Role of Pathogenic and Physiological Autoantibodies against Central Nervous System Antigens.

Andleeb Zameer and Unalissa Freso, Biological Sciences, New York City College of Technology

AbstractThis research project was done as part of the Emerging Scholars Program at The New York City College of Technology under the direction of Professor Andleeb Zameer in Biological Sciences. Autoantibodies are mostly studied in the context of disease and pathology seen in autoimmune disorders. There are many different types of autoimmune disorders that are thought to be mediated by autoantibodies. Among autoimmune disorders of the Central Nervous System (CNS), pathological autoantibodies often lead to sever neurologic deficits via inflammatory processes such as encephalitis. In some instances, however, autoantibodies function as a barrier for diagnostic process and/or disease progression. The existence of naturally occurring physiological autoantibodies have been known for a long time, and their role in maintaining homeostasis is supported by several studies. This project will further explore the current status of the role of pathogenic autoantibodies in the CNS autoimmune disorder and will contrast this with the role of naturally occurring physiological autoantibodies. Conclusions will be derived based on the existing data and the questions that are still unanswered will be highlighted and future directions proposed.

IntroductionOur natural environment contains numerous potential hazards threatening the human body from the very beginning. Therefore, defense strategies have evolved to protect us against a variety of external pathogens (1).Tight junctions between the endothelial cells lining the BBB keep the serum/cerebrospinal fluid (CSF) ratios for restricted proteins to about 200:1 (3). Preventing the unrestricted entry of substances into the CNS helps provide an ideal environment for the functioning of the CNS (3). Disruption of the blood-brain barrier (BBB) is a highly pathological event associated with autoimmune disorders and an event thought to be mediated by pro-inflammatory cytokines. Due to the altered BBB, trafficking of immune cells can be greatly increased in autoimmune conditions leading to widespread inflammation and damage to cells in the CNS (4). One specific part of the defense mechanism is managed by rhe adaptive immune sytem, resulting the activation of B lymphocytes tha secrete anitgen-specific antibodies. Physiological and pathological autoantibodies targeting antigens in the CNS are of specail interest fro several reasond. Both B lymphocytes and antibodies have only limited acess to the BBB (5). Therefore, only a few autoanitbodies have been described targeting antigens in the CNS in comparison to the numerous autoantibodies directed against antigens of the peripheral nervous sysytem (PNS).

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Fig. 1 : The principal network of mammal regulatory metasystem. When challenged by external and internal stressors, functional homeostasis regulates itself through coordinated interactions between neuroendocrine and immune systems. Different forms of mental and neurodegenerative CNS illnesses are proposed to ensue in genetically susceptible organisms when disturbances in their regulatory metasystem become severe and chronic. Kapadia and Sakic, 2011 (Ref. 6)

Fig. 2: The BBB is intimately involved with the neuroimmune system. An intact BBB maintains the relative isolation of brain from the immune system.

Fig. 3 : Summary of putative cellular mechanisms underlying neuronal damage in autoimmune/inflammatory diseases of the CNS. When the BBB is breached, various immune cells and mediators can compromise the viability of brain cells at different stages of disease progress, age, and genetic deficits in affected individuals. These factors include cytotoxic T cells, macrophages, BRA to surface and intracellular receptors, the C5b-9 MAC, MMPs, and ROS.Kapadia and Sakic, 2011 (Ref. 6)

Fig. 4In the diagram, cells are transfected with afl uorescent-tagged protein (green) to track the antigen, and the binding of the patient’s antibodies (white) to the antigen (eg, NMDAR) is detected with a secondaryantibody labelled with red fl uorescence. In the image below, colocalisation is shown in yellow (×5000). (B) Neuronal antigens. The AChR is shown as an example of apentameric, ligand-binding receptor; GlyRs are similar to AChR in size and structure. The NMDA receptor is tetrameric. The VGKC is shown as a tetramer of Kv1.2subunits with intracellular β subunits; note the small extracellular domains. CASPR2, which has one transmembrane domain, and LGI1, which is a secreted proteinthat, once secreted, binds with other proteins in the membrane, are both part of VGKC complexes, and are now recognised as targets for antibodies previouslythought to be directed against VGKCs.

Fig. 5 : Proposed molecular mechanisms of neuronal damage by BRA. Auto reactive antibodies to neuronal epitopes may compromise function and viability of central neurons by blocking activity of surface receptors (1), upregulate neuronal activity by sustained binding to excitatory neurons (2), bind to ion channels functionally related to neurotransmitter and neuroregulatory systems (3), and internalized antibody may bind to cell components such as nuclear components and mitochondria (4). Kapadia and Sakic, 2011 (Ref. 6)

Fig. 6 : Key aspects of inflammatory neurodegeneration in MS. Activation of T cells and antigen-presenting cells of the CNS, including activated macrophages and microglia as well as dendritic cells, results in the release of proinflammatory as well as cytotoxic molecules, such as cytokines and reactive oxygen species (ROS). Additionally, cell contact-dependent mechanisms of T cell-induced neuronal damage, involving perforin, FasL and TRAIL have been described. Herz at al., Exp. Neurol 2010, 225:9-17

ConclusionsThe experimental and clinical evidence in the field concerning both groups of autoantibodies (pathological and physiological) has grown considerably in the last decade. Our understanding of the origin and regulation of pathological autoantibodies has particularly expanded, and the pathways leading to a certain disease have been elucidated in some of the autoantibody-associated disorders. However, these autoantibodies are currently used for diagnostic purposes. Currently, no innovative therapeutic approaches have been developed based on pathological autoantibodies. In contrast, our understanding of the evidence and the role of naturally occurring autoantibodies(Nabs) is still scarce, and much research is required to unravel their function and possible use for therapeutic application. However, the concept of immune-mediated control pathologically aggregated proteins is intriguing and may open up new targets for disease modification,

AcknowledgementsThe presenter would like to acknowledge the Emerging Scholars Program at City Tech. And also, the presenter would like to thank Professor Zameer for his support, leadership and efforts.