The tumor necrosis factor (TNF) superfamily of cytokines includes both soluble and membrane-bound proteins that regulate immune responses. A member of the human TNF family, BLyS (B lymphocyte stimulator), was identified that induced B cell proliferation and immunoglobulin secretion. BLyS expression on human monocytes could be up-regulated by interferon-gamma. Soluble BLyS functioned as a potent B cell growth factor in costimulation assays. Administration of soluble recombinant BLyS to mice disrupted splenic B and T cell zones and resulted in elevated serum immunoglobulin concentrations. The B cell tropism of BLyS is consistent with its receptor expression on B-lineage cells. The biological profile of BLyS suggests it is involved in monocyte-driven B cell activation.
Activation of microglia by classical inflammatory mediators can convert astrocytes to a neurotoxic A1 phenotype in a variety of neurological diseases1,2. Development of agents that could inhibit the formation of A1 reactive astrocytes could be used to treat these diseases for which there are no disease modifying therapies. Glucagon-like peptide-1 receptor (GLP-1R) agonists have been touted as potential neuroprotective agents for neurologic disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD)3-13. The mechanisms by which GLP-1R agonists are neuroprotective are not known. Here we show that a potent, brain penetrant long acting GLP-1R agonist NLY01 protects against the loss of dopamine neurons and behavioral deficits in the α-synuclein preformed fibril (α-syn PFF) model of sporadic PD14,15. NLY01 also prolongs the life and reduces the behavioral deficits and neuropathological abnormalities in the human A53T α-synuclein (hA53T) transgenic (Tg) model of α-synucleinopathy induced neurodegeneration16. We found that NLY01 is a potent GLP-1R agonist with favorable properties that is neuroprotective via the direct prevention of microglial mediated conversion of astrocytes to an A1 neurotoxic phenotype. In light of NLY01 favorable properties it should be evaluated in the treatment of PD and related neurologic disorders characterized by microglial activation.
Increased levels of B lymphocyte stimulator (BLyS) are associated with systemic autoimmunity in animal models of spontaneous autoimmune disease, and transgenic animals expressing BLyS develop typical autoimmune disease. Here, we demonstrate significant elevations of BLyS in the patients with systemic lupus erythematosus (SLE). The BLyS isolated from the sera of SLE patients had the same m.w. as the natural soluble form and was able to stimulate B cell activation in vitro. Increased BLyS in SLE patients was partially associated with higher levels of anti-dsDNA Ab of the IgG, IgM, and IgA classes, but not associated with the disease activity. Our results suggest that BLyS may be a useful marker for early activation of an autoimmune diathesis and likely plays a critical role in triggering activation of self-Ag-driven autoimmune B cells in human SLE. BLyS may provide an effective therapeutic target in systemic autoimmunity.
Objective To determine whether serum levels of B lymphocyte stimulator (BLyS) are elevated in patients with systemic immune–based rheumatic diseases and correlate with serum Ig levels and/or autoantibody titers. Methods Sera from 185 patients with various systemic immune–based rheumatic diseases (95 with systemic lupus erythematosus [SLE], 67 with rheumatoid arthritis [RA], 23 with other diagnoses) were assayed for BLyS and Ig. In 7 patients who required arthrocentesis of a swollen knee, coincident serum and synovial fluid samples were assayed for BLyS. Medical charts were retrospectively reviewed for elevated autoantibody titers and proteinuria within a 1‐month period before or after collection of sera for BLyS and Ig determination. Sera concurrently collected from 48 normal healthy subjects served as controls. Results Serum BLyS levels were elevated in 38 of 185 patients (21%) and correlated significantly with serum IgG levels. Serum BLyS levels did not correlate with the patients' age, sex, race, or medications, but correlated positively with anti–double‐stranded DNA antibody titers among SLE patients and with rheumatoid factor titers among seropositive RA patients. In contrast, serum BLyS levels correlated inversely with nephrotic‐range proteinuria among SLE patients. In every case tested, BLyS levels in clinically inflamed synovial fluids were greater than those in simultaneously obtained sera. Conclusion BLyS may be an important factor in driving polyclonal hypergammaglobulinemia and elevated autoantibody titers in patients with systemic immune–based rheumatic diseases. Local production of BLyS in the joints may contribute to joint pathology. Patients with elevated serum BLyS levels may be ideal candidates for therapeutic targeting of BLyS.
IntroductionThe tumor necrosis factor (TNF) family of ligands encompasses an ever-growing group of proteins, characterized by homologous cysteine-rich domains, that participates in the regulation of diverse immune and inflammatory responses. [1][2][3][4] All the members, with the exception of lymphotoxin-␣, are type II membrane proteins. Their effects are mediated either by cell contact, through the interaction of the membrane-bound form of the ligand with its corresponding receptor, or by processing and shedding of the soluble form of the ligand. 2,[5][6][7] In addition, many of the proteins, including CD27L, CD30L, OX40L, CD40L, FasL, and 4-1BBL, have moderate-sized cytoplasmic regions that are capable of delivering signals when engaged by their receptors. [7][8][9][10] The expression pattern of the family members is usually promiscuous, ranging from the broad cellular expression of TNF-␣ to a more restricted localization, such as that of CD40L expressed only on T cells. Moreover, the expression of the molecules is, in general, dependent on the activation state of the cells, being usually low or undetectable on resting cells.Recently, we described a novel member of the TNF family of ligands, B-lymphocyte stimulator (BLyS), which was identified by searching an expressed sequence tag (EST) database for homology with known TNF-like molecules. 11 The protein has been reported also as TALL-1 (TNF-and ApoL-related leukocyte-expressed ligand 1), BAFF (B-cell activator factor belonging to the TNF family), or THANK (TNF homologue that activates apoptosis, NF-B, and JNK). 12-14 The human BLyS gene encodes for a 285 amino acid (aa) protein presenting a transmembrane region between aa 47 and 73 and lacking a putative signal peptide sequence. The recombinant soluble protein (aa 134-285) binds selectively to human primary B cells and tumor cell lines of the B lineage. 11BLyS was shown to induce B-cell proliferation in standard costimulation assays with Staphylococcus aureus Cowan I (SAC I) or antihuman immunoglobulin M (IgM). BLyS administration in mice resulted in a 5-and 2-fold increase in serum IgM and IgA, respectively. 11 In addition, mice transgenic for BAFF developed autoimmune disorders such as increased germinal center formation, production of autoantibodies, and Ig deposition in kidneys. 15 Collectively, these findings suggest that BLyS has a crucial role in the humoral immune response and that regulation of BLyS expression might consequently modulate B-cell function. Our aim was, therefore, to study synthesis and release of BLyS from cells of myeloid lineage and to investigate the regulation of BLyS expression in response to cytokines. Materials and methods Medium and reagentsThe complete medium used for monocyte culture consisted of RPMI 1640 medium (Gibco BRL, Rockville, MD) supplemented with 10% (vol/vol) heat-inactivated fetal bovine serum (FBS), 2 M L-glutamine, and 50 g/mL gentamycin (Biofluids, Rockville, MD). The following recombinant human (rh) reagents were used: interferon-␥ (rhIFN-␥), interleukin-10 (...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.