(CNS) actions such as synaptic plasticity, memory and vision, have been described in patients with cerebellar syndrome associated with lymphoma . Anti-metabotropic glutamate receptor type 1 (mGluR1) antibodies are a marker of a treatable form of cerebellar ataxia which may also be associated with lymphoma .
Septins have also been recently identified as target antigens of autoimmunity (Fig. 1). Septins are cytoskeletal proteins with multiple roles in cell division, cellular polarization, morphogenesis and membrane trafficking. Autoantibodies against septin-3 have been newly described in patients with paraneoplastic cerebellar ataxia . Anti-septin-5 antibodies have been previously characterized in patients with non-paraneoplastic cerebellar ataxia, while anti-septin-7 antibodies were found in patients with encephalopathy with prominent neuropsychiatric features . Thus, the different anti-septin antibodies appear to be associated with different clinical phenotypes.
Autoantibodies against aquaporin-4 (AQP4) are a highly specific, pathogenic marker for neuromyelitis optica spectrum disorders (NMOSD), a group of inflammatory demyelinating disorders of the CNS affecting the optic nerve, spinal column and brainstem. CBA is the gold standard for anti-AQP4-IgG testing and is now included in the diagnostic algorithm for NMOSD .
Autoantibodies against myelin oligodendrocyte glycoprotein (MOG) are a marker for MOG antibody-associated encephalomyelitis (MOG-EM), which is clinically similar to NMOSD but is now recognized as a distinct disease . Recent evidence suggests that MOG-EM may be more common than NMOSD. Determination of AQP4 and MOG antibodies helps to delimit the diseases from each other and also from multiple sclerosis (MS), which can resemble NMOSD clinically in the initial stages.
Autoantibodies against the flotillin-1/2 heterocomplex, a peripheral membrane protein that is involved in axon outgrowth and regeneration of the optic nerve, have been observed in a subset of about 1–2% of patients with bona fide MS , but not in patients with other neural autoantibody-associated diseases or in healthy blood donors. This suggests that anti-flotillin antibodies may be specific for MS, although their clinical and pathological relevance has not yet been clarified.
Autoantibodies against nodal/paranodal proteins are emerging biomarkers for a novel class of neuropathies known as autoimmune nodopathies . These diseases have clinical similarity to Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy (CIDP) but are pathologically distinct. The antibodies target membrane proteins located at or around the nodes of Ranvier – gaps in the myelin sheath that facilitate fast conduction of nerve signals. The target antigens include neurofascin 186 (NF186), neurofascin 155 (NF155), contactin 1 (CNTN1) and contactin-associated protein 1 (CASPR1). The autoantibodies are considered pathogenic, and the resulting immune reactions result in slowed conduction or even complete failure of impulse transmission. Autoimmune nodopathies manifest as acute, subacute or chronic onset sensory-motor neuropathies with distinct clinical phenotypes.
Diagnostic test systems
The testing landscape for autoimmune neurological syndromes is continually evolving . Autoantibody detection in conjunction with clinical evaluation and radiographic findings can facilitate diagnosis and prognosis of these diseases. IFA is an indispensable method for autoantibody determination. Tissue sections of nerves, cerebellum, hippocampus and intestine enable comprehensive screening of neural autoantibodies, whereas transfectedcell substrates provide easy, monospecific detection of defined autoantibodies. CBA technology is particularly suitable for neuronal cell-surface antigens, which are often conformation-dependent and fragile and thus unsuitable for the expression and purification procedures required for solid-phase methods such as ELISA or immunoblot. Further, as the antigens do not need to be obtained in purified form, the assays can be developed rapidly, enabling novel parameters to be incorporated promptly into the test repertoire. CBAs are now a core component of serological differential diagnostics for certain neurological diseases, for example anti-NMDAR encephalitis and NMOSD.
CBAs with CE mark are currently available from EUROIMMUN for the detection of autoantibodies against NMDAR, AMPAR 1/2, GABABR, LGI1, CASPR2, DPPX, IgLON5, GAD65, Zic4, DNER/Tr, AQP4, MOG, AChR and MuSK. Further CBAs are commercially available for research use, for example for the detection of antibodies against NF155, NF186, CASPR1, CNTN1, GABAAR, mGluR1, mGluR5, AK5 and flotillin-1/2. Multiple antibodies can be investigated in parallel using BIOCHIP Mosaics composed of different tissue and cell substrates which are incubated simultaneously. BIOCHIP Mosaics with CE mark are available tailored to different diagnostic applications, for example autoimmune encephalitis (Fig. 2), myasthenia gravis and NMOSD. Immunoblots are suitable for detection of antibodies against more stable antigens, including many intracellular antigens. With multiplex line blots, many different antibodies can be analysed in parallel. In blots of the EUROLINE range, the antigens are contained on individual membrane chips, allowing antigens with widely different properties to be combined in applicationoriented profiles. Multiplex EUROLINE profiles are available for detection of up to twelve PNS-associated antibodies (Fig. 3), encompassing the antigens amphiphysin, CV2, PNMA2 (Ma2/Ta), Ri, Yo, Hu, recoverin, SOX1, titin, Zic4, GAD65 and DNER/Tr, as well as for detection of different anti-ganglioside antibodies.