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1.
Medicine (Baltimore) ; 98(51): e18321, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31860983

RESUMO

Oral lichen planus (OLP) exhibits variations in severity and response to corticosteroid therapy. This study aims to assess the histopathological features of OLP at the time of diagnosis and their relationship in response to corticosteroid therapy.In this retrospective study, OLP patients were selected if a histopathological report was available. Data were collected regarding patients' demographics and medical history. Clinical and histological data were also obtained. The outcomes were histopathological findings, clinical form of OLP, number of exacerbations per year, and the response to corticosteroid therapy.In this study, 100 OLP patients were enrolled. Basal layer hydropic degeneration and band-like subepithelial lymphocytes infiltrate were observed in all patients. Plasma cells, identified in 62% of OLP patients, were significantly associated with fewer disease exacerbations and better response to corticosteroid treatment.Identifying histopathological features that may affect the clinical course would be clinically helpful in tailoring patient management.


Assuntos
Glucocorticoides/uso terapêutico , Líquen Plano Bucal/tratamento farmacológico , Líquen Plano Bucal/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Tecido Conjuntivo/metabolismo , Progressão da Doença , Relação Dose-Resposta a Droga , Epitélio/metabolismo , Epitélio/patologia , Feminino , Fibrina/metabolismo , Humanos , Hiperplasia , Masculino , Pessoa de Meia-Idade , Plasmócitos/metabolismo , Estudos Retrospectivos , Linfócitos T/metabolismo
3.
DNA Cell Biol ; 38(11): 1387-1401, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31549881

RESUMO

Immune cell infiltration is associated with the prognosis of cancer. This study focused on the immune infiltration profiling and their association with survival outcome in nonsmall cell lung cancer (NSCLC). Research data were obtained from the Gene Expression Omnibus and The Cancer Genome Atlas databases. CIBERSORT algorithm was applied to assess the relative proportions of 22 kinds of immune cells. Log-rank test was performed to compare the survival outcome of patients with different proportions of immune cells. The estimated hazard ratios were presented with forest plot. Multivariate Cox regression analysis was conducted to estimate the adjusted associations between different types of infiltrating immune cells and survival prognosis controlling for other clinical features and confounders. With the CIBERSORT approach, we assessed the proportions of 22 infiltrating immune cells of 2050 cases with NSCLC. By conducting survival analysis, we found different survival outcomes among cases with different proportions of certain types of infiltrating immune cells. Among the cell subsets investigated, plasma cells (hazard ratio [HR] = 0.775, 95% confidence interval [CI]: 0.669-0.898) and regulatory T cells (HR = 1.258, 95% CI: 1.091-1.451) were associated with survival outcome of NSCLC patients controlling for other covariates. Subgroup analysis suggested a good consistency and robustness of our results. Our findings might provide useful information for prognosis prediction and cellular study in NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Linfócitos do Interstício Tumoral/metabolismo , Transcriptoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Plasmócitos/metabolismo , Prognóstico , Análise de Sobrevida , Linfócitos T Reguladores/metabolismo
5.
Pathologica ; 111(2): 76-78, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31388200

RESUMO

Russell body gastritis is caused by an accumulation of plasma cells within the gastric mucosa. These plasma cells are characterized by eosinophilic cytoplasmic inclusions of immunoglobulin which are called "Russell bodies". We report a case of Russell body gastritis in a 28-year-old male who presented with abdominal pain and rectal bleeding. Endoscopy showed erosions with edema and vascular congestion in the gastric body and antrum. The biopsy showed chronic gastritis with plasma cell infiltration of the lamina propria. Many plasma cells contained cytoplasmic Russell bodies which stained positive for CD138, CD79a, Kappa and lambda light chains. The Russell bodies were negative for pancytokeratin, excluding signet ring cell carcinoma. Russell body gastritis is an uncommon, benign reactive condition.


