Brain-reactive antibodies and disease

Abstract

Autoimmune diseases currently affect 5-7% of the world's population; in most diseases there are circulating autoantibodies. Brain-reactive antibodies are present in approximately 2-3% of the general population but do not usually contribute to brain pathology. These antibodies penetrate brain tissue only early in development or under pathologic conditions. This restriction on their pathogenicity and the lack of correlation between serum titers and brain pathology have, no doubt, contributed to a delayed appreciation of the contribution of autoantibodies in diseases of the central nervous system. Nonetheless, it is increasingly clear that antibodies can cause damage in the brain and likely initiate or aggravate multiple neurologic conditions; brain-reactive antibodies contribute to symptomatology in autoimmune disease, infectious disease, and malignancy.

Figure 1

Anatomical organization of the neurovascular and cerebroventricular systems of the central nervous system (CNS). Most CNS tissue is vascularized by a dense network of blood vessels that exhibit characteristic cellular and physiological features of the blood-brain barrier (BBB). The BBB thus constitutes a critically important interface between the CNS and systemic immunity. Other important interfaces between the CNS and the immune system exist within the ventricular system. Within the circumventricular organs, endothelial cells form a fenestrated capillary network. Within the choroid plexus, specialized epithelial cells filter blood to generate cerebrospinal fluid (CSF), an interstitial fluid that fills the ventricles and the meninges of the CNS. These epithelial cells exhibit barrier properties, including tight junctions, similar to those at the BBB. The CSF communicates with the perivascular space surrounding CNS blood vessels and drains into the lymphatic and venous circulation.

Figure 2

Diverse mechanisms of antibody entry into the central nervous system (CNS) at the neurovascular interface. Anatomy and cell types: The neurovascular network forms a dense and intricate organ system in which numerous specialized cell types cooperate to form distinct classes of blood vessels with unique functions in regulating antibody access to the CNS parenchyma. The immediate barrier for preventing antibody entry into the CNS is the blood-brain barrier formed by CNS endothelial cells. These cells form tight junctions that restrict paracellular diffusion of soluble factors and exhibit limited transcytosis and a relatively limited propensity for leukocyte adhesion under resting conditions. Astrocytes surround the basal surfaces of vessels with their foot processes and basement membranes. Most of the neurovascular surface area is composed of capillary microvessels, in which exchange of soluble factors occurs and in which astrocyte-derived membranes are apposed to endothelial-derived basement membranes. In larger postcapillary venules, a distinct perivascular space is observed between the astrocytic endfeet and the endothelial wall, where resident cells include pericytes (which induce barrier properties) and perivascular macrophages (which are thought to transduce inflammatory signals). Possible mechanisms of antibody entry: Under normal physiological conditions, entry of immunoglobulins into the CNS is negligible. This restriction may be disrupted or bypassed under certain pathologic circumstances. Activation of CNS endothelial cells can result from activation of luminal receptors, including Toll-like receptors, cytokine receptors, and hormone receptors. Activation of perivascular macrophages might result from endothelial cell activation, which can further enhance disruption of tight junctions, permitting paracellular diffusion, increasing transcellular transport of soluble factors, and upregulating leukocyte adhesion molecules. Leukocyte adhesion to activated endothelial cells is likely to amplify relevant inflammatory signals, even in the absence of overt transmigration into the CNS. These processes are more likely to occur in brain microvascular capillaries. CNS inflammation may also cause inside-out disruption of the BBB. Antibodies with specificity for cell surface molecules expressed by endothelial cells or perhaps by other neurovascular cells may enter the CNS by antigen binding and engaging transcytotic trafficking through receptor-mediated antibody entry. Leukocyte infiltration may result in local antibody production by B lymphocytes and a locally disrupted BBB. Finally, antibody penetration into the CNS may be counteracted by antibody efflux effected by polarized FcRn (neonatal Fc receptor for immunoglobulin) on endothelial cells.