A collaborative study with Euroimmun, published recently in the journal Brain, has identified septin multimer as a novel target of autoimmunity in patients with severe motor neuropathy. The autoantibodies may represent a new biomarker for a rare but clinically significant disease subgroup.
What are septins?
Septins are a family of ubiquitously expressed cytoskeletal proteins involved in a wide range of cellular processes, including cell division, polarisation, migration, membrane trafficking, subcellular compartmentalisation, receptor signalling and cytokinesis. In humans, there are thirteen known septin isoforms, which assemble into complex multimeric structures.
Septin-3, septin-5, and septin-7 have already been described as autoantibody targets in diseases of the central nervous system presenting with cerebellar ataxia, encephalopathy and myelopathy.
Identification of target antigen
The discovery originated from three patients diagnosed with lower motor neuron disease (LMND), a clinical variant of amyotrophic lateral sclerosis (ALS). All three patients displayed a novel and distinct autoantibody binding pattern in indirect immunofluorescence assays (IFA) performed on peripheral nerve tissue. The staining targeted the Schmidt-Lanterman incisures, paranodes and abaxonal myelin.
Immunoprecipitation combined with mass spectrometry identified several septin proteins as target antigens. In cell-based assays (CBA), the three patient sera demonstrated strong binding to a septin multimer composed of septin-3, -5, -6, -7, -11, but only weak reactivity to individual septin monomers. Further evidence from neutralisation tests and knockout models confirmed that the autoantibodies recognise a conformational epitope only present after septin multimer formation.
A rare but specific autoantibody
To assess the prevalence of septin multimer autoantibodies, a cohort of patients with different neuropathies and healthy controls was retrospectively tested by tissue-based IFA and CBA. The disease cohorts included chronic inflammatory demyelinating polyradiculopathy, Guillain-Barré syndrome, multifocal neuropathy, diabetic neuropathy, other inflammatory neuropathies, ALS and multiple sclerosis.
All disease controls and healthy donors were negative for septin multimer autoantibodies, indicating that these autoantibodies are rare but specific.
Disease stabilisation with immunotherapy
One patient received extensive immunotherapy, resulting in disease stabilisation for several years, which corresponded with a decline in septin multimer autoantibody titers in CBA.
In contrast, the remaining two patients received either no immunotherapy or insufficient treatment due to late identification of the septin multimer autoimmunity. Both experienced rapid disease progression with fatal outcomes.
Why this study matters
The findings show that septin multimer autoimmunity can occur in severe inflammatory neuropathies resembling LMND and may define a novel subgroup of autoantibody-associated neuropathies.
Experimental data suggest that the autoantibodies may play a pathogenic role. Additionally, their absence across multiple neurological disease cohorts supports their potential utility as a disease-specific marker.
Further research should clarify the frequency and relevance of septin multimer autoantibodies as biomarkers and elucidate their role in the disease process.
Read the study: Arlt FA, et al. Septin multimer autoantibodies in severe motor neuropathy mimicking lower motor neuron disease. Brain. 149(8):2731-2746. (2026).
Learn more about our research at www.neuro-company.com
