Friederike Arlt1, Yong Guo1, Michael Gilligan1, Surendra Dasari1, Reghann LaFrance-Corey1, Connie Lesnick1, Divyanshu Dubey1, John Mills1, Sean Pittock1, Anastasia Zekeridou1, Ramona Miske2, Madeleine Scharf2, Elias T. Spiliotis3, Andrew McKeon1
1Mayo Clinic, 2Institute for Experimental Immunology, affiliated with EUROIMMUN Medizinische Labordiagnostika AG, 3Department of Cell Biology, University of Virginia, School of Medicine
Objective:
To identify novel septin-directed IgGs among previously unclassified neural autoantibodies (UNAs).
Background:
Septins are a family of 13 different proteins involved in various cellular processes including cytoskeletal organization and vesicle trafficking. We have previously reported septin-5- and -7-IgGs in patients with neurological autoimmunity; paraneoplastic causation occurs infrequently (<20%). We report additional septin autoimmune targets identified in our UNA discovery pipeline.
Design/Methods:
UNAs (538) were identified by TIIFA during routine testing from 03/2023 to 02/2025. Sixteen showed septin-5/-7-IgG-like staining patterns - characterized by synaptic cerebellar molecular layer predominance, and stronger thalamic than hippocampal or cortical signal - but were negative on corresponding cell-based assays (CBAs). All samples were screened for septin IgGs using protein microarrays and PhIP-Seq. Septin antigen specificity was confirmed with septin-specific CBAs and confocal TIIFA colocalization studies. Clinical data were retrospectively reviewed, tumor specimens assessed for septin expression, and live-cell binding tested in primary neuronal cultures.
Results:
Six sera demonstrated reactivity to septin-3, septin-4, septin-6, or septin-9. Septin-3-IgG was detected in a cerebellar ataxia patient (consistent with prior report); our patient had spindle cell sarcoma. Septin-4-IgG was identified in 2 patients with cancer (thymoma and vulva squamous cell carcinoma) and brainstem syndromes, one responding to immunotherapy. Septin-4 expression was detected in the available thymoma tissue. Septin-6-IgG was detected in paraneoplastic encephalopathy with lung cancer. Septin-9-IgG was detected in 2 cases: 1 with coexisting septin-7-IgG and pancreatic adenocarcinoma-associated encephalopathy, and 1 with septin-9-IgG and immune checkpoint-inhibitor-related myeloradiculoplexopathy with squamous cell lung carcinoma. CSF was available only for the septin-3-IgG patient and showed strong positive binding to live rodent hippocampal neurons. Serum IgG showed no binding in any of the six patients.
Conclusions:
Septin autoimmunity is diverse, with specific septin reactivity relating to distinct clinical phenotypes. All patients in this cohort had associated malignancies, supporting the necessity for tumor screening.
Generative AI Usage
No, did not use generative AI in the drafting or editing in this abstract.
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