scholarly journals Tumor-associated macrophages as major source of APRIL in gastric MALT lymphoma

Blood ◽  
2011 ◽  
Vol 117 (24) ◽  
pp. 6612-6616 ◽  
Author(s):  
Fabio Munari ◽  
Silvia Lonardi ◽  
Marco A. Cassatella ◽  
Claudio Doglioni ◽  
Maria Giulia Cangi ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Malt Lymphoma ◽  
Cell Activation ◽  
Gastric Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphoid Hyperplasia ◽  
Gastric Malt Lymphoma ◽  
Direct Stimulation

Abstract Lymphoid hyperplasia of gastric mucosa associated with Helicobacter pylori (HP) infection represents a preneoplastic condition of the mucosa associated lymphoid tissue (MALT), which may evolve to a B-cell lymphoma. While it is well established that the initial neoplastic proliferation of B cells is antigen-driven and dependent on the helper activity of HP-specific T cells, it needs to be elucidated which cytokine or soluble factor(s) promote B-cell activation and lymphomagenesis. Herein, we originally report that gastric MALT lymphoma express high levels of a proliferation inducing ligand (APRIL), a novel cytokine crucial in sustaining B-cell proliferation. By immunohistochemistry, we demonstrate that APRIL is produced almost exclusively by gastric lymphoma-infiltrating macrophages located in close proximity to neoplastic B cells. We also show that macrophages produce APRIL on direct stimulation with both HP and HP-specific T cells. Collectively, our results represent the first evidence for an involvement of APRIL in gastric MALT lymphoma development in HP-infected patients.

scholarly journals Novel Insights of Lymphomagenesis of Helicobacter pylori-Dependent Gastric Mucosa-Associated Lymphoid Tissue Lymphoma

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 547 ◽  
Author(s):  
Sung-Hsin Kuo ◽  
Ming-Shiang Wu ◽  
Kun-Huei Yeh ◽  
Chung-Wu Lin ◽  
Ping-Ning Hsu ◽  
...  
Keyword(s):  
T Cells ◽  
Helicobacter Pylori ◽  
B Cells ◽  
Gastric Mucosa ◽  
B Cell ◽  
Malt Lymphoma ◽  
Lymphoid Tissue ◽  
B Cell Lymphoma ◽  
Gastric Malt Lymphoma ◽  
First Line

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is the most common subtype of gastric lymphoma. Most gastric MALT lymphomas are characterized by their association with the Helicobacter pylori (HP) infection and are cured by first-line HP eradication therapy (HPE). Several studies have been conducted to investigate why most gastric MALT lymphomas remain localized, are dependent on HP infection, and show HP-specific intratumoral T-cells (e.g., CD40-mediated signaling, T-helper-2 (Th2)-type cytokines, chemokines, costimulatory molecules, and FOXP3+ regulatory T-cells) and their communication with B-cells. Furthermore, the reason why the antigen stimuli of these intratumoral T-cells with tonic B-cell receptor signaling promote lymphomagenesis of gastric MALT lymphoma has also been investigated. In addition to the aforementioned mechanisms, it has been demonstrated that the translocated HP cytotoxin-associated gene A (CagA) can promote B-cell proliferation through the activation of Src homology-2 domain-containing phosphatase (SHP-2) phosphorylation-dependent signaling, extracellular-signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK), B-cell lymphoma (Bcl)-2, and Bcl-xL. Furthermore, the expression of CagA and these CagA-signaling molecules is closely associated with the HP-dependence of gastric MALT lymphomas (completely respond to first-line HPE). In this article, we summarize evidence of the classical theory of HP-reactive T-cells and the new paradigm of direct interaction between HP and B-cells that contributes to the HP-dependent lymphomagenesis of gastric MALT lymphomas. Although the role of first-line HPE in the treatment of HP-negative gastric MALT lymphoma remains uncertain, several case series suggest that a proportion of HP-negative gastric MALT lymphomas remains antibiotic-responsive and is cured by HPE. Considering the complicated interaction between microbiomes and the genome/epigenome, further studies on the precise mechanisms of HP- and other bacteria-directed lymphomagenesis in antibiotic-responsive gastric MALT lymphomas are warranted.

