RESUMO
Primary cutaneous marginal zone lymphoma (PCMZL) can be subdivided into 2 groups based on immunoglobulin (Ig) heavy chain usage: IgM-positive cases that constitute a less common and more T-helper type 1-driven process, and more common heavy chain class-switched cases that are predominantly T-helper type 2-driven. Although some report a significant IgG4-positive subset, others have found a much smaller proportion. To further evaluate the proportion of IgG4-positive PCMZL, to address whether IgG4-positive cases have any distinctive characteristics, and to assess whether additional features separating IgM-positive and class-switched cases could be identified, the clinicopathologic features of 26 PCMZL obtained from 19 patients were investigated. Twenty of 26 (77%) PCMZL were heavy chain class-switched (19 IgG-positive, 1 IgA-positive), including 9 that were IgG4-positive (35%). IgG4-positive and other class-switched PCMZL were morphologically similar. IgM-positive cases occurred in older individuals (median: 69 vs. 46.5 y; P=0.0001), more often involved the subcutis (P=0.002), demonstrated plasma cells diffusely scattered versus at the periphery of the lymphoid infiltrate (P=0.005), uniformly showed follicular colonization (P=0.0001), contained more numerous B cells (P=0.0004), and were more likely to have a T-cell CD4:CD8 ratio of <3:1 (P=0.03). None of the IgM-positive PCMZL harbored a MYD88 L265P mutation. No significant differences in clinical outcome were documented. These results highlight the high frequency of IgG4-positive PCMZL, which are otherwise similar to other class-switched cases, provide additional evidence supporting the distinction between class-switched and IgM-positive cases, and emphasize the indolent nature of at least the class-switched PCMZL, which may warrant their categorization as a clonal chronic lymphoproliferative disorder.
Assuntos
Biomarcadores Tumorais/genética , Switching de Imunoglobulina , Imunoglobulina G/genética , Imunoglobulina M/genética , Linfoma de Zona Marginal Tipo Células B/imunologia , Neoplasias Cutâneas/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/imunologia , Feminino , Predisposição Genética para Doença , Humanos , Linfoma de Zona Marginal Tipo Células B/genética , Linfoma de Zona Marginal Tipo Células B/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Fator 88 de Diferenciação Mieloide/genética , Fenótipo , Plasmócitos/imunologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Linfócitos T/imunologiaRESUMO
Antibody class switch recombination (CSR) to IgG, IgA, or IgE is a hallmark of adaptive immunity, allowing antibody function diversification beyond IgM. CSR involves a deletion of the IgM/IgD constant region genes placing a new acceptor Constant gene, downstream of the VDJH exon. CSR depends on non-coding (CSRnc) transcription of donor Iµ and acceptor IH exons, located 5' upstream of each CH coding gene. Although, our knowledge of the role of CSRnc transcription has advanced greatly, its extension and importance in healthy and diseased humans is scarce. We analyzed CSRnc transcription in 70,603 publicly available RNA-seq samples, including GTEx, TCGA, and the Sequence Read Archive using recount2, an online resource consisting of normalized RNA-seq gene and exon counts, as well as, coverage BigWig files that can be programmatically accessed through R. CSRnc transcription was validated with a qRT-PCR assay for Iµ, Iγ3, and Iγ1 in humans in response to vaccination. We mapped IH transcription for the human IGH locus, including the less understood IGHD gene. CSRnc transcription was restricted to B cells and is widely distributed in normal adult tissues, but predominant in blood, spleen, MALT-containing tissues, visceral adipose tissue and some so-called "immune privileged" tissues. However, significant Iγ4 expression was found even in non-lymphoid fetal tissues. CSRnc expression in cancer tissues mimicked the expression of their normal counterparts, with notable pattern changes in some common cancer subsets. CSRnc transcription in tumors appears to result from tumor infiltration by B cells, since CSRnc transcription was not detected in corresponding tumor-derived immortal cell lines. Additionally, significantly increased Iδ transcription in ileal mucosa in Crohn's disease with ulceration was found. In conclusion, CSRnc transcription occurs in multiple anatomical locations beyond classical secondary lymphoid organs, representing a potentially useful marker of effector B cell responses in normal and pathological immune responses. The pattern of IH exon expression may reveal clues of the local immune response (i.e., cytokine milieu) in health and disease. This is a great example of how the public recount2 data can be used to further our understanding of transcription, including regions outside the known transcriptome.
