Aquaporin 4 are water channel proteins, primarily located in astrocytes, are the target antigen in Neuromyelitis optica spectrum disorder. Usually NMO- IgG is not associated with any cancer.AQP4 is present in two major isoforms produced by alternative splicing: a relatively long (M1) isoform withtranslation initiation at Met-1, and a shorter (M23)isoform with translation initiation at Met-23.
AQP4 monomers assemble as tetramers. AQP4 tetramers uniquely further aggregate in cellplasma membranes to form supramolecular assemblescalled orthogonal arrays of particles (OAPs). OAPs wereoriginally visualised in membranes by freeze-fractureelectron microscopy.AQP4 is most strongly expressed in the CNS, but is also present in epithelial cells in the kidney (collectingduct), the stomach (parietal cells), airways, glands, andskeletal muscle. AQP4 is expressed in astrocytes in thebrain, spinal cord, and optic nerve, and is particularlyconcentrated at pial and ependymal surfaces in contactwith the CSF. At the cell level, AQP4 expression ispolarised to foot processes of astrocytes in contact withblood vessels.
AQP4 is also expressed in so-calledsupportive cells,similar to astrocytesin sensoryorgans such as Muller cells in the retina. Pathologicalchanges associated with Neuromyelitis optica mostlyoccur in the spinal cord and optic nerve, and to a lesserextent in the brain, with a notable absence ofabnormalities in peripheral AQP4-expressing tissues.Myelin Oligodendrocyte Glycoprotein (MOG) Autoimmunity:Target protein in MOG autoimmunity is Myelin oligodendrocyte Glycoprotein, belongs to immunoglobulin superfamily. It is expressed exclusively on the outer surface of myelin sheath and oligodendrocyte’s plasma membrane.
MOG is a most important surface marker of myelin for oligodendrocyte maturation. It forms only a minor component of myelin approximately 0.05%. Functions of MOG are regulation of microtubule stability, cell adhesion molecule and mediator between myelin and immune system. After various cell based immune assays high titre of MOG is associated with multiple sclerosis, acute disseminated encephalomyelitis, seronegative NMO or clinically isolated syndrome like optic neuritis or transverse myelitis. MOG antibody titres are highly significant for paediatric age group compared to adults.Glial Fibrillary Acidic Protein (GFAP)Autoimmunity:Astrocytesare major type of glial cells in CNS. Astrocytes play an important role in homeostatic function of CNS.
Astrocytes express a reactive phenotype in ischemia, CNS trauma and neurodegenerative disease. Glial fibrillary acidic protein are main intermediate filament protein in astrocytes. GFAP are up regulated in reactive phenotype of astrocytes. Recentlyisoforms of GFAP are found to be biomarker for steroid-responsive autoimmune meningoencephalomyelitis. Some neoplasms associated are gastroesophageal adenocarcinoma and prostrate carcinoma.
Rarely associated with myeloma, melanoma and carcinoid tumor.Evaluation of antibodies and various methods to detect antibodies: Paired serum and CSF should be ideally tested in patients with suspected autoimmune disorder.Various method to detect antibodies are indirect immunohistochemistry,western blot,Radioimmunoprecipitation assay, cell based assay, ELISA. Non synaptic nuclear or cytoplasmic antibodies are best detected by western blot assay. Ion channel targeted antibodies are predominately detected by Radioimmunoprecipitation assay. Cell based assays are good to detect antibodies targeted against surface antigens. Through the immunohistochemistry method most of the antibodies can be detected.
Limitation for IHC are presence of multiple antibodies and non specific binding of antibodies. Low titre antibodies are confirmed using western blot assay.Evaluation of Malignancy:Patients with positive family history of malignancy, risk factors like smoking or classical paraneoplastic syndromes should be evaluated extensively for malignancy. Following investigations helps to identify associated malignancy;CT scan of chest,abdomen, and pelvis; testicular ultrasound; mammography; andprostate-specific antigen. Diagnostic yield can be increased by PET imaging when most of the diagnostic tests are negative. Drawback for PET imaging is low sensitivity in detecting gonadal tumours, Neuroblastoma or Thymoma.
In such case MRI imaging shows good sensitivity.Treatment:Various treatment options available are IV methylprednisolone,IV immunoglobulin (IVIg) or plasma exchange. IV methylprednisolone is considered as first line of treatment.
In case patients can’t tolerate IV steroids, IV immunoglobulin can be used. In patient’s refractory to treatment or contraindication with IV steroids and IVIg, plasma exchange can be tried in those patients. The duration and intensity of treatment depends on the severity of the clinical syndrome. Rapid escalation of treatment can be considered in clinically unstable patients who requires intensive care support.