scholarly journals MALT lymphoma: epidemiology, clinical diagnosis and treatment

2018 ◽  
Vol 11 (3) ◽  
pp. 187-193 ◽  
Author(s):  
Petruta Violeta Filip ◽  
◽  
Denisa Cuciureanu ◽  
Laura Sorina Diaconu ◽  
Ana Maria Vladareanu ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
B Cell ◽  
Malt Lymphoma ◽  
Cell Lymphoma ◽  
Gastric Lymphoma ◽  
Eradication Therapy ◽  
B Cell Lymphoma ◽  
Gastric Malt Lymphoma ◽  
H Pylori

Primary gastric lymphoma (PGL) represents a rare pathology, which can be easily misdiagnosed because of unspecific symptoms of the digestive tract. Histologically, PGL can vary from indolent marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) to aggressive diffuse large B-cell lymphoma (DLBCL). During the years, clinical trials revealed the important role of Helicobacter pylori (H. pylori) in the pathogenesis of gastric MALT lymphoma. Infection with Helicobacter pylori is an influential promoter of gastric lymphomagenesis initiation. Long-term studies revealed that eradication therapy could regress gastric lymphomas.

scholarly journals Cytotoxic T Cells inH. pylori-Related Gastric Autoimmunity and Gastric Lymphoma

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Mathijs P. Bergman ◽  
Mario M. D'Elios
Keyword(s):  
T Cells ◽  
B Cell ◽  
Cell Activation ◽  
Fas Ligand ◽  
Cell Lymphoma ◽  
Gastric Lymphoma ◽  
B Cell Lymphoma ◽  
Low Grade ◽  
Ligand Interaction ◽  
H Pylori

Helicobacter pyloriinfection is the major cause of gastroduodenal pathologies, but only a minority of infected patients develop gastric B-cell lymphoma, gastric autoimmunity, or other life threatening diseases, as gastric cancer or peptic ulcer. The type of host immune response againstH. pylori, particularly the cytolytic effector functions of T cells, is crucial for the outcome of the infection. T cells are potentially able to kill a target via different mechanisms, such as perforins or Fas-Fas ligand interaction. InH. pylori-infected patients with gastric autoimmunity cytolytic T cells, that cross-recognize different epitopes ofH. pyloriproteins and -ATPase autoantigen, infiltrate the gastric mucosa and lead to gastric atrophy via long-lasting activation of Fas ligand-mediated appotosis and perforin-induced cytotoxicity. On the other hand, gastric T cells from MALT lymphoma exhibit defective perforin- and Fas-Fas ligand-mediated killing of B cells, with consequent abnormal help for B-cell proliferation, suggesting that deregulated and exhaustiveH. pylori-induced T cell-dependent B-cell activation can support both the onset and the promotion of low-grade B-cell lymphoma.

scholarly journals Revisiting the Full Spectrum of Helicobacter pylori-Related Gastric Lymphoma

2021 ◽  
Author(s):  
Sung-Hsin Kuo ◽  
Kun-Huei Yeh ◽  
Chung-Wu Lin ◽  
Li-Tzong Chen ◽  
Ming-Shiang Wu ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
B Cells ◽  
B Cell ◽  
Malt Lymphoma ◽  
Early Stage ◽  
Gastric Lymphoma ◽  
Gastric Malt Lymphoma ◽  
Histological Features ◽  
Cytotoxin Associated Gene A ◽  
Src Homology 2 Domain

