A Third Locus for Eosinophilia on Chromosome 1 of the MES Rats

Abstract

Matsumoto Eosinophilia Shinshu (MES) is a rat strain that spontaneously develops eosinophilia and eosinophil-related inflammatory lesions in many organsThe etiology of the majority of idiopathic HES cases and the mechanisms of eosinophilopoiesis remain poorly understood.Matsumoto Eosinophilia Shinshu (MES) is a rat strain that develops eosinophilia spontaneously [3][4][5][6]8]. In these rats a marked increase in peripheral blood eosinophils (>500/µl) occurs at about 9 weeks of age, with eosinophilia progressing with age until the number of eosinophils eventually exceeds the level that is characteristic of human hypereosinophilia (>1,500/µl). The abnormal eosinophilic proliferation takes place in the bone marrow and is associated with enlargement of the mesenteric lymph nodes. This enlargement is the result of infiltration of eosinophils into the lymph nodes, Eosinophil is a type of white blood cell that plays an important role in the innate immune system, especially in counteracting parasitic infections. The normal range for blood eosinophils is 40-400/µl in humans and 15-120/µl in rats. The term eosinophilia refers to conditions in which abnormally high numbers of eosinophils are found in either blood (600-1,500/µl) or tissues [1]. Eosinophilia may occur in a number of diseased conditions, which include parasitic infections, allergies, collagen vascular diseases, and neoplastic disorders. Another morbid condition distinct from these secondary eosinophilias, idiopathic hypereosinophilic syndrome (idiopathic HES), is a condition in which eosinophilia persists without any apparent etiology [7].

Pivotal Advance: Eosinophilia in the MES rat strain is caused by a loss–of–function mutation in the gene for cytochrome b(–245), alpha polypeptide (Cyba)

“…In a previous study, we performed chromosomal mapping of the gene(s) associated with eosinophilia in MES rats by breeding (ACI ϫ MES) ϫ MES backcross progeny and demonstrated that the major locus for eosinophilia (eos1) is located at the telomeric region of chromosome 19 [8,9]. On the basis of those data, we then initiated positional cloning of eos1.…”

BN.MES-Cybames Congenic Rats Manifest Focal Necrosis with Eosinophilic Infiltration in the Liver without Blood Eosinophilia

“…We concede that the F 2 population is currently too small, but we are now expanding the (MES × BN.MES-Cyba mes )F 2 population in order to perform chromosomal mapping and subsequent positional cloning of the gene(s) for the phenotypes. In our previous study, quantitative trait loci for blood eosinophil counts were revealed on chromosome 2 (eosinophilia 2; eos2) [11] and chromosome 1 (eosinophilia 3; eos3) [14] in (MES × ACI) × MES backcross progeny. The alleles derived from MES on both loci had an additive effect, increasing the blood eosinophil level.…”

“…Eosinophil-related gastroenteritis and aortitis are also observed. The primary cause of eosinophilia in MES rats is a loss-of-function mutation in the gene for cytochrome b(-245), alpha polypeptide (Cyba; also known as p22 phox ), which is an essential component of the superoxide-generating NADPH oxidase complex [11,14,15]. As animal models for eosinophilia, three transgenic mouse strains overexpressing IL-5 with different genetic backgrounds have been developed [5,10,27].…”

Genes for Difference in Eosinophilic Phenotype between MES and BN.MES-Cybames Rats Are on Chromosomes 9, 5, and 1

“…The gene on chromosome 1 of the BN rats was responsible for decreases in both blood and bone marrow eosinophil levels. In our previous study, a QTL for blood eosinophil count (eosinophilia 3; eos3) was revealed on chromosome 1 in (MES × ACI) × MES backcross progeny [19]. The allele derived from MES had an additive effect, increasing the blood eosinophil level.…”

“…Eosinophil-related gastroenteritis or aortitis are also observed. The primary cause of eosinophilia in MES rats is a loss-of-function mutation in the gene for cytochrome b(-245), alpha polypeptide (Cyba; also known as p22 phox ), which is an essential component of the superoxide-generating NADPH oxidase complex [14,19,20]. In a previous study, we bred and characterized a congenic rat strain in which the mutant Cyba mes gene was introduced into the background of a BN strain (BN.MESCyba mes ) [37].…”