Assuntos
Linfócitos B/imunologia , Genes de Cadeia Pesada de Imunoglobulina/imunologia , Switching de Imunoglobulina/imunologia , Transcrição Gênica/imunologia , Éxons VDJ/imunologia , Adulto , Linfócitos B/patologia , Linhagem Celular Transformada , Bases de Dados de Ácidos Nucleicos , Feminino , Humanos , Masculino , Neoplasias/imunologiaRESUMO
Galectin-3 is a ß-galactoside-binding protein with an inhibitory role in B cell differentiation into plasma cells in distinct lymphoid tissues. We use a model of chronic schistosomiasis, a well-characterized experimental disease hallmarked by polyclonal B cell activation, in order to investigate the role of galectin-3 in controlling IgA production through peritoneal B1 cells. Chronically infected, galectin-3-deficient mice (Lgals3(-/-)) display peritoneal fluid hypercellularity, increased numbers of atypical peritoneal IgM(+)/IgA(+) B1a and B1b lymphocytes and histological disturbances in plasma cell niches when compared with Lgals3(+/+) mice. Similar to our infection model, peritoneal B1 cells from uninfected Lgals3(-/-) mice show enhanced switching to IgA after in vitro treatment with interleukin-5 plus transforming growth factor-ß (IL-5 + TGF-ß1). A higher number of IgA(+) B1a lymphocytes was found in the peritoneal cavity of Lgals3(-/-)-uninfected mice at 1 week after i.p. injection of IL-5 + TGF-ß1; this correlates with the increased levels of secreted IgA detected in the peritoneal fluid of these mice after cytokine treatment. Interestingly, a higher number of degranulated mast cells is present in the peritoneal cavity of uninfected and Schistosoma mansoni-infected Lgals3(-/-) mice, indicating that, at least in part, mast cells account for the enhanced differentiation of B1 into IgA-producing B cells found in the absence of galectin-3. Thus, a novel role is revealed for galectin-3 in controlling the expression of surface IgA by peritoneal B1 lymphocytes; this might have important implications for manipulating the mucosal immune response.
Assuntos
Linfócitos B/citologia , Linfócitos B/metabolismo , Diferenciação Celular , Galectina 3/deficiência , Imunoglobulina A/metabolismo , Peritônio/citologia , Regulação para Cima , Animais , Contagem de Células , Degranulação Celular , Proliferação de Células , Forma Celular , Doença Crônica , Galectina 3/metabolismo , Imunoglobulina A/sangue , Switching de Imunoglobulina , Imunoglobulina M/sangue , Interleucina-5 , Mastócitos/fisiologia , Mesentério/metabolismo , Camundongos Endogâmicos C57BL , Omento/metabolismo , Fenótipo , Plasmócitos/metabolismo , Esquistossomose/sangue , Esquistossomose/imunologia , Esquistossomose/parasitologia , Esquistossomose/patologia , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Circulating human IgM expressing memory B cells have been incompletely characterized. Here, we compared the phenotype and in vitro functional response (capacity to proliferate and differentiate to antibody secreting cells) in response to CpG and a cytokine cocktail (IL-2, IL-6, and IL-10) of sorted naïve B cells, IgM memory B cells and isotype-switched circulating memory B cells. Compared to naïve B cells, IgM memory B cells had lower integrated mean fluorescence intensity (iMFI) of BAFF-R, CD38, CD73, and IL-21R, but higher iMFI of CD95, CD11c, TLR9, PD-1, and CD122. Compared to switched memory B cells, IgM memory B cells had higher iMFI of BAFF-R, PD-1, IL-21R, TLR9, and CD122, but lower iMFI of CD38, CD95, and CD73. Four days after receiving the CpG/cytokine cocktail, higher frequencies of IgM than switched memory B cells-and these in turn greater than naïve cells-proliferated and differentiated to antibody secreting cells. At this time point, a small percentage (median of 7.6%) of stimulated IgM memory B cells changed isotype to IgG. Thus, among the heterogeneous population of human circulating IgM memory B cells a subset is capable of a rapid functional response to a CpG/cytokine stimulus in vitro.
