RESUMO
Antibody secreting cells (ASCs) circulate after vaccination and infection and migrate to the BM where a subset known as long-lived plasma cells (LLPCs) persists and secrete antibodies for a lifetime. The mechanisms by which circulating ASCs become LLPCs are not well elucidated. Here, we show that human blood ASCs have distinct morphology, transcriptomes, and epigenetics compared with BM LLPCs. Compared with blood ASCs, BM LLPCs have decreased nucleus/cytoplasm ratio but increased endoplasmic reticulum and numbers of mitochondria. LLPCs up-regulate pro-survival genes MCL1, BCL2, and BCL-XL while simultaneously down-regulating pro-apoptotic genes HRK1, CASP3, and CASP8 Consistent with reduced gene expression, the pro-apoptotic gene loci are less accessible in LLPCs. Of the pro-survival genes, only BCL2 is concordant in gene up-regulation and loci accessibility. Using a novel in vitro human BM mimetic, we show that blood ASCs undergo similar morphological and molecular changes that resemble ex vivo BM LLPCs. Overall, our study demonstrates that early-minted blood ASCs in the BM microniche must undergo morphological, transcriptional, and epigenetic changes to mature into apoptotic-resistant LLPCs.
Assuntos
Epigênese Genética , Regulação da Expressão Gênica , Impressão Genômica , Plasmócitos/citologia , Plasmócitos/metabolismo , Adolescente , Adulto , Formação de Anticorpos/genética , Formação de Anticorpos/imunologia , Apoptose/genética , Biomarcadores , Sobrevivência Celular , Feminino , Heterogeneidade Genética , Histocitoquímica , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Plasmócitos/imunologia , Plasmócitos/ultraestrutura , Fatores de Tempo , Adulto JovemRESUMO
Plasma cell leukaemia (PCL) is a rare and very aggressive plasma cell disorder. Preventing a dismal outcome of PCL requires early diagnosis with appropriate analytical tools. Therefore, the investigation of 33 patients with primary and secondary PCL was done when the quantity of circulating plasma cells (PCs) using flow cytometry (FC) and morphology assessment was evaluated. The phenotypic profile of the PCs was also analysed to determine if there is an association with clinical outcomes and to evaluate the prognostic value of analysed markers. Our results revealed that FC is an excellent method for identifying circulating PCs as a significantly higher number was identified by FC than by morphology (26·7% vs. 13·5%, P = 0·02). None of secondary PCL cases expressed CD19 or CD20. A low level of expression with similar positivity of CD27, CD28, CD81 and CD117 was found in both PCL groups. A decrease of CD44 expression was detected only in secondary PCL. Expression of CD56 was present in more than half of PCL cases as well as cytoplasmic nestin. A decreased level of platelets, Eastern Cooperative Oncology Group score of 2-3 and lack of CD20+ PC were associated with a higher risk of death. FC could be incorporated in PCL diagnostics not only to determine the number of circulating PCs, but also to assess their phenotype profile and this information should be useful in patients' diagnosis and possible prognosis.
Assuntos
Contagem de Células Sanguíneas , Citometria de Fluxo/métodos , Leucemia Plasmocitária/sangue , Células Neoplásicas Circulantes , Plasmócitos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/análise , Antígenos de Neoplasias/análise , Contagem de Células Sanguíneas/métodos , Medula Óssea/patologia , Células da Medula Óssea/química , Detecção Precoce de Câncer , Reações Falso-Negativas , Feminino , Humanos , Imunofenotipagem , Estimativa de Kaplan-Meier , Leucemia Plasmocitária/mortalidade , Masculino , Pessoa de Meia-Idade , Plasmócitos/química , Plasmócitos/ultraestrutura , Intervalo Livre de ProgressãoRESUMO
Efficient IgA transcytosis is critical for the maintenance of a homeostatic microbiota. In the canonical model, locally-secreted dimeric (d)IgA reaches the polymeric immunoglobulin receptor (pIgR) on intestinal epithelium via simple diffusion. A role for integrin αE(CD103)ß7 during transcytosis has not been described, nor its expression by intestinal B cell lineage cells. We found that αE-deficient (αE-/-) mice have a luminal IgA deficit, despite normal antibody-secreting cells (ASC) recruitment, local IgA production and increased pIgR expression. This deficit was not due to dendritic cell (DC)-derived retinoic acid (RA) nor class-switching defects, as stool from RAG-/- mice reconstituted with αE-/- B cells was also IgA deficient. Flow cytometric, ultrastructural and transcriptional profiling showed that αEß7-expressing ASC represent an undescribed subset of terminally-differentiated intestinal plasma cells (PC) that establishes direct cell to cell contact with intestinal epithelium. We propose that IgA not only reaches pIgR through diffusion, but that αEß7+ PC dock with E-cadherin-expressing intestinal epithelium to directly relay IgA for transcytosis into the intestinal lumen.