Early stage gastric diffuse large B-cell lymphomas (DLBCLs) with histological features of mucosa-associated lymphoid tissue (MALT) origin (DLBCL[MALT]) are also closely related to Helicobacter pylori (HP) infection, apart from the classical gastric MALT lymphoma, and are cured by HP eradication therapy (HPE). Whether some gastric “pure” DLBCLs (without histological features of MALT) are also HP-related is clinically very important, since this subtype of gastric lymphoma is relatively common in the population and is still universally treated with intensive systemic chemotherapy. A large proportion of early stage gastric “pure” DLBCL can achieve long-term complete remission after HPE. However, the precise mechanisms of HP-dependent (with complete regression of tumors after HPE) lymphomagenesis of gastric “pure” DLBCL, DLBCL(MALT), and MALT lymphoma remain uncertain. In the classical conception, gastric MALT lymphoma is indirectly caused by HP through T-cell stimulation, with the aid of costimulatory molecules. To explore the direct interactions between HP and lymphoma B-cells of HP-dependent gastric MALT lymphoma, DLBCL(MALT), and “pure” DLBCLs, we assessed the participation of HP-encoded cytotoxin-associated gene A (CagA) in the lymphomagenesis of these tumors. We discovered that CagA oncogenic protein and its regulated signaling molecules including phospho-Src homology-2 domain-containing phosphatase (p-SHP-2) and phospho-extracellular signal-regulated kinase (p-ERK) correlated significantly with HP-dependence of gastric MALT lymphoma. This finding supports previous observations that the CagA protein of HP can be translocated into B-cell lymphoma cells, thereby leading to survival signals. Furthermore, we demonstrated that HP-positive and CagA-expressing gastric “pure” DLBCLs behave in a less biologically aggressive manner, and have better clinical outcomes; this is a distinguishing entity, and its cell origin may include germinal center B cells. In addition, we found that the expression of CagA, p-SHP-2, and p-ERK correlated significantly with the HP-dependence of gastric DLBCL(MALT) and “pure” DLBCL. These findings indicate that the spectrum of HP-related gastric lymphomas including MALT lymphoma, DLBCL(MALT), and “pure” DLBCL, is much wider than was previously thought. Further explorations of the spectrum, lymphomagenesis, and therapeutics of HP-related gastric lymphoma are warranted.

scholarly journals Hyaluronate-CD44 Interactions Can Induce Murine B-Cell Activation

Blood ◽  
1997 ◽  
Vol 89 (8) ◽  
pp. 2901-2908 ◽  
Author(s):  
Asimah Rafi ◽  
Mitzi Nagarkatti ◽  
Prakash S. Nagarkatti
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Critical Role ◽  
Surface Glycoprotein ◽  
B Cell Differentiation ◽  
B Cell Activation ◽  
Cell Surface Glycoprotein ◽  
Immunodeficient Mice

Abstract CD44 is a widely distributed cell surface glycoprotein whose principal ligand has been identified as hyaluronic acid (HA), a major component of the extracellular matrix (ECM). Recent studies have demonstrated that activation through CD44 leads to induction of effector function in T cells and macrophages. In the current study, we investigated whether HA or monoclonal antibodies (MoAbs) against CD44 would induce a proliferative response in mouse lymphocytes. Spleen cells from normal and nude, but not severe combined immunodeficient mice, exhibited strong proliferative responsiveness to stimulation with soluble HA or anti-CD44 MoAbs. Furthermore, purified B cells, but not T cells, were found to respond to HA. HA was unable to stimulate T cells even in the presence of antigen presenting cells (APC) and was unable to act as a costimulus in the presence of mitogenic or submitogenic concentrations of anti-CD3 MoAbs. In contrast, stimulation of B cells with HA in vitro, led to B-cell differentiation as measured by production of IgM antibodies in addition to increased expression of CD44 and decreased levels of CD45R. The fact that the B cells were responding directly to HA through its binding to CD44 and not to any contaminants or endotoxins was demonstrated by the fact that F(ab)2 fragments of anti-CD44 MoAbs or soluble CD44 fusion proteins could significantly inhibit the HA-induced proliferation of B cells. Also, HA-induced proliferation of B cells was not affected by the addition of polymixin B, and B cells from lipopolysaccharide (LPS)-unresponsive C3H/HeJ strain responded strongly to stimulation with HA. Furthermore, HA, but not chondroitin-sulfate, another major component of the ECM, induced B-cell activation. It was also noted that injection of HA intraperitoneally, triggered splenic B cell proliferation in vivo. Together, the current study demonstrates that interaction between HA and CD44 can regulate murine B-cell effector functions and that such interactions may play a critical role during normal or autoimmune responsiveness of B cells.

