Siglecs and Immune Regulation

Pillai, Shiv; Netravali, Ilka Arun; Cariappa, Annaiah; Mattoo, Hamid

doi:10.1146/annurev-immunol-020711-075018

Cited by 310 publications

(336 citation statements)

References 171 publications

(188 reference statements)

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“…These are Factor H regulates C3 and nucleosomes in apoptosis M Martin et al inhibitory receptors of the sialic acid-binding Ig-like lectin family, which attenuate immune responses and dampen inflammation. 27 FH binds to sialic acid 28 and seems to facilitate the interaction of cis sialic acids and siglec receptors on the monocytes, which enhances their inhibitory response.…”

Section: Discussionmentioning

confidence: 99%

Factor H uptake regulates intracellular C3 activation during apoptosis and decreases the inflammatory potential of nucleosomes

et al. 2016

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Factor H (FH) binds apoptotic cells to limit the inflammatory potential of complement. Here we report that FH is actively internalized by apoptotic cells to enhance cathepsin L-mediated cleavage of endogenously expressed C3, which results in increased surface opsonization with iC3b. In addition, internalized FH forms complexes with nucleosomes, facilitates their phagocytosis by monocytes and induces an anti-inflammatory biased cytokine profile. A similar cytokine response was noted for apoptotic cells coated with FH, confirming that FH diminishes the immunogenic and inflammatory potential of autoantigens. These findings were supported by in vivo observations from CFH − / − MRL-lpr mice, which exhibited higher levels of circulating nucleosomes and necrotic cells than their CFH +/+ littermates. This unconventional function of FH broadens the established view of apoptotic cell clearance and appears particularly important considering the strong associations with genetic FH alterations and diseases such as systemic lupus erythematosus and age-related macular degeneration. Factor H (FH), one of the most abundant plasma proteins, is the major soluble inhibitor of the alternative complement pathway. Apoptotic cells bind FH while triggering complement activation by binding of C1 complex, which ensures efficient opsonization and removal of apoptotic debris but prevents excessive complement activation and inflammation. 1,2 Dysregulation of complement contributes significantly to the pathology of many diseases. 3 Recently, novel roles and intracellular location for complement have been identified suggesting that its functions exceed our current understanding. 4 After previously identifying the ligands for FH on the apoptotic cell surface as dsDNA, histones and annexin A2, 5 we sought to explore the functional consequences of the FH-apoptotic cell interaction in the context of the chronic autoimmune disorder systemic lupus erythematosus (SLE) and age-related macular degeneration (AMD). Aberrant apoptosis and impaired clearance of apoptotic cells are of central importance in the pathogenesis of SLE and lead to formation of autoantibodies. 6-8 Anti-chromatin autoantibodies are a hallmark of SLE and anti-annexin A2 autoantibodies are also frequently observed in SLE patients. 9 Interestingly, the corresponding autoantigens are exactly those that we identified as ligands for FH on the apoptotic cell surface, suggesting a possibility of disturbance of FH function in SLE. Glomerulonephritis is one typical manifestation of human SLE 10 and mutations in FH and another complement inhibitor CD46 are associated with earlier onset of nephritis in SLE patients. 11 FH-deficient (CFH − / − ) mice spontaneously develop membranoproliferative glomerulonephritis, which is dependent on C3 activation. 12 When crossed with the MRL-lpr mouse strain, a model of lupus, the originated CFH − / − MRLlpr mice exhibit accelerated lupus nephritis and die at younger age than their CFH +/+ MRL-lpr littermates. 13,14 AMD is the leading cause of visual impairm...