Assuntos
Imunoglobulina A/imunologia , Integrinas/genética , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Plasmócitos/imunologia , Plasmócitos/metabolismo , Transcitose/imunologia , Animais , Diferenciação Celular/imunologia , Expressão Gênica , Regulação da Expressão Gênica , Imunoglobulina A/metabolismo , Imunoglobulina A Secretora/imunologia , Integrinas/deficiência , Integrinas/metabolismo , Mucosa Intestinal/ultraestrutura , Ativação Linfocitária , Camundongos , Camundongos Knockout , Modelos Biológicos , Plasmócitos/citologia , Plasmócitos/ultraestruturaAssuntos
Medula Óssea/ultraestrutura , Histiocitose/etiologia , Imunoglobulinas/análise , Corpos de Inclusão/ultraestrutura , Leucoencefalopatias/etiologia , Linfonodos/ultraestrutura , Macroglobulinemia de Waldenstrom/complicações , Idoso , Cloridrato de Bendamustina/uso terapêutico , Histiócitos/ultraestrutura , Histiocitose/metabolismo , Histiocitose/patologia , Humanos , Corpos de Inclusão/química , Leucoencefalopatias/metabolismo , Leucoencefalopatias/patologia , Masculino , Plasmócitos/ultraestrutura , Síndrome , Macroglobulinemia de Waldenstrom/diagnóstico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/patologiaRESUMO
Crystal-storing histiocytosis (CSH) is a non-neoplastic histiocytic proliferation containing crystalline material, usually associated with an underlying lymphoproliferative or plasmacytic disorder. The crystalline structures are typically derived from kappa light chain immunoglobulins. The lesions of CSH are comprised of sheets of histiocytes with abundant eosinophilic cytoplasm containing variably prominent, elongated crystals. This rare phenomenon is important to recognize, as it is known to morphologically obscure an underlying neoplasm. Histologically, the cells of CSH may closely mimic Gaucher cells, as well as the "pseudo-Gaucher" cells sometimes encountered in chronic myeloid leukemia. The distinction between the cells of CSH and that of histologic mimics may be made more definitively through the use of electron microscopy, as the crystalline inclusions seen in CSH display characteristic size, shape, and localization within the cells. Here, we report 2 rare cases of CSH diagnosed by morphology, immunohistochemistry, and ultrastructural examination. The first case presented was diagnosed concurrently with plasma cell myeloma, and the second case discussed was diagnosed in association with marginal zone lymphoma.
Assuntos
Histiocitose , Cadeias kappa de Imunoglobulina/metabolismo , Plasmócitos , Idoso , Idoso de 80 Anos ou mais , Feminino , Histiocitose/metabolismo , Histiocitose/patologia , Humanos , Imuno-Histoquímica , Masculino , Microscopia Eletrônica , Plasmócitos/metabolismo , Plasmócitos/ultraestruturaRESUMO
The treatment of AL amyloidosis aims to eradicate the plasma cell clone and eliminate toxic free light chain production. Only in a minority of patients the plasma cell clone is completely eradicated; residual light chain production may still exist while clonal relapse may occur. We used sensitive next-generation flow cytometry (NGF) to detect minimal residual disease (MRD) in AL amyloidosis patients at complete haematologic response. MRD evaluation was feasible in 51 of 52 (98%) tested patients and at a median sensitivity of 2.3 × 10-6 MRD was undetectable in 23 (45%). An organ response occurred in 86% of MRDneg vs 77% in MRDpos; renal response in 15/17(88%) of MRDneg vs in 14/16(87.5%) of MRDpos and cardiac response in 10/10(100%) of MRDneg vs 11/15(73%) of MRDpos patients. After a median follow-up of 24 months post MRD testing, no MRDneg patient had a haematologic relapse vs 6/28(21%) MRDpos (p = .029). Pooling haematologic and organ progressions, 9 (32%) MRDpos patients had disease progression vs only 1 (4%) MRDneg patient (p = .026). In conclusion, MRD detection using NGF has profound clinical implications, so that AL patients with undetectable MRD have a very high probability of organ response and a very low probability of haematologic relapse.