Assuntos
Mucosa Gástrica/patologia , Gastrite/patologia , Corpos de Inclusão/patologia , Plasmócitos/patologia , Adulto , Mucosa Gástrica/metabolismo , Gastrite/diagnóstico , Gastrite/metabolismo , Humanos , Corpos de Inclusão/metabolismo , Masculino , Plasmócitos/metabolismo
6.
Mediators Inflamm ; 2019: 4312016, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281227

RESUMO

Background: Plasma cell mastitis (PCM) is one of the most frequently encountered inflammatory diseases of the nonlactating breast. However, its pathogenesis has remained unknown. Methods: In this study, we observed the ultrastructure changes of PCM by a transmission electron microscope. The transcriptome expression difference of exosomes was detected by RNA-Seq; then, we confirmed the key difference genes by western blot and immunohistochemistry. Finally, we established the mouse PCM model by tissue homogenate injection to validate the role of exosomes on the progression of PCM. Results: The analysis of the exosomal transcriptome expression difference between PCM and normal mammary tissues using RNA-Seq showed the differential genes and enrichment pathways involved in the course of PCM. The decreased HSP90AA1 and EEF2, excessive production of p-AKT, and p-mTOR were consistent with clinical specimens. Inhibition of exosome secretion significantly inhibited inflammatory cell infiltration, and the mammary duct had maintained a better structure in the PCM mouse model. Conclusion: Our results revealed the role of exosomes acting as critical signal introduction facilitators in the progression of plasma cell mastitis and identified potential key genes in the regulation of this process. These results will help to dissect the molecular mechanism of PCM and provide therapeutic targets.


Assuntos
Exossomos/metabolismo , Mastite/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Plasmócitos/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Adulto , Animais , Feminino , Humanos , Imuno-Histoquímica , Mastite/patologia , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade , Plasmócitos/metabolismo , Plasmócitos/ultraestrutura , Transdução de Sinais/fisiologia , Transcriptoma/genética , Adulto Jovem
7.
Zhonghua Gan Zang Bing Za Zhi ; 27(7): 541-546, 2019 Jul 20.
Artigo em Chinês | MEDLINE | ID: mdl-31357781

RESUMO

Objective: To study the correlation between the level of T-bet expression and liver damage in peripheral plasma cells of patients with autoimmune hepatitis (AIH) in order to provide reference for the study of pathogenesis and development of diseases. Methods: The peripheral venous blood and clinical examination data of 29 cases with AIH and 6 healthy volunteers were collected. The percentage of subpopulations of peripheral blood B cells and the proportion of T-bet(+) cells in each subgroup were detected by flow cytometry. Plasma cells (CD19(+)CD10(-)CD27(hi)CD38(hi)), primary B cells (CD19(+)CD10(-)CD27(-)IgD(+)), transitional B cells (CD19(+)CD10(+)), and memory B cells (CD19(+)CD10(-)CD27(+)IgD(-)) were the included subsets of B cells. Serum immunoglobulin G (IgG) and alanine aminotransferase (ALT) levels, the proportion of B cells in peripheral blood subsets and IgG level, the proportion of T-bet(+) cells in each subset and the proportion of T-bet(+) plasma cells in each subset in B cells, the proportion of T-bet(+) plasma cells and the level of serum ALT were analyzed for correlation analysis. Statistical analysis was performed using two independent sample t-tests and linear regression. Results: The serum IgG level of AIH patients with abnormal ALT (19.47 ± 1.039)g/L was significantly higher than that of normal ALT patients (15.5 ± 1.069)g/L, and the difference was statistically significant (t = 2.65, P < 0.05). The percentage of peripheral plasma cells in B cells of AIH patients (2.80 ± 0.14) % was higher than that of healthy volunteers (0.73 ± 0.09) %, and the difference was statistically significant (P < 0.01). The percentage of T-bet(+) cells in peripheral plasma cells of AIH patients (23.54 ± 1.61) % was higher than that of healthy volunteers (6.59±0.59) % , and the difference was statistically significant (P < 0.01). The correlation analysis showed that the proportion of T-bet(+) cells in peripheral plasma cells of AIH patients was positively correlated with the proportion of plasma cells to B cells (r = 0.224 7, P < 0.01), and the percentage of peripheral plasma cells to B cells was positively correlated with the level of serum IgG (r = 0.299 1, P < 0.01). Serum IgG level was correlated with the level of ALT, reflecting an indicator of liver damage (t = 2.65, P < 0.05). Conclusion: The increase of T-bet expression in the peripheral plasma cells of AIH patients is associated with liver damage, which is a new mechanism of AIH pathogenesis and disease progression.