Assuntos
Subpopulações de Linfócitos B/citologia , Linfócitos B/citologia , Diferenciação Celular/imunologia , Proliferação de Células/fisiologia , Imunoglobulina M/imunologia , Subpopulações de Linfócitos B/efeitos dos fármacos , Subpopulações de Linfócitos B/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Switching de Imunoglobulina , Memória Imunológica/efeitos dos fármacos , Memória Imunológica/imunologia , Interleucina-10/farmacologia , Interleucina-2/farmacologia , Interleucina-6/farmacologiaRESUMO
Cyberbullying is a new form of violence that is expressed through electronic media and has given rise to concern for parents, educators and researchers. In this paper, an association between cyberbullying and adolescent mental health will be assessed through a systematic review of two databases: PubMed and Virtual Health Library (BVS). The prevalence of cyberbullying ranged from 6.5% to 35.4%. Previous or current experiences of traditional bullying were associated with victims and perpetrators of cyberbullying. Daily use of three or more hours of Internet, web camera, text messages, posting personal information and harassing others online were associated with cyberbullying. Cybervictims and cyberbullies had more emotional and psychosomatic problems, social difficulties and did not feel safe and cared for in school. Cyberbullying was associated with moderate to severe depressive symptoms, substance use, ideation and suicide attempts. Health professionals should be aware of the violent nature of interactions occurring in the virtual environment and its harm to the mental health of adolescents.
Cyberbullying, uma nova forma de violência expressa por meio da mídia eletrônica, tem preocupado pais, educadores e pesquisadores. A associação entre cyberbullying e a saúde mental dos adolescentes será revisada. Revisão sistemática em duas bases de dados: PubMed e a Biblioteca Virtual em Saúde (BVS). A prevalência do cyberbullying variou entre 6,5% a 35,4%. Bullying tradicional prévio ou atual estava associado às vítimas e agressores do cyberbullying. Uso diário de três ou mais horas de Internet, web câmera, mensagens de texto, postar informações pessoais e assediar outros online estavam associados ao cyberbullying. "Cybervítimas" e cyberbullies tinham mais problemas emocionais, psicossomáticos, dificuldades sociais, e não se sentiam seguros e cuidados na escola. O cyberbullying estava associado à sintomatologia depressiva moderada e grave, uso de substâncias, ideação e tentativas de suicídio. Profissionais de saúde devem conhecer as interações de natureza violenta que ocorrem no ambiente virtual e de seus agravos para a saúde mental dos adolescentes.
Se revisa la asociación entre el acoso cibernético y la salud mental de los adolescentes. Se realiza una revisión sistemática de dos bases de datos: PubMed y la Biblioteca Virtual en Salud (BVS). La prevalencia de ciberacoso varió de un 6,5% a un 35,4%. Los acosos cibernéticos tradicionales -pasados o actuales- se asociaron con las víctimas y los acosadores cibernéticos. El uso diario de tres o más horas de Internet, cámara web, mensajes de texto, la publicación de información personal y acosar a los demás se asociaron con el acoso cibernético. Cibervíctimas y acosadores cibernéticos tenían más problemas emocionales, psicosomáticos, dificultades sociales y no se sentían seguros y cuidados en la escuela. El ciberacoso se asoció con síntomas de moderados a graves de depresión, abuso de sustancias, ideación suicida e intentos de suicidio. Los profesionales de salud deben conocer la naturaleza violenta de las interacciones que se producen en el entorno virtual y sus peligros para la salud mental de los adolescentes.
Assuntos
Animais , Camundongos , Formação de Anticorpos/imunologia , Poli(ADP-Ribose) Polimerases/deficiência , Linfócitos B/imunologia , Proliferação de Células , Células Cultivadas , Centro Germinativo/imunologia , Imunização , Switching de Imunoglobulina/imunologia , Imunoglobulinas/sangue , Lipopolissacarídeos/imunologia , Ativação Linfocitária/imunologia , Cooperação Linfocítica/imunologia , Camundongos Mutantes , Poli(ADP-Ribose) Polimerases/metabolismo , Linfócitos T/imunologiaRESUMO
BACKGROUND: The impact of exposure to multiple pathogens concurrently or consecutively on immune function is unclear. Here, immune responses induced by combinations of the bacterium Salmonella Typhimurium (STm) and the helminth Nippostrongylus brasiliensis (Nb), which causes a murine hookworm infection and an experimental porin protein vaccine against STm, were examined. METHODOLOGY/PRINCIPAL FINDINGS: Mice infected with both STm and Nb induced similar numbers of Th1 and Th2 lymphocytes compared with singly infected mice, as determined by flow cytometry, although lower levels of secreted Th2, but not Th1 cytokines were detected by ELISA after re-stimulation of splenocytes. Furthermore, the density of FoxP3+ T cells in the T zone of co-infected mice was lower compared to mice that only received Nb, but was greater than those that received STm. This reflected the intermediate levels of IL-10 detected from splenocytes. Co-infection compromised clearance of both pathogens, with worms still detectable in mice weeks after they were cleared in the control group. Despite altered control of bacterial and helminth colonization in co-infected mice, robust extrafollicular Th1 and Th2-reflecting immunoglobulin-switching profiles were detected, with IgG2a, IgG1 and IgE plasma cells all detected in parallel. Whilst extrafollicular antibody responses were maintained in the first weeks after co-infection, the GC response was less than that in mice infected with Nb only. Nb infection resulted in some abrogation of the longer-term development of anti-STm IgG responses. This suggested that prior Nb infection may modulate the induction of protective antibody responses to vaccination. To assess this we immunized mice with porins, which confer protection in an antibody-dependent manner, before challenging with STm. Mice that had resolved a Nb infection prior to immunization induced less anti-porin IgG and had compromised protection against infection. CONCLUSION: These findings demonstrate that co-infection can radically alter the development of protective immunity during natural infection and in response to immunization.