Assuntos
Citometria de Fluxo/métodos , Amiloidose de Cadeia Leve de Imunoglobulina/sangue , Peptídeo Natriurético Encefálico/sangue , Neoplasia Residual/sangue , Adulto , Idoso , Células da Medula Óssea/patologia , Células da Medula Óssea/ultraestrutura , Feminino , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/complicações , Amiloidose de Cadeia Leve de Imunoglobulina/patologia , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/complicações , Neoplasia Residual/diagnóstico , Neoplasia Residual/patologia , Plasmócitos/patologia , Plasmócitos/ultraestrutura , PrognósticoRESUMO
Cytogenetic abnormalities are a recognized factor in the pathogenesis of multiple myeloma (MM). While chromosomal translocations involving the IGH gene have been investigated and reported, the implications of deletions or amplifications in the IGH gene have been less frequently examined. We conducted a retrospective analysis of 260 patients with MM from Northern Israel. Fluorescent in situ hybridization (FISH) analysis of separated CD-138 positive cells was done on bone marrow samples collected between 2016 and 2018. We used IGH break apart probes to identify IGH abnormalities and performed statistical analysis of clinical and prognostic features, comparing the different cytogenetic groups. Deletions in the variable region of the IGH (IGHv) were found in 17.3 % (n = 45) of patients and correlated with significantly worse progression free survival (PFS) after two years of follow up (p = 0.008), as well as with a worse response to 1st line treatment (p = 0.037). The median PFS was 7.1 and 17.7 months in patients with and without IGHv deletion, respectively. PFS differences remained significant (p = 0.017) in subgroup analysis of patients with high-risk cytogenetics (n = 108, 19 with IGHv deletion). Overall survival was not significantly different in the two groups. Constant region (IGHc) amplifications, were less frequently found (6.15 %, n = 16), yet significantly correlated with worse PFS after two years of follow up (p = 0.023). This difference remained valid in the high-risk subgroup (p = 0.001). In Conclusion, we identified that deletion of the IGH variable region and amplification in the IGH constant region, are both associated with poor prognosis and inferior outcome in MM.
Assuntos
Genes de Cadeia Pesada de Imunoglobulina , Mieloma Múltiplo/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Feminino , Seguimentos , Amplificação de Genes , Deleção de Genes , Humanos , Regiões Constantes de Imunoglobulina/genética , Região Variável de Imunoglobulina/genética , Hibridização in Situ Fluorescente , Israel/epidemiologia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Plasmócitos/ultraestrutura , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos , Teniposídeo/administração & dosagem , Resultado do TratamentoAssuntos
Medula Óssea/patologia , Corpos de Inclusão/ultraestrutura , Mieloma Múltiplo/patologia , Plasmócitos/ultraestrutura , Núcleo Celular/ultraestrutura , Amarelo de Eosina-(YS) , Humanos , Imunoglobulina A/análise , Corpos de Inclusão Intranuclear/ultraestrutura , Masculino , Pessoa de Meia-Idade , Proteínas do Mieloma/análise , Coloração e RotulagemAssuntos
Betacoronavirus , Células Sanguíneas/ultraestrutura , Infecções por Coronavirus/sangue , Pneumonia Viral/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Contagem de Células Sanguíneas , COVID-19 , Linhagem da Célula , Tamanho Celular , Infecções por Coronavirus/terapia , Oxigenação por Membrana Extracorpórea , Feminino , Hematopoese , Humanos , Masculino , Pessoa de Meia-Idade , Neutrófilos/ultraestrutura , Pandemias , Plasmócitos/ultraestrutura , Pneumonia Viral/terapia , SARS-CoV-2 , Sensibilidade e EspecificidadeRESUMO
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 JovemAssuntos
Núcleo Celular/patologia , Plasmócitos/patologia , Plasmocitoma/diagnóstico , Adulto , Biópsia , Cálcio/sangue , Núcleo Celular/ultraestrutura , Creatinina/sangue , Deleção de Genes , Hepatomegalia/diagnóstico por imagem , Técnicas Histológicas , Humanos , Fígado/diagnóstico por imagem , Fígado/patologia , Fígado/ultraestrutura , Masculino , Plasmócitos/citologia , Plasmócitos/ultraestrutura , Plasmocitoma/diagnóstico por imagem , Plasmocitoma/genética , Plasmocitoma/ultraestrutura , Tomografia Computadorizada por Raios XRESUMO
Ultrastructure of plasma cells in Harderian gland was investigated using the transmission electron microscopy. For this research, we examined the glands of 32 laying hens collected at 1, 7, 20 and 40 days and 4, 6, 8 and 12 months of the birds' ages. The research showed that the stroma of the gland contains a large number of lymphocytes and plasma cells. Most of the plasma cells are mature, but morphologically do not show productive activity. Only some individual plasma cells, situated under the secretory epithelium of primary and secondary ducts, have extremely dilated cisternae of rough endoplasmic reticulum which contain moderately dense, granular material. The morphology of these cells indicates that they are in active stage of immunoglobulin production. Also, we identified plasma cells with two types of Russell bodies. One type of these bodies was small, round or oval, while the other had irregular, angular shape. It was noted that one plasma cell never contains both type of Russell bodies at the same time. These cells were often affected by apoptosis. Among them, in deeper part of the stroma, were situated the small plasmablast cells.
