Dissertation committee:
Δημήτριος Μπούμπας, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Γεώργιος Μπερτσιάς, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, Πανεπιστήμιο Κρήτης
Παναγιώτης Βεργίνης, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, Πανεπιστήμιο Κρήτης
Αντώνης Φανουριάκης, Επίκουρος Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Δημήτριος Βασιλόπουλος, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Κλειώ Μαυραγάνη, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Πρόδρομος Σιδηρόπουλος, Καθηγητής, Ιατρική Σχολή, Πανεπιστήμιο Κρήτης
Summary:
Neuropsychiatric systemic lupus erythematosus (NPSLE) is an emerging frontier in lupus care encompassing a wide spectrum of clinical manifestations. Despite recent progress in the field, understanding of NPSLE in terms of diagnosis, pathogenesis and
treatment remains deficient, because of limited access to tissue, diversity and complexity of clinical manifestations, and overlap with non-SLE related neuropsychiatric events.
As part of my thesis, we established the Attikon SLE cohort, one of the largest in the world with close to 800 patients, and utilized it to study NPSLE. In this cohort, neuropsychiatric disease as presenting manifestation was present in 11.5% of patients,
while 17.6% of patients exhibited at least one lupus-related neuropsychiatric event until most recent follow-up. Of note, neuropsychiatric involvement at onset, was independently associated with transition from mild/moderate to more severe disease.
Demyelinating events were observed in 3.7% of SLE patients, equally distributed between primary SLE-demyelination and overlap SLE-MS. We also identified a significant number of patients with demyelination who did not fulfill criteria for either
MS or SLE and these patients exhibit lupus-like autoimmune features and may represent a distinct entity, which we coined ‘demyelination with autoimmune features’.
In reference to NPSLE pathogenesis, I used the NZB/W-F1 mouse model, which develops spontaneous nephritis at 6 months of age, to study neuropsychiatric disease. In this strain, at the pre-nephritic stage (age 3 months), although the blood brain barrier (BBB) remains intact, we found hippocampus-related behavioral deficits resembling human diffuse neuropsychiatric disease, including depression, anxiety, decreased cognition and impaired coordination. This phenotype is mediated by disrupted hippocampal neurogenesis, with hippocampal neural stem cells (hiNSCs) exhibiting increased proliferation combined with decreased differentiation and survival due to excessive apoptosis. This is accompanied by activation of the microglia towards an inflammatory-state with increased secretion of pro-inflammatory cytokines and chemokines. Later in the course of the disease, when mice develop nephritis (6 months) a disrupted BBB allows immune components of peripheral blood, particularly B-cells, to penetrate into the hippocampus, further enhancing inflammation with locallyincreased levels of IL-6, IL-12, IL-18 and IL-23. Among these cytokines, IL-6 and IL18 directly induce apoptosis of adult hiNSCs ex vivo, while for the remaining cytokines there are no receptors to exert effects on adult hiNSCs. Of note, in contrast to the prenephritic stage, an interferon (IFN)-α signature was present in this stage. We conclude that an intact BBB with microglial activation disrupting the formation of new neurons within the hippocampus represent early neuropsychiatric changes in NPSLE. In the
NZB/W-F1 model, neuropsychiatric disease is an early event that occurs prior to generalized lupus immunologic activity. Early intervention targeting activation of microglia/inhibition of IL-6 or IL-18, or protection of neurons may be a reasonable
therapeutic strategy, while in later stages IFN targeting may be more effective.
Keywords:
Systemic Lupus Erythematosus, Neuropsychiatric Lupus, Microglia, Neurogenesis