Assuntos
Nippostrongylus/imunologia , Vacinas contra Salmonella/imunologia , Salmonella typhimurium/imunologia , Infecções por Strongylida/imunologia , Animais , Anticorpos Antibacterianos/sangue , Anticorpos Anti-Helmínticos/sangue , Coinfecção/imunologia , Citocinas/biossíntese , Imunização , Switching de Imunoglobulina , Imunoglobulina G/sangue , Camundongos , Camundongos Endogâmicos BALB C , Linfócitos T/imunologiaRESUMO
Mutations in the transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) were previously found to be associated with hypogammaglobulinemia in humans. It has been shown that proliferation inducing ligand (APRIL) elicits class switch recombination (CSR) by inducing recruitment of MyD88 to a TACI highly conserved cytoplasmic domain (THC). We have identified a patient with hypogammaglobulinemia carrying a missense mutation (S231R) predicted to affect the THC. Aiming to evaluate the relevance of this novel mutation of TACI in CSR induction, we tested the ability of TACI, TLR9, or/and CD40 ligands to trigger CSR in naive B cells and B-cell lines carrying S231R. IgG secretion was impaired when triggered by TACI or/and TLR9 ligands on S231R-naive B cells. Likewise, these stimuli induced less expression of activation-induced cytidine deaminase, I(γ)1-C(µ), and I(γ)1-C(µ), while induction by optimal CD40 stimulation was indistinguishable from controls. These cells also showed an impaired cooperation between TACI and TLR9 pathways, as well as a lack of APRIL-mediated enhancement of CD40 activation in suboptimal conditions. Finally, after APRIL ligation, S231R-mutated TACI failed to colocalize with MyD88. Collectively, these results highlight the requirement of an intact MyD88-binding site in TACI to trigger CSR.
Assuntos
Switching de Imunoglobulina/genética , Mutação , Fator 88 de Diferenciação Mieloide/metabolismo , Proteína Transmembrana Ativadora e Interagente do CAML/genética , Recombinação V(D)J , Adolescente , Linfócitos B/imunologia , Linfócitos B/metabolismo , Sítios de Ligação , Antígenos CD40/metabolismo , Células Cultivadas , Imunodeficiência de Variável Comum/genética , Imunodeficiência de Variável Comum/imunologia , Humanos , Ligação Proteica , Transdução de Sinais , Proteína Transmembrana Ativadora e Interagente do CAML/química , Proteína Transmembrana Ativadora e Interagente do CAML/metabolismoRESUMO
There are >2 million new cases of leishmaniasis annually, and no effective vaccine has been developed to prevent infection. In murine infection, Leishmania mexicana, which lives intracellularly in host macrophages, has developed pathways to hijack host IgG to induce a suppressive IL-10 response through FcγRs, the cell-surface receptors for IgG. To guide vaccine development away from detrimental Ab responses, which can accompany attempts to induce cell-mediated immunity, it is crucial to know which isotypes of IgG are pathogenic in this infection. We found that IgG1 and IgG2a/c induce IL-10 from macrophages in vitro equally well but through different FcγR subtypes: IgG1 through FcγRIII and IgG2a/c through FcγRI primarily, but also through FcγRIII. In sharp contrast, mice lacking IgG1 develop earlier and stronger IgG2a/c, IgG3, and IgM responses to L. mexicana infection and yet are more resistant to the infection. Thus, IgG1, but not IgG2a/c or IgG3, is pathogenic in vivo, in agreement with prior studies indicating that FcγRIII is required for chronic disease. This calls into question the assumption that macrophages, which should secrete IL-10 in response to IgG1 and IgG2a/c immune complexes, are the most important source of IL-10 generated by IgG-FcγR engagement in L. mexicana infection. Further investigations are required to better determine the cell type responsible for this immunosuppressive FcγRIII-induced IL-10 pathway and whether IgG2a/c is protective.
