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1.
Arq Bras Oftalmol ; 87(2): e20220091, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38451678

RESUMO

Hepatitis C virus infection may be implicated in 12.7% of ocular adnexal marginal zone lymphomas. We present the first case of an orbital-systemic mucosa-associated lymphoid tissue lymphoma that responded to hepatitis C virus medical treatment. A 62-year-old male with a right-sided orbital mass was diagnosed with stage IIA orbital marginal zone lymphoma in addition to hepatitis C virus infection based on clinical, imaging, laboratory, and histological examinations. The systemic and orbital responses were achieved 1 year after undergoing hepatitis C virus treatment with glecaprevir/pibrentasvir. The association between the hepatitis C virus infection and orbital-systemic mucosa-associated lymphoid tissue lymphoma is relevant. Accordingly, patients with orbital mucosa-associated lymphoid tissue lymphoma should be assessed for hepatitis C virus seroreactivity for therapeutic and prognostic purposes.


Assuntos
Hepatite C , Linfoma de Zona Marginal Tipo Células B , Masculino , Humanos , Pessoa de Meia-Idade , Hepacivirus , Linfoma de Zona Marginal Tipo Células B/complicações , Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Hepatite C/complicações , Hepatite C/tratamento farmacológico , Tecido Linfoide , Mucosa
2.
J Investig Med High Impact Case Rep ; 12: 23247096241238531, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38494775

RESUMO

Extranodal marginal zone B-cell lymphoma (ENMZL) of mucosa-associated lymphoid tissue (MALT), a rare subtype of B-cell lymphoma, is typically associated with Helicobacter pylori (H pylori) infection, especially in gastric cases. However, this article presents 2 unique cases of H pylori-negative colonic ENMZL, challenging the conventional understanding of the disease. The first case involves an 80-year-old male diagnosed with Stage 1E ENMZL in the descending colon, and the second describes a 74-year-old male with sigmoid colon ENMZL. Both cases lacked H pylori infection, adding complexity to their management. Accompanying these case studies is a comprehensive literature review, delving into the epidemiology, pathology, clinical features, diagnosis, and treatment of H pylori-negative ENMZL, with a focus on gastrointestinal involvement. This review highlights the importance of considering H pylori-negative cases in ENMZL diagnosis and management, illustrating the need for further research and individualized treatment approaches in this uncommon lymphoma subtype.


Assuntos
Infecções por Helicobacter , Helicobacter pylori , Linfoma de Zona Marginal Tipo Células B , Neoplasias Gástricas , Masculino , Humanos , Idoso de 80 Anos ou mais , Idoso , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Linfoma de Zona Marginal Tipo Células B/terapia , Linfoma de Zona Marginal Tipo Células B/patologia , Neoplasias Gástricas/patologia , Infecções por Helicobacter/complicações , Infecções por Helicobacter/tratamento farmacológico , Tecido Linfoide/patologia
3.
Biomed Pharmacother ; 173: 116382, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38460368

RESUMO

Lymphoid organs are the main structural components of the immune system. In the current research, the mixture of poly lactic-co-glycolic acid (PLGA), polycaprolactone (PCL), and M13 phage or its RGD-modified form was used in the construction of a fibrillar scaffold using the electrospinning method. The constructs were transplanted intra-abdominally and examined for the formation of lymphoid-like tissues at different time intervals. The confocal and scanning electron microscopy demonstrate that M13 phage-containing scaffolds provide a suitable environment for lymph node-isolated fibroblasts. Morphological analysis demonstrate the formation of lymph node-like tissues in the M13 phage-containing scaffolds after transplantation. Histological analysis confirm both blood and lymph angiogenesis in the implanted construct and migration of inflammatory cells to the M13 phage-containing scaffolds. In addition, flow cytometry and immunohistochemistry analysis showed the homing and compartmentalization of dendritic cells (DCs), B and T lymphocytes within the PLGA/PCL/M13 phage-RGD based scaffolds and similar to what is seen in the mouse lymphoid tissues. It seems that the application of M13 phage could improve the generation of functional lymphoid tissues in the electrospun scaffolds and could be used for lymphoid tissue regeneration.


