title: Anti-MOG antibodies are under polygenic regulation with the most significant control coming from the C-type lectin-like gene locus.
abstract: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that is genetically complex. There is evidence supporting a role of myelin oligodendrocyte glycoprotein (MOG) humoral immunity in MS. We aimed to determine the genetic regulation of anti-MOG antibodies and their involvement in disease, by using MOG-induced experimental autoimmune encephalomyelitis (EAE) in rat, an animal model that closely mimics human MS. We show polygenic regulation of anti-MOG antibodies in two backcross populations, including a major genetic determinant for antibody expression on chromosome 4, Amig3. We fine-mapped the region to 539 kilobases (kb) consisting of a complex of seven C-type lectin receptor genes (Dcir4, Dcir3, Dcir2, Dcir1, Dcar1, Mcl and Mincle) that was captured in the APLEC congenic strain. We confirmed that Amig3 regulates anti-MOG antibody levels in MOG-EAE, and further showed that immune reactions during initiation of EAE were skewed toward increased numbers of B cells in the EAE-protected APLEC strain, together with higher anti-MOG IgG1 and lower IgG2b levels. Taken together, our data demonstrated complex regulation of the antibody response during EAE and that skewing the antibody response toward Th2 contributed to protection from EAE.
authors.affiliation: Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Flytzani
authors.forename: P
authors.initials: P
authors.lastname: Stridh
authors.forename: A O
authors.initials: AO
authors.lastname: Guerreiro-Cacais
authors.forename: M
authors.initials: M
authors.lastname: Marta
authors.forename: M T
authors.initials: MT
authors.lastname: Hedreul
authors.forename: M
authors.initials: M
authors.lastname: Jagodic
authors.forename: T
authors.initials: T
authors.lastname: Olsson
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002874:Chromosome Mapping; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007074:Immunoglobulin G / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D037181:Lectins, C-Type / Q000235:genetics* / Q000378:metabolism; D020412:Multifactorial Inheritance; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology*; D040641:Quantitative Trait Loci; D051381:Rats; D011919:Rats, Inbred Strains; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D007074:Immunoglobulin G; D037181:Lectins, C-Type; C571328:Mog protein, rat; D063308:Myelin-Oligodendrocyte Glycoprotein