Assuntos
Anticorpos Antiprotozoários/efeitos adversos , Imunoglobulina G/efeitos adversos , Leishmania mexicana/imunologia , Leishmaniose Cutânea/imunologia , Leishmaniose Cutânea/parasitologia , Animais , Anticorpos Antiprotozoários/sangue , Anticorpos Antiprotozoários/fisiologia , Células da Medula Óssea/imunologia , Células da Medula Óssea/parasitologia , Células da Medula Óssea/patologia , Células Cultivadas , Doença Crônica , Feminino , Switching de Imunoglobulina , Imunoglobulina G/sangue , Imunoglobulina G/fisiologia , Imunoglobulina M/efeitos adversos , Imunoglobulina M/biossíntese , Imunoglobulina M/sangue , Imunofenotipagem , Leishmaniose Cutânea/patologia , Macrófagos/imunologia , Macrófagos/parasitologia , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos TransgênicosRESUMO
Interaction of chronic lymphocytic leukemia (CLL) B cells with tissue microenvironment has been suggested to favor disease progression by promoting malignant B-cell growth. Previous work has shown expression in peripheral blood (PB) of CLL B cells of activation-induced cytidine deaminase (AID) among CLL patients with an unmutated (UM) profile of immunoglobulin genes and with ongoing class switch recombination (CSR) process. Because AID expression results from interaction with activated tissue microenvironment, we speculated whether the small subset with ongoing CSR is responsible for high levels of AID expression and could be derived from this particular microenvironment. In this work, we quantified AID expression and ongoing CSR in PB of 50 CLL patients and characterized the expression of different molecules related to microenvironment interaction. Our results show that among UM patients (1) high AID expression is restricted to the subpopulation of tumoral cells ongoing CSR; (2) this small subset expresses high levels of proliferation, antiapoptotic and progression markers (Ki-67, c-myc, Bcl-2, CD49d, and CCL3/4 chemokines). Overall, this work outlines the importance of a cellular subset in PB of UM CLL patients with a poor clinical outcome, high AID levels, and ongoing CSR, whose presence might be a hallmark of a recent contact with the microenvironment.
Assuntos
Citidina Desaminase/sangue , Citidina Desaminase/genética , Switching de Imunoglobulina , Leucemia Linfocítica Crônica de Células B/enzimologia , Leucemia Linfocítica Crônica de Células B/genética , Subpopulações de Linfócitos B/enzimologia , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/patologia , Sequência de Bases , Biomarcadores Tumorais/genética , Proliferação de Células , Primers do DNA/genética , Expressão Gênica , Humanos , Leucemia Linfocítica Crônica de Células B/imunologia , Mutação , Prognóstico , RNA Mensageiro/sangue , RNA Mensageiro/genética , RNA Neoplásico/sangue , RNA Neoplásico/genéticaRESUMO
The relationship among the phenotypes resistance to infection, virus replication in the brain and isotype production was investigated in genetically modified High (H) or Low (L) antibody responder mouse lines. Although they express the same innate susceptibility to rabies infection, these lines differ as to different viral replication rates in the central nervous system and L mice showed a higher permissible state. After intramuscular infection with the Pasteur rabies strain (PV), the H-L interline differences on the earlier stage of virus replication were 1000 and 80 folds on days 5 and 6, respectively. The isotype profile in sera of the experimentally infected mice reflected an interline difference of 25 folds for IgG2a throughout the infection period, and for the IgE production the H-L difference was highly significant only at the beginning of the process. These results confirm the multi-specific effect of antibody immune responsiveness and the general isotype distribution of antibodies in these genetically selected mice. Contrary to the clear correlation between antibody responsiveness and the acquired resistance to rabies infection, the present study demonstrates that the constitutive genetic character of High and Low responder individuals does not intervene in the degree of resistance following infection. Altogether, this study contributes to the knowledge of the protective role of the general innate responsiveness on the pathological pattern to rabies virus infection