Assuntos
Hepatite Autoimune/patologia , Plasmócitos/metabolismo , Proteínas com Domínio T/metabolismo , Subpopulações de Linfócitos B/metabolismo , Citometria de Fluxo , Humanos
8.
World J Gastroenterol ; 25(19): 2308-2314, 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31148902

RESUMO

IgG4-related disease (IgG4-RD) is a chronic-fibroinflammatory disorder affecting a wide range of organs. Elevation of serum IgG4 concentrations and abundant infiltration of IgG4-expressing plasma cells are key diagnostic features of this autoimmune disease. Although common organ involvement of IgG4-RD includes the salivary glands, pancreas, and bile duct, hepatic involvement is less well established. Recently, five studies identified a subtype of autoimmune hepatitis (AIH), called IgG4-associated AIH (IgG4-AIH). IgG4-AIH is diagnosed based on significant accumulation of IgG4-expressing plasmacytes in the liver in patients who met the diagnostic criteria for classical AIH. Although four of the five reports regarded IgG4-AIH based on hepatic accumulation of IgG4-positive cells alone, one report diagnosed IgG4-AIH based on both hepatic accumulation of IgG4-positive cells and elevated serum concentrations of IgG4. IgG4-AIH diagnosed based on the latter criteria may be a hepatic manifestation of IgG4-RD whereas IgG4-AIH diagnosed based on the former criteria may be a subtype of AIH. In this review article, we summarize and discuss clinicopathological features of IgG4-AIH.


Assuntos
Hepatite Autoimune/imunologia , Doença Relacionada a Imunoglobulina G4/complicações , Imunoglobulina G/sangue , Hepatite Autoimune/sangue , Hepatite Autoimune/diagnóstico , Humanos , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Doença Relacionada a Imunoglobulina G4/sangue , Doença Relacionada a Imunoglobulina G4/imunologia , Fígado/citologia , Fígado/imunologia , Fígado/patologia , Plasmócitos/imunologia , Plasmócitos/metabolismo
9.
Int J Hematol ; 110(3): 322-330, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31183814

RESUMO

The development of effective therapies has enabled long-term survival for many patients with multiple myeloma (MM). However, the administration of antibody drugs, such as daratumumab, which bind to plasma cell (PC) surface proteins, may prevent PC detection by flow cytometry. We propose VS38 as an alternative antibody for CD38. VS38 recognizes cytoskeleton-linking membrane protein 63 (CLIMP-63) on the rough endoplasmic reticulum, and this protein may be expressed in secretory cells. We investigated VS38 staining in normal hematopoietic cells from five control samples, as well as PCs from 21 patients with plasma cell disorder (PCD). In normal hematopoietic cells, although VS38-stained monocytes, myeloid cells, and a subpopulation of B cells, PCs were significantly and brightly stained by VS38. There was no significant difference in VS38 staining between normal and abnormal PCs obtained from five patients with monoclonal gammopathy of undetermined significance. Furthermore, PCs in 21 PCD cases were clearly identified by VS38 in all cases, in contrast to CD38, even in daratumumab-administered patients whose CD38 epitopes on PCs were masked. These results suggest that the use of the VS38 antibody in flow cytometry contributes to PC detection, independent of therapeutic treatment.


Assuntos
Anticorpos Monoclonais , Antineoplásicos Imunológicos/química , Citometria de Fluxo , Proteínas de Membrana/sangue , Mieloma Múltiplo/sangue , Proteínas de Neoplasias/sangue , Plasmócitos/metabolismo , ADP-Ribosil Ciclase 1/sangue , Humanos , Glicoproteínas de Membrana/sangue , Mieloma Múltiplo/patologia , Plasmócitos/patologia
10.
PLoS Genet ; 15(6): e1007721, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31199803

RESUMO

B-cell activation yields abundant cell death in parallel to clonal amplification and remodeling of immunoglobulin (Ig) genes by activation-induced deaminase (AID). AID promotes affinity maturation of Ig variable regions and class switch recombination (CSR) in mature B lymphocytes. In the IgH locus, these processes are under control of the 3' regulatory region (3'RR) super-enhancer, a region demonstrated in the mouse to be both transcribed and itself targeted by AID-mediated recombination. Alternatively to CSR, IgH deletions joining Sµ to "like-switch" DNA repeats that flank the 3' super-enhancer can thus accomplish so-called "locus suicide recombination" (LSR) in mouse B-cells. Using an optimized LSR-seq high throughput method, we now show that AID-mediated LSR is evolutionarily conserved and also actively occurs in humans, providing an activation-induced cell death pathway in multiple conditions of B-cell activation. LSR either focuses on the functional IgH allele or is bi-allelic, and its signature is mainly detected when LSR is ongoing while it vanishes from fully differentiated plasma cells or from "resting" blood memory B-cells. Highly diversified breakpoints are distributed either within the upstream (3'RR1) or downstream (3'RR2) copies of the IgH 3' super-enhancer and all conditions activating CSR in vitro also seem to trigger LSR although TLR ligation appeared the most efficient. Molecular analysis of breakpoints and junctions confirms that LSR is AID-dependent and reveals junctional sequences somehow similar to CSR junctions but with increased usage of microhomologies.


