HLA-dependency and possible clinical relevance of intrathecally synthesized anti-IgLON5 IgG4 in anti-IgLON5 disease

Anti-IgLON5 disease is a rare autoimmune disorder with IgLON5 autoantibodies predominantly of the IgG4 subclass. The clinical relevance of the pathogenic effects of anti-IgLON5 IgG1 and IgG4 is unclear. IgLON5-specific IgG1-4 levels were measured in 46 sera and 20 cerebrospinal fluid (CSF) samples from 13 HLA-subtyped anti-IgLON5 disease patients (6 female, 7 male) using flow cytometry. Intervals between two consecutive serum or CSF samplings were analyzed for treatment, changes of anti-IgLON5 IgG1/IgG4 levels and disease severity. Intrathecal anti-IgLON5 IgG4 synthesis (IS) was assessed. The median age at onset was 66 years (range 54-75) and follow-up 25 months (range 0-83). IgLON5-specific IgG4 predominance was observed in 38/46 (83%) serum and 11/20 (55%) CSF samples. Anti-IgLON5 IgG4 levels prior clinical improvement in CSF but not serum were significantly lower than in those prior stable/progressive disease. Compared to IgLON5 IgG4 levels in serum, CSF levels in HLA-DRB1*10:01 carriers were significantly higher than in non-carriers. Indeed, IgLON5-specific IgG4 IS was demonstrated in 4/5 HLA-DRB1*10:01 carriers but also in one non-carrier. Immunotherapy was associated with decreased anti-IgGLON5 IgG serum levels. In CSF, lower anti-IgLON5 IgG was associated with combinations of corticosteroids and/or azathioprine plus intravenous immunoglobulins or rituximab. Our findings might indicate that CSF IgLON5-specific IgG4 is clinically relevant and frequently produced intrathecally, especially in HLA-DRB1*10:01 carriers. More intense immunotherapy induce clinical improvement and may be able to target intrathecally produced anti-IgLON5 IgG. Further studies need to confirm whether anti-IgLON5 IgG4 IS is a suitable prognostic and predictive biomarker in anti-IgLON5 disease.