Assuntos
Glicóis , Tecidos Suporte , Camundongos , Animais , Tecidos Suporte/química , Bacteriófago M13 , Poliésteres/química , Tecido Linfoide , Oligopeptídeos , Engenharia Tecidual
4.
Cell Mol Immunol ; 21(4): 412-413, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38538700
6.
Diagn Pathol ; 19(1): 49, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38459547

RESUMO

The histological diagnosis of extranodal marginal zone lymphoma of the mucosa-associated lymphoid tissue (MALT lymphoma) is difficult for pathologists. Recently, digital pathology systems have been widely used to provide tools that can objectively measure lesions on slides. In this study, we measured the extent of marginal zone expansion in suspected MALT lymphoma cases and compared the results with those of a molecular clonality test. In total, 115 patients who underwent an IGH gene rearrangement test for suspected MALT lymphoma were included in this study. All cases were histologically classified into three patterns; "small lymphoid aggregates with no germinal center (Pattern 1)," "lymphoid follicles with germinal center (Pattern 2)" and " fused marginal zone or diffuse small lymphocytic proliferation (Pattern 3)." The proportions of monoclonality in Pattern 1, 2, and 3 were 25.0%, 55.0%, and 97.9%, respectively. The ratios of marginal zone thickness to germinal center diameter and entire lymphoid follicle area to germinal center area were measured in Pattern 2 cases using a digital pathology system. Combining the width cutoff of 1.5 and the areal cutoff of 3.5, the sensitivity, specificity, positive predictive value, and negative predictive value for MALT lymphoma were 96.97%, 70.37%, 80.00%, and 95.00%, respectively. In conclusion, through objective measurement of the marginal zone, suspected cases of MALT lymphoma requiring a molecular clonality test can be effectively selected.


Assuntos
Linfoma de Zona Marginal Tipo Células B , Humanos , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Linfoma de Zona Marginal Tipo Células B/genética , Linfoma de Zona Marginal Tipo Células B/patologia , Seleção de Pacientes , Linfócitos/patologia , Tecido Linfoide/patologia , Linfonodos/patologia
7.
Trends Immunol ; 45(3): 211-223, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38402045

RESUMO

The diverse gut microbiota, which is associated with mucosal health and general wellbeing, maintains gut-associated lymphoid tissues (GALT) in a chronically activated state, including sustainment of germinal centers in a context of high antigenic load. This influences the rules for B cell engagement with antigen and the potential consequences. Recent data have highlighted differences between GALT and other lymphoid tissues. For example, GALT propagates IgA responses against glycans that show signs of having been generated in germinal centers. Other findings suggest that humans are among those species where GALT supports the diversification, propagation, and possibly selection of systemic B cells. Here, we review novel findings that identify GALT as distinctive, and able to support these processes.


Assuntos
Linfócitos B , Microbiota , Humanos , Tecido Linfoide , Centro Germinativo , Mucosa Intestinal , Imunidade nas Mucosas
8.
J Virol ; 98(2): e0165223, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38299866