Assuntos
Linfócitos B/imunologia , Citidina Desaminase/genética , Região de Troca de Imunoglobulinas/genética , Imunoglobulinas/imunologia , Alelos , Animais , Diferenciação Celular/genética , Citidina Desaminase/imunologia , Marcação de Genes , Humanos , Região de Troca de Imunoglobulinas/imunologia , Tecido Linfoide/imunologia , Camundongos , Tonsila Palatina/imunologia , Tonsila Palatina/metabolismo , Plasmócitos/imunologia , Plasmócitos/metabolismo , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/imunologia , Sequências Reguladoras de Ácido Nucleico
11.
J Cutan Pathol ; 46(9): 678-683, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31070801

RESUMO

A 28-year-old woman of Chinese descent, with congenital chronic hepatitis B presented with a 7-year history of erythematous-brown papules and plaques on her groins, axillae, and forehead. A first skin biopsy showed findings consistent with two concomitant, yet highly uncommon cutaneous diseases. The presence of lymphoid nodules with germinal centers and clustered polyclonal plasma cells was consistent with cutaneous plasmocytosis. Second, a diffuse proliferation of non-atypical small vessels (CD31+, CD34+, and HHV8-) in a hypercellular stroma peppered with angulated giant cells (CD163+, CD68-) was suggestive of multinucleate cell angiohistiocytoma (MCAH). Interestingly, the second biopsy of a different plaque on the forehead showed only plasmacytosis and the clinical appearance of both plaques and papules alluded to the distinct presence of both concurrent entities. We speculate the immune modulating effects of chronic hepatitis B may have led to a polyclonal plasmacytic proliferation within the dermis. Furthermore, MCAH has been reported in conjunction with other inflammatory skin diseases such as hidradenitis suppurativa and as such we propose that the MCAH lesion in our case may have arisen as a secondary, reactive process to the cutaneous plasmacytosis.


Assuntos
Células Gigantes , Neoplasias de Cabeça e Pescoço , Histiocitoma , Plasmócitos , Neoplasias Cutâneas , Adulto , Derme/metabolismo , Derme/patologia , Feminino , Testa/patologia , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Hepatite B Crônica/metabolismo , Hepatite B Crônica/patologia , Histiocitoma/metabolismo , Histiocitoma/patologia , Humanos , Plasmócitos/metabolismo , Plasmócitos/patologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia
12.
Ann Hematol ; 98(7): 1713-1720, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31053880

RESUMO

Symptomatic multiple myeloma (MM) is a plasma cell neoplasm that represents the final stage of a continuum of clinical conditions that start from monoclonal gammopathy of unknown significance (MGUS), then transits in the more advance, but still asymptomatic, smoldering MM (SMM), with a final evolution in symptomatic MM. To investigate SMM microenvironment modifications, we studied 16 patients diagnosed at our hospital. Eight of them (group A) developed MM within 2 years from diagnosis while the others (group B) had stable SMM. Samples were bone marrow biopsies at diagnosis and after 2 years (± 4 months) and were analyzed by immunohistochemical analysis. Firstly, we found a significant increase in both CD4+ cells (11 vs 17%, p < 0.01) and CD8+ cells (15 vs 18%, p < 0.01) between diagnosis and at follow-up samples (whole cohort). This was associated to an increase in the CD4+/CD8+ ratio (0.74 vs 0.93, p < 0.01). Secondly, we discovered an increased expression of T cell inhibitory molecules during SMM evolution. In fact, plasma cell PD-L1 and microenvironment cell LAG3 expression increased from 1 to 12% (p = 0.03) and 4 to 10% (p = 0.04), respectively, from diagnosis to follow-up. Also, plasma cells and microenvironment cells HLA-DR expression augmented during SMM evolution from 7 to 10% (p = 0.04) and 29 to 39% (p = 0.01), respectively. When comparing group A vs group B, we found an increased CD68-KP1+ cell infiltration in favor of group B at diagnosis (23 vs 28%, p = 0.01) and a greater plasma cell infiltration at follow-up (50 vs 26%, p < 0.01). Our findings suggest how immune escape mechanisms appear earlier during multiple myeloma evolution, and that LAG3 could be a possible immunologic target in this setting.


