scholarly journals Proteins Phosphorylated during Stress-induced Apoptosis Are Common Targets for Autoantibody Production in Patients with Systemic Lupus Erythematosus

1997 ◽  
Vol 185 (5) ◽  
pp. 843-854 ◽  
Author(s):  
Paul J. Utz ◽  
Maria Hottelet ◽  
Peter H. Schur ◽  
Paul Anderson
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Apoptotic Cell ◽  
Systemic Lupus ◽  
Serine Threonine Kinase ◽  
Autoantibody Production ◽  
Threonine Kinase ◽  
Phosphorylated Proteins ◽  
Induced Apoptosis

Proteins cleaved by interleukin-1β converting enzyme family proteases during apoptosis are common targets for autoantibody production in patients with systemic lupus erythematosus (SLE). We have tested the possibility that proteins phosphorylated in cells undergoing apoptosis are also targets for autoantibody production in patients with autoimmune disease. Sera from 9/12 patients containing antinuclear antibodies (10/12 meeting diagnostic criteria for SLE or a lupus overlap syndrome), precipitated new phosphoproteins from lysates derived from Jurkat T cells treated with apoptotic stimuli (i.e., Fas-ligation, gamma irradiation, ultraviolet irradiation), but not with an activation (i.e., CD3-ligation) stimulus. Sera derived from individual patients precipitated different combinations of seven distinct serine-phosphorylated proteins. None of these phosphoproteins were included in precipitates prepared using sera from patients with diseases that are not associated with autoantibody production or using serum from rheumatoid arthritis patients. Protein phosphorylation precedes, or is coincident with, the induction of DNA fragmentation, and is not observed when apoptosis is inhibited by overexpression of bcl-2. Serum from four patients precipitated a serine/threonine kinase from apoptotic cell lysates that phosphorylates proteins of 23-, 34-, and 46-kD in in vitro kinase assays. Our results suggest that proteins phosphorylated during apoptosis may be preferred targets for autoantibody production in patients with SLE.

scholarly journals Hidden autoantibodies against common serum proteins in murine systemic lupus erythematosus. Detection by in vitro plaque-forming cell assay.

1985 ◽  
Vol 161 (6) ◽  
pp. 1587-1592 ◽  
Author(s):  
P L Cohen ◽  
R G Rapoport ◽  
R A Eisenberg
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Cell Activation ◽  
Serum Proteins ◽  
B Cell Activation ◽  
Systemic Lupus ◽  
Autoantibody Production ◽  
Murine Systemic Lupus Erythematosus

The autoantibodies found in human and murine systemic lupus erythematosus (SLE) are generally directed against cells or components of cells such as nuclear antigens. This predilection may be due to the unusual immunogenicity of certain autoantigens, or to unusual patterns of antibody crossreactivity. Alternatively, the observed spectrum of reactivities may reflect the in vivo absorption of those autoantibodies directed against soluble antigens. To test whether hitherto undetected autoantibodies against serum proteins might exist in murine SLE, we developed assays that were independent of the possibility of absorption of autoantibodies by serum autoantigens; large numbers of plaque-forming cells (PFC) directed against mouse albumin and mouse transferrin were easily detected in the spleens of MRL/Mp-lpr/lpr, BXSB, and NZB mice. The secreted antibodies were relatively specific for the mouse proteins, since only limited cross-reactivity was seen with albumin and transferrins of other species in inhibition experiments. The production of these hidden antibodies could not be the result of diffuse polyclonal B cell activation, since the PFC to mouse transferrins and albumin were not always accompanied by comparable numbers of PFC against related albumins and transferrins. The results indicate that autoantibody production in murine lupus is a generalized phenomenon, not limited to the production of autoantibodies to nuclear or other cell-bound antibodies. However, the relative specificity of the autoantibodies for self-antigens indicates that diffuse polyclonal B cell activation cannot be the mechanism responsible, and argues that a selective mechanism, probably driven by antigen, accounts for production of autoantibodies in SLE.

scholarly journals Impaired Function of PD-1+ Follicular Regulatory T Cells in Systemic Lupus Erythematosus

2021 ◽  
Author(s):  
Izumi Kurata ◽  
Natsuko Mikami ◽  
Ayako Ohyama ◽  
Atsumu Osada ◽  
Yuya Kondo ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Cytotoxic T Lymphocyte ◽  
Systemic Lupus ◽  
Autoantibody Production ◽  
Functional Changes ◽  
Follicular Helper ◽  
Programmed Death 1 ◽  
Antibody Levels

