. In immunized mice, CD4 T cells specific for vWFA2 were detected, and their induction required presence of B cells, dendritic cells, and macrophages. Anti-vWFA2 autoantibodies located at the lamina densa bound to the dermal side of salt-split skin and induced blisters when transferred into healthy mice. Absence of CD8 T cells at time of immunization had no effect, whereas depletion of CD4 T cells during the same time period delayed autoantibody production and blisters. Collectively, we demonstrate the pathogenic relevance of Abs targeting the vWFA2 domain of COL7 and show the requirement of APC-induced CD4 T cells to induce experimental EBA.
Assuntos
Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Células Dendríticas/imunologia , Epidermólise Bolhosa Adquirida/imunologia , Macrófagos/imunologia , Animais , Autoanticorpos/imunologia , Autoantígenos/imunologia , Autoimunidade/imunologia , Biomarcadores Tumorais/imunologia , Proteínas de Ligação ao Cálcio , Colágeno Tipo VII/imunologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Proteínas da Matriz Extracelular/imunologia , Humanos , Immunoblotting , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Estrutura Terciária de Proteína , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Autoantibodies are believed to be maintained by either the continuous generation of short-lived plasma cells in secondary lymphoid tissues or by long-lived plasma cells localized in bone marrow and spleen. Here, we show in a mouse model for the autoimmune blistering skin disease epidermolysis bullosa acquisita (EBA) that chronic autoantibody production can also be maintained in inflamed lymph nodes, by plasma cells exhibiting intermediate lifetimes. After EBA induction by immunization with a mCOL7c-GST-fusion protein, antigen-specific plasma cells and CD4 T cells were analyzed. Plasma cells were maintained for months in stable numbers in the draining lymph nodes, but not in spleen and bone marrow. In contrast, localization of mCOL7c-GST -specific CD4 T cells was not restricted to lymph nodes, indicating that availability of T cell help does not limit plasma cell localization to this site. BrdU-incorporation studies indicated that pathogenic mCOL7c- and non-pathogenic GST-specific plasma cells resemble intermediates between short-and long-lived plasma cells with half-lives of about 7 weeks. Immunization with mCOL7c-GST also yielded considerable numbers of plasma cells neither specific for mCOL7c- nor GST. These bystander-activated plasma cells exhibited much shorter half-lives and higher population turnover, suggesting that plasma cell lifetimes were only partly determined by the lymph node environment but also by the mode of activation. These results indicate that inflamed lymph nodes can harbor pathogenic plasma cells exhibiting distinct properties and hence may resemble a so far neglected site for chronic autoantibody production.