Terminal plasmocytoid differentiation of malignant B cells induced by autotumor-reactive CD4+ T cells in one case of splenic marginal zone B-cell lymphoma

Blood ◽  
2002 ◽  
Vol 99 (1) ◽  
pp. 388-390 ◽  
Author(s):  
Thierry Bonnefoix ◽  
Jian-Qing Mi ◽  
Pascal Perron ◽  
Mary Callanan ◽  
Cosima Semoun ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Cd4 T Cells ◽  
Marginal Zone ◽  
Cell Lymphoma ◽  
B Cell Lymphoma

scholarly journals T Cell Accumulation in B Cell Follicles Is Regulated by Dendritic Cells and Is Independent of B Cell Activation

2003 ◽  
Vol 197 (2) ◽  
pp. 195-206 ◽  
Author(s):  
Simon Fillatreau ◽  
David Gray
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
B Cell Activation ◽  
Cell Accumulation ◽  
Antigen Presenting ◽  
Deficient Mice

We investigated the mechanism of CD4 T cell accumulation in B cell follicles after immunization. Follicular T cell numbers were correlated with the number of B cells, indicating B cell control of the niche that T cells occupy. Despite this, we found no role for B cells in the follicular migration of T cells. Instead, T cells are induced to migrate into B cell follicles entirely as a result of interaction with dendritic cells (DCs). Migration relies on CD40-dependent maturation of DCs, as it did not occur in CD40-deficient mice but was reconstituted with CD40+ DCs. Restoration was not achieved by the activation of DCs with bacterial activators (e.g., lipopolysaccharide, CpG), but was by the injection of OX40L–huIgG1 fusion protein. Crucially, the up-regulation of OX40L (on antigen-presenting cells) and CXCR-5 (on T cells) are CD40-dependent events and we show that T cells do not migrate to follicles in immunized OX40-deficient mice.

scholarly journals Interaction of B cells with activated T cells reduces the threshold for CD40-mediated B cell activation

1999 ◽  
Vol 11 (1) ◽  
pp. 71-79 ◽  
Author(s):  
Gerry G. B. Klaus ◽  
Mary Holman ◽  
Caroline Johnson-Léger ◽  
Jillian R. Christenson ◽  
Marilyn R. Kehry
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
B Cell Activation ◽  
Activated T Cells

Critical Role for CD81 in B Cell Activation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1342-1342
Author(s):  
Mrinmoy Sanyal ◽  
Rosemary Fernandez ◽  
Shoshana Levy
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Cell Function ◽  
Calcium Influx ◽  
Critical Role ◽  
B Cell Lymphoma ◽  
Free Calcium ◽  
B Cell Activation ◽  
Deficient Mice

Abstract CD81 is a component of the CD19/CD21 signaling complex in B cells. CD81 was originally discovered as target of an anti-proliferative antibody in a human B cell lymphoma. However, the exact role of CD81 in B cell function is not known. Here we studied B cells from CD81 knockout mice. We demonstrate that upon BCR induction these B cells flux higher intracellular free calcium ion; increase the phosphorylation of BCR-related proximal and distal substrates and increase their proliferation. Similarly, polyclonal activation of CD81-deficient B cells with LPS induced increased proliferation and antibody secretion. Consistent with these intrinsic B cell capabilities, CD81-deficient mice mounted significantly higher immune response upon antigenic stimulation. In addition, bone marrow perisinusoidal B cells (IgM+IgD+) capable of mounting T-independent immune responses against blood-borne pathogens were over represented in CD81-deficient mice. These cells also displayed increased calcium influx kinetics as splenic B cells and produced higher amounts of antibody after polyclonal stimulation. Taken together, these results suggest that CD81 is involved in suppressing B cell activation.

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