Novel Autoantibody against Septin-3 Discovered in Neurological Disease

Septins are cytoskeletal proteins that play multiple roles in cell division, cellular polarization, morphogenesis, and membrane trafficking. Septin-5 and septin-7 are already known target antigens of autoantibodies in neurological diseases. Now, scientists have discovered autoantibodies against septin-3 in patients with paraneoplastic cerebellar ataxia.

In a collaborative study between EUROIMMUN (Lübeck, Germany), the University of Heidelberg (Heidelberg, Germany), and other German clinics, researchers analyzed three patient sera with similar immunofluorescence staining patterns on cerebellar and hippocampal sections. They identified septin-3, -5, -6, -7, and -11 as candidate target antigens using immunoprecipitation and mass spectrometry. These proteins were then expressed recombinantly in HEK293 cells either individually, as complexes, or in combinations missing individual septins. The cells were used in recombinant-cell indirect immunofluorescence assays (RC-IIFA) to detect corresponding autoantibodies.

The three patient sera reacted with recombinant cells co-expressing septin-3/5/6/7/11, while none of the control sera did. Different septin combinations confirmed the autoantibodies' specificity for septin-3. In RC-IIFA analyses, patient sera reacted only with cells expressing septin-3, either individually or in complexes. The specificity was further verified by eliminating tissue IIFA reactivity through prior neutralization of autoantibodies with recombinant septin-3. All three patients presented with progressive cerebellar syndrome and responded poorly to immunotherapy. All had cancer (2 melanomas and 1 small-cell lung cancer). Expression of septin-3 was demonstrated in resected tumor tissue available from one patient.

The authors concluded that septin-3 is a novel autoantibody target in patients with paraneoplastic cerebellar syndromes. Due to the different clinical phenotypes reported in patients with anti-septin-3, -5, and -7 autoimmunity, these autoantibodies may serve as markers for different clinical presentations. As a result, septin-3 IgG-associated autoimmune cerebellar ataxia might represent a new paraneoplastic neurological syndrome (PNS). The suggested strategy for determining anti-septin autoantibodies is RC-IIFA with the complex septin-3/5/6/7/11 as a screening tool to investigate serological samples with a characteristic staining pattern on neuronal tissue sections. Autoantibodies against individual septins can then be confirmed by RC-IIFA expressing single antigens.

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University of Heidelberg