It is known that this GI wall is considerably leaky and the immune system continuously samples luminal contents for immunological surveillance; undoubtedly immune reactions to protein in food are not uncommon (Berer, et al., 2011; Fasano, 2011; Ochoa-Reparaz, et al., 2011). white matter in the brain and spinal cord causing inflammatory infiltrates, demyelination, axonal damage and necrosis resulting in sensory loss and paralysis (Jarius, et al., 2008). In three-quarters of cases, NMO is usually associated with the development of IgG1 antibodies that bind selectively to aquaporin 4 (AQP4) (Dujmovic, et al., 2011; Jarius and Wildemann, 2010; Kim, et al., 2012; Kim, et al., 2010; Lennon, et al., 2005; Petzold, et al., 2010), a water channel belonging to the aquaporin family. AQP4 is the predominant water channel in the CNS and is expressed in astrocytes, ependymocytes and endothelial cells, but not in neurons (Nagelhus, et al., EG00229 2004; Nesic, et al., 2006). It is highly distributed in the astrocytic foot processes at the blood brain barrier in contact with brain microvessels or subarachnoid space (Nagelhus, et al., 2004). By contributing to regulation of activity-dependent extracellular volume changes EG00229 that impact solute concentration and electrical activity, it helps to modulate normal neuronal transmission and excitability (Nagelhus, et al., 2004). NMO-IgG1 antibodies are damaging to astrocytes and presumably cause demyelination in the spinal cord and optic nerve (Kinoshita, et al., 2009; Kinoshita, et al., 2010). The reason for the development of these autoantibodies and their precise role in the etiology of this disease is usually unclear (Roemer, et al., 2007; Verkman, et al., 2011), although it has been recently shown that intracerebral injection of IgG from NMO patients and human match into mice causes development of pathological features characteristic of NMO (Saadoun, et al., 2010; Verkman, et al., 2011). The pathogenesis of NMO entails binding of IgG1 to AQP4 and match activation, which leads to loss of AQP4 in lesions through tissue damage (Jarius, et al., 2008; Phuan, et al., 2012). Deposition of immunoglobulins, match and inflammatory infiltrates cause demyelination and tissue destruction that correlates with regions where AQP4 is usually expressed. Since IgG1 is usually produced in peripheral tissues, its access to the extracellular space of the CNS is usually greater in areas EG00229 where blood brain barrier permeability is usually higher or compromised, allowing antibodies to reach their target antigens (Bradl and Rabbit Polyclonal to mGluR2/3 Lassmann, 2008; Lennon, et al., 2005). AQP4 has 6 membrane spanning -helices and 2 pre-helices. Several studies have documented the relative reactivity of NMO serum to AQP4 epitopes, and both conformational as well as linear epitopes have been explained (Crane, et al., 2011; Graber, et al., 2008; Jarius, et al., 2008; Kampylafka, et al., 2011; Mader, et al., 2010; Petzold, et al., 2010; Tani, et al., 2009). For example, a major epitope for AQP4-IgG has been reported to occur within amino acids 207 to 232 (Crane, et al., 2011; Graber, et al., 2008; Mader, et al., 2010; Tani, et al., 2009). We hypothesize here that pathogenic antibodies to AQP4 may be brought on by exposure to environmental proteins that have similarity to this epitope (loopE:207-232). We compared protein sequences in nature to this selected sequence to determine which may be most likely to cross-react with this epitope. A recent report suggested that T cells may be important EG00229 in the pathophysiology of NMO (Kalluri, et al., 2011). NMO T-cell epitopes were characterized and it was demonstrated that a peptide in the N-terminus region of AQP4, namely 22-IMVAFKGVWTQAFWK-36 was likely the core immunogenic T cell epitope (Kalluri, et al., 2011). Here we describe our bioinformatics comparison of human AQP4 to other proteins in nature to investigate the occurrence of epitopic molecular mimicry. Cross-reactivity of sera from NMO subjects to one of the sequences selected was investigated and is reported here as well. Methods Structural neighbor analysis Structural neighbor searches for main, secondary and tertiary structure similarities to the reported structure of human AQP4 (Ho, et al., 2009) were carried out using the National Center for Biotechnology Information (NCBI) Vector Alignment Search Tool (VAST). This tool is usually a computer algorithm that uses geometric criteria to identify comparable protein 3-dimensional structures, including distant homologs that cannot be.