Regulation of Decay Accelerating Factor Primes Human Germinal Center B Cells for Phagocytosis

Dernstedt, Andy; Leidig, Jana; Holm, Anna; Kerkman, Priscilla F; Mjösberg, Jenny; Ahlm, Clas; Henriksson, Johan; Hultdin, Magnus; Forsell, Mattias N.E.

doi:10.3389/fimmu.2020.599647

Cited by 9 publications

(12 citation statements)

References 50 publications

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“…Other studies employing germline C3ar1/C5ar1 -deficient animals showed that B cell-expressed C3aR1/C5aR1 signals drive early activation events (including upregulation of AID and BCL-6), but potential links to GC dynamics and GC-dependent affinity maturation were not addressed 46 . A recent 2021 paper 47 reported DAF downregulation on human GC B cells, largely confirming our findings. The authors suggested that DAF downregulation would enhance phagocytosis of GC B cells and could possibly also facilitate interaction with T cells; mechanisms that we did not directly test in our study but could directly/indirectly impact affinity maturation and positive selection in the GC 48 , 49 , contributing to the phenotypes that we detect in our models.…”

Section: Discussionsupporting

confidence: 92%

Dynamic regulation of B cell complement signaling is integral to germinal center responses

Čumpelik

Héja

et al. 2021

Nat Immunol

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B cell maturation within germinal centers (GCs) generates diversified B cell pools and high-affinity B cell antigen receptors (BCRs) for pathogen clearance. Increased receptor affinity is achieved by iterative cycles of T cell-dependent, affinity-based B cell positive selection and clonal expansion by incompletely understood mechanisms. Here, we found that as part of a physiologic program, GC B cells repressed expression of decay-accelerating factor (DAF/CD55) and other complement C3-convertase regulators via Bcl-6, but increased C5b-9 inhibitor (CD59) expression. These changes permitted C3 cleavage on GC B cell surfaces, without membrane attack complex formation, and activated C3a-receptor and C5a-receptor signals required for positive selection. Genetic disruption of this pathway in antigen-activated B cells, by conditional transgenic DAF overexpression or deletion of C3a and C5a receptors, limited mTOR activity in response to BCR-CD40 signaling, causing premature GC collapse and impaired affinity maturation. These results reveal that coordinated shifts in complement regulation within the GC provide crucial signals underlying GC B cell positive selection.

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Section: Discussionsupporting

confidence: 92%

Dynamic regulation of B cell complement signaling is integral to germinal center responses

Čumpelik

Héja

et al. 2021

Nat Immunol

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“…Indeed, CD55 localised to germinal centres, the sites of B-cell expansion and selection, and the presence of B cells in the germinal centres was confirmed by Pax-5 staining. This finding is supported by recent data showing CD55 localisation in tonsil germinal centres and that its expression on B-cell surfaces regulates their complement-dependent phagocytosis for maintaining homeostasis [38]. Furthermore, our data showed that CD55 staining in lymphoid aggregates was independent of H. pylori status and that their presence was not associated with gastric mucosal CD55 mRNA levels.…”

Section: Discussionsupporting

confidence: 91%

The active form of Helicobacter pylori vacuolating cytotoxin induces decay‐accelerating factor CD55 in association with intestinal metaplasia in the human gastric mucosa

Kaneko

Zaitoun

Letley

et al. 2022

The Journal of Pathology

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High-level expression of decay-accelerating factor, CD55, has previously been found in human gastric cancer (GC) and intestinal metaplasia (IM) tissues. Therapeutic effects of CD55 inhibition in cancer have been reported. However, the role of Helicobacter pylori infection and virulence factors in the induction of CD55 and its association with histological changes of the human gastric mucosa remain incompletely understood. We hypothesised that CD55 would be increased during infection with more virulent strains of H. pylori, and with more marked gastric mucosal pathology. RT-qPCR and immunohistochemical analyses of gastric biopsy samples from 42 H. pylori-infected and 42 uninfected patients revealed that CD55 mRNA and protein were significantly higher in the gastric antrum of H. pylori-infected patients, and this was associated with the presence of IM, but not atrophy, or inflammation. Increased gastric CD55 and IM were both linked with colonisation by vacA i1-type strains independently of cagA status, and in vitro studies using isogenic mutants of vacA confirmed the ability of VacA to induce CD55 and sCD55 in gastric epithelial cell lines. siRNA experiments to investigate the function of H. pylori-induced CD55 showed that CD55 knockdown in gastric epithelial cells partially reduced IL-8 secretion in response to H. pylori, but this was not due to modulation of bacterial adhesion or cytotoxicity. Finally, plasma samples taken from the same patients were analysed for the soluble form of CD55 (sCD55) by ELISA. sCD55 levels were not influenced by IM and did not correlate with gastric CD55 mRNA levels. These results suggest a new link between active vacA i1-type H. pylori, IM, and CD55, and identify CD55 as a molecule of potential interest in the management of IM as well as GC treatment.

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“…This labeling occurs by binding phosphatidylserine that is externalized on the surface of cells undergoing apoptosis (69). Recently, a molecule called decay accelerating factor (DAF) has also been proposed to regulate GC B cell phagocytosis (70). Such signals likely help TBMs distinguish between healthy B cells and B cells undergoing apoptosis.…”

Section: A New Gc Modelmentioning

confidence: 99%

Compartments and Connections Within the Germinal Center

Kennedy

Clark

2021

Front. Immunol.

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Protective high affinity antibody responses emerge through an orchestrated developmental process that occurs in germinal centers (GCs). While GCs have been appreciated since 1930, a wealth of recent progress provides new insights into the molecular and cellular dynamics governing humoral immunity. In this review, we highlight advances that demonstrate that fundamental GC B cell function, selection, proliferation and SHM occur within distinct cell states. The resulting new model provides new opportunities to understand the evolution of immunity in infectious, autoimmune and neoplastic diseases.

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Regulation of Decay Accelerating Factor Primes Human Germinal Center B Cells for Phagocytosis

Cited by 9 publications

References 50 publications

Dynamic regulation of B cell complement signaling is integral to germinal center responses

Dynamic regulation of B cell complement signaling is integral to germinal center responses

The active form of Helicobacter pylori vacuolating cytotoxin induces decay‐accelerating factor CD55 in association with intestinal metaplasia in the human gastric mucosa

Compartments and Connections Within the Germinal Center

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