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1.
Z Gastroenterol ; 57(11): 1298-1303, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31739375

RESUMO

BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) can involve different organs and is diagnosed by a combination of clinicopathological features, including storiform fibrosclerosis infiltrated by numerous IgG4-positive plasma cells that frequently forms tumor-like lesions with or without associated obliterative phlebitis. Involvement of the stomach is rare and can occur as part of a multiorgan involvement of IgG4-RD or as isolated gastric involvement. CASE REPORT: We report 2 female patients with therapy-refractory gastric ulcers associated with gastric wall thickening and lymphadenopathy that were highly suggestive of gastric cancer or lymphoma. Biopsies failed to confirm a diagnosis, and IgG4-RD was diagnosed only after surgical resection in both patients. The previous literature on gastric IgG4-RD is summarized and shows different characteristics in patients with multiorgan IgG4-RD and isolated gastric IgG4-RD. As reported for autoimmune pancreatitis type 1, patients with multiorgan IgG4-RD are mainly elderly men with frequently elevated serum IgG4 concentrations. In contrast, isolated gastric IgG4-RD predominantly affects female patients with normal serum IgG4 levels. Surgical resection is commonly performed due to the clinical suspicion of malignancy and the absence of findings indicative of IgG4-RD on biopsy. Today, diagnosis is confirmed histopathologically only after resection. CONCLUSION: IgG4-RD should be taken into account when gastric malignancy is suspected endoscopically or radiologically and biopsies fail to confirm the presence of a malignancy (especially subepithelial tumors or refractory gastric ulcers). Serum IgG4 concentrations are insufficient to confirm localized gastric IgG4-RD. Diagnostic workups need to be improved to avoid unnecessary surgical resections with the attendant potential morbidity and mortality.


Assuntos
Doença Relacionada a Imunoglobulina G4/diagnóstico , Imunoglobulina G/sangue , Plasmócitos/imunologia , Idoso , Biomarcadores/análise , Diagnóstico Diferencial , Feminino , Humanos , Doença Relacionada a Imunoglobulina G4/imunologia , Doença Relacionada a Imunoglobulina G4/cirurgia , Linfadenopatia/etiologia , Neoplasias Gástricas/diagnóstico
2.
Immunology ; 158(3): 194-205, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31433857

RESUMO

The gut has the largest commensal bacterial population in the body and its composition can be impacted by host factors such as production of immunoglobulin A (IgA). Eosinophils in the gut have been implicated in the production of antibacterial factors and maintenance of IgA-secreting plasma cells. We used an eosinophil-deficient mouse (∆dblGATA-1-/- ) and littermate controls to investigate the role of eosinophils in the regulation of the microbiota, with particular emphasis on mucus-resident species in the small and large intestine. We found no differences in IgA production or IgA-expressing plasma cells between naive littermates in the small or large intestine. However, denaturing gel gradient electrophoresis revealed differences in the bacterial communities of the mucus and stools between wild-type mice and ∆dblGATA-1-/- mice, with the greatest separation between the mucus microbial communities. Mucus-resident bacteria in ∆dblGATA-1-/- mice had reduced diversity in the mucus compared with the stools. A quantitative PCR panel of selected bacteria showed that the most significant differences in the microbiota were between mucus-resident bacteria and those in stool, such as the abundance of Clostridiales and Bacteroides. Our data implicate eosinophils in the regulation of the microbiota, especially the bacteria most hyperlocal to the gut barrier. Although we see differences between host genotypes in the overall microbial communities, further work is required to establish specifically which bacteria are different between these groups. Most importantly, the data revealed that the mucus and stool microbiota are discrete communities. Stool analysis alone may be insufficient to comprehensively explore and define the role of the gut microbiota in health and disease.