Abstract Objective: Aberrant autoantibody production is characteristic of systemic lupus erythematosus (SLE) but follicular regulatory T (TFR) cells potentially can suppress this abnormality. Here, we investigate functional changes in TFR cells from SLE patients. Methods: Circulating TFR cells were collected from 19 SLE patients and 14 healthy controls to compare molecular expression and in vitro suppressive capacity of follicular helper T (TFH) cell proliferation. We then tested IL-2 in SLE-TFR cells to check restoration of suppressor function. Results: Programmed death-1 (PD-1) expression in SLE-TFR cells was positively correlated with anti-DNA antibody levels and disease activity. These cells had impaired suppressive function for TFH cells with decreased expression of suppression mediators forkhead box p3 (Foxp3), cytotoxic T-lymphocyte antigen 4 (CTLA4), and IL-2 receptor alpha (IL2Rα). In vitro IL-2 stimulation restored expression of these molecules. Conclusion: SLE-TFR cells have functional TFH suppression defects but low-dose IL-2 therapy could be useful to restore this ability.

scholarly journals Impaired function of PD-1+ follicular regulatory T cells in systemic lupus erythematosus

2021 ◽  
Author(s):  
Izumi Kurata ◽  
Natsuko Mikami ◽  
Ayako Ohyama ◽  
Atsumu Osada ◽  
Yuya Kondo ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Low Dose ◽  
Cytotoxic T Lymphocyte ◽  
Systemic Lupus ◽  
Autoantibody Production ◽  
Functional Changes ◽  
Follicular Helper ◽  
The Stability

Aberrant autoantibody production is characteristic of systemic lupus erythematosus (SLE), but follicular regulatory T (TFR) cells potentially can suppress this abnormality. We investigate functional changes in TFR cells from SLE patients. Circulating TFR cells were collected from 19 SLE patients and 14 healthy controls (HC) to compare molecular expression and in vitro suppressive capacity of follicular helper T (TFH) cell proliferation. To reveal the stability of Foxp3 in TFR, pyrosequencing of conserved non-coding sequence (CNS) 2 at the Foxp3 gene locus was performed. We then tested IL-2 in SLE-TFR cells to check restoration of suppressor function. Programmed death-1 (PD-1) expression in SLE-TFR cells was positively correlated with anti-DNA antibody levels and disease activity. These cells had impaired suppressive function for TFH cells with decreased expression of suppression mediators forkhead box p3 (Foxp3), cytotoxic T-lymphocyte antigen 4 (CTLA4), and IL-2 receptor alpha (IL2Rα). Pyrosequencing identified hyper-methylation in CNS2 region of SLE-TFR cells comparing to HC. With In vitro IL-2 stimulation, PD-1 expression of TFR cells significantly decreased along with increased expression of Foxp3 and CTLA-4, especially in low-dose. Thus, SLE-TFR cells have functionally defective to TFH suppression, but low-dose IL-2 therapy might be useful to restore this ability.

scholarly journals THU0035 OX40L EXPRESSING NEUTROPHILS INDUCE CD4 T FOLLICULAR AND PERIPHERAL HELPER CELL DIFFERENTIATION IN SYSTEMIC LUPUS ERYTHEMATOSUS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 230.2-231
Author(s):  
A. Pappalardo ◽  
E. Wojciechowski ◽  
I. Odriozola ◽  
I. Douchet ◽  
N. Merillon ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cells ◽  
B Cells ◽  
Lupus Erythematosus ◽  
Cd4 T Cells ◽  
Close Contact ◽  
Memory B Cells ◽  
Systemic Lupus ◽  
Research Support