Assuntos
Antígenos CD/biossíntese , Antígeno B7-H1/biossíntese , Regulação Neoplásica da Expressão Gênica , Antígenos HLA-DR/biossíntese , Mieloma Múltiplo/metabolismo , Proteínas de Neoplasias/biossíntese , Mieloma Múltiplo Latente , Biópsia , Medula Óssea/metabolismo , Medula Óssea/patologia , Relação CD4-CD8 , Feminino , Humanos , Masculino , Mieloma Múltiplo/patologia , Plasmócitos/metabolismo , Plasmócitos/patologia , Estudos Retrospectivos , Mieloma Múltiplo Latente/metabolismo , Mieloma Múltiplo Latente/patologia , Evasão Tumoral , Microambiente Tumoral
13.
Life Sci Alliance ; 2(3)2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31097471

RESUMO

A fast antibody response can be critical to contain rapidly dividing pathogens. This can be achieved by the expansion of antigen-specific B cells in response to T-cell help followed by differentiation into plasmablasts. MicroRNA-155 (miR-155) is required for optimal T-cell-dependent extrafollicular responses via regulation of PU.1, although the cellular processes underlying this defect are largely unknown. Here, we show that miR-155 regulates the early expansion of B-blasts and later on the survival and proliferation of plasmablasts in a B-cell-intrinsic manner, by tracking antigen-specific B cells in vivo since the onset of antigen stimulation. In agreement, comparative analysis of the transcriptome of miR-155-sufficient and miR-155-deficient plasmablasts at the peak of the response showed that the main processes regulated by miR-155 were DNA metabolic process, DNA replication, and cell cycle. Thus, miR-155 controls the extent of the extrafollicular response by regulating the survival and proliferation of B-blasts, plasmablasts and, consequently, antibody production.


Assuntos
Subpopulações de Linfócitos B/metabolismo , MicroRNAs/genética , Plasmócitos/metabolismo , Animais , Formação de Anticorpos/genética , Formação de Anticorpos/imunologia , Subpopulações de Linfócitos B/imunologia , Biomarcadores , Proliferação de Células , Sobrevivência Celular/genética , Imunofenotipagem , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Camundongos , Camundongos Knockout , Plasmócitos/imunologia
14.
Cell ; 177(3): 524-540, 2019 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-31002794

RESUMO

B cells and the antibodies they produce have a deeply penetrating influence on human physiology. Here, we review current understanding of how B cell responses are initiated; the different paths to generate short- and long-lived plasma cells, germinal center cells, and memory cells; and how each path impacts antibody diversity, selectivity, and affinity. We discuss how basic research is informing efforts to generate vaccines that induce broadly neutralizing antibodies against viral pathogens, revealing the special features associated with allergen-reactive IgE responses and uncovering the antibody-independent mechanisms by which B cells contribute to health and disease.


Assuntos
Linfócitos B/metabolismo , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/metabolismo , Antígenos/imunologia , Linfócitos B/imunologia , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Humanos , Memória Imunológica , Plasmócitos/imunologia , Plasmócitos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Vacinas/imunologia
15.
Blood ; 133(24): 2597-2609, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-30962205

