Aberrant Genetic Control of Invariant TCR-Bearing NKT Cell Function in New Zealand Mouse Strains: Possible Involvement in Systemic Lupus Erythematosus Pathogenesis

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a loss of tolerance toward self-nucleic acids, autoantibody production, interferon expression and signaling, and a defect in the regulatory T (Treg) cell compartment. In this work, we identified that platelets from patients with active SLE preferentially interacted with Treg cells via the P-selectin/P-selectin glycoprotein ligand-1 (PSGL-1) axis. Selectin interaction with PSGL-1 blocked the regulatory and suppressive properties of Treg cells and particularly follicular Treg cells by triggering Syk phosphorylation and an increase in intracytosolic calcium. Mechanistically, P-selectin engagement on Treg cells induced a down-regulation of the transforming growth factor–β axis, altering the phenotype of Treg cells and limiting their immunosuppressive responses. In patients with SLE, we found an up-regulation of P- and E-selectin both on microparticles and in their soluble forms that correlated with disease activity. Last, blocking P-selectin in a mouse model of SLE improved cardinal features of the disease, such as anti-dsDNA antibody concentrations and kidney pathology. Overall, our results identify a P-selectin–dependent pathway that is active in patients with SLE and validate it as a potential therapeutic avenue.

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Beta Cell Function is Disrupted in Patients with Systemic Lupus Erythematosus

Rheumatology ◽

10.1093/rheumatology/keaa874 ◽

2020 ◽

Author(s):

Alicia García-Dorta ◽

Juan Carlos Quevedo-Abeledo ◽

Íñigo Rua-Figueroa ◽

Antonia M de Vera-González ◽

Alejandra González-Delgado ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Beta Cell ◽

Lupus Erythematosus ◽

Cell Function ◽

Multivariable Analysis ◽

Serum Levels ◽

Cell Secretion ◽

Systemic Lupus ◽

Proinsulin Processing ◽

Beta Cell Secretion

Abstract Introduction To investigate how markers of beta cell secretion (proinsulin-processing metabolites) are expressed in systemic lupus erythematosus (SLE) patients and their potential relation to features associated with the disease such as activity or damage. Methods 144 SLE patients and 69 nondiabetic sex- and age-matched controls were assessed. Beta-cell secretion molecules, as measured by insulin, split and intact proinsulins, and C-peptide levels were analyzed in both groups. Multiple regression analysis was performed to compare proinsulin propeptides between groups and to explore the interrelations with SLE features. Analyses were adjusted for glucocorticoid intake and for insulin resistance classic risk factors. Results Fully multivariable analysis demonstrated that regardless of glucocorticoid use, SLE patients exhibited higher levels of split proinsulin. Likewise, the split proinsulin-to-insulin ratio was upregulated in patients with SLE undergoing glucocorticoid therapy (beta coef. 0.19 [95%CI 0.07–0.30], p= 0.002) or not (beta coef. 0.09 [95%CI 0.01–0.17), p= 0.025). Similar results were found for the intact proinsulin-to-insulin ratio, although differences were only statistically significant for patients taking glucocorticoids (beta coef. 0.08 [95%CI 0.03–0.12], p= 0.001). SLE damage score was associated with higher serum levels of intact (beta coef. 0.51 [95%CI 0.17–0.86] pmol/l, p= 0.004) and split proinsulins (beta coef. 1.65 [95%CI 0.24–3.06] pmol/l, p= 0.022) after multivariable analysis, including disease duration and prednisone use. Conclusion Among patients with SLE, proinsulin-processing metabolites, a marker of beta-cell disruption, are upregulated compared with matched controls. This disproportionate hyperproinsulinemia can be explained by the damage produced by the disease and occurs independently of prednisone use.

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1607101113 ◽

2016 ◽

Vol 113 (38) ◽

pp. 10637-10642 ◽

Cited By ~ 45

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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Infections in early systemic lupus erythematosus pathogenesis

Systemic Lupus Erythematosus ◽

10.1016/b978-0-12-814551-7.00024-6 ◽

2021 ◽

pp. 203-210

Author(s):

Rebecka Bourn ◽

Samantha Slight-Webb ◽

Judith A. James

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Systemic Lupus ◽

Systemic Lupus Erythematosus Pathogenesis

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Interference of levamisole with inhibition of E-rosette formation by Hodgkin's disease and systemic lupus erythematosus cytotoxic sera

Blood ◽

10.1182/blood.v53.5.1002.1002 ◽

1979 ◽

Vol 53 (5) ◽

pp. 1002-1006 ◽

Cited By ~ 13

Author(s):

GS Del Giacco ◽

S Tognella ◽

AL Leone ◽

F Locci ◽

P Cornaglia ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cell ◽

Lupus Erythematosus ◽

Hodgkin's Disease ◽

Cell Function ◽

Human Peripheral Blood ◽

Hodgkin’S Disease ◽

Peripheral Blood Lymphocytes ◽

Systemic Lupus ◽

T Cell Function

Abstract A new system has been used to test the influence of levamisole on T- cell function. Evidence has been produced that prior exposure to the drug “protects” normal human peripheral blood lymphocytes from the inhibition that cytotoxic sera from patients with Hodgkin's disease and systemic lupus erythematosus exhibit on their E-rosette-forming capacity. Also, damage of this T-cell function already induced by Hodgkin's sera may be partially corrected.

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