Transdifferentiation of cardiac fibroblasts, a fetal factor in anti-SSA/Ro-SSB/La antibody-mediated congenital heart block

被引:71
作者
Clancy, RM
Askanase, AD
Kapur, RP
Chiopelas, E
Azar, N
Miranda-Carus, ME
Buyon, JP
机构
[1] NYU, Dept Rheumatol, Sch Med, Hosp Joint Dis, New York, NY 10003 USA
[2] Univ Washington, Dept Labs, Childrens Hosp, Seattle, WA 98105 USA
[3] Univ Washington, Dept Labs, Reg Med Ctr, Seattle, WA 98105 USA
关键词
D O I
10.4049/jimmunol.169.4.2156
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
The signature lesion of autoantibody-associated congenital heart block (CHB) is fibrosis of the conducting tissue. To date, participation of myofibroblasts in the cascade to injury has been unexplored. The importance of myofibroblast/macrophage cross-talk is demonstrated by the novel finding of these cell types in the heart of a neonate dying of CHB. This clue to pathogenesis prompted consideration of the mechanism by which maternal anti-SSA/Ro-SSB/La Abs initiate an inflammatory response and promote fibrosis. Isolated cardiocytes from 16-24 wk abortuses were rendered apoptotic by exposure to poly (2-) hydroxyethylmethacrylate; flow cytometry confirmed surface expression of RoALa. Apoptotic cardiocytes were incubated with affinity-purified Abs to 52 and 60 kDa Ro from CHB mothers (opsonized) or IgG fractions from healthy donors (nonopsonized). Macrophages cultured with opsonized apoptotic cardiocytes expressed proinflammatory markers, supported by a three-fold increase in active alpha(v)beta(3) integrin. Fetal cardiac fibroblasts exposed to supernatants obtained from macrophages incubated with opsonized apoptotic cardiocytes (