Identification of genetic loci controlling the characteristics and severity of brain and spinal cord lesions in experimental allergic encephalomyelitis.
Experimental allergic encephalomyelitis (EAE) is the principal genetically determined animal model for multiple sclerosis (MS), the major inflammatory disease of the central nervous system (CNS). Although genetics clearly play a role in susceptibility to MS, attempts to identify the underlying genes have been disappointing. Considerable variation exists between MS patients with regard to the severity of clinical signs, mechanism of demyelination, and location of CNS lesions, confounding the interpretation of genetic data. A mouse-human synteny mapping approach may allow the identification of candidate susceptibility loci for MS based on the location of EAE susceptibility loci. To date, 16 regions of the mouse genome have been identified that control susceptibility or clinical signs of EAE. In this work, we examined the genetic control of histopathological lesions of EAE in an F2 intercross population generated from the EAE susceptible SJL/J and EAE resistant B10.S/DvTe mouse strains. Composite interval mapping was used to identify 10 quantitative trait loci (QTL), including seven newly identified loci controlling the distribution and severity of CNS lesions associated with murine EAE. QTL on chromosome 10 control lesions in the brain, whereas QTL on chromosomes 3, 7, and 12 control lesions in the spinal cord. Furthermore, sexually dimorphic QTL on chromosomes 2, 9, and 11 control CNS lesions in females, whereas QTL on chromosomes 10, 11, 12, 16, and 19 control lesions in males. Our results suggest that the severity and location of CNS lesions in EAE are genetically controlled, and that the genetic component controlling the character and severity of the lesions can be influenced by sex.
Department of Veterinary Pathobiology, The University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
R J
RJ
Butterfield
E P
EP
Blankenhorn
R J
RJ
Roper
J F
JF
Zachary
R W
RW
Doerge
C
C
Teuscher
D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology; D003711:Demyelinating Diseases / Q000235:genetics / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000473:pathology; D005260:Female; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018895:Microsatellite Repeats; D019655:Quantitative Trait, Heritable; D012720:Severity of Illness Index; D012737:Sex Factors; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology