Background and Aims
The role of eradication therapy in Helicobacter pylori‐negative gastric mucosa‐associated lymphoid tissue (MALT) lymphoma remains controversial. The aim of this study was to ...investigate the efficacy of H. pylori eradication therapy as a first‐line treatment for H. pylori‐negative gastric MALT lymphoma.
Methods
A literature search of studies published until October 2019 was performed using electronic databases. Studies that reported treatment response to eradication therapy as an initial treatment for patients with H. pylori‐negative gastric MALT lymphoma were eligible for inclusion. The primary outcome was the complete remission rate after eradication therapy.
Results
Twenty‐five studies were included in the analyses. The overall pooled complete remission rate was 29.3% (95% confidence interval CI, 22.2%–37.4%, I2 = 41.5%). There was no publication bias, and the sensitivity analyses showed consistent results. The pooled complete remission rates were lower in the subgroups of studies that had a higher incidence of translocation t(11;18)(q21;q21) (19.9%, 95% CI, 11.6%–32.0%), studies that used serological tests to exclude H. pylori infection (27.5%, 95% CI, 20.1%–36.4%), and studies where non‐response to eradication therapy was determined at <12 months after treatment (27.0%, 95% CI, 15.5%–42.7%). Meta‐regression analysis revealed that the pooled estimate was not significantly different in terms of the characteristics of individual studies.
Conclusions
Although the complete remission rate after eradication therapy is not high, it can be used as an initial treatment option in a subset of patients with H. pylori‐negative gastric MALT lymphoma. Further studies to identify subgroups of patients who may benefit from eradication therapy are needed.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
CD4
T follicular helper (T
) cells are key targets for human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) replication and contribute to the virus reservoir under antiretroviral ...therapy (ART). Here, we describe a novel CD3
CD20
double-positive (DP) lymphocyte subset, resident in secondary lymphoid organs of humans and rhesus macaques (RMs), that appear predominantly after membrane exchange between T
and B cells. DP lymphocytes are enriched in cells displaying a T
phenotype (CD4
PD1
CXCR5
), function (interleukin 21 positive IL-21
), and gene expression profile. Importantly, expression of CD40L upon brief
mitogen stimulation identifies, by specific gene-expression signatures, DP cells of T
-cell origin versus those of B-cell origin. Analysis of 56 RMs showed that DP cells (i) significantly increase following SIV infection, (ii) are reduced after 12 months of ART in comparison to pre-ART levels, and (iii) expand to a significantly higher frequency following ART interruption. Quantification of total SIV-gag DNA on sorted DP cells from chronically infected RMs showed that these cells are susceptible to SIV infection. These data reinforce earlier observations that CD20
T cells are infected and expanded by HIV infection, while suggesting that these cells phenotypically overlap activated CD4
T
cells that acquire CD20 expression via trogocytosis and can be targeted as part of therapeutic strategies aimed at HIV remission.
The HIV reservoir is largely composed of latently infected memory CD4
T cells that persist during antiretroviral therapy and constitute a major barrier toward HIV eradication. In particular, CD4
T follicular helper cells have been demonstrated as key targets for viral replication and persistence under ART. In lymph nodes from HIV-infected humans and SIV-infected rhesus macaques, we show that CD3
CD20
lymphocytes emerge after membrane exchange between T cells and B cells and are enriched in phenotypic, functional, and gene expression profiles found in T follicular helper cells. Furthermore, in SIV-infected rhesus macaques, these cells expand following experimental infection and after interruption of ART and harbor SIV DNA at levels similar to those found in CD4
T cells; thus, CD3
CD20
lymphocytes are susceptible to SIV infection and can contribute to SIV persistence.
