Protective molecules and their cognate antibodies: new players in autoimmunity.
Auto- immunity highlights
Impairment of the clearance of apoptotic material seems to contribute to autoantigen exposure, which can initiate or maintain an autoimmune response in predisposed individuals. Complement component C1q, Creactive protein (CRP), serum amyloid P (SAP), mannose-binding lectin (MBL), apolipoprotein A-1 (Apo A-1) and long pentraxin 3 (PTX3) are molecules involved in the removal of apoptotic bodies and pathogens, and in other antiinflammatory pathways. For this reason they have been called "protective" molecules. C1q has a key role in the activation of the complement cascade and acts as a bridging molecule between apoptotic bodies and macrophages favouring phagocytosis. In addition to other functions, CRP, SAP and MBL bind to the surface of numerous pathogens as well as cellular debris and activate the complement cascade, thus stimulating their clearance by immune cells. The role of PTX3 is more controversial. In fact, PTX also promotes the clearance of microorganisms, but the activation of the complement cascade through C1q and removal of apoptotic material can be either stimulated or inhibited by this molecule. Antibodies against protective molecules have been recently reported in systemic lupus erythematosus and other autoimmune rheumatic diseases. Some of them seem to be pathogenetic and others protective. Thus, protective molecules and their cognate antibodies may constitute a regulatory network involved in autoimmunity. Dysregulation of this system might contribute to the development of autoimmune diseases in predisposed individuals.
10.1007/s13317-010-0010-8
Serum Amyloid P Component Binds Fungal Surface Amyloid and Decreases Human Macrophage Phagocytosis and Secretion of Inflammatory Cytokines.
Behrens Nicole E,Lipke Peter N,Pilling Darrell,Gomer Richard H,Klotz Stephen A
mBio
In patients with invasive fungal diseases, there is often little cellular inflammatory response. We tested the idea that binding of the human constitutive plasma protein serum amyloid P component (SAP) (also called PTX2) to dampens the innate immune response to this fungus. Many pathogenic fungi have cell surface amyloid-like structures important for adhesion and biofilm formation. Human SAP bound to fungi that expressed functional cell surface amyloid, but SAP had minimal binding to fungi with reduced expression of cell surface amyloid. In the absence of SAP, phagocytosis of fungi by human macrophages was potentiated by expression of amyloid on the fungi. SAP binding to fungi inhibited their phagocytosis by macrophages. Macrophages pretreated with SAP displayed reduced fungal phagocytosis, reduced secretion of inflammatory cytokines (IFN-γ, IL-6, and TNF-α), and increased secretion of the anti-inflammatory cytokine IL-10. SAP bound to fungi or added to the medium upregulated the expression of the anti-inflammatory receptor CD206 on macrophages. These findings suggest that SAP bound to amyloid-like structures on fungal cells dampens the host cellular immune response in fungal diseases such as invasive candidiasis. Macrophages are a key part of our innate immune system and are responsible for recognizing invading microbes, ingesting them, and sending appropriate signals to other immune cells. We have found that human macrophages can recognize invading yeast pathogens that have a specific molecular pattern of proteins on their surfaces: these proteins have structures similar to the structures of amyloid aggregates in neurodegenerative diseases like Alzheimer's disease. However, this surface pattern also causes the fungi to bind a serum protein called serum amyloid P component (SAP). In turn, the SAP-coated yeasts are poorly recognized and seldom ingested by the macrophages, and the macrophages have a more tolerant and less inflammatory response in the presence of SAP. Therefore, we find that surface structures on the yeast can alter how the macrophages react to invading microbes.
10.1128/mBio.00218-19
Serum amyloid P component controls chromatin degradation and prevents antinuclear autoimmunity.
Bickerstaff M C,Botto M,Hutchinson W L,Herbert J,Tennent G A,Bybee A,Mitchell D A,Cook H T,Butler P J,Walport M J,Pepys M B
Nature medicine
Serum amyloid P component (SAP), a highly conserved plasma protein named for its universal presence in amyloid deposits, is the single normal circulating protein that shows specific calcium-dependent binding to DNA and chromatin in physiological conditions. The avid binding of SAP displaces H1-type histones and thereby solubilizes native long chromatin, which is otherwise profoundly insoluble at the physiological ionic strength of extracellular fluids. Furthermore, SAP binds in vivo both to apoptotic cells, the surface blebs of which bear chromatin fragments, and to nuclear debris released by necrosis. SAP may therefore participate in handling of chromatin exposed by cell death. Here we show that mice with targeted deletion of the SAP gene spontaneously develop antinuclear autoimmunity and severe glomerulonephritis, a phenotype resembling human systemic lupus erythematosus, a serious autoimmune disease. The SAP-/- mice also have enhanced anti-DNA responses to immunization with extrinsic chromatin, and we demonstrate that degradation of long chromatin is retarded in the presence of SAP both in vitro and in vivo. These findings indicate that SAP has an important physiological role, inhibiting the formation of pathogenic autoantibodies against chromatin and DNA, probably by binding to chromatin and regulating its degradation.
