Abstract
Neuropsychiatric symptoms in systemic lupus erythematosus (SLE) are not uncommon, yet the mechanisms underlying disease initiation and progression in the brain are incompletely understood. Although the role of T cells in other lupus target organs such as the kidney is well defined, which T cells contribute to the pathogenesis of neuropsychiatric SLE is not known. The present study was aimed at characterizing the CD4 T cell populations that are present in the choroid plexus (CP) of MRL/MpJ-faslpr mice, the primary site of brain infiltration in this classic lupus mouse model which exhibits a prominent neurobehavioral phenotype. T cells infiltrating the CP of MRL/MpJ-faslpr mice were characterized and subset identification was done by multiparameter flow cytometry. We found that the infiltrating CD4 T cells are activated and have an effector phenotype. Importantly, CD4 T cells have a T follicular helper cell (TFH) like phenotype, as evidenced by their surface markers and signature cytokine, IL-21. In addition, CD4 TFH cells also secrete significant levels of IFN-γ and express Bcl-6, thereby conforming to a potentially pathogenic T helper population that can drive the disease progression. Interestingly, the regulatory axis comprising CD4 T regulatory cells is diminished. These results suggest that accumulation of CD4 TFH in the brain of MRL/MpJ-faslpr mice may contribute to the neuropsychiatric manifestations of SLE, and point to this T cell subset as a possible novel therapeutic candidate.
Highlights
IntroductionSigns and symptoms of primary neuropsychiatric disease in systemic lupus erythematosus (SLE) (i.e., due to lupus itself rather than iatrogenic or other causes) include a broad range of clinical manifestations, such as cognitive disorders, seizures, stroke, psychosis, and depression [1]
Signs and symptoms of primary neuropsychiatric disease in systemic lupus erythematosus (SLE) include a broad range of clinical manifestations, such as cognitive disorders, seizures, stroke, psychosis, and depression [1]
We found that there was a significant population of CD4+ and CD8+ T cells in the choroid plexus (CP) of MRL/lpr mice, which was almost absent in MRL/+ controls (Figures 1B,C)
Summary
Signs and symptoms of primary neuropsychiatric disease in systemic lupus erythematosus (SLE) (i.e., due to lupus itself rather than iatrogenic or other causes) include a broad range of clinical manifestations, such as cognitive disorders, seizures, stroke, psychosis, and depression [1]. The immunopathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE) is complex and multifactorial, involving adhesion molecule upregulation together with inflammatory cytokines and/or neuropathic autoantibodies that reach the brain through abnormally permeable brain. The presence of affinity matured autoantibodies along with lymphocyte infiltrates in brain autopsy tissue from SLE patients with neurological disease support a role for T cells in the pathogenesis of NPSLE [4]. The role of T cells in the immunopathogenesis of SLE outside the central nervous system (CNS) has been widely studied. T cells from SLE patients display aberrant T cell signaling, activation, and function [5]. In addition to abnormal T cell function, SLE is characterized by differential expression of various T cell subsets. Suppressive T cell subsets such as T regulatory cells (Tregs) are decreased in SLE, contributing to an imbalance in immune homeostasis [12]
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