Assuntos
Eosinófilos/imunologia , Microbioma Gastrointestinal/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Animais , Humanos , Imunoglobulina A/imunologia , Mucosa Intestinal/patologia , Camundongos , Camundongos Knockout , Plasmócitos/imunologia
3.
Immunity ; 51(2): 337-350.e7, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31375460

RESUMO

Class-switch recombination (CSR) is a DNA recombination process that replaces the immunoglobulin (Ig) constant region for the isotype that can best protect against the pathogen. Dysregulation of CSR can cause self-reactive BCRs and B cell lymphomas; understanding the timing and location of CSR is therefore important. Although CSR commences upon T cell priming, it is generally considered a hallmark of germinal centers (GCs). Here, we have used multiple approaches to show that CSR is triggered prior to differentiation into GC B cells or plasmablasts and is greatly diminished in GCs. Despite finding a small percentage of GC B cells expressing germline transcripts, phylogenetic trees of GC BCRs from secondary lymphoid organs revealed that the vast majority of CSR events occurred prior to the onset of somatic hypermutation. As such, we have demonstrated the existence of IgM-dominated GCs, which are unlikely to occur under the assumption of ongoing switching.


Assuntos
Linfócitos B/imunologia , Centro Germinativo/imunologia , Switching de Imunoglobulina , Plasmócitos/imunologia , Linfoma Plasmablástico/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Diferenciação Celular , Células Cultivadas , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Filogenia , Receptores de Antígenos de Linfócitos B/metabolismo
4.
Mol Immunol ; 114: 162-170, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31352232

RESUMO

Clinically, most patients with primary nephrotic syndrome (PNS) have low serum IgG levels, which is an important factor in infection and in PNS relapse.To some extent, the mechanisms involved remain largely unknown. Here, we aimed to investigate the pathogenesis of the decreased IgG levels in PNS. Peripheral blood was collected from patients with PNS and closely age- and sex-matched healthy individuals. The frequency, phenotype and molecular function of different circulating B cell and T follicular helper cell (TFH) subsets were examined by flow cytometry. The function of the CD40/CD40 L interaction in immunoglobulin class-switch recombination (CSR) was evaluated by assessing the induction of activation-induced deaminase (AID) expression with CD40 L stimulation. We revealed an increase in the levels of circulating total plasmablasts, plasma cells and mature-naive B cells and a decrease in the levels of germinal centre-like B cells and CD19+IgG+ B cells in PNS. In addition, although the expression of CD86 on the surface of B cells and the expression of the inducible costimulator (ICOS) on the surface of TFH cells both were increased, the expression of CD40 L on the surface of TFH cells was decreased. Moreover, upon stimulation with CD40 L in vitro, the mRNA expression of AID in peripheral blood mononuclear cells (PBMCs) was decreased in patients with PNS compared with that in healthy controls. Our results indicate that the immunoglobulin CSR of B cells was partly dysfunctional and provide insights into the potential involvement of impaired TFH cell-dependent B cell responses in the pathogenesis of low IgG levels through downregulating CD40 L expression on TFH cells in PNS.


Assuntos
Linfócitos B/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Síndrome Nefrótica/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Adolescente , Autoanticorpos/imunologia , Ligante de CD40/imunologia , Criança , Pré-Escolar , Feminino , Centro Germinativo/imunologia , Humanos , Proteína Coestimuladora de Linfócitos T Induzíveis/imunologia , Lactente , Interleucinas/imunologia , Leucócitos Mononucleares/imunologia , Masculino , Síndrome Nefrótica/sangue , Plasmócitos/imunologia
5.
Medicine (Baltimore) ; 98(29): e16390, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31335688