10.1038/9544
Autoantibodies against protective molecules--C1q, C-reactive protein, serum amyloid P, mannose-binding lectin, and apolipoprotein A1: prevalence in systemic lupus erythematosus.
Shoenfeld Yehuda,Szyper-Kravitz Martine,Witte Torsten,Doria Andrea,Tsutsumi Akito,Tatsuya Abe,Dayer Jean-Michel,Roux-Lombard Pascale,Fontao Lionel,Kallenberg Cees G M,Bijl Marc,Matthias Torsten,Fraser Abigail,Zandman-Goddard Gisele,Blank Miri,Gilburd Boris,Meroni Pier Luigi
Annals of the New York Academy of Sciences
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of several autoantibodies. Among the multiple factors involved in SLE development, apoptotic defects and impaired clearance of cellular debris have gained considerable interest, as they contribute to autoantigen overload. Several molecules of the innate immunity, also participate in the removal of damaged and apoptotic cells. Among them are C1q, C-reactive protein (CRP), serum amyloid P protein (SAP), mannose-binding lectin (MBL), and apolipoprotein A1 (APO A1). To evaluate the prevalence of autoantibodies against CRP, SAP, MBL, APO A1, and C1q among SLE patients, and their relationship with disease activity, a total of 150 SLE patients were screened for the presence of elevated antibody titers against C1q, CRP, SAP, MBL, and APO A1, utilizing the enzyme-linked immunosorbent assay (ELISA) method. Disease activity was assessed using the ECLAM or SLEDAI scores. The study population comprised two groups of patients: 100 patients with quiescent disease (median ECLAM score 2) comprised the first group, and 50 patients with active disease (median SLEDAI score 16) comprised group 2. Elevated titers of anti-CRP antibodies were significantly elevated only in group 1 (10% versus 4% of controls). Antibodies against SAP were evaluated only among patients in group 1, and were found at a significant high prevalence (20%). Elevated titers of anti-MBL antibodies were significantly elevated only in group 1 (15% versus 3.6%); and antibodies directed against APO A1 were significantly elevated in 21% of group 1, and 50% of group 2 patients. Elevated titers of anti-C1q were evaluated only in group 2, and were found at a significant prevalence of 66%. Significant correlation with disease activity was found only for anti-APO A1 antibodies, and only in group 1. Several patients harbored more than one of the autoantibodies tested. In patients with SLE, autoantibodies directed against protective molecules, that is, acute-phase proteins involved in the disposal of cellular and nuclear debris, can be detected. These autoantibodies may play a pathogenic role in the development or perpetuation of autoimmunity in SLE.
10.1196/annals.1422.025
Pentraxins (CRP, SAP) in the process of complement activation and clearance of apoptotic bodies through Fcγ receptors.
Du Clos Terry W,Mold Carolyn
Current opinion in organ transplantation
PURPOSE OF REVIEW:Ischemia/reperfusion injury and organ allograft rejection both entail excessive cell and tissue destruction. A number of innate immune proteins, including the pentraxins, participate in the removal of this potentially inflammatory and autoimmunogenic material. The classical pentraxins, C-reactive protein (CRP) and serum amyloid P component (SAP) are serum opsonins, which bind to damaged membranes and nuclear autoantigens. Understanding the role of pentraxins in inflammation has been advanced by the recent identification and structural analysis of their receptor interactions. RECENT FINDINGS:The ligand-binding, complement-activating and opsonic properties of pentraxins have been known for some time. However, the establishment of Fcγ receptors as the primary receptors for pentraxins is a recent finding with important implications for CRP and SAP functions. The crystal structure of SAP in complex with FcγRIIa was recently solved, leading to new insights into function and new opportunities for pentraxin-based therapeutics. In addition, new approaches to inhibit CRP synthesis or binding are being developed based on clinical associations between CRP levels and cardiovascular disease. SUMMARY:This review will summarize data on the function of pentraxins in clearance of injured tissue and cells and discuss the implications of this clearance pathway for autoimmunity and ischemia/reperfusion injury.
10.1097/MOT.0b013e32834253c7
Serum amyloid P component and C-reactive protein opsonize apoptotic cells for phagocytosis through Fcgamma receptors.
