Gut IgA Class Switch Recombination in the Absence of CD40 Does Not Occur in the Lamina Propria and Is Independent of Germinal Centers

Bergqvist, Peter; Gärdby, Eva; Stensson, Anneli; Bemark, Mats; Lycke, Nils

doi:10.4049/jimmunol.177.11.7772

Cited by 142 publications

(164 citation statements)

References 75 publications

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“…Nevertheless, both pathways for IgA CSR require B cell proliferation and expression of activation-induced cytidine deaminase (AID) (31)(32)(33). Our recent study in CD40-deficient mice, and also previous studies in ICOS-or CD28-deficient mice, supports the hypothesis that near normal IgA plasma cell levels can be found in the LP in the complete absence of GCs in Peyer's patches (PPs) (8,30). We proposed previously that such IgA CSR could have occurred at alternative sites outside of the GALT.…”

supporting

confidence: 63%

“…We proposed previously that such IgA CSR could have occurred at alternative sites outside of the GALT. However, we failed to find evidence for IgA CSR in the noorganized LP of the small intestine or in the peritoneal cavity, two of the reportedly strongest candidates for IgA CSR (20,30,34). A recent study has, however, pointed to the nonorganized LP of the colon as a possible site for IgA CSR (11).…”

contrasting

confidence: 43%

“…Whereas IgA production is near normal in the absence of CD40, it is dramatically impaired in APRIL-or BAFF-deficient mice (27)(28)(29)(30). Moreover, the action of these molecules is independent of CD40 and TGFb (9,11,21,25).…”

mentioning

confidence: 90%

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T Cell-Independent IgA Class Switch Recombination Is Restricted to the GALT and Occurs Prior to Manifest Germinal Center Formation

Bergqvist

Stensson

Lycke

et al. 2010

The Journal of Immunology

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Recently, we reported that CD40−/− mice, exhibiting exclusively T cell-independent IgA class switch recombination (CSR), demonstrated near normal levels of IgA plasma cells in the gut lamina propria (LP), despite the complete lack of germinal centers (GCs). In this study, we have extended our analysis focusing on how to reconcile these findings using flow cytometry and molecular markers for IgA CSR. In agreement with our previous results with small intestinal LP, the colon LP was found to host IgA CSR only when lymphoid follicles were present. Thus, no IgA CSR was observed in the nonorganized colon LP. By contrast, the Peyer’s patch (PP) was the dominant IgA CSR site in both CD40−/− and wild type (WT) mice, and they both hosted similar levels of mRNA expression for B cell activating factor of the TNF family, a proliferation inducing ligand, and inducible NO synthase, potential switch-factors for IgA. Unexpectedly, we found that PP B cells undergoing IgA CSR were GL7-intermediate. These cells had not undergone somatic hypermutations (SHMs), whereas GL7-high cells in WT PP, which exhibited GCs, were heavily mutated. Moreover, IgA plasma cells in the LP of CD40−/− mice demonstrated few mutations in their Ig V regions, whereas WT LP B cells from different sites showed extensive SHMs, which were also clonally related. Therefore, IgA CSR can occur in PP at a stage preceding manifest GC (GL7-intermediate), whereas SHM require GC formations (GL7-high). These findings reconcile that IgA CSR can occur in PP in the absence of GC with the fact that CD40−/− mice host near normal levels of IgA plasma cells in the LP.

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supporting

confidence: 63%

contrasting

confidence: 43%

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T Cell-Independent IgA Class Switch Recombination Is Restricted to the GALT and Occurs Prior to Manifest Germinal Center Formation

Bergqvist

Stensson

Lycke

et al. 2010

The Journal of Immunology

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“…Sections of PP from naïve and infected mice were prepared for immunohistochemistry as previously described [47]. Detection of surface markers was carried out at room temperature for 30-60 min using the following mAb that were biotinylated or conjugated to FITC: anti-CD11c (HL3), B220 (RA3-6B2), Ly6C (AL-21), Ly6G (1A8) or appropriate isotype controls.…”

Section: Immunohistochemistry and Laser Capture Microdissection Micromentioning

confidence: 99%

Monocyte and neutrophil recruitment during oral Salmonella infection is driven by MyD88‐derived chemokines