RESUMO

CCR5-tropic simian/human immunodeficiency viruses (SHIV) with clade C transmitted/founder envelopes represent a critical tool for the investigation of HIV experimental vaccines and microbicides in nonhuman primates, although many such isolates lead to spontaneous viral control post infection. Here, we generated a high-titer stock of pathogenic SHIV-C109p5 by serial passage in two rhesus macaques (RM) and tested its virulence in aged monkeys. The co-receptor usage was confirmed before infecting five geriatric rhesus macaques (four female and one male). Plasma viral loads were monitored by reverse transcriptase-quantitative PCR (RT-qPCR), cytokines by multiplex analysis, and biomarkers of gastrointestinal damage by enzyme-linked immunosorbent assay. Antibodies and cell-mediated responses were also measured. Viral dissemination into tissues was determined by RNAscope. Intravenous SHIV-C109p5 infection of aged RMs leads to high plasma viremia and rapid disease progression; rapid decrease in CD4+ T cells, CD4+CD8+ T cells, and plasmacytoid dendritic cells; and wasting necessitating euthanasia between 3 and 12 weeks post infection. Virus-specific cellular immune responses were detected only in the two monkeys that survived 4 weeks post infection. These were Gag-specific TNFα+CD8+, MIP1ß+CD4+, Env-specific IFN-γ+CD4+, and CD107a+ T cell responses. Four out of five monkeys had elevated intestinal fatty acid binding protein levels at the viral peak, while regenerating islet-derived protein 3α showed marked increases at later time points in the three animals surviving the longest, suggesting gut antimicrobial peptide production in response to microbial translocation post infection. Plasma levels of monocyte chemoattractant protein-1, interleukin-15, and interleukin-12/23 were also elevated. Viral replication in gut and secondary lymphoid tissues was extensive.IMPORTANCESimian/human immunodeficiency viruses (SHIV) are important reagents to study prevention of virus acquisition in nonhuman primate models of HIV infection, especially those representing transmitted/founder (T/F) viruses. However, many R5-tropic SHIV have limited fitness in vivo leading to many monkeys spontaneously controlling the virus post acute infection. Here, we report the generation of a pathogenic SHIV clade C T/F stock by in vivo passage leading to sustained viral load set points, a necessity to study pathogenicity. Unexpectedly, administration of this SHIV to elderly rhesus macaques led to extensive viral replication and fast disease progression, despite maintenance of a strict R5 tropism. Such age-dependent rapid disease progression had previously been reported for simian immunodeficiency virus but not for R5-tropic SHIV infections.


Assuntos
Infecções por HIV , HIV , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Replicação Viral , Animais , Feminino , Masculino , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Envelhecimento , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Quimiocina CCL2/imunologia , Quimiocina CCL2/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/patologia , Progressão da Doença , HIV/classificação , HIV/crescimento & desenvolvimento , HIV/patogenicidade , HIV/fisiologia , Infecções por HIV/imunologia , Infecções por HIV/patologia , Infecções por HIV/virologia , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucinas/imunologia , Interleucinas/metabolismo , Intestinos/virologia , Tecido Linfoide/virologia , Macaca mulatta/imunologia , Macaca mulatta/metabolismo , Inoculações Seriadas , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/patologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/classificação , Vírus da Imunodeficiência Símia/crescimento & desenvolvimento , Vírus da Imunodeficiência Símia/patogenicidade , Vírus da Imunodeficiência Símia/fisiologia , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Carga Viral , Tropismo Viral , Virulência , Receptores CCR5/metabolismo
9.
Arkh Patol ; 86(1): 21-26, 2024.
Artigo em Russo | MEDLINE | ID: mdl-38319268

RESUMO

BACKGROUND: Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) consist of lymphocyte predominant cell or LP-cell. Despite their origin from active germinal centers, in some cases LP-cells express IgD, which is characteristic of naive B-lymphocytes of the mantle zone. Due to the rarity of NLPHL, assessing the frequency of IgD-positive cases is difficult. This marker can serve not only for differential diagnosis with other diseases, but also indicate the possible heterogeneity of NLPHL, which is currently represented by six immunoarchitectural patterns. OBJECTIVE: To determine the frequency of IgD-positive cases of NLPHL in children with subsequent assessment of the association with types of immunoarchitectural patterns. MATERIAL AND METHODS: The study included 52 cases of NLPHL, which were divided to typical and atypical patterns. Differences between two groups were compared using Fisher's exact tests. RESULTS: IgD expression was found in LP-cells in 26 of 52 cases (50%) and was positively correlated with atypical types (typical - 5/23, 21.7% vs atypical - 21/29, 72.4%, p=0.0003), among which pattern C was most common. CONCLUSION: Due to the high incidence of IgD-positive cases in NLPHL, this marker may be useful in differential diagnosis with histologic mimics. At the same time, positive IgD status was associated with atypical patterns, which may likely determine the different biology of neoplastic cells within the same form.