Mold Carolyn,Baca Rebecca,Du Clos Terry W
Journal of autoimmunity
Serum amyloid P component (SAP) and C-reactive protein (CRP) are opsonins that react with nuclear autoantigens targeted in systemic autoimmunity. CRP and SAP bind to apoptotic and necrotic cells, which are potential sources of these autoantigens. We have recently determined that the receptors for CRP on phagocytic cells are Fcgamma receptors. The goal of this study was to determine whether CRP and SAP promote phagocytosis of apoptotic cells and to identify the receptors involved. Apoptosis was induced in human neutrophils (PMN) and the Jurkat T-cell line by UV-irradiation. SAP treatment of apoptotic human PMN increased ingestion by autologous macrophages. Both SAP and CRP increased ingestion of apoptotic, but not normal Jurkat cells by J-774 macrophages and mouse peritoneal macrophages. Neither SAP nor CRP increased ingestion of apoptotic Jurkat cells by macrophages from FcR gamma-chain deficient mice, which lack FcgammaRI and FcgammaRIII. Inhibition of FcgammaRIII-mediated uptake using mAb 2.4G2 eliminated opsonization by SAP, but not by CRP. These results indicate that pentraxins promote uptake of apoptotic cells through FcgammaRI and/or FcgammaRIII. Ingestion through these receptors is expected to alter the pattern of cytokine production and antigen presentation in response to apoptotic cells.
10.1006/jaut.2002.0615
Macrophage differentiation and polarization via phosphatidylinositol 3-kinase/Akt-ERK signaling pathway conferred by serum amyloid P component.
Zhang Weijuan,Xu Wei,Xiong Sidong
Journal of immunology (Baltimore, Md. : 1950)
Macrophage differentiation and polarization is influenced by, and act on, many processes associated with autoimmunity. However, the molecular mechanisms underlying macrophage polarization in systemic lupus erythematosus (SLE) remain largely debated. We previously demonstrated that macrophage M2b polarization conferred by activated lymphocyte-derived (ALD)-DNA immunization could initiate and propagate murine lupus nephritis. Serum amyloid P component (SAP), a conserved acute-phase protein in mice, has been reported to bind to DNA and modulate immune responses. In this study, murine SAP was shown to promote macrophage-mediated ALD-DNA uptake through binding to ALD-DNA (SAP/ALD-DNA). Moreover, macrophage phenotypic switch from a proinflammatory M2b phenotype induced by ALD-DNA alone to an anti-inflammatory M2a phenotype stimulated with SAP/ALD-DNA were found because of PI3K/Akt-ERK signaling activation. Both in vivo SAP supplements and adoptive transfer of ex vivo programmed M2a macrophages induced by SAP/ALD-DNA into SLE mice could efficiently alleviate lupus nephritis. Importantly, increased IL-10 secretion, accompanied by anti-inflammatory effect exerted by M2a macrophages, was found to predominantly impede macrophage M2b polarization. Furthermore, neutralization of IL-10 notably reduced the suppressive effect of M2a macrophages. Our results demonstrate that binding of SAP to ALD-DNA could switch macrophage phenotypic polarization from proinflammatory M2b to anti-inflammatory M2a via PI3K/Akt-ERK signaling activation, thus exerting protective and therapeutic interventions on murine lupus nephritis. These data provide a possible molecular mechanism responsible for modulation of macrophage polarization in the context of lupus nephritis and open a new potential therapeutic avenue for SLE.
10.4049/jimmunol.1002315
The role of SAP and the SLAM family in autoimmunity.
Chan Alice Y,Westcott Jill M,Mooney Jill M,Wakeland Edward K,Schatzle John D
Current opinion in immunology
The signaling lymphocyte activation molecule (SLAM) family of receptors and their associated signaling adaptors play a pivotal role in the regulation of various stages of cellular immunity. They regulate lymphocyte-lymphocyte interactions involved in both cell-mediated and humoral immune responses. Recent evidence indicates that members of this family of receptors and signaling intermediates are also involved in autoimmunity. These include strictly correlative studies showing increased expression of various family members in immune effectors involved in rheumatoid arthritis and in inflammatory bowel disease, as well as more direct evidence (from various knockout strains of mice) for their role in autoimmune processes such as experimental allergic encephalomyelitis and lupus. Additional studies defining naturally occurring polymorphic variations in the SLAM family show a direct role in initiating the break in tolerance that is an essential step in the progression towards autoimmunity.
10.1016/j.coi.2006.09.010
SLAM Associated Protein Signaling in T Cells: Tilting the Balance Toward Autoimmunity.
Gartshteyn Yevgeniya,Askanase Anca D,Mor Adam
Frontiers in immunology
T cell activation is the result of the integration of signals across the T cell receptor and adjacent co-receptors. The signaling lymphocyte activation molecules (SLAM) family are transmembrane co-receptors that modulate antigen driven T cell responses. Signal transduction downstream of the SLAM receptor is mediated by the adaptor protein SLAM Associated Protein (SAP), a small intracellular protein with a single SH2 binding domain that can recruit tyrosine kinases as well as shield phosphorylated sites from dephosphorylation. Balanced SLAM-SAP signaling within T cells is required for healthy immunity, with deficiency or overexpression prompting autoimmune diseases. Better understanding of the molecular pathways involved in the intracellular signaling downstream of SLAM could provide treatment targets for these autoimmune diseases.
10.3389/fimmu.2021.654839