Rydström

Wick

2009

Eur J Immunol

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Oral Salmonella infection recruits phagocytes to Peyer's patches (PP) and MLN. The chemokines induced in infected PP and MLN, the cellular sources during infection and the TLR signaling pathways involved in vivo are not known. Here, we show that CCL2, CXCL9 and CXCL2 mRNA are up-regulated in PP and MLN coincident with the first arrival of monocytes and neutrophils. Laser capture microdissection microscopy revealed that chemokine mRNA up-regulation was differently distributed in PP. Despite this, recruited monocytes and neutrophils formed inflammatory cell clusters throughout PP. Monocytes and neutrophils purified from infected mice preferentially produced CXCL2 and small amounts of CCL2, and neutrophils from infected mice migrated towards CXCL2 and CCL3. Furthermore, phagocyte recruitment to PP and MLN was intact in mice lacking TLR4 alone and when signaling through TLR4 and TLR5 was simultaneously absent; however, recruitment was compromised in MyD88 À/À and more so in MyD88 À/À TLR4 À/À double knockout mice. Phagocyte release into the blood, however, was only marginally reduced in MyD88 À/À TLR4 À/À mice. Defective phagocyte recruitment to PP and MLN of MyD88 À/À TLR4 À/À mice was paralleled by low chemokine induction. These data provide insight into the chemokines and TLR signaling pathways that orchestrate the early phagocyte response to oral Salmonella infection.Key words: Chemokine . Monocyte . Salmonella . TLR IntroductionMonocytes and neutrophils are critical in the first line of defense against bacteria. They develop in the bone marrow, are released into the circulation and enter tissues in response to infection. Murine monocytes in the blood are a heterogeneous population and have been divided into two main subsets based on whether they are present in steady state or recruited under inflammatory conditions [1]. Inflammatory Gr-1 hi CCR2 hi CX 3 CR1 low monocytes, which have also been called TipDC upon entering a tissue, are a source of molecules important in controlling bacterial infection, particularly iNOS and TNF-a [2][3][4].Salmonella enterica serovar Typhimurium (S. typhimurium) is a Gram-negative facultative intracellular bacterium that infects via the oral route. Orally acquired Salmonella exits the gut lumen primarily by crossing the follicle-associated epithelium overlying Peyer's patches (PP) via M cells (reviewed in [5]). The bacteria are then further spread to the MLN, most likely by DC, and to the spleen and liver via the blood [5,6]. After oral infection with S. typhimurium, neutrophils and Gr-1 hi CCR2 hi inflammatory monocytes accumulate in PP and MLN, the first organs encountering the bacteria, beginning 2-3 days after infection [3].Chemokines are the main mediators involved in the recruitment and migration of leukocytes to and within tissues. An array of chemokines is induced by inflammation and recruits monocytes, neutrophils and other cells to sites of infection. The chemokine receptors CCR2 and CXCR2 are required for monocytes and neutrophils, respectively, to egress from the bone ...

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“…in T-cell-deficient mice, CD40 −/− mice, CD28 −/− mice, etc.) [5][6][7]. However, the precise contribution of T-cell-dependent and TI pathways to IgA production is not known.…”

Section: Introductionmentioning

confidence: 99%

B‐1‐cell subpopulations contribute differently to gut immunity

et al. 2013

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IntroductionIgA is the major class of Ab present in mucosal tissues of mammals. IgA constitutes a key defense mechanism against invasion by inhaled or ingested pathogens. IgA is also found at significant concentrations in the serum of many species, where it mediates the elimination of pathogens that have breached the mucosa [1].Among the various MALTs, IgA-producing cells are present in highest numbers in GALTs constituted by Peyer's patches (PPs), isolated lymphoid follicles (ILFs), and solitary intestinal lymphoid Correspondence: Dr. Bishnudeo Roy e-mail: Bishnudeo.Roy@helmholtz-hzi.de tissue (SILT) [2,3]. B cells, present in the B-cell follicles of such organized structures, form GCs upon Ag encounter. Under the influence of various cellular and molecular factors -T cells and cytokines, for instance -these B cells are thought to switch from IgM to IgA [4].Multiple pathways of IgA induction have been reported. The T-cell-dependent pathway of IgA induction is well known and, it is clear that IgA can also be induced in T-cell-independent (TI) manner (e.g. in T-cell-deficient mice, CD40 −/− mice, CD28 −/− mice, etc.) [5][6][7]. However, the precise contribution of T-cell-dependent and TI pathways to IgA production is not known.An important contribution of B-1 cells to TI responses has been suggested [6,8,9]. Peritoneal cavity (PEC) B-1 cells have also been claimed to contribute significantly to IgA-producing plasma cell (PC) Eur. J. Immunol. 2013Immunol. . 43: 2023Immunol. -2032. Importantly, according to phenotype, origin, and function, PEC B-1 cells can be divided into B-1a and B-1b subpopulations [12,13]. Phenotypically, B-1a cells are characterized as B220 lo CD19 hi IgM hi IgD lo CD43 + Mac-1 + CD5 int . B-1b cells share all the aforementioned markers with B-1a cells except CD5. With respect to differential contribution of these two B-1-cell subtypes to IgA production, recently, we could show that most of the IgA-secreting cells in the PEC of unmanipulated mice belonged to B-1b-cell subpopulation [14]. Additionally, IgA-derived VH regions from B-1b cells also contained frequent single nucleotide exchanges indicative of somatic hypermutation (SHM) [14]. Thus, a contribution of PEC B-1b cells to IgA production and hence to gut-associated immunity is quite likely. However, in spite of evidential suggestions for the contribution of B-1 cells to the intestinal PC pool, their contribution under unmanipulated conditions remains uncertain. This is partly due to the lack of appropriate markers to distinguish PCs according to their origin. In this context, a sequence-based approach to address this question should become very useful.In the present work, to investigate the participation of PEC B-1 cells in the gut-associated IgA production we have made use of the transgenic mouse model known as the L2 mouse line [15]. Mice of this line are characterized by the expression of a transgenic λ light chain obtained from the plasmacytoma MOPC315 (λ2 315 ). PEC of these mice contains almost exclusively CD5 + B-1a cells, whi...

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Gut IgA Class Switch Recombination in the Absence of CD40 Does Not Occur in the Lamina Propria and Is Independent of Germinal Centers

Cited by 142 publications

References 75 publications

T Cell-Independent IgA Class Switch Recombination Is Restricted to the GALT and Occurs Prior to Manifest Germinal Center Formation

T Cell-Independent IgA Class Switch Recombination Is Restricted to the GALT and Occurs Prior to Manifest Germinal Center Formation

Monocyte and neutrophil recruitment during oral Salmonella infection is driven by MyD88‐derived chemokines

B‐1‐cell subpopulations contribute differently to gut immunity

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