RESUMO

INTRODUCTION: Sjögren's syndrome (SS) often causes lymphoproliferative disorders such as malignant lymphoma and macroglobrinemia. Approximately 5% of long-term follow-up SS patients develop malignant lymphoma. Recently, the tumor necrosis factor receptor superfamily cluster of differentiation 30 (CD30) has been thought to be implicated in malignant cells in organs affected by Hodgikin lymphoma or in a prognostic marker of diffuse large B cell lymphoma. In this study, we investigated CD30 expression in lacrimal gland and conjunctiva in patients with SS. METHODS: We examined lacrimal gland and conjunctival tissues for the diagnosis from 3 female SS patients with a median age of 51 and 3 female chronic graft-versus-host disease (cGVHD) patients with a median age of 41. Histological analysis of these tissues of the remaining samples was conducted by methods including immunohistochemistry and electron microscopy (#20090277). We analyzed the expression and localization of cluster of differentiation 4 (CD4), cluster of differentiation 8 (CD8), cluster of differentiation 20 (CD20), CD30, and Interferon-γ in tissue sections prepared from lacrimal glands and conjunctiva in 3 each of SS and cGVHD patients. RESULTS: There were more B cells and plasma cells in lobules of SS-affected lacrimal glands than in those of their cGVHD-affected counterparts. Interferon-γ was expressed on endothelia of capillaries in SS-affected lacrimal gland and conjunctival tissues whereas it was expressed on fibroblasts in their GVHD-affected equivalents. Furthermore, lacrimal glands and conjunctiva disordered by SS had a greater number of CD30 cells than those disordered by cGVHD. CONCLUSION: Our results suggest that CD30 cells are increased in lacrimal glands and conjunctiva affected by SS and that a subset of SS patients are thereby at risk of development malignant lymphoma.


Assuntos
Túnica Conjuntiva , Doença Enxerto-Hospedeiro , Antígeno Ki-1 , Aparelho Lacrimal , Linfoma/diagnóstico , Síndrome de Sjogren , Adulto , Linfócitos B/imunologia , Túnica Conjuntiva/imunologia , Túnica Conjuntiva/patologia , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/patologia , Humanos , Imuno-Histoquímica , Interferon gama/sangue , Antígeno Ki-1/análise , Antígeno Ki-1/imunologia , Aparelho Lacrimal/imunologia , Aparelho Lacrimal/patologia , Microscopia Eletrônica/métodos , Pessoa de Meia-Idade , Fragmentos de Peptídeos/sangue , Plasmócitos/imunologia , Prognóstico , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/patologia
6.
World Neurosurg ; 131: 87-89, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31356970

RESUMO

BACKGROUND: Intraorbital and intracerebral cavernous malformation (CM) lesions are considered independent entities. Purely cerebral CMs have variable biology with recent evidence depicting inflammation as an important player and a risk factor for aggressiveness. We describe a case of concomitant left intraaxial and extraaxial CMs, linked by the ipsilateral basal vein, where the extraaxial component has developed an aggressive behavior. CASE DESCRIPTION: A 35-year-old female patient presented with a rapid and progressive exophthalmos and loss of vision on the left eye. Cranial magnetic resonance and angiography examinations demonstrated a left craniofacial CM and large intraorbital component. The lesion was connected through a large basal vein to a cerebral intraventricular CM. Transconjunctival resection showed typical findings of CM. A complete histopathology and immunostaining analysis was performed and revealed a clear acute lymphomononuclear reaction with a predominant immune cellular inflammation. CONCLUSIONS: A case of intraorbital and extracranial cavernomatous mass, connected to a cerebral intraventricular CM through a large basal vein, has presented with an aggressive course. A complete histopathologic and immunohistochemical analysis of the orbital mass has pictured a clear immune-cellular inflammatory reaction adding to the amounting evidence of association between inflammation and site aggressiveness in the setting of CMs.