Assuntos
Doença de Hodgkin , Criança , Humanos , Tecido Linfoide , Diagnóstico Diferencial , Linfócitos
10.
Nat Commun ; 15(1): 1261, 2024 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-38341416

RESUMO

While CD4+ T cells are a prerequisite for CD8+ T cell-mediated protection against intracellular hepatotropic pathogens, the mechanisms facilitating the transfer of CD4-help to intrahepatic CD8+ T cells are unknown. Here, we developed an experimental system to investigate cognate CD4+ and CD8+ T cell responses to a model-antigen expressed de novo in hepatocytes and reveal that after initial priming, effector CD4+ and CD8+ T cells migrate into portal tracts and peri-central vein regions of the liver where they cluster with type-1 conventional dendritic cells. These dendritic cells are locally licensed by CD4+ T cells and expand the number of CD8+ T cells in situ, resulting in larger effector and memory CD8+ T cell pools. These findings reveal that CD4+ T cells promote intrahepatic immunity by amplifying the CD8+ T cell response via peripheral licensing of hepatic type-1 conventional dendritic cells and identify intrahepatic perivascular compartments specialized in facilitating effector T cell-dendritic cell interactions.


Assuntos
Linfócitos T CD4-Positivos , Fígado , Tecido Linfoide , Antígenos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Fígado/imunologia , Humanos , Tecido Linfoide/imunologia
11.
J Immunol ; 212(5): 813-824, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38224204

RESUMO

The MHC class I molecule H-2Dk conveys resistance to acute murine CMV infection in both C57L (H-2Dk transgenic) and MA/My mice. M.H2k/b mice are on an MA/My background aside from a C57L-derived region spanning the MHC (Cmv5s), which diminishes this resistance and causes significant spleen histopathology. To hone in on the effector elements within the Cmv5s interval, we generated several Cmv5-recombinant congenic mouse strains and screened them in vivo, allowing us to narrow the phenotype-associated interval >6-fold and segment the genetic mechanism to at least two independent loci within the MHC region. In addition, we sought to further characterize the Cmv5s-associated phenotypes in their temporal appearance and potential direct relationship to viral load. To this end, we found that Cmv5s histopathology and NK cell activation could not be fully mirrored in the MA/My mice with increased viral dose, and that marginal zone destruction was the first apparent Cmv5s phenotype, being reliably quantified as early as 2 d postinfection in the M.H2k/b mice, prior to divergence in viral load, weight loss, or NK cell phenotype. Finally, we further dissect NK cell involvement, finding no intrinsic differences in NK cell function, despite increased upregulation of activation markers and checkpoint receptors. In conclusion, these data dissect the genetic and immunologic underpinnings of Cmv5 and reveal a model in which polymorphism within the MHC region of the genome leads to the development of tissue damage and corrupts protective NK cell immunity during acute viral infection.


Assuntos
Infecções por Citomegalovirus , Muromegalovirus , Camundongos , Animais , Antígenos de Histocompatibilidade Classe I/genética , Células Matadoras Naturais , Tecido Linfoide , Camundongos Endogâmicos C57BL
12.
Immunol Lett ; 266: 106838, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38278305

RESUMO

OBJECTIVES: Idiopathic membranous nephropathy (MN) is an autoimmune disease characterized by specific antibodies. However, the underlying mechanisms by which lymphocytes promote the development of MN remain poorly understood. This study aims to determine the changes of B-cell subsets and their clinical significance in MN patients. METHODS: We included a cohort of 21 idiopathic MN patients with new onset or a relapse, 19 healthy controls (HCs) and 10 patients with minimal change disease (MCD). Immunohistochemistry and flow cytometry were performed to assess the B-cell infiltration in renal biopsy tissues and peripheral blood, respectively. RESULTS: Idiopathic MN patients (including new-onset and relapse groups) had lower percentages of marginal-zone B (MZB) and non-switched memory B cells, and higher percentages of plasmablasts than HCs (P < 0.01). Particularly, the new-onset group had lower percentages of switched memory B cells and MZB cells, and higher percentages of Naïve B cells than HCs (P<0.05). Interestingly, the percentage of plasmablasts was significantly correlated with urine protein to creatinine ratio, serum albumin, IgG, anti-M-type phospholipase A2 receptor antibody level and age in MN patients (P < 0.05). MN with Ehrenreich-Churg stage Ⅱ-Ⅳ had a lower median percentage of MZB and non-switched memory B cells, while a higher median percentage of plasmablasts than those in MN patients with stage Ehrenreich-Churg I (P < 0.05). CONCLUSION: Idiopathic MN patients had specific changes in B-cell subsets proportions in peripheral blood. Further studies are needed to precisely determine the roles of B-cell subsets in MN.