Assuntos
Galinhas/anatomia & histologia , Glândula de Harder/citologia , Plasmócitos/ultraestrutura , Fatores Etários , Animais , Núcleo Celular/ultraestrutura , Retículo Endoplasmático/ultraestrutura , Feminino , Complexo de Golgi/ultraestrutura , Glândula de Harder/ultraestrutura , Imunoglobulinas/biossíntese , Microscopia Eletrônica de Transmissão/veterinária , Plasmócitos/imunologiaRESUMO
Insight into processes leading to rupture of intracranial aneurysms (IAs) may identify biomarkers for rupture or lead to management strategies reducing the risk of rupture. We characterized and quantified (ultra)structural differences between unruptured and ruptured aneurysmal walls. Six unruptured and 6 ruptured IA fundi were resected after microsurgical clipping and analyzed by correlative light microscopy for quantitative analysis (proportion of the vessel wall area) and transmission electron microscopy for qualitative ultrastructural analysis. Quantitative analysis revealed extensive internal elastic lamina (IEL) thickening in ruptured IA (36.3% ± 15%), while thin and fragmented IEL were common in unruptured IA (5.6% ± 7.1%). Macrophages were increased in ruptured IA (28.3 ± 24%) versus unruptured IA (2.7% ± 5.5%), as were leukocytes (12.85% ± 10% vs 0%). Vasa vasorum in ruptured but not in unruptured IA contained vast numbers of inflammatory cells and extravasation of these cells into the vessel wall. In conclusion, detection of thickened IEL, leaky vasa vasorum, and heavy inflammation as seen in ruptured IA in comparison to unruptured IA may identify aneurysms at risk of rupture, and management strategies preventing development of vasa vasorum or inflammation may reduce the risk of aneurysmal rupture.
Assuntos
Aneurisma Roto/patologia , Vasos Sanguíneos/patologia , Vasos Sanguíneos/ultraestrutura , Aneurisma Intracraniano/patologia , Técnicas Estereotáxicas , Adulto , Idoso , Endotélio/patologia , Endotélio/ultraestrutura , Feminino , Humanos , Masculino , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade , Músculo Liso/patologia , Músculo Liso/ultraestrutura , Plasmócitos/patologia , Plasmócitos/ultraestrutura , Adulto JovemAssuntos
Doença das Cadeias Pesadas/patologia , Linfoma Difuso de Grandes Células B/patologia , Plasmócitos/ultraestrutura , Doença das Cadeias Pesadas/sangue , Humanos , Cadeias mu de Imunoglobulina/sangue , Linfoma Difuso de Grandes Células B/sangue , Linfoma Difuso de Grandes Células B/química , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/sangue , Vacúolos/ultraestruturaRESUMO
The name plasma cell was introduced by the anatomist Heinrich H. von Hartz-Waldeyer in 1875. Plasma cells derive from small B lymphocytes after their activation. A fully mature plasma cell lacks surface immunoglobulin expression. Its form is round or oval, with characteristic basophilic cytoplasm and an eccentric nucleus that contains coarse heterochromatin. Antigen activation of mature B cells leads initially to germinal center development, the transient generation of plasmablasts that secrete antibody while still dividing, and short-lived extrafollicular plasma cells that secrete antigen-specific germ line-encoded antibodies. Plasma cells are characterized by the co-expression of CD138 and CD38, which allows their identification in flow cytometry in bone marrow, peripheral blood, or cell suspensions from tissues. The identification of plasma cells as antibody producers was a key discovery that paved the way for the development of monoclonal antibodies.