Assuntos
Veias Cerebrais/diagnóstico por imagem , Neoplasias do Ventrículo Cerebral/diagnóstico por imagem , Hemangioma Cavernoso do Sistema Nervoso Central/diagnóstico por imagem , Neoplasias Primárias Múltiplas/diagnóstico por imagem , Neoplasias Orbitárias/diagnóstico por imagem , Adulto , Linfócitos B/imunologia , Linfócitos B/patologia , Angiografia Cerebral , Feminino , Hemangioma Cavernoso do Sistema Nervoso Central/imunologia , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Hemangioma Cavernoso do Sistema Nervoso Central/cirurgia , Humanos , Inflamação/imunologia , Inflamação/patologia , Macrófagos/imunologia , Macrófagos/patologia , Imagem por Ressonância Magnética , Neoplasias Primárias Múltiplas/imunologia , Neoplasias Primárias Múltiplas/patologia , Neoplasias Primárias Múltiplas/cirurgia , Neoplasias Orbitárias/imunologia , Neoplasias Orbitárias/patologia , Neoplasias Orbitárias/cirurgia , Plasmócitos/imunologia , Plasmócitos/patologia
7.
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
8.
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
9.
Ophthalmic Plast Reconstr Surg ; 35(4): e92-e94, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31219941

RESUMO

Langerhans cell histiocytosis (LCH) is a clonal neoplastic proliferation of Langerhans-type cells. Orbital LCH is infrequent, typically manifesting as an isolated lytic bony lesion with an adjacent soft tissue mass in a child. Isolated lacrimal gland involvement by LCH is extremely rare, with only 2 previously reported cases. The authors describe a 37-year-old woman with a 6-month history of painless right upper eyelid swelling and diffuse right lacrimal gland enlargement without bony changes on computed tomography scan. Excisional biopsy of the lacrimal gland demonstrated concurrent LCH, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, and increased IgG4-expressing plasma cells. Work-up was negative for systemic hematolymphoid malignancy and IgG4-related disease. This case illustrates the association between LCH, mucosa-associated lymphoid tissue lymphoma, and elevated IgG4 plasma cells in the lacrimal gland, and we review the emerging theories proposed to explain this phenomenon.


Assuntos
Histiocitose de Células de Langerhans/complicações , Imunoglobulina G/imunologia , Doenças do Aparelho Lacrimal/complicações , Aparelho Lacrimal/diagnóstico por imagem , Linfoma de Zona Marginal Tipo Células B/complicações , Plasmócitos/imunologia , Adulto , Biópsia , Feminino , Histiocitose de Células de Langerhans/diagnóstico , Histiocitose de Células de Langerhans/imunologia , Humanos , Imunoglobulina G/metabolismo , Doenças do Aparelho Lacrimal/diagnóstico , Doenças do Aparelho Lacrimal/imunologia , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Linfoma de Zona Marginal Tipo Células B/imunologia , Plasmócitos/patologia , Tomografia Computadorizada por Raios X
10.
Biomed Res Int ; 2019: 6387924, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31223621

RESUMO

Follicular helper T cells (Tfh cells) are closely related to the occurrence and development of antibody-mediated rejection (AMR) after renal transplantation. Exosomes play a key role in the rejection after organ transplantation. However, whether Tfh-derived exosomes are involved in AMR has not been reported. We collected peripheral blood from 42 kidney transplant patients and found no significant differences in CD4+CXCR5+ and CD4+CXCR5+CXCR3+CCR6-exosomes between AMR and non-AMR groups, whereas the proportion of CD4+CXCR5+CXCR3-exosomes was significantly higher in AMR group than that in non-AMR group; CTLA-4 expression of CD4+CXCR5+exosomes was significantly lower in AMR group than that in non-AMR group. HLA-G expression was not significantly different between two groups. We further separated CD4+CXCR5+cells from patients by magnetic beads. Coculture experiments showed that Tfh cell-derived exosomes in AMR patients significantly promoted B cell proliferation and differentiation, compared with non-AMR group, the percentage of B cells and plasma cells increased by 87.52% and 110.2%, respectively. In conclusion, our study found that Tfh cell-derived exosomes could promote the proliferation and differentiation of B cells and they may play an important role in the development of AMR after renal transplantation.


