Abstract
Galectin-8 (Gal-8) is a member of a glycan-binding protein family that regulates the immune system, among other functions, and is a target of antibodies in autoimmune disorders. However, its role in multiple sclerosis (MS), an autoimmune inflammatory disease of the central nervous system (CNS), remains unknown. We study the consequences of Gal-8 silencing on lymphocyte subpopulations and the development of experimental autoimmune encephalitis (EAE), to then assess the presence and clinical meaning of anti-Gal-8 antibodies in MS patients. Lgals8/Lac-Z knock-in mice lacking Gal-8 expression have higher polarization toward Th17 cells accompanied with decreased CCR6+ and higher CXCR3+ regulatory T cells (Tregs) frequency. These conditions result in exacerbated MOG35-55 peptide-induced EAE. Gal-8 eliminates activated Th17 but not Th1 cells by apoptosis and ameliorates EAE in C57BL/6 wild-type mice. β-gal histochemistry reflecting the activity of the Gal-8 promoter revealed Gal-8 expression in a wide range of CNS regions, including high expression in the choroid-plexus. Accordingly, we detected Gal-8 in human cerebrospinal fluid, suggesting a role in the CNS immune-surveillance circuit. In addition, we show that MS patients generate function-blocking anti-Gal-8 antibodies with pathogenic potential. Such antibodies block cell adhesion and Gal-8-induced Th17 apoptosis. Furthermore, circulating anti-Gal-8 antibodies associate with relapsing-remitting MS (RRMS), and not with progressive MS phenotypes, predicting clinical disability at diagnosis within the first year of follow-up. Our results reveal that Gal-8 has an immunosuppressive protective role against autoimmune CNS inflammation, modulating the balance of Th17 and Th1 polarization and their respective Tregs. Such a role can be counteracted during RRMS by anti-Gal-8 antibodies, worsening disease prognosis. Even though anti-Gal-8 antibodies are not specific for MS, our results suggest that they could be a potential early severity biomarker in RRMS.
Highlights
Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS) that damages myelin and axons in the brain and spinal cord [1, 2]
Observations in remitting form of MS (RRMS) patients, as well as in the MS preclinical mouse model of experimental autoimmune encephalomyelitis (EAE), suggest that disease pathogenesis and resolution depends on a fine balance between the autoimmune inflammation mediated by effector Th1 and Th17 lymphocytes [3, 5] and the immune tolerance promoted by suppressive regulatory T cells (Tregs) [6, 7]
Our results demonstrate a crucial role of Gal-8 and its function-blocking antibodies in the pathogenesis of MS
Summary
Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS) that damages myelin and axons in the brain and spinal cord [1, 2]. A subset of patients (20%) exhibits primary progressive MS (PPMS) displaying worse evolution than RRMS patients from the beginning [1]. Such wide variations in the phenotype and aggressiveness of the disease are reflected in the characteristic heterogeneity in presentation, evolution and treatment responses of RRMS [1, 3, 4]. Observations in RRMS patients, as well as in the MS preclinical mouse model of experimental autoimmune encephalomyelitis (EAE), suggest that disease pathogenesis and resolution depends on a fine balance between the autoimmune inflammation mediated by effector Th1 and Th17 lymphocytes [3, 5] and the immune tolerance promoted by suppressive regulatory T cells (Tregs) [6, 7]. Their study might reveal new determinants of worse disease evolution and suggest new prognostic and/or therapeutic approaches
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