Background:Neutrophils have been described as potent antigen-presenting cells able to activate T cells by MHC/TCR interaction and costimulatory molecules in tumor immunity. However, little is known about the direct interaction between neutrophils and CD4 T cells with respect to systemic lupus erythematosus (SLE). We have previously shown that OX40L expressed by monocytes from SLE patients promote the differentiation of naïve and memory cells into IL21 secreting T cells that are able to help B cells1,2.Objectives:In this study, we investigate OX40L expression on neutrophils from SLE patients and contribution of these OX40L+neutrophils in SLE pathogenesis to modulation of the B cell helper role of CD4 T cells.Methods:Surface expression of co-stimulatory molecules (OX40L, ICOSL, GITRL, 4-1BBL) on neutrophils from SLE patients and healthy donors (HD) was measured by flow cytometry (FC). Neutrophils from HD were stimulated with TLR7 or TLR8 agonists and IFNα after 5 hours of culture, OX40L expression was measured by FC and Western Blotting. CD4 T cells were cultured with the stimulated neutrophils for 3 days. At the end of the co-culture, percentages of IL21-expressing T follicular (Tfh) and peripheral helper (Tph) cells measured by FC. These generated T cells were also cultured in the presence of memory B cells. After 5 days of co-culture, plasmablast generation and Ig levels were assessed by FC and ELISA, respectively. Inhibition of OX40-OX40L interaction in vitro was achieved using ISB 830, a novel anti-OX40 mAb currently used in clinical trials.Results:Among the co-stimulatory molecules tested, percentages of OX40L+neutrophils in SLE (n=54) were increased compared to HD (n=25)(mean + SD: HD = 1,34%±1.62 vs SLE = 4,53%±8.1; p=0.29). OX40L expression positively correlated with SLE disease activity score (SLEDAI) (p = 0,04; r = 0,31) and with anti-DNA antibodies (p= 0,04, r = 0,33). Of note, the percentage of OX40L+neutrophils was higher in anti-sm-RNP+patients (n=16, mean= 9%±9.8), compared to anti-sm-RNP-patients (n=27, mean = 1,4%±2.5; p = 0,02). The percentage of OX40L+neutrophils was higher in patients with class III or IV lupus nephritis, and inflammatory infiltrate within the kidney biopsy disclosed OX40L+neutrophils, in close contact with T cells. Neutrophils from HD express OX40L with TLR8 agonist, or IFNα priming followed by TLR7 agonist. When memory CD4 T cells were cultured in the presence of TLR8-stimulated neutrophils, the proportion of IL21-expressing Tfh (CXCR5+PD1+) and Tph (CXCR5-PD1hi) were increased, compared to culture with unstimulated neutrophils. This process was dependent on OX40-OX40L interactions, since in vitro treatment with the anti-OX40 blocking antibody ISB 830, inhibited the differentiation of memory T cells into Tfh and Tph. Both generated Tfh and Tph were able to promote the differentiation of memory B cells into Ig-secreting plasmablasts.Conclusion:Our results disclose an unprecedented phenomenon where cross-talk between TLR7/8-activated neutrophils and CD4 lymphocytes operates through OX40L-OX40 costimulation, and neutrophils promote the differentiation of pro-inflammatory Tfh and Tph, as well as IL21 production. Therefore, OX40L/OX40 should be considered as a potentially therapeutic axis in SLE patients.References:[1]Jacquemin et al. Immunity 2015;[2]Jacquemin et al. JCI Insight 2018Disclosure of Interests:Angela Pappalardo Grant/research support from: Ichnos Sciences, Elodie Wojciechowski: None declared, Itsaso Odriozola: None declared, Isabelle Douchet: None declared, Nathalie Merillon: None declared, Andrea Boizard-Moracchini: None declared, Pierre Duffau: None declared, Estibaliz Lazaro: None declared, Marie-Agnes Doucey Employee of: Ichnos Sciences, Lamine Mbow Employee of: Ichnos Sciences, Christophe Richez Consultant of: Abbvie, Amgen, Mylan, Pfizer, Sandoz and UCB., Patrick Blanco Grant/research support from: Ichnos Sciences

scholarly journals OP0039 ALPN-303, AN ENHANCED, POTENT DUAL BAFF/APRIL ANTAGONIST ENGINEERED BY DIRECTED EVOLUTION FOR THE TREATMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) AND OTHER B CELL-RELATED AUTOIMMUNE DISEASES

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 21.2-21
Author(s):  
S. R. Dillon ◽  
L. S. Evans ◽  
K. E. Lewis ◽  
J. Yang ◽  
M. W. Rixon ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Autoimmune Diseases ◽  
B Cell ◽  
Directed Evolution ◽  
Human Lymphocyte ◽  
Lupus Erythematosus ◽  
Plasma Cells ◽  
Systemic Lupus ◽  
Cynomolgus Monkeys