Assuntos
Exossomos/imunologia , Rejeição de Enxerto/imunologia , Isoanticorpos/imunologia , Transplante de Rim , Plasmócitos/imunologia , Adulto , Proliferação de Células , Exossomos/patologia , Feminino , Regulação da Expressão Gênica/imunologia , Rejeição de Enxerto/patologia , Antígenos HLA-G/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Plasmócitos/patologia , Linfócitos T Auxiliares-Indutores/patologia
11.
J Cutan Pathol ; 46(9): 698-708, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31095757

RESUMO

We review the spectrum of cutaneous disorders associated with inflammatory and neoplastic plasmacytic pathology. Because plasma cells are derived from B-lymphocytes our overview includes discussion of certain lymphoplasmacytic proliferations. It is structured along histopathological lines, addressing conditions characterized by (a) cutaneous plasma cell infiltrates, (b) deposits of plasma cell products or their derivatives in the skin and (c) miscellaneous, poorly understood cutaneous complications of plasmacytic disorders. Lesions arising primarily in the skin and those due to cutaneous involvement by multisystem disorders are addressed. The range includes a spectrum of tumefactive and circulatory manifestations. We highlight key clinical and pathological features of the different conditions and outline recent advances in our understanding of these entities. By emphasizing the dermatopathological characteristics of this spectrum of disorders we hope to hone the diagnostic accuracy of practitioners in the field.


Assuntos
Plasmócitos , Dermatopatias , Pele , Humanos , Plasmócitos/imunologia , Plasmócitos/patologia , Pele/imunologia , Pele/patologia , Dermatopatias/diagnóstico , Dermatopatias/imunologia , Dermatopatias/patologia
12.
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
13.
Int Heart J ; 60(3): 688-694, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31105154

RESUMO

The prevalence and extent of immunoglobulin G4 (IgG4)-positive cell infiltration were investigated in 282 surgical samples of aortic wall and aortic valve. Tissue infiltration of IgG4-positive cells was observed in 24 (17.3%) of 139 aortic valve samples and 46 (32%) of 143 aortic wall samples, and the condition of IgG4-positive cell infiltration > 30/hpf together with IgG4/CD138 ratio > 40% was observed in 2 (1.4%) of aortic valve samples and 14 (9.8%) of aortic wall samples. Among 275 patients, preoperative serum IgG4 level was available in 48 patients (50 samples), and it was > 135 mg/dL in only one patient. Of these 48 patients with serum IgG4 measurement, 29 patients had aortic valve stenosis and 12 had aortic aneurysm. Compared with 23 aortic stenosis patients without tissue infiltration of IgG4-positive cells in the aortic valve, six patients with IgG4-positive cell infiltration had a more prevalent smoking history (26% versus 83%) and borderline significantly higher serum IgG4 (median, 24.5 mg/dL versus 55.5 mg/dL), although either preoperative peak pressure gradient between left ventriculum and aorta or aortic valve area did not differ significantly between groups. Compared with six aortic aneurysm patients without tissue infiltration of IgG4-positive cells in the aortic wall, six patients with IgG4-positive cell infiltration had borderline significantly higher serum IgG4 (median, 28.9 mg/dL versus 68.2 mg/dL). The current study showed that tissue IgG4-positive infiltration is not a rare occurrence in the aortic stenosis and aortic aneurysm. Clinical significance of tissue IgG4-postive cell infiltration in these patients requires further investigation.


Assuntos
Aneurisma Aórtico/imunologia , Estenose da Valva Aórtica/imunologia , Doença Relacionada a Imunoglobulina G4/sangue , Imunoglobulina G/sangue , Plasmócitos/patologia , Idoso , Idoso de 80 Anos ou mais , Aorta/anatomia & histologia , Aorta/citologia , Aorta/diagnóstico por imagem , Aorta/cirurgia , Aneurisma Aórtico/sangue , Aneurisma Aórtico/patologia , Valva Aórtica/citologia , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/cirurgia , Estenose da Valva Aórtica/sangue , Estenose da Valva Aórtica/patologia , Ecocardiografia/métodos , Feminino , Humanos , Doença Relacionada a Imunoglobulina G4/imunologia , Doença Relacionada a Imunoglobulina G4/patologia , Masculino , Pessoa de Meia-Idade , Plasmócitos/imunologia , Período Pré-Operatório , Estudos Retrospectivos
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
16.
Nat Commun ; 10(1): 1911, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015454