RESUMO

CD30 is expressed on a variety of B-cell lymphomas, such as Hodgkin lymphoma, primary effusion lymphoma, and a diffuse large B-cell lymphoma subgroup. In normal tissues, CD30 is expressed on some activated B and T lymphocytes. However, the physiological function of CD30 signaling and its contribution to the generation of CD30+ lymphomas are still poorly understood. To gain a better understanding of CD30 signaling in B cells, we studied the expression of CD30 in different murine B-cell populations. We show that B1 cells expressed higher levels of CD30 than B2 cells and that CD30 was upregulated in IRF4+ plasmablasts (PBs). Furthermore, we generated and analyzed mice expressing a constitutively active CD30 receptor in B lymphocytes. These mice displayed an increase in B1 cells in the peritoneal cavity (PerC) and secondary lymphoid organs as well as increased numbers of plasma cells (PCs). TI-2 immunization resulted in a further expansion of B1 cells and PCs. We provide evidence that the expanded B1 population in the spleen included a fraction of PBs. CD30 signals seemed to enhance PC differentiation by increasing activation of NF-κB and promoting higher levels of phosphorylated STAT3 and STAT6 and nuclear IRF4. In addition, chronic CD30 signaling led to B-cell lymphomagenesis in aged mice. These lymphomas were localized in the spleen and PerC and had a B1-like/plasmablastic phenotype. We conclude that our mouse model mirrors chronic B-cell activation with increased numbers of CD30+ lymphocytes and provides experimental proof that chronic CD30 signaling increases the risk of B-cell lymphomagenesis.


Assuntos
Linfócitos B/imunologia , Linfócitos B/patologia , Transformação Celular Neoplásica/patologia , Antígeno Ki-1/imunologia , Linfoma de Células B/metabolismo , Animais , Antígeno Ki-1/metabolismo , Linfoma de Células B/imunologia , Linfoma de Células B/patologia , Camundongos , Camundongos Transgênicos , Plasmócitos/metabolismo , Plasmócitos/patologia , Células Precursoras de Linfócitos B/metabolismo , Células Precursoras de Linfócitos B/patologia , Transdução de Sinais/fisiologia
16.
EBioMedicine ; 41: 465-478, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30857944

RESUMO

BACKGROUND: Acute viral infections induce a rapid and transient increase in antibody-secreting plasmablasts. At convalescence, memory B cells (MBC) and long-lived plasma cells (LLPC) are responsible for long-term humoral immunity. Following an acute viral infection, the specific properties and relationships between antibodies produced by these B cell compartments are poorly understood. METHODS: We utilized a controlled human challenge model of primary dengue virus serotype 2 (DENV2) infection to study acute and convalescent B-cell responses. FINDINGS: The level of DENV2 replication was correlated with the magnitude of the plasmablast response. Functional analysis of plasmablast-derived monoclonal antibodies showed that the DENV2-specific response was dominated by cells producing DENV2 serotype-specific antibodies. DENV2-neutralizing antibodies targeted quaternary structure epitopes centered on domain III of the viral envelope protein (EDIII). Functional analysis of MBC and serum antibodies from the same subjects six months post-challenge revealed maintenance of the serotype-specific response in both compartments. The serum response mainly targeted DENV2 serotype-specific epitopes on EDIII. INTERPRETATION: Our data suggest overall functional alignment of DENV2-specific responses from the plasmablast, through the MBC and LLPC compartments following primary DENV2 inflection. These results provide enhanced resolution of the temporal and specificity of the B cell compartment in viral infection and serve as framework for evaluation of B cell responses in challenge models. FUNDING: This study was supported by the Bill and Melinda Gates Foundation and the National Institutes of Health.


Assuntos
Linfócitos B/metabolismo , Dengue/diagnóstico , Doença Aguda , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Linfócitos B/citologia , Linfócitos B/imunologia , Dengue/virologia , Vírus da Dengue/genética , Vírus da Dengue/isolamento & purificação , Mapeamento de Epitopos , Epitopos/imunologia , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/virologia , Estudos Longitudinais , Plasmócitos/citologia , Plasmócitos/metabolismo , Sorogrupo , Proteínas do Envelope Viral/imunologia
17.
Blood Cancer J ; 9(3): 32, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30846679