Assuntos
Alergia e Imunologia , Plasmócitos/imunologia , Plasmócitos/metabolismo , Alergia e Imunologia/história , Animais , Anticorpos Monoclonais , Diferenciação Celular , História da Medicina , História do Século XIX , Humanos , Imunidade , Plasmócitos/citologia , Plasmócitos/ultraestruturaAssuntos
Corpos de Inclusão , Gamopatia Monoclonal de Significância Indeterminada/diagnóstico , Plasmócitos/patologia , Sedimentação Sanguínea , Células da Medula Óssea/patologia , Células da Medula Óssea/ultraestrutura , Creatinina/sangue , Feminino , Humanos , Corpos de Inclusão/imunologia , Corpos de Inclusão/patologia , Pessoa de Meia-Idade , Gamopatia Monoclonal de Significância Indeterminada/imunologia , Gamopatia Monoclonal de Significância Indeterminada/patologia , Mieloma Múltiplo/etiologia , Plasmócitos/ultraestrutura , Coloração e RotulagemRESUMO
The Harderian gland (HG) in birds is the dominant orbital gland, which plays an important role in immunological response. Tissue sections taken from adult females of Bilgorajska goose were stained with hematoxylin-eosin, Azan, PAS, AB pH 2.5, AF and HDI. Based on the histological structure the HG in Bilgorajska geese had compound tubular structure with multiple lobules and two types of epithelial cells lining the tubules. Epithelial cells in the central part of the lobes were dark in color and contained serous fluid, while in the deeper layers, epithelial cells were lightly coloured and contained mucous fluid. Histochemical studies showed the presence of neutral mucopolysaccharides and carboxylated acid mucopolysaccharides in the secretory cells. The small number of single plasma cells were present in HDI staining below the basement membrane of the secondary and primary ducts, near the crypts of the main duct. TEM study demonstrated that plasma cells had a large nucleus with condensed heterochromatin and were rich in rough endoplasmic reticulum. The knowledge of gland's structure, and above all an analysis of the immune system components may affect clinical practice and properly conducted immunization of birds.
Assuntos
Células Epiteliais , Glândulas Exócrinas , Gansos , Glucuronidase , Heterocromatina , Liases , Plasmócitos , Animais , Células Epiteliais/metabolismo , Células Epiteliais/ultraestrutura , Glândulas Exócrinas/metabolismo , Glândulas Exócrinas/ultraestrutura , Feminino , Gansos/anatomia & histologia , Gansos/metabolismo , Glucuronidase/metabolismo , Heterocromatina/metabolismo , Heterocromatina/ultraestrutura , Liases/metabolismo , Plasmócitos/metabolismo , Plasmócitos/ultraestruturaAssuntos
Líquido Cefalorraquidiano/citologia , Corpos de Inclusão/patologia , Mieloma Múltiplo/líquido cefalorraquidiano , Plasmócitos/patologia , Cor , Corantes , Citodiagnóstico/métodos , Evolução Fatal , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/patologia , Plasmócitos/ultraestruturaRESUMO
The cornerstone of humoral immunity is the differentiation of B cells into antibody-secreting plasma cells. This process is tightly controlled by a regulatory gene network centered on the transcriptional repressor B lymphocyte-induced maturation protein 1 (Blimp1). Proliferation of activated B cells is required to foster Blimp1 expression but needs to be terminated to avoid overshooting immune reactions. Activator protein 1 (AP-1) transcription factors become quickly up-regulated upon B cell activation. We demonstrate that Fra1, a Fos member of AP-1, enhances activation-induced cell death upon induction in activated B cells. Moreover, mice with B cell-specific deletion of Fra1 show enhanced plasma cell differentiation and exacerbated antibody responses. In contrast, transgenic overexpression of Fra1 blocks plasma cell differentiation and immunoglobulin production, which cannot be rescued by Bcl2. On the molecular level, Fra1 represses Blimp1 expression and interferes with binding of the activating AP-1 member c-Fos to the Blimp1 promoter. Conversely, overexpression of c-Fos in Fra1 transgenic B cells releases Blimp1 repression. As Fra1 lacks transcriptional transactivation domains, we propose that Fra1 inhibits Blimp1 expression and negatively controls plasma cell differentiation through binding to the Blimp1 promoter. In summary, we demonstrate that Fra1 negatively controls plasma cell differentiation by repressing Blimp1 expression.