Background:BAFF and APRIL are TNF superfamily members that form homo- and heteromultimers that bind TACI and BCMA on B cells; BAFF also binds BAFF-R. BAFF and APRIL support B cell development, differentiation, and survival, particularly for plasmablasts and plasma cells, and play critical roles in the pathogenesis of B cell-related autoimmune diseases. In nonclinical models, inhibition of either BAFF or APRIL alone mediates relatively modest effects, whereas their co-neutralization dramatically reduces B cell function, including antibody production. Fc fusions of wild-type (WT) TACI (e.g. atacicept and telitacicept) target both BAFF and APRIL and have demonstrated promising clinical potential in e.g. systemic lupus erythematosus (SLE) and IgA nephropathy but have not yet clearly exhibited long-term and/or complete disease remissions.Objectives:To generate a dual BAFF/APRIL antagonist with inhibitory activity superior to WT TACI and BCMA and with the potential to improve clinical outcomes in B cell-mediated diseases.Methods:Our directed evolution platform was used to identify a potent variant TNFR domain (vTD) of TACI that exhibits significantly enhanced affinity for BAFF and APRIL as compared to WT TACI; this TACI vTD domain was fused to a human IgG Fc to generate the therapeutic candidate ALPN-303. ALPN-303 was evaluated for functional activity in: 1) human lymphocyte assays, 2) the NOD.Aec1Aec2 spontaneous model of Sjogren’s syndrome (SjS), 3) the bm12-induced mouse model of lupus, 4) the (NZB/NZW)F1 spontaneous model of lupus, and 5) preclinical rodent and cynomolgus monkey pharmacokinetic/pharmacodynamic studies.Results:ALPN-303 inhibited BAFF- and APRIL-mediated signaling in vitro in human lymphocyte assays, with significantly lower IC50 values than WT TACI-Fc and belimumab comparators. In all mouse models evaluated, administration of ALPN-303 rapidly and significantly reduced key lymphocyte subsets including plasma cells, germinal center B cells, and follicular T helper cells. ALPN-303 significantly reduced autoantibodies and sialadenitis in the spontaneous SjS model, inhibited glomerular IgG deposition in the bm12-induced model of lupus, and potently suppressed anti-dsDNA autoAbs, blood urea nitrogen levels, proteinuria, sialadenitis, kidney lesions, and renal immune complex deposition in the NZB/W lupus model. As compared to WT TACI-Fc, ALPN-303 exhibited higher serum exposure and significantly and persistently decreased titers of serum IgM, IgG, and IgA antibodies in mice and cynomolgus monkeys (Figure 1).Figure 1.ALPN-303 induces more potent suppression, as compared to WT TACI-Fc, of serum immunoglobulins following a single 9 mg/kg IV infusion (on Day 0; arrows) in female cynomolgus monkeys.Conclusion:ALPN-303 is a potent BAFF/APRIL antagonist derived from our directed evolution platform that consistently demonstrates encouraging immunomodulatory activity and efficacy in vitro and in vivo, superior in preclinical studies to anti-BAFF antibody and WT TACI-Fc. This novel Fc fusion molecule demonstrates favorable preliminary developability characteristics, including higher serum exposures and more potent immunosuppressive activities, which may enable lower clinical doses and/or longer dosing intervals than WT TACI-Fc therapeutics. ALPN-303 may thus be an attractive development candidate for the treatment of multiple autoimmune and inflammatory diseases, particularly B cell-related diseases such as SLE, SjS, and other connective tissue diseases. Preclinical development is underway to enable the initiation of clinical trials later this year.Disclosure of Interests:Stacey R. Dillon Shareholder of: Alpine Immune Sciences, Bristol Myers Squibb, Employee of: Alpine Immune Sciences, Bristol Myers Squibb, Lawrence S. Evans Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Katherine E. Lewis Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Jing Yang Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Mark W. Rixon Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Joe Kuijper Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Dan Demonte Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Janhavi Bhandari Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Steve Levin Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Kayla Kleist Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Sherri Mudri Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Susan Bort Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Daniel Ardourel Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Michelle A. Seaberg Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Rachel Wang Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Chelsea Gudgeon Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Russell Sanderson Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Martin F. Wolfson Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Jan Hillson Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Stanford L. Peng Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences

scholarly journals Leptin promotes systemic lupus erythematosus by increasing autoantibody production and inhibiting immune regulation

2016 ◽  
Vol 113 (38) ◽  
pp. 10637-10642 ◽  
Author(s):  
Elaine V. Lourenço ◽  
Aijing Liu ◽  
Giuseppe Matarese ◽  
Antonio La Cava
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cells ◽  
New Zealand ◽  
Renal Disease ◽  
Lupus Erythematosus ◽  
Cellular Level ◽  
Presentation Of Self ◽  
Systemic Lupus ◽  
Autoantibody Production

Leptin is an adipocytokine that plays a key role in the modulation of immune responses and the development and maintenance of inflammation. Circulating levels of leptin are elevated in systemic lupus erythematosus (SLE) patients, but it is not clear whether this association can reflect a direct influence of leptin on the propathogenic events that lead to SLE. To investigate this possibility, we compared the extent of susceptibility to SLE and lupus manifestations between leptin-deficient (ob/ob) and H2-matched leptin-sufficient (wild-type, WT) mice that had been treated with the lupus-inducing agent pristane. Leptin deficiency protected ob/ob mice from the development of autoantibodies and renal disease and increased the frequency of immunoregulatory T cells (Tregs) compared with leptin-sufficient WT mice. The role of leptin in the development of SLE was confirmed in the New Zealand Black (NZB) × New Zealand White (NZW)F1 (NZB/W) mouse model of spontaneous SLE, where elevated leptin levels correlated with disease manifestations and the administration of leptin accelerated development of autoantibodies and renal disease. Conversely, leptin antagonism delayed disease progression and increased survival of severely nephritic NZB/W mice. At the cellular level, leptin promoted effector T-cell responses and facilitated the presentation of self-antigens to T cells, whereas it inhibited the activity of regulatory CD4 T cells. The understanding of the role of leptin in modulating autoimmune responses in SLE can open possibilities of leptin-targeted therapeutic intervention in the disease.

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