Glioblastoma is one of the most lethal forms of adult cancer with a median survival of around 15 months. A potential treatment strategy involves targeting glioblastoma stem‐like cells (GSC), which ...constitute a cell autonomous reservoir of aberrant cells able to initiate, maintain, and repopulate the tumor mass. Here, we report that the expression of the paracaspase mucosa‐associated lymphoid tissue l (MALT1), a protease previously linked to antigen receptor‐mediated NF‐κB activation and B‐cell lymphoma survival, inversely correlates with patient probability of survival. The knockdown of MALT1 largely impaired the expansion of patient‐derived stem‐like cells in vitro, and this could be recapitulated with pharmacological inhibitors, in vitro and in vivo. Blocking MALT1 protease activity increases the endo‐lysosome abundance, impairs autophagic flux, and culminates in lysosomal‐mediated cell death, concomitantly with mTOR inactivation and dispersion from endo‐lysosomes. These findings place MALT1 as a new druggable target involved in glioblastoma and unveil ways to modulate the homeostasis of endo‐lysosomes.
Synopsis
This study unveils that the paracaspase activity of MALT1, which was previously linked to antigen receptor‐mediated NF‐κB activation and lymphomas, is decisive for the expansion of glioblastoma stem‐like cells (GSC), highlighting potential therapeutic strategies against brain cancers.
Expression and catalytic activity of MALT1 are required for GSC expansion.
Pharmacological targeting of MALT1 is lethal to GSCs and reduces the expansion of established tumors in mice.
MALT1 depletion results in an increased endo‐lysosomal compartment and decreased mTOR signaling.
MALT1 expression negatively correlates to that of RNA‐binding protein Quaking to control endo‐lysosomal biogenesis.
Protease MALT1 impairs lysosome biogenesis and increases mTOR signalling and autophagic flux in glioma stem cells.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Microfold cells (M cells) are responsible for antigen uptake to initiate immune responses in the gut-associated lymphoid tissue (GALT). Receptor activator of nuclear factor-κB ligand (RANKL) is ...essential for M cell differentiation. Follicle-associated epithelium (FAE) covers the GALT and is continuously exposed to RANKL from stromal cells underneath the FAE, yet only a subset of FAE cells undergoes differentiation into M cells. Here, we show that M cells express osteoprotegerin (OPG), a soluble inhibitor of RANKL, which suppresses the differentiation of adjacent FAE cells into M cells. Notably, OPG deficiency increases M cell number in the GALT and enhances commensal bacterium-specific immunoglobulin production, resulting in the amelioration of disease symptoms in mice with experimental colitis. By contrast, OPG-deficient mice are highly susceptible to Salmonella infection. Thus, OPG-dependent self-regulation of M cell differentiation is essential for the balance between the infectious risk and the ability to perform immunosurveillance at the mucosal surface.
T cell help to B cells is a fundamental aspect of adaptive immunity and the generation of immunological memory. Follicular helper CD4 T (T(FH)) cells are the specialized providers of B cell help. ...T(FH) cells depend on expression of the master regulator transcription factor Bcl6. Distinguishing features of T(FH) cells are the expression of CXCR5, PD-1, SAP (SH2D1A), IL-21, and ICOS, among other molecules, and the absence of Blimp-1 (prdm1). T(FH) cells are important for the formation of germinal centers. Once germinal centers are formed, T(FH) cells are needed to maintain them and to regulate germinal center B cell differentiation into plasma cells and memory B cells. This review covers T(FH) differentiation, T(FH) functions, and human T(FH) cells, discussing recent progress and areas of uncertainty or disagreement in the literature, and it debates the developmental relationship between T(FH) cells and other CD4 T cell subsets (Th1, Th2, Th17, iTreg).
