Anti-dsDNA IgE: a potential non-invasive test for prediction of lupus nephritis relapse.

OBJECTIVES: Discontinuation or continuation of maintenance immunosuppressive therapy (MIST) after a severe lupus nephritis (LN) requires measuring the risk of relapse but reliable clinical and biological markers are lacking. The WIN-IgE study assesses the value of serum anti-dsDNA IgE autoantibodies as a biomarker for the prediction of relapse in severe LN. METHODS: WIN-IgE is an ancillary study of the WIN-Lupus study (NCT01284725), a prospective controlled clinical trial which evaluated the discontinuation of MIST after 2-3 years in class III or IV±V LN with active lesions. WIN-IgE included all patients with available serum collected at randomisation for continuation or discontinuation of MIST. In these sera, anti-dsDNA antibodies, IgE and IgG, were quantified by ELISA and compared between patients who experienced LN relapse and those who did not during the 24 months of follow-up. RESULTS: 52 patients were included, 25 in the MIST continuation group and 27 in the MIST discontinuation group, 12 experienced a biopsy-proven relapse of LN. Initial anti-dsDNA IgE antibodies levels were higher in patients with subsequent LN relapse. Anti-dsDNA IgG was not associated with relapse. Survival without LN relapse was lower in patients with anti-dsDNA IgE levels above vs below a threshold of 1.9 arbitrary units (p=0.019), particularly in the subgroup of patients randomised to discontinue MIST (p=0.002). In all patients, anti-dsDNA IgE above 1.9 arbitrary units had a positive predictive value of 0.8 for severe LN relapse. CONCLUSIONS: These results suggest blood anti-dsDNA IgE as a non-invasive predictive marker of LN relapse.

PD-L1- and IL-4-expressing basophils promote pathogenic accumulation of T follicular helper cells in lupus.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by anti-nuclear autoantibodies whose production is promoted by autoreactive T follicular helper (TFH) cells. During SLE pathogenesis, basophils accumulate in secondary lymphoid organs (SLO), amplify autoantibody production and disease progression through mechanisms that remain to be defined. Here, we provide evidence for a direct functional relationship between TFH cells and basophils during lupus pathogenesis, both in humans and mice. PD-L1 upregulation on basophils and IL-4 production are associated with TFH and TFH2 cell expansions and with disease activity. Pathogenic TFH cell accumulation, maintenance, and function in SLO were dependent on PD-L1 and IL-4 in basophils, which induced a transcriptional program allowing TFH2 cell differentiation and function. Our study establishes a direct mechanistic link between basophils and TFH cells in SLE that promotes autoantibody production and lupus nephritis.

CT-M8 Mice: A New Mouse Model Demonstrates That Basophils Have a Nonredundant Role in Lupus-Like Disease Development.

Tissue-specific mouse models are essential tools to decipher the role of each cell compartment and/or their expressed genes in the pathophysiology of diseases. Here, we describe a new knock-in mouse model allowing expression of both the fluorescent protein tdTomato and the CRE recombinase selectively in the basophil compartment under the control of the Mcpt8 gene. These "CT-M8" mice did not show any abnormalities in their peripheral distribution of major immune cell populations nor their basophil function. CT-M8 mice allowed the identification of basophils by immunofluorescence and flow cytometry and basophil-specific Cre-mediated floxed gene deletion. Breeding of our CT-M8 mice with the ROSA26flox-stop-DTA mice led to the generation of basophil-deficient mice with no detectable abnormalities in other cell compartments. These mice were then used to document basophil involvement in systemic lupus erythematosus (SLE) pathophysiology since we previously reported by transient depletion of these cells during the course of an ongoing disease that they support and amplify autoantibody production in two distinct lupus-like mouse models (Lyn-/- and pristane-induced). Here, constitutive basophil deficiency prevented pristane-induced lupus-like disease development by limiting autoantibody titers and renal damages. Therefore, basophils have a nonredundant role in pristane-induced lupus-like disease and are involved in both its induction and amplification. This CT-M8 new mouse model will allow us to finely decipher the role of basophils and their expressed genes in health and disease.