Assuntos
Subpopulações de Linfócitos B , Glomerulonefrite Membranosa , Adulto , Humanos , Glomerulonefrite Membranosa/diagnóstico , Plasmócitos , Tecido Linfoide/metabolismo , Anticorpos , Recidiva
13.
Zhonghua Bing Li Xue Za Zhi ; 53(1): 12-15, 2024 Jan 08.
Artigo em Chinês | MEDLINE | ID: mdl-38178740

RESUMO

The 5th edition of the World Health Organization classification of hematolymphoid tumors (WHO Blue Book) is soon to be published. Significant revisions have been made in the chapters on histiocytic/dendritic cell neoplasms and stroma-derived neoplasms of lymphoid tissues, leading to the reclassification and renaming of specific diseases. This article provides a concise interpretation and summary of these updates, highlighting the differences from the fourth edition. Pertinent changes from clinical pathological diagnosis to treatment and prognosis are explored, with an emphasis on recent advancements in molecular genetics. Newly introduced disease classifications are discussed, and the section on follicular dendritic cell sarcoma contributed by the author is detailed to assist readers in quickly understanding and assimilating the new classification standards.


Assuntos
Sarcoma de Células Dendríticas Foliculares , Neoplasias de Tecidos Moles , Humanos , Tecido Linfoide/patologia , Neoplasias de Tecidos Moles/patologia , Sarcoma de Células Dendríticas Foliculares/genética , Sarcoma de Células Dendríticas Foliculares/patologia , Células Dendríticas/patologia , Organização Mundial da Saúde
14.
Cell Rep Methods ; 4(1): 100685, 2024 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-38211593

RESUMO

The molecular and immunological properties of tissue-resident resting CD4 T cells are understudied due to the lack of suitable gene editing methods. Here, we describe the ex vivo culture and gene editing methodology ediTONSIL for CD4 T cells from human tonsils. Optimized CRISPR-Cas9 RNP nucleofection results in knockout efficacies of over 90% without requiring exogenous activation. Editing can be performed on multiple cell types in bulk cultures or on isolated CD4 T cells that can be labeled and reintroduced into their tissue environment. Importantly, CD4 T cells maintain their tissue-specific properties such as viability, activation state, or immunocompetence following reassembly into lymphoid aggregates. This highly efficient and versatile gene editing workflow for tonsillar CD4 T cells enables the dissection of molecular mechanisms in ex vivo cultures of human lymphoid tissue and can be adapted to other tonsil-resident cell types.


Assuntos
Linfócitos T CD4-Positivos , Tonsila Palatina , Humanos , Edição de Genes , Tecido Linfoide
15.
EBioMedicine ; 100: 104965, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38215691

RESUMO

BACKGROUND: Simian immunodeficiency viruses (SIV) have been jumping between non-human primates in West/Central Africa for thousands of years and yet, the HIV-1 epidemic only originated from a primate lentivirus over 100 years ago. METHODS: This study examined the replicative fitness, transmission, restriction, and cytopathogenicity of 22 primate lentiviruses in primary human lymphoid tissue and both primary human and chimpanzee peripheral blood mononuclear cells. FINDINGS: Pairwise competitions revealed that SIV from chimpanzees (cpz) had the highest replicative fitness in human or chimpanzee peripheral blood mononuclear cells, even higher fitness than HIV-1 group M strains responsible for worldwide epidemic. The SIV strains belonging to the "HIV-2 lineage" (including SIVsmm, SIVmac, SIVagm) had the lowest replicative fitness. SIVcpz strains were less inhibited by human restriction factors than the "HIV-2 lineage" strains. SIVcpz efficiently replicated in human tonsillar tissue but did not deplete CD4+ T-cells, consistent with the slow or nonpathogenic disease observed in most chimpanzees. In contrast, HIV-1 isolates and SIV of the HIV-2 lineage were pathogenic to the human tonsillar tissue, almost independent of the level of virus replication. INTERPRETATION: Of all primate lentiviruses, SIV from chimpanzees appears most capable of infecting and replicating in humans, establishing HIV-1. SIV from other Old World monkeys, e.g. the progenitor of HIV-2, replicate slowly in humans due in part to restriction factors. Nonetheless, many of these SIV strains were more pathogenic than SIVcpz. Either SIVcpz evolved into a more pathogenic virus while in humans or a rare SIVcpz, possibly extinct in chimpanzees, was pathogenic immediately following the jump into human. FUNDING: Support for this study to E.J.A. was provided by the NIH/NIAID R01 AI49170 and CIHR project grant 385787. Infrastructure support was provided by the NIH CFAR AI36219 and Canadian CFI/Ontario ORF 36287. Efforts of J.A.B. and N.J.H. was provided by NIH AI099473 and for D.H.C., by VA and NIH AI AI080313.


