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).
MES is a rat strain that spontaneously develops severe blood eosinophilia as a hereditary trait. Herein, we report that eosinophilia in MES rats is caused by 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. The MES rat has a deletion of four nucleotides, including the 5' splice donor GpT of intron 4 of the Cyba gene. As a consequence of the deletion, a 51-nucleotide sequence of intron 4 is incorporated into the Cyba transcripts. Leukocytes from the MES strain lack both CYBA protein and NADPH oxidase activity. Nevertheless, unlike patients with chronic granulomatous disease, who suffer from infections with pathogens due to similar genetic defects in NADPH oxidase, MES rats retain normal innate immune defense against Staphylococcus aureus infection. This is due to large quantities of peritoneal eosinophils in MES rats, which phagocytose and kill the bacteria. MES rat has a balance defect due to impaired formation of otoconia in the utricles and saccules. Eosinophilia of the MES rat was normalized by introduction of a normal Cyba transgene. The mechanisms by which impairment of NADPH oxidase leads to eosinophilia in the MES rat are elusive. However, our study highlights the essential role of NADPH oxidase in homeostatic regulation of innate immunity beyond conventional microbicidial functions.
Mori
Masayuki
M
Department of Aging Biology, Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine, Matsumoto 390-8621, Japan. masamori@shinshu-u.ac.jp
Li
Guixin
G
Hashimoto
Maiko
M
Nishio
Ayako
A
Tomozawa
Hiroshi
H
Suzuki
Nobuyoshi
N
Usami
Shin-ichi
S
Higuchi
Keiichi
K
Matsumoto
Kiyoshi
K
D000818:Animals; D001483:Base Sequence; D003573:Cytochrome b Group / Q000032:analysis / Q000235:genetics* / Q000502:physiology*; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D017931:DNA Primers / Q000737:chemistry; D004802:Eosinophilia / Q000209:etiology*; D005260:Female; D006706:Homeostasis; D007113:Immunity, Innate / Q000502:physiology; D007438:Introns / Q000235:genetics; D007962:Leukocytes / Q000201:enzymology / Q000502:physiology; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D019255:NADPH Oxidases / Q000032:analysis / Q000235:genetics / Q000502:physiology; D022821:RNA Splice Sites / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D017384:Sequence Deletion; D019076:Transgenes
D003573:Cytochrome b Group; D017931:DNA Primers; D022821:RNA Splice Sites; D012333:RNA, Messenger; D004247:DNA; D019255:NADPH Oxidases; C515768:Cyba protein, rat