RESUMO

We compared the outcomes of 310 patients with newly diagnosed multiple myeloma with del(17p) detected by FISH to patients with high-risk translocations (HRT) (n = 79) and standard-risk (SR) cytogenetics (n = 541). The median progression-free survival (PFS) following initial therapy for the three groups was 21.1, 22, and 30.1 months, respectively (P = 0.437- del(17p) vs. HRT); the median overall survival (OS) was 47.3, 79.1, and 109.8 months, respectively, (P = 0.007- del(17p) vs. HRT). PFS and OS for patients with relative loss of 17p (n = 21) were comparable to other patients with del(17p). The PFS was similar between the del(17p) and HRT groups when stratified for age, ISS stage or treatment. The OS of del(17p) and HRT groups were similar in presence of advanced age, ISS III stage or if patients did not receive a proteasome-inhibitor containing induction. ISS III stage, high LDH and HRT, but not the percentage of cells with del(17p) predicted shorter OS in patients with del(17p). The median OS for low (ISS I, normal LDH and no HRT), intermediate (neither low nor high-risk) and high-risk (ISS III and either elevated LDH or coexistent HRT) groups among del(17p) patients were 96.2, 45.4, and 22.8 months, respectively, allowing further risk stratification.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 17 , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica , Biomarcadores Tumorais , Aberrações Cromossômicas , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Hibridização in Situ Fluorescente , Quimioterapia de Indução , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Estadiamento de Neoplasias , Plasmócitos/metabolismo , Plasmócitos/patologia , Prognóstico
18.
Gastroenterology ; 156(6): 1890-1904.e16, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30711627

RESUMO

BACKGROUND & AIMS: Little is known about the composition and generation of plasma cell subsets in patients with hepatocellular carcinoma (HCC) and how these associate with outcomes. We investigated whether, or how, plasma cells differentiate and function in patients with HCC and mice with liver tumors. METHODS: We analyzed subset composition and distribution of plasma cells in HCC samples from 342 patients who underwent curative resection at the Cancer Center of Sun Yat-sen University in China; samples of non-tumor liver tissue were used as controls. We associated plasma cell profiles with patient outcomes. Tissue-derived leukocytes were analyzed by flow cytometry and real-time polymerase chain reaction. The ability of macrophages to regulate plasma cell differentiation was determined in ex vivo cultures of cells from human HCC tissues. C57BL/6 and BALB/c mice were given injections of Hepa1-6 cells, which formed hepatomas, or H22 cells, which formed ascitic hepatomas. Gene expression patterns were analyzed in human HCC, mouse hepatoma, and non-tumor tissues by real-time polymerase chain reaction. Mice with hepatomas were given injections of GSK126 (an inhibitor of histone H3 lysine 27 methyltransferase [EZH2]) and 5-AZA-dC (an inhibitor of DNA methyltransferases); tumor tissues were analyzed by immunofluorescence and immunohistochemistry for the presence of immune cells and cytokines. RESULTS: B cells isolated from HCCs had somatic hypermutations and class-switch recombinations to the IgG phenotype that were not observed in non-tumor tissues. Increased level of plasma cells correlated with poor outcomes of patients. Activated CD4+ T cells from HCCs stimulated C-X-C motif chemokine 10 (CXCL10) production by macrophages. CXCL10 bound CXC chemokine receptor 3 on B cells and signaled via extracellular signal-regulated kinase to cause them to become IgG-producing plasma cells. IgG activated Fc receptors on macrophages and induced them to produce interleukin 6, interleukin 10, and C-C motif chemokine ligand 20 (CCL20). In mice with hepatomas, depletion of B cells prevented generation of these macrophage, increased the anti-tumor T cell response, and reduced growth of hepatomas. However, these effects were lost after injection of CXC chemokine receptor 3-positive plasma cells. Human HCC and mouse hepatoma tissues had increased expression of DNA methyltransferase 1 and EZH2 compared with non-tumor tissues. Injection of mice with GSK126 and 5-AZA-dC induced expression of CXCL10 by tumor cells and caused plasma cell polarization, suppression of the anti-tumor T cell response, and hepatoma growth. CONCLUSIONS: Human HCC tissues contain B cells with class-switch recombinations to the IgG phenotype. Activated CD4+ T cells from HCCs stimulate CXCL10 production by macrophages; CXCL10 binds CXC chemokine receptor 3 on B cells and causes them to become IgG-producing plasma cells. IgG activates Fc receptor in macrophages to produce cytokines that reduce the anti-tumor immune response. In mice with hepatomas, depletion of B cells prevented generation of these macrophages, increased the anti-tumor T cell response, and reduced growth of hepatomas. This pathway involves increased expression of DNA methyltransferase 1 and EZH2 by HCC and hepatoma cells.