Assuntos
HIV-1 , Lentivirus de Primatas , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Animais , Humanos , Pan troglodytes , Virulência , Leucócitos Mononucleares , Primatas , Tecido Linfoide , Ontário
16.
Fish Shellfish Immunol ; 146: 109415, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38296004

RESUMO

It is assumed that cells corresponding to innate lymphoid cells (ILCs) in humans, in addition to lymphoid tissue inducer cells (LTi), are also found in teleosts. In this systematic group of organisms, however, they are a poorly understood cell population. In contrast to the data on ILCs in humans, which also remain incomplete despite advanced research, in teleosts, these cells require much more attention. ILCs in teleosts have been presented as cells that may be evolutionary precursors of NK cells or ILCs identified in mammals, including humans. It is a highly heterogeneous group of cells in both humans and fish and their properties, as revealed by studies in humans, are most likely to remain strictly dependent on the location of these cells and the physiological state of the individual from which they originate. They form a bridge between innate and adaptive immunity. The premise of this paper is to review the current knowledge of ILCs in teleosts, taking into account data on similar cells in humans. A review of the knowledge concerning these particular cells, elements of innate immunity mechanisms as equivalent to, or perhaps dominant over, adaptive immunity mechanisms in teleosts, as presented, may inspire the need for further research.


Assuntos
Imunidade Inata , Linfócitos , Humanos , Animais , Células Matadoras Naturais , Linfócitos T Auxiliares-Indutores , Tecido Linfoide , Imunidade Adaptativa , Mamíferos
17.
Haematologica ; 109(3): 809-823, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-37381758

RESUMO

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is widely used for treatment of patients with relapsed/refractory or treatment-naïve chronic lymphocytic leukemia (CLL). A prominent effect of ibrutinib is to disrupt the retention of CLL cells from supportive lymphoid tissues, by altering BTK-dependent adhesion and migration. To further explore the mechanism of action of ibrutinib and its potential impact on non-leukemic cells, we quantified multiple motility and adhesion parameters of human primary CLL cells and non-leukemic lymphoid cells. In vitro, ibrutinib affected CCL19-, CXCL12- and CXCL13-evoked migration behavior of CLL cells and non-neoplastic lymphocytes, by reducing both motility speed and directionality. De-phosphorylation of BTK induced by ibrutinib in CLL cells was associated with defective polarization over fibronectin and inability to assemble the immunological synapse upon B-cell receptor engagement. In patients' samples collected during a 6-month monitoring of therapy, chemokine-evoked migration was repressed in CLL cells and marginally reduced in T cells. This was accompanied by profound modulation of the expression of chemokine receptors and adhesion molecules. Remarkably, the relative expression of the receptors governing lymph node entry (CCR7) versus exit (S1PR1) stood out as a reliable predictive marker of the clinically relevant treatment-induced lymphocytosis. Together, our data reveal a multifaceted modulation of motility and adhesive properties of ibrutinib on both CLL leukemic cell and T-cell populations and point to intrinsic differences in CLL recirculation properties as an underlying cause for variability in treatment response.


