Neuron-specific Humoral and Cellular Immune Correlates of Structural and Functional Brain Connectomics in Neuropsychiatric Lupus

IRCCS San Raffaele200 enrolled

Overview

Systemic lupus erythematosus (SLE) is the prototype systemic autoimmune disease. Neuropsychiatric SLE (NPSLE) is a major cause of morbidity. Its pathophysiology remains unclear and target autoantigens have not yet been identified. Site- specific autoantigen expression might correlate with imaging abnormalities. Based on existing expertise on the use of peptide/protein arrays and on antigen-specific T cell tracking, we plan to identify new fingerprints and targets for NPSLE. SLE patients +/- NPSLE and healthy subjects will undergo advanced magnetic resonance imaging. Three-dimensional data on structural or functional brain architecture will be integrated with brain transcriptome atlases and candidate antigens for autoreactive autoantibodies and T lymphocytes identified and validated. The evidence will add to current knowledge on NPSLE pathophysiology, provide new multimodal diagnostic tools for better patient care and a platform for innovative, personalized treatments.

Study Type

OBSERVATIONAL

Enrollment

200

Conditions

Systemic Lupus Erythematosus

Interventions

MRIDIAGNOSTIC_TEST

brain MRI

Eligibility

Sex: ALLMin age: 15 Years

Medical Language ↔ Plain English

Inclusion Criteria: Patients with SLE * Diagnosis of SLE according to the ACR 1997, SLICC 2012 or EULAR/ACR 2019 criteria * age ≥ 18 years (reference centre) * age 15-17 years (affiliated centre) Healthy subjects * Charlson's Comorbidity Index=0 and no chronic treatment * age ≥ 18 years (reference centre) * age 15-17 years (affiliated centre) Exclusion Criteria: * History of T-cell neoplasia * Active B-cell neoplasia or history of B-cell neoplasia of less than five years * Contraindications to MRI * Pregnancy * Ongoing or past treatment with T-depleting agents * History of brain cancer * History of congenital brain disorders * Cerebral disorders secondary to trauma, toxins or other metabolic or environmental factors unrelated to SLE according to the Investigator's evaluation * Any other condition conferring excessive physical and psychological risk to the subject according to the Investigator's opinion

Outcomes

Primary Outcomes

To detect regional brain functional abnormalities in patients with SLE through advanced magnetic resonance imaging (MRI).

All study subjects will be assessed at baseline through 3T MRI. Repeat MRI will be performed after at least 12 months or in case of new neuropsychiatric events in all patients with SLE. The MRI protocol will include conventional structural sequences (3D fluid-attenuated inversion recovery \[FLAIR\], 3D T1-weighted inversion recovery prepared gradient echo), advanced structural sequences (diffusion-weighted \[DW\] pulsed-gradient spin-echo \[PSGE\] single-shot echo-planar imaging, optimized for an accurate estimation of the neuriteorientation dispersion and density imaging \[NODDI\] model), and functional MRI sequences acquired in resting-state condition.

Time frame: 12 months (extensions allowed for existing images before study onset)

To identify autoantigen-specific circulating antibodies associated with neuropsychiatric morbidity and imaging features in patients with SLE.

High-throughput peptide and/or protein arrays customised according to the data derived from neuroimaging-annotated transcriptome analyses and/or from previous evidence from immune studies performed in a large multicentre cohort of patients with SLE (ZEUS study: NCT02403115) will be used to define candidate antigen targets for autoantibodies. Serum samples will be collected longitudinally at time of clinical evaluation and neuroimaging and analysed by ELISA.

Time frame: 12 months (extensions allowed for existing MRI images before study onset)

To correlate antigen-specific CD4+ T-cell dynamics over time with the spectrum of SLE, NPSLE and associated MRI findings.

Major histocompatibility complex (MHC) multimers bound to relevant autoepitopes identified through in silico analyses of data from neuroimaging-annotated transcriptome analyses and/or from previous evidence from immune studies performed in a large multicentre cohort of patients with SLE (ZEUS study: NCT02403115) will be used to detect and track antigen-specific CD4+ T-cells. Further characterisation of T-cells will be performed in terms of differentiation and polarisation. In vitro T-cell reactivity assays with relevant autoepitopes will also be performed