Ectopic lymphoid-like structures (ELSs) are often observed in cancer, yet their function is obscure. Although ELSs signify good prognosis in certain malignancies, we found that hepatic ELSs indicated ...poor prognosis for hepatocellular carcinoma (HCC). We studied an HCC mouse model that displayed abundant ELSs and found that they constituted immunopathological microniches wherein malignant hepatocyte progenitor cells appeared and thrived in a complex cellular and cytokine milieu until gaining self-sufficiency. The egress of progenitor cells and tumor formation were associated with the autocrine production of cytokines previously provided by the niche. ELSs developed via cooperation between the innate immune system and adaptive immune system, an event facilitated by activation of the transcription factor NF-κB and abolished by depletion of T cells. Such aberrant immunological foci might represent new targets for cancer therapy.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The fetal immune system develops in a rather sterile environment relative to the outside world and, therefore, lacks antigenic education. Soon after birth, the newborn is exposed to the hostile ...environment of pathogens. Recently, animal- and limited human-based studies have indicated that help from the mother, upon transfer of leukocytes and their products via breast milk feeding, greatly assists the newborn’s immune system. Here, I discuss the newest advances on how milk leukocytes impact early life immunity, with an emphasis on the development of the infant T cell repertoire and early immune responses in the periphery and gut-associated lymphoid tissue. A deeper understanding of these novel mechanistic insights may inform potential translational approaches to improving immunity in infants.
Neonates are born with many immune components that are not fully developed. Through ingestion of breast milk, the transfer of maternal immune cells and their products, which begins in utero, continues after birth to aid the development of the neonatal immune system.A broader range of leukocyte types than previously recognized was recently identified in human breast milk.Neonatal conditions of the digestive tract enable the survival of milk cells and facilitate their trafficking to the infant’s tissues.Infants acquire immune protection from milk lymphocytes that originate from the gut and upper respiratory mucosa of the mother. These maternal cells have important roles in the protection and education of the developing immune system.Transferred maternal immunity via milk leukocytes affects short and long-term infant immune functions, shedding light on the potential ability of these maternal cells to modulate immune-related pediatric diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Lymphoid cells that express the nuclear hormone receptor RORγt are involved in containment of the large intestinal microbiota and defense against pathogens through the production of interleukin 17 ...(IL-17) and IL-22. They include adaptive IL-17-producing helper T cells (T(H)17 cells), as well as innate lymphoid cells (ILCs) such as lymphoid tissue-inducer (LTi) cells and IL-22-producing NKp46+ cells. Here we show that in contrast to T(H)17 cells, both types of RORγt+ ILCs constitutively produced most of the intestinal IL-22 and that the symbiotic microbiota repressed this function through epithelial expression of IL-25. This function was greater in the absence of adaptive immunity and was fully restored and required after epithelial damage, which demonstrates a central role for RORγt+ ILCs in intestinal homeostasis. Our data identify a finely tuned equilibrium among intestinal symbionts, adaptive immunity and RORγt+ ILCs.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Human memory B cells and marginal zone (MZ) B cells share common features such as the expression of CD27 and somatic mutations in their IGHV and BCL6 genes, but the relationship between them is ...controversial. Here, we show phenotypic progression within lymphoid tissues as MZ B cells emerge from the mature naïve B cell pool via a precursor CD27
CD45RB
population distant from memory cells. By imaging mass cytometry, we find that MZ B cells and memory B cells occupy different microanatomical niches in organised gut lymphoid tissues. Both populations disseminate widely between distant lymphoid tissues and blood, and both diversify their IGHV repertoire in gut germinal centres (GC), but nevertheless remain largely clonally separate. MZ B cells are therefore not developmentally contiguous with or analogous to classical memory B cells despite their shared ability to transit through GC, where somatic mutations are acquired.
Innate lymphoid cells (ILCs) contribute to barrier immunity, tissue homeostasis, and immune regulation at various anatomical sites throughout the body. How ILCs maintain their presence in lymphoid ...and peripheral tissues thus far has been unclear. We found that in the lymphoid and nonlymphoid organs of adult mice, ILCs are tissue-resident cells that were maintained and expanded locally under physiologic conditions, upon systemic perturbation of immune homeostasis and during acute helminth infection. However, at later time points after infection, cells from hematogenous sources helped to partially replenish the pool of resident ILCs. Thus, ILCs are maintained by self-renewal in broadly different microenvironments and physiological settings. Such an extreme "sedentary" lifestyle is consistent with the proposed roles of ILCs as sentinels and local keepers of tissue function.
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BFBNIB, NMLJ, NUK, ODKLJ, PNG, SAZU, UL, UM, UPUK
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