Assuntos
Adenina/análogos & derivados , Leucemia Linfocítica Crônica de Células B , Piperidinas , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Movimento Celular , Tecido Linfoide , Linfócitos
18.
Br J Haematol ; 204(1): 31-44, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38054330

RESUMO

Marginal zone lymphoma (MZL) is the most common indolent lymphoma primarily arising in the central nervous system (CNS). To date, 207 cases of primary CNS MZL (PCNSMZL) were published, mostly as single case reports or small case series. It most commonly presents as extra-axial dural-based masses, more frequently in middle-aged women, displaying an insidious onset, with a long history of symptoms preceding the diagnosis. PCNSMZL can be radiographically mistaken for meningioma. PCNSMZL consists of CD20+ , CD3- small B lymphocytes with varying degrees of plasmacytic differentiation and low proliferation index. Trisomy 3, but not MALT1 or IgH translocation, is a common genetic abnormality. Other recurrent genetic abnormalities involve TNFAIP3 and NOTCH2. Ethiopathogenesis was poorly investigated. Due to its rarity, standard of care remains to be defined; it exhibits an excellent prognosis after varied treatments, such as surgery, radiotherapy, chemotherapy or their combinations. Nevertheless, each treatment should be considered after an accurate analysis of overtreatment risk. Short follow-up is a major limitation in reported PCNSMZL cases, which restrains our knowledge on long-term results and iatrogenic sequels. This review was focussed on presentation, differential diagnoses, pathological findings, treatment options and clinical outcomes of PCNSMZL; recommendations for best clinical practice are provided.


Assuntos
Linfoma de Zona Marginal Tipo Células B , Pessoa de Meia-Idade , Humanos , Feminino , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Linfoma de Zona Marginal Tipo Células B/terapia , Linfoma de Zona Marginal Tipo Células B/genética , Linfócitos B/patologia , Tecido Linfoide/patologia , Translocação Genética , Sistema Nervoso Central/patologia
19.
Nat Immunol ; 25(1): 142-154, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38049580

RESUMO

Spleen marginal zone (MZ) B cells are important for antibody responses against blood-borne antigens. The signals they use to detect exposure to blood are not well defined. Here, using intravital two-photon microscopy in mice, we observe transient contacts between MZ B cells and red blood cells that are in flow. We show that MZ B cells use adhesion G-protein-coupled receptor ADGRE5 (CD97) for retention in the spleen. CD97 function in MZ B cells depends on its ability to undergo autoproteolytic cleavage and signaling via Gα13 and ARHGEF1. Red blood cell expression of the CD97 ligand CD55 is required for MZ B cell homeostasis. Applying a pulling force on CD97-transfected cells using an optical C-trap and CD55+ beads leads to accumulation of active RhoA and membrane retraction. Finally, we show that CD97 deficiency leads to a reduced T cell-independent IgM response. Thus, our studies provide evidence that MZ B cells use mechanosensing to position in a manner that enhances antibody responses against blood-borne antigens.


Assuntos
Linfócitos B , Tecido Linfoide , Camundongos , Animais , Baço/metabolismo , Transdução de Sinais , Antígenos CD55/metabolismo , Eritrócitos
20.
Dev Comp Immunol ; 151: 105096, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37952587

RESUMO

Chickens exhibit a distinct immune architecture characterised by the absence of draining lymph nodes and the presence of a well-developed mucosa-associated lymphoid tissue. The structure and spatiotemporal development of chicken lymphoid tissues in the intestine are poorly documented. The macroscopically indistinct structure of chicken Peyer's patches has impeded studies into their development. The generation of CSF1R-eGFP reporter transgenic chickens enables visualisation of the development, organisation and extent of chicken lymphoid tissues by unique macroscopic views. CSF1R-eGFP reporter transgenic chickens were used to investigate the distribution and spatiotemporal development of PP and caecal tonsils in embryonic day 18 to 8-week-old chickens. Peyer's patch anlagen are present at ED18 with a similar frequency and distribution pattern observed in 2- and 8-week-old chickens. These findings can support in ovo and post-hatch mucosal vaccination strategies and the development of vaccine delivery systems targeted to the specialized epithelium overlying the Peyer's patches.


Assuntos
Galinhas , Nódulos Linfáticos Agregados , Animais , Tecido Linfoide , Intestinos , Epitélio , Animais Geneticamente Modificados , Mucosa Intestinal
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