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Section: Discussionmentioning

confidence: 99%

Factor H uptake regulates intracellular C3 activation during apoptosis and decreases the inflammatory potential of nucleosomes

et al. 2016

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“…Siglec-10 belongs to a major subfamily of Ig-like lectins that mediate sialic acid recognition by their terminal Ig like domains 5 to regulate innate and adaptive immune responses. 6 The data suggest that sialic acid structures of CD52 binds to Ig-like domain of Siglec-10 because suppression was lost by cleavage of Nglycans from CD52-Fc by peptide Nglycosidase or by removal of sialic acid residues by neuraminidase. Suppression was also blocked by antibody to the extracellular domain of Siglec-10 and by soluble Siglec-10-Fc.…”

mentioning

confidence: 95%

Immune regulation by CD52-expressing CD4 T cells

et al. 2013

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T-cell regulation by CD52-expressing CD4 T cells appears to operate by two different and possibly synergistic mechanisms. The first is by its release from the cell surface of CD4 T cells that express high levels of CD52 that then binds to the inhibitory sialic acid-binding immunoglobulin-like lectins-10 (Siglec-10) receptor to attenuate effector T-cell activation by impairing phosphorylation of T-cell receptor associated lck and zap-70. The second mechanism appears to be by crosslinkage of the CD52 molecules by an as yet unidentified endogenous ligand that is mimicked by a bivalent anti-CD52 antibody that results in their expansion.

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“…This confirms that the cells are truly activated because the suppression of Siglec-G expression correlates with cell activation. 23 The data indicate that IL-15 mediates B-1a cell activation in the absence of the pathogenic stimuli that are associated with Siglec-G downregulation. The treatment of B-1a cells with the pathogen-associated molecule LPS downregulated Siglec-G by 21% (P,0.05).…”

Section: Il-15 Induces B-1a Cell Activation and Ablates The Siglec-gmentioning

confidence: 93%

“…Siglec-G belongs to a superfamily of immunoglobulin-like lectins with the ability to recognize sialic acid-containing structures, functions as a negative regulator of B-1 cells and inhibits BCR-mediated signaling. 23 Siglec-G 2/2 mice have increased numbers of B-1a cells with a lower apoptosis rate, 32 indicating that it has a negative impact on cell activation. We show for the first time that the downregulation of Siglec-G correlates with the degree of IL-15 mediated activation in B-1a cells.…”

Section: Il-15 Augmented Igm and Iga Expressionmentioning

confidence: 99%

IL-15 temporally reorients IL-10 biased B-1a cells toward IL-12 expression

et al. 2015

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Interleukin (IL)-15 is known to strongly modulate T-cell function; however, its role in controlling mucosal immunity, including its ability to modulate B-1a cell activity, remains to be elucidated. Here, we show that IL-15 upregulates activation molecules and the costimulatory molecule CD80 on viable B-1a cells. Cell activation was accompanied by the depletion of sialic acid-binding immunoglobulin-like lectin (Siglec)-G, an inhibitor of cell activation that is present on B-1a cells. The IL-15 receptor CD122 was stimulated on B-1a cells by the cytokine showing its direct involvement in IL-15-mediated responses. IL-10 is responsible for the long term survival of B-1a cells in culture, which is initially promoted by IL-15. The upregulation of IL-10 was followed by the appearance of suppressor of cytokine signaling (SOCS)1 in the presence of IL-15 and the loss of IL-10. This resulted in the cells switching to IL-12 expression. This anti-inflammatory to pro-inflammatory shift in the B-1a cell character was independent of the cell-specific marker CD5, which remained highly expressed throughout the in vitro life of the cells. The presence of the immunosuppressive receptor programmed cell death (PD)-1 and its ligand PD-L2 were features of a predominantly IL-10 response. PD-1 and PD-L2 can mediate juxtacrine signaling. However, the abrogation of PD-1 and its ligand was observed when the cells expressed IL-12. This demonstrates an inverse relationship between the receptor and ligand and the pro-inflammatory cytokine. The induction of IgM and IgA, which can play pivotal roles in mucosal immunity, was promoted in the presence of IL-15. Collectively, the data implicate IL-15 as the master cytokine that induces B-1a cells to mount a mucosal immune response. Cellular & Molecular Immunology

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Siglecs and Immune Regulation

Cited by 310 publications

References 171 publications

Factor H uptake regulates intracellular C3 activation during apoptosis and decreases the inflammatory potential of nucleosomes

Factor H uptake regulates intracellular C3 activation during apoptosis and decreases the inflammatory potential of nucleosomes

Immune regulation by CD52-expressing CD4 T cells

IL-15 temporally reorients IL-10 biased B-1a cells toward IL-12 expression

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