Neuroinflammation Research Group

Anti-IgLON5 (IgLON5-IgG)-associated disease is a newly defined clinical entity. This literature review aims to evaluate its pathogenesis, which remains a pivotal question. Features that favour a primary neurodegenerative mechanism include the non-inflammatory tauopathy neuropathological signature and overrepresentation of microtubule-associated protein tau (MAPT) H1/H1 genotype as seen in other sporadic tauopathies. In contrast, the cell-surface localisation of IgLON5, capability of anti-IgLON5 antibodies to exert direct in vitro pathogenicity and disrupt IgLON5 interactions with its binding partners, human leukocyte antigen (HLA)-DRB1*10:01 and HLA-DQB1*05:01 allele preponderance with high affinity binding of IgLON5 peptides, and responsiveness to immunotherapy favour a primary autoimmune process. The presentation and course of anti-IgLON5-associated disease is heterogenous; hence, we hypothesise that a multitude of immune mechanisms are likely simultaneously operational in this disease cohort.

Jane Andersen, Bronte Jeffrey, Winny Varikatt, Michael Rodriguez, Ming-Wei Lin, David A Brown

A CSF-restricted MOG-IgG profile is rare, with over half of these patients having an alternate non-MOGAD diagnosis confirmed. We strongly recommend the use of serum as the biospecimen of preference in testing for MOG IgG. We additionally urge caution in the interpretation of CSF-restricted MOG-IgG in unselected patients who do not have clinical, radiological or ancillary investigations consistent with MOGAD.

David A Brown, Nevin John, Jeanette Lechner-Scott, Allan Kermode, Irene Tan, Anthony Fok, Stephen Reddel, Nigel Wolfe, Katherine Buzzard, Marzena Fabis-Pedrini, Sudarshini Ramanathan, Christopher Kneebone, Con Yiannikas, Benjamin Trewin, Molly Reynolds, Magdalena Lerch, Snehal Shah, Russel C Dale, Fabienne Brillot

GDF15 regulates its anorexic effects through the hindbrain area postrema (AP) and nucleus of the solitary tract (NTS) neurons where its receptor, glial-derived neurotrophic factor receptor alpha-like (GFRAL), is expressed. The actions of GDF15 may interact with other appetite regulators elevated in obesity, such as leptin. Here, we report that in mice with high-fat-diet-induced obesity (HFD), the combined infusion of GDF15 and leptin causes significantly greater weight and adiposity loss than either treatment alone, indicating potentiation between GDF15 and leptin. Furthermore, obese, leptin-deficient ob/ob mice are less responsive to GDF15, as are normal mice treated with a competitive leptin antagonist. GDF15 and leptin induce more hindbrain neuronal activation in HFD mice than either treatment alone does. We report extensive connections between GFRAL- and LepR-expressing neurons and find LepR knockdown in the NTS to reduce the GDF15-mediated activation of AP neurons. Overall, these findings suggest that leptin signaling pathways in the hindbrain increase GDF15’s metabolic actions.

Samuel N Breit, Rakesh Manandhar, Hong-Ping Zhang, Michelle Lee-Ng, David A Brown, Vicky Wang-Wei Tsai

There is increasing interest in GDF15 analogs as therapeutic agents for obesity. In this issue of Cell Metabolism, Benichou et al. report the first clinical trial of such a drug in obese humans.

Samuel N Breit, David A Brown, Vicky Wang Wei Tsai