Assuntos
Carcinoma Hepatocelular/genética , Epigênese Genética , Imunoglobulina G/metabolismo , Neoplasias Hepáticas/genética , Macrófagos/metabolismo , Plasmócitos/metabolismo , Adulto , Idoso , Animais , Antimetabólitos Antineoplásicos/farmacologia , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Diferenciação Celular , Linhagem Celular Tumoral , Quimiocina CCL20/metabolismo , Quimiocina CXCL10/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Decitabina/farmacologia , Progressão da Doença , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Indóis/farmacologia , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Fígado/patologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Contagem de Linfócitos , Masculino , Camundongos , Pessoa de Meia-Idade , Transplante de Neoplasias , Fenótipo , Plasmócitos/imunologia , Piridonas/farmacologia , Receptores CXCR3/metabolismo , Receptores Fc/metabolismo , Transdução de Sinais , Transcriptoma
19.
Am J Dermatopathol ; 41(7): 505-510, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30601206

RESUMO

Lichen myxedematosus is a chronic cutaneous mucinosis that can present on a spectrum from localized cutaneous lesions to systemic disease of scleromyxedema. The clinical presentation of localized cutaneous lichen myxedematosus is waxy lichenoid papules, nodules, and/or plaques that have histopathologic findings of mucin deposition and a variable degree of fibroblast proliferation. There is an absence of serum paraproteins, and there are no other systemic causes of cutaneous mucinosis such as thyroid disease. The pathogenesis of lichen myxedematosus is unknown. We report 3 cases of localized cutaneous lichen myxedematosus with a light chain-restricted plasmacytic component by in situ hybridization. Our findings deliver an insight for disease pathogenesis and highlight for the first time, the significance of plasma cells in lesions of localized cutaneous lichen myxedematosus. We suggest that plasma cell light chain restriction could represent a clue to distinguish localized cutaneous disease from systemic disease.


Assuntos
Cadeias kappa de Imunoglobulina/metabolismo , Cadeias lambda de Imunoglobulina/metabolismo , Plasmócitos/metabolismo , Escleromixedema/metabolismo , Escleromixedema/patologia , Adulto , Biópsia , Dermatoses Faciais/metabolismo , Dermatoses Faciais/patologia , Humanos , Cadeias kappa de Imunoglobulina/genética , Cadeias lambda de Imunoglobulina/genética , Hibridização In Situ , Masculino , Pele/patologia , Adulto Jovem
20.
Mol Immunol ; 107: 61-70, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30660991

RESUMO

Although sharing the same subunit Ebi3, IL-27 (p28/Ebi3) and IL-35 (p35/Ebi3) have different biological functions, suggesting that Ebi3 subunit may functions as a carrier. Our data demonstrated that activated T cells and B cells effectively up-regulated Ebi3 expression. In addition, Ebi3 effectively promoted T-cell activation and the differentiation of helper T 1 (Th1), Th17, and Foxp3+ regulatory T (Treg) cells induced by Th1, Th17, and Treg polarizing condition, respectively. Naturally, Ebi3 could promote B-cell activation and the production of CD138+ plasma cells (PC) induced by LPS. Conversely, neutralizing anti-Ebi3 antibody could significantly suppress T/B-cell activation and production of Th1, Th17, Tregs, and PC induced by Th1, Th17, Treg polarizing condition, and LPS, respectively. Furthermore, we found that Ebi3 time-dependently induced STAT3 activation in CD4+T cells and B cells. Conversely, STAT3-/- effectively reduced Ebi3 expression and the production of Th1, Th17, Tregs, and plasma cells. Finally, we showed that gp130 but not IL-27Rα mediates Ebi3-induced STAT3 activation. These results suggest that Ebi3 promotes Th- and B-cell differentiation via gp130-STAT3 signaling pathway. Thus, autocrine Ebi3 may play an important role in the differentiation of Th and B cells and thus in infection, inflammation, and autoimmune disorders.


Assuntos
Linfócitos B/citologia , Linfócitos B/metabolismo , Diferenciação Celular , Divisão Celular , Antígenos de Histocompatibilidade Menor/metabolismo , Receptores de Citocinas/metabolismo , Fator de Transcrição STAT3/metabolismo , Linfócitos T/citologia , Linfócitos T/metabolismo , Animais , Comunicação Autócrina , Receptor gp130 de Citocina/metabolismo , Ativação Linfocitária/imunologia , Camundongos Endogâmicos C57BL , Plasmócitos/citologia , Plasmócitos/metabolismo , Transdução de Sinais , Regulação para Cima
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