Superantigen- and TLR-Dependent Activation of Tonsillar B Cells after Receptor-Mediated Endocytosis

Jendholm, Johan; Mörgelin, Matthias; Vidakovics, Laura Perez; Carlsson, Michael C.; Leffler, Hakon; Cardell, Lars-Olaf; Riesbeck, Kristian

doi:10.4049/jimmunol.0803032

Cited by 29 publications

(38 citation statements)

References 55 publications

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“…catarrhalis can be found adjacent to B cells in tonsils [6] and we have recently shown that this pathogen is internalized by tonsillar B cells [13]. Intracellular survival of bacteria in B cells would thus be a potential escape mechanism in the host.…”

Section: Resultsmentioning

confidence: 98%

“…catarrhalis would theoretically also contain MID as vesicles basically comprise outer membrane components, i.e., LPS, phospholipids and outer membrane proteins. The potential of OMV to carry and long-distance deliver diverse virulence factors prompted us to hypothesize that Moraxella OMV can activate human B cells as has been proven with whole bacteria [13],[14]. The initial step in B cell activation requires M .…”

Section: Resultsmentioning

confidence: 99%

“…catarrhalis on IgD + human B cells [12]. Cross-linking of the BCR leads to receptor-mediated endocytosis of whole bacteria and a lower threshold for pathogen recognition receptor (PRR) signalling in the B cell [13]. Toll-like receptor (TLR) 9 is the most important PRR in M .…”

Section: Introductionmentioning

confidence: 99%

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B Cell Activation by Outer Membrane Vesicles—A Novel Virulence Mechanism

et al. 2010

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Secretion of outer membrane vesicles (OMV) is an intriguing phenomenon of Gram-negative bacteria and has been suggested to play a role as virulence factors. The respiratory pathogens Moraxella catarrhalis reside in tonsils adjacent to B cells, and we have previously shown that M. catarrhalis induce a T cell independent B cell response by the immunoglobulin (Ig) D-binding superantigen MID. Here we demonstrate that Moraxella are endocytosed and killed by human tonsillar B cells, whereas OMV have the potential to interact and activate B cells leading to bacterial rescue. The B cell response induced by OMV begins with IgD B cell receptor (BCR) clustering and Ca2+ mobilization followed by BCR internalization. In addition to IgD BCR, TLR9 and TLR2 were found to colocalize in lipid raft motifs after exposure to OMV. Two components of the OMV, i.e., MID and unmethylated CpG-DNA motifs, were found to be critical for B cell activation. OMV containing MID bound to and activated tonsillar CD19+ IgD+ lymphocytes resulting in IL-6 and IgM production in addition to increased surface marker density (HLA-DR, CD45, CD64, and CD86), whereas MID-deficient OMV failed to induce B cell activation. DNA associated with OMV induced full B cell activation by signaling through TLR9. Importantly, this concept was verified in vivo, as OMV equipped with MID and DNA were found in a 9-year old patient suffering from Moraxella sinusitis. In conclusion, Moraxella avoid direct interaction with host B cells by redirecting the adaptive humoral immune response using its superantigen-bearing OMV as decoys.

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

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B Cell Activation by Outer Membrane Vesicles—A Novel Virulence Mechanism

et al. 2010

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“…However, their existence has been reported in some respiratory Gram-negative bacteria. Examples include protein D from Haemophilusinfluenzae [19] and Moraxella IgD-binding protein from Moraxella catarrhalis [20], both of which bind human IgD with high affinity. Thus, it is reasonable to believe that mast cells recognize the invasion of some Gram-negative bacteria through sensing their immunoglobulin-binding proteins in antigenindependent manners.…”

Section: Indirect Recognitionmentioning

confidence: 99%

Mast Cells as Critical Effectors of Host Immune Defense against Gram-negative Bacteria

Matsuguchi

2012

CMC

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Mast cells are best known as central effector cells in IgE-mediated type I allergic diseases including asthma and hay fever. An increasing amount of evidence, however, has demonstrated that mast cells are sentinel cells playing a critical role in host defense against invading microbes. Mast cells are located immediately beneath the epithelial surfaces exposed to the outer environment, such as genitourinary and gastrointestinal tracts, skin, and airways. This review discusses recent studies on the critical roles of mast cells in host defense against Gram-negative bacterial infection. Mast cells are equipped with multiple receptors detecting the invading Gram-negative bacteria in both direct (opsonin-independent) and indirect (opsonin-dependent) mechanisms. The former includes Toll-like receptors (TLRs), CD48, and nucleotide-binding oligomerization (NOD) proteins, while the latter includes Fcγ receptors (FcγRs) and complement receptors. In addition to the detecting systems, mast cells are also armed with versatile tools to combat and kill Gram-negative bacteria. In response to the recognition of the Gram-negative bacterial infection, mast cells secrete various types of mediators which either regulate host immune system or directly attack the bacteria. Mast cells can also phagocytize and subsequently display the bacterial antigens on their cell surfaces. Moreover, recent findings have revealed the formation of extra-cellular traps by mast cells. Finally this review will especially focus on recent findings on LPS signaling in mast cells, both the functional outcome and the molecular mechanisms.

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“…However, in light of the finding that many human IgM 2 /IgD + plasmablasts express IgD with hypermutated VH (35) and VL (39) regions that are predicted to be incapable of binding Ag, combined with the fact that secreted IgD made by stimulated IgM 2 /IgD + plasmablasts binds to Moraxella catarrhalis and Haemophilus influenzae type a and type b (40), it is plausible that catfish secreted IgD, which was shown to be expressed in serum (22), functions through its Fc portion. For example, the IgDbinding proteins of M. catarrhalis and H. influenzae were shown to be stimulatory for human IgM 2 /IgD + B cells and bind human IgD via the Cd1 domain (68)(69)(70)(71)(72), Furthermore, in a recent study, it was demonstrated that IgD cross-linking by the superantigen M. catarrhalis IgD-binding protein leads to IgD-mediated endocytosis and B cell proliferation, because the engulfed bacteria activate various TLRs (mainly TLR 9) (73). Therefore, it is feasible that catfish IgM 2 /IgD + B cells, or even a certain subset of IgM + / IgD + B cells, could become activated by an "unidentified" pathogen, which has developed IgD-binding properties.…”

Section: /Igdmentioning

confidence: 99%