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.