RESUMO

Multiple myeloma is a malignancy of antibody-secreting plasma cells. Most patients benefit from current therapies, however, 20% of patients relapse or die within two years and are deemed high risk. Here we analyze structural variants from 795 newly-diagnosed patients as part of the CoMMpass study. We report translocations involving the immunoglobulin lambda (IgL) locus are present in 10% of patients, and indicative of poor prognosis. This is particularly true for IgL-MYC translocations, which coincide with focal amplifications of enhancers at both loci. Importantly, 78% of IgL-MYC translocations co-occur with hyperdiploid disease, a marker of standard risk, suggesting that IgL-MYC-translocated myeloma is being misclassified. Patients with IgL-translocations fail to benefit from IMiDs, which target IKZF1, a transcription factor that binds the IgL enhancer at some of the highest levels in the myeloma epigenome. These data implicate IgL translocation as a driver of poor prognosis which may be due to IMiD resistance.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Cadeias lambda de Imunoglobulina/genética , Mieloma Múltiplo/diagnóstico , Proteínas do Mieloma/genética , Translocação Genética , Antineoplásicos/uso terapêutico , Variações do Número de Cópias de DNA , Resistencia a Medicamentos Antineoplásicos/imunologia , Elementos Facilitadores Genéticos , Loci Gênicos , Genoma Humano , Humanos , Fator de Transcrição Ikaros/genética , Fator de Transcrição Ikaros/imunologia , Fatores Imunológicos/uso terapêutico , Lenalidomida/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Mieloma Múltiplo/mortalidade , Plasmócitos/imunologia , Plasmócitos/patologia , Prognóstico , Ligação Proteica , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/imunologia , Recidiva , Análise de Sobrevida , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Sequenciamento Completo do Genoma
17.
J Immunol ; 202(9): 2529-2534, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30936294

RESUMO

Systemic lupus erythematosus severity correlates with elevated serum levels of type I IFNs, cytokines produced in large quantities by plasmacytoid dendritic cells (pDC) in response to engagement of TLR7 and TLR9 with endocytosed nucleic acids. B cell adaptor for PI3K (BCAP) promoted many aspects of TLR7-driven lupus-like disease, including Isg15 and Ifit1 expression in blood and an immature pDC phenotype associated with higher IFN production. BCAP-/- mice produced significantly less serum IFN-α than wild-type mice after injection of TLR9 agonist, and BCAP promoted TLR7 and TLR9-induced IFN-α production specifically in pDC. TLR-induced IFN-α production in pDC requires DOCK2-mediated activation of Rac1 leading to activation of IKKα, a mechanism we show was dependent on BCAP. BCAP-/- pDC had decreased actin polymerization and Rac1 activation and reduced IKKα phosphorylation upon TLR9 stimulation. We show a novel role for BCAP in promoting TLR-induced IFN-α production in pDC and in systemic lupus erythematosus pathogenesis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/imunologia , Células Dendríticas/imunologia , Interferon-alfa/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Glicoproteínas de Membrana/imunologia , Plasmócitos/imunologia , Receptor 7 Toll-Like/imunologia , Receptor Toll-Like 9/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Citocinas/genética , Citocinas/imunologia , Células Dendríticas/patologia , Feminino , Proteínas Ativadoras de GTPase/genética , Proteínas Ativadoras de GTPase/imunologia , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/imunologia , Interferon-alfa/genética , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/patologia , Masculino , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Knockout , Neuropeptídeos/genética , Neuropeptídeos/imunologia , Plasmócitos/patologia , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/imunologia , Receptor 7 Toll-Like/genética , Receptor Toll-Like 9/genética , Ubiquitinas/genética , Ubiquitinas/imunologia , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/imunologia
18.
Science ; 363(6430): 993-998, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30819965

