How a rare immune disease broaches our first line of defence

Dr Robb Wesselingh is undertaking a PhD
  in addition to his clinical work

by Anne Crawford

Autoimmune encephalitides (AIE) are a group of autoimmune conditions affecting the central nervous system with symptoms that include drug-resistant seizures, amnesia and confusion. A rare disease characterised just over a decade ago, it causes major disruption to the lives of patients who have it; at worst the diseases can be fatal.

Dr Robb Wesselingh, a neurologist at the Alfred Hospital, saw the effects AIE was having on his patients and decided to undertake a PhD to investigate it further. “It really had an impact on their lives, some had to take years off work,” he said.

AIE occurs when the immune system incorrectly attacks proteins in the body, in this case specific proteins found on neurons in the brain, causing neuroinflammation. The neurons stop working and a variety of symptoms occur depending on where the neural dysfunction is in the brain. The attacks are acute and while the symptoms can be treated with immunotherapy, patients often have ongoing complaints, Dr Wesselingh said.

Dr Wesselingh is pursuing a line of inquiry into AIE that has been all but overlooked in the field.

He noted that while considerable literature on the disease has looked into the contribution of the adaptive immune system and its pathogen-specific foot soldiers (T cells, B cells and other antigen-fighting cells), the impact of the innate immune system - the broader first line of defence preventing the spread of pathogens - has been less well-investigated.

He conducted a review of the available literature, published recently in Frontiers of Immunology, which confirmed what he suspected. “There’s a real paucity of literature into innate cells such as monocytes and microglia, yet a lot of adaptive responses are driven by innate responses from those cells.”

The review used multiple sclerosis (MS), also a central nervous system disorder, as a model for understanding AIE. The authors found a lot of work conducted on mouse models of MS showing that cells such as monocytes and neutrophils associated with the innate immune system had infiltrated the CNS and broken down the blood-brain barrier, which prevents many of the adaptive immune cells – T cells and B cells – from infiltrating.

“This seems to be quite an important step. If you can suppress these cells in the AIE model you could suppress a lot of its activity as well.”

He said there was a “smattering” of small studies (two to 10 patient samples) looking at innate system molecules that suggested that there were a lot of infiltrating monocytes and macrophils, and microglial proliferation at the site of the pathology.

The review also found that while most therapies were based on the adaptive system, a few were emerging acting on the innate system, including IL-6 receptor blockers (Interleukin 6, known as IL-6, is involved in the immune system's response to infection and injury).

Dr Wesselingh said the review indicated a gap of knowledge into which further research could be conducted, potentially to provide future biomarkers and treatment goals for patients with AIE. Studying AIE could also assist scientists in understanding the mechanisms of CNS autoimmunity and its genesis.

Dr Wesselingh is part of Dr Mastura Monif’s group in the Department of Neuroscience, which is leading a growing consortium of institutions collecting biosamples, clinical data and clinical histories to further explore this rare disease.

Wesselingh R, Butzkueven H, Buzzard K, Tarlinton D, O'Brien TJ, Monif M. Innate Immunity in the Central Nervous System: A Missing Piece of the Autoimmune Encephalitis Puzzle? Front Immunol. 2019 Sep 10;10:2066. doi: 10.3389/fimmu.2019.02066. eCollection 2019.