Inflammation in the CNS presents unique challenges, as the need to avoid collateral damage that may compromise functional integrity of the retina or brain is as important as the need to eliminate the pathogen.5
It is now widely accepted that unrestrained neuroinflammatory responses deriving from excessive secretion of cytokines by inflammatory cells contributes to neuronal or photoreceptor cell deficit that precede neurodegenerative changes in uveitis, multiple sclerosis, Alzheimer disease or age-related macular degeneration. Uveitis and multiple sclerosis are classical T cell mediated CNS autoimmune diseases that provide useful framework for understanding cross-talk between cytokines secreted by cells of the innate system (IL-12, IL-23 and IL-27) and cytokines produced by adaptive immune cells (IL-2, IL-17 and IFN-γ). The fact that these cytokines, as well as, neuronal-protective cytokines (CNTF, IGF-1, OSM and LIF) utilize STAT pathways, provides opportunity to study how aberrant regulation of STAT pathways contribute to pathogenic autoimmunity and other neurodegenerative diseases. Mice with targeted deletion of STAT proteins in T cells have therefore been used to characterize the role of each STAT member in CNS autoimmune diseases. In this review, we have focused on experimental findings in mouse models of multiple sclerosis and uveitis because most of what we know about the role of STATs in CNS autoimmune diseases derives from these models.
Multiple sclerosis (MS) is an autoimmune disease characterized by immunological response to myelin, a dielectric (electrically insulating) material that forms the myelin sheath surrounding the axon of neurons. In MS, encephalitogenic lymphocytes attack and destroy myelinated neurons, thereby interfering with synaptic transmission and communication between neurons. A characteristic feature of MS is its recurrent cycles of debilitating neurological disease.6
Experimental autoimmune encephalomyelitis (EAE), induced in various rodent models by immunization with spinal cord or brain homogenate in CFA, has provided valuable insights into immunopathogenic mechanisms of MS.6
Uveitis is a diverse group of intraocular inflammatory diseases that includes birdshot retinochoroidopathy, Behcet disease and ocular sarcoidosis, and is characterized by the destruction of uveal tissue by autoreactive uveitogenic T cells.7
Experimental autoimmune uveitis (EAU) is an animal disease that shares essential pathological features with human uveitis.8
EAU is the animal model of uveitis and is a predominantly T cell-mediated intraocular inflammatory disease induced in susceptible species by active immunization with retinal protein extracts in CFA.8
Uveitis is also a relapsing-remitting CNS autoimmune disease.
Encephalitogenic or uveitogenic T cells that mediate EAE or EAU, respectively, preferentially enter the CNS across BBB or BOB as a result of the expression of P-selectins, LFA-1, chemokines (MIP-1 and RANTES) and chemokine receptors by the inflammatory cells. In fact, antibodies directed against ICAM-1 or LFA-1 have been used to inhibit EAU9
underscoring the importance of adhesion molecules in pathogenesis of both diseases. Furthermore, integrins and osteopontin that promote chemotactic properties of leukocytes are important for homing of uveitogenic cells into neuroretina.11,12
Numerous studies have sought to identify STAT pathways that mediate recruitment of encephalitogenic or uveitogenic T cells into the brain or retina as they are considered to be potential therapeutic targets in MS and uveitis.