RESUMO

Immunoglobulin A (IgA) is the major secretory immunoglobulin isotype found at mucosal surfaces, where it regulates microbial commensalism and excludes luminal factors from contacting intestinal epithelial cells (IECs). IgA is induced by both T cell-dependent and -independent (TI) pathways. However, little is known about TI regulation. We report that IEC endoplasmic reticulum (ER) stress induces a polyreactive IgA response, which is protective against enteric inflammation. IEC ER stress causes TI and microbiota-independent expansion and activation of peritoneal B1b cells, which culminates in increased lamina propria and luminal IgA. Increased numbers of IgA-producing plasma cells were observed in healthy humans with defective autophagy, who are known to exhibit IEC ER stress. Upon ER stress, IECs communicate signals to the peritoneum that induce a barrier-protective TI IgA response.


Assuntos
Estresse do Retículo Endoplasmático , Células Epiteliais/imunologia , Imunidade nas Mucosas , Imunoglobulina A/imunologia , Mucosa Intestinal/imunologia , Animais , Autofagia , Proteínas Relacionadas à Autofagia/genética , Humanos , Inflamação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasmócitos/imunologia , Técnicas de Cultura de Tecidos , Proteína 1 de Ligação a X-Box/genética
19.
Proc Natl Acad Sci U S A ; 116(15): 7425-7430, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30910977

RESUMO

Serum IgG, which is mainly generated from IgG-secreting plasma cells in the bone marrow (BM), protects our body against various pathogens. We show here that the protein SiiE of Salmonella is both required and sufficient to prevent an efficient humoral immune memory against the pathogen by selectively reducing the number of IgG-secreting plasma cells in the BM. Attenuated SiiE-deficient Salmonella induces high and lasting titers of specific and protective Salmonella-specific IgG and qualifies as an efficient vaccine against Salmonella A SiiE-derived peptide with homology to laminin ß1 is sufficient to ablate IgG-secreting plasma cells from the BM, identifying laminin ß1 as a component of niches for IgG-secreting plasma cells in the BM, and furthermore, qualifies it as a unique therapeutic option to selectively ablate IgG-secreting plasma cells in autoimmune diseases and multiple myeloma.


Assuntos
Células da Medula Óssea/imunologia , Imunidade Humoral , Imunoglobulina G/imunologia , Memória Imunológica , Plasmócitos/imunologia , Salmonella/imunologia , Animais , Células da Medula Óssea/citologia , Imunoglobulina G/genética , Laminina/genética , Laminina/imunologia , Camundongos , Camundongos Knockout , Plasmócitos/citologia , Salmonella/genética
20.
Immunol Rev ; 288(1): 85-96, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30874350

RESUMO

T follicular helper (Tfh) cells play a crucial role in orchestrating the humoral arm of adaptive immune responses. Mature Tfh cells localize to follicles in secondary lymphoid organs (SLOs) where they provide help to B cells in germinal centers (GCs) to facilitate immunoglobulin affinity maturation, class-switch recombination, and generation of long-lived plasma cells and memory B cells. Beyond the canonical GC Tfh cells, it has been increasingly appreciated that the Tfh phenotype is highly diverse and dynamic. As naive CD4+ T cells progressively differentiate into Tfh cells, they migrate through a variety of microanatomical locations to obtain signals from other cell types, which in turn alters their phenotypic and functional profiles. We herein review the heterogeneity of Tfh cells marked by the dynamic phenotypic changes accompanying their developmental program. Focusing on the various locations where Tfh and Tfh-like cells are found, we highlight their diverse states of differentiation. Recognition of Tfh cell heterogeneity has important implications for understanding the nature of T helper cell identity specification, especially the plasticity of the Tfh cells and their ontogeny as related to conventional T helper subsets.


Assuntos
Linfócitos B/imunologia , Centro Germinativo/imunologia , Plasmócitos/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Afinidade de Anticorpos , Diferenciação Celular , Plasticidade Celular , Humanos , Imunidade Humoral , Memória Imunológica
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