Autoimmune Neurology & MS: Updates and Advances in the Immunobiology and Approaches in Autoimmune Encephalitis*

Autoimmune and MS SIG Topic: Updates and Advances in the Immunobiology and Approaches in Autoimmune Encephalitis

Immunogenetic and Whole Exome Sequencing studies were conducted in 11 GAD-positive patients: 8 with sporadic Stiff Person Syndrome (SPS) and 3 from a three-generation family with very-high GAD-ab titers but diverse symptomatology (one GAD-epilepsy/SPS, two only with diabetes). Two immune genes were identified, ORAI1 that codes for calcium release-channel protein activating T-lymphocytes, and LILRA4 that encodes an IgG-like cell surface protein on plasmacytoid-dendritic cells. Importantly, seven genetic polymorphisms in Kallikrein-10 (KLK10) gene were shared by all 9 SPS patients, verified by Sanger sequencing, but not in GAD-positive family with diabetes or GAD-negative controls. KLK10, a peptidase expressed on choroid plexus epithelium and neuroendocrine organs initiating systemic inflammatory responses via proteolytic cascades, is a novel genetic marker in SPS patients. Along with ORAI1 and LILRA4 , KLK10 may facilitate GAD- autoimmunity by altering protease activity or the expression of neuron-to-immune cell signaling being an interplay between genetic predisposition and immune dysregulation.

In people with multiple sclerosis (pwMS), a higher baseline number of paramagnetic rim lesion (PRL) predicts greater future disability progression. However, the impact of preventing new PRL formation or resolving existing PRLs on clinical outcomes remains unknown. In this study, we detected PRLs in 155 pwMS using 3T MRI at baseline and 5-year follow-up. We assessed the relationship between PRL appearance or disappearance and confirmed disability progression (CDP) and progression independent of relapse activity (PIRA). We found that a faster annualized PRL disappearance rate was associated with reduced rates of CDP and PIRA. Additionally, pwMS with no new PRLs at follow-up had lower PIRA rates than those with 1+ new PRLs. Using the model-based beta values, we estimate that accelerating the PRL disappearance rate could reduce the 5-year population-level prevalence of PIRA by up to 29%. Our findings underscore the need for novel DMTs targeting chronic active inflammation.

Infectious triggers are well known for certain autoimmune conditions, such as ADEM (Acute Demyelinating Encephalomyelitis) and Gullain-Barré Syndrome. In the most common form of autoimmune encephalitis (AE), NMDA receptor encephalitis (NMDARE), about half of patients have a viral prodrome. Indeed, some patients who develop NMDARE do so after a herpes simplex virus (HSV) infection of the brain. Further studies have revealed additional herpes infections leading to other types of AE. The recent global pandemic saw reports of AE after infection with Covid-19. This presentation will cover what is currently known about infectious triggers of AE and potential future directions that the field is heading.

This session will discuss treatment approaches and considerations in children with autoimmune encephalitis (AE). Moreover, improved understanding is needed whether continued symptoms are reflective of ongoing inflammation versus the after effects of AE. Moreover, AE should also be considered in context of the developing brain and effects on quality of life, including education and the family unit.