Immunologic response enhances atherosclerosis-type 1 helper T cell (Th1)-to-type 2 helper T cell (Th2) shift and calcified atherosclerosis in Bacillus Calmette-Guerin (BCG)-treated apolipoprotein E-knockout (apo E-/-) mice.
Although immunocompetent hosts develop protective type 1 helper T cell (Th1) responses in mycobacterial infections, seroepidemiologic studies show that patients with atherosclerosis commonly express high antibody titers against mycobacterial heat shock protein (HSP) 65 and may develop a nonprotective type 2 helper T cell (Th2) response and advanced disease. These studies were undertaken to define mycobacterial dose requirements and kinetics for development of antibodies to HSP65, the Th1 to Th2 shift of immune response, and calcified atherosclerotic lesion development in the apo E-/- mouse. Fourteen-week apo E-/- female mice were treated intraperitoneally (ip) with heat-killed M. bovis Bacillus Calmette-Guerin (BCG), and 14 days later, cross-sections from the ascending aortas were stained for measurement of lesion size and calcium deposition. At 14 days, 0.01-mg BCG induced Th1 responses against HSP65. In contrast, 1-mg BCG induced splenic PGE2-releasing macrophages with a Th1-to-Th2 shift of responses to HSP65, which was PGE2-dependent. Treatment with 1-mg BCG significantly lowered bone density with increases in marrow osteoclastogenesis and development of calcified lesions in the aorta. At 14 days, 0.01-mg BCG induced Th1-dependent HSP65 responses and did not advance atherosclerosis. In contrast, for 1-mg BCG, a PGE2-dependent Th1-to-Th2 shift of responses to HSP65 and evidence of bone resorption are associated with advanced calcified atherosclerotic lesions.
Shibata
Yoshimi
Y
College of Biomedical Sciences, Florida Atlantic University, Boca Raton, FL 33431-0991, USA. yshibata@fau.edu
Ohata
Hiroyoshi
H
Yamashita
Makiko
M
Tsuji
Shoutaro
S
Bradfield
John F
JF
Nishiyama
Akihito
A
Henriksen
Ruth Ann
RA
Myrvik
Quentin N
QN
D000818:Animals; D000906:Antibodies / Q000097:blood; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000276:immunology* / Q000473:pathology; D001500:BCG Vaccine / Q000494:pharmacology*; D015519:Bone Density; D002114:Calcinosis / Q000276:immunology* / Q000473:pathology; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D016867:Immunocompromised Host; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013154:Spleen / Q000166:cytology; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
D000906:Antibodies; D001057:Apolipoproteins E; D001500:BCG Vaccine; D015232:Dinoprostone