![]() ![]() These studies strongly suggest that positive selection via BCR signaling is critical for B-1a cell development and/or maintenance. Moreover, mice harboring mutations in BCR signaling molecules such as Btk exhibit a reduction in B-1a B cell numbers ( Khan et al., 1995b), whereas mice with deficiencies in BCR coinhibitory molecules such as CD72 have increased frequencies of B-1a cells ( Pan et al., 1999). Early studies from Hayakawa and colleagues showed that the absence of a specific self-antigen, such as Thy-1, results in the absence of self-reactive B-1a specificities to that antigen ( Khan et al., 1995a). Other specificities include nucleic acids, LPS, and carbohydrates. For example, the most common B-1a specificity is for phosphatidylcholine (PtC), a phospholipid present within the plasma membranes of eukaryotic cells ( Mercolino et al., 1988). More recently B-1a cells have been implicated as a source of microbiota-reactive, class-switched IgG and IgA antibodies, which are important for intestinal homeostasis ( Kroese et al., 1989 Kroese et al., 1993 Lalor, 1991 Kroese et al., 1996 Bos et al., 1996 Macpherson et al., 2000 Koch et al., 2016 Savage et al., 2017).ī-1a cell-derived antibodies are often reactive with self epitopes ( Hayakawa et al., 1999 Mercolino et al., 1988 Yang et al., 2015). B-1a cells are the main producers of serum IgM antibodies ( Lalor et al., 1989a Baumgarth et al., 1999 Ohdan et al., 2000 Haas et al., 2005 Choi and Baumgarth, 2008 Holodick et al., 2009), which promote tissue homeostasis and provide protection against infections ( Haas et al., 2005 Choi and Baumgarth, 2008 Boes et al., 1998 Ochsenbein et al., 1999 Boes et al., 2000 Ehrenstein et al., 2000 Baumgarth et al., 2000 Alugupalli et al., 2003 Notley et al., 2011 Vas et al., 2013). Unlike follicular B cells, termed B-2, B-1a cells are rapidly recruited to sites of infection and produce antibodies independently of T cell help. ![]() Strikingly, we find that both the colonization of a microbiota as well as microbial-sensing TLRs are required for anti-microbiota B-1a responses, whereas nucleic-acid sensing TLRs are required for anti-PtC responses, demonstrating that linked activation of BCR and TLRs controls steady state B-1a responses to both self and microbiota-derived antigens.ī-1a cells were discovered 35 years ago and have characteristics that bridge the innate and adaptive immune system ( Herzenberg et al., 1986). Moreover, we show that Toll-like receptors (TLRs) are critical for shaping the Ig repertoire of B-1a cells as well as regulating their antibody production. Here, we use a novel reporter mouse to demonstrate that production of self- and microbiota-reactive antibodies is linked to BCR signaling in B-1a cells. ![]() The mechanisms that regulate the B-1a immunoglobulin (Ig) repertoire and their antibody secretion remain poorly understood. They are the main producers of ‘natural’ IgM, spontaneously secreted serum antibodies predominately reactive to self antigens, like phosphatidylcholine (PtC), or antigens expressed by the intestinal microbiota. B-1a cells play an important role in mediating tissue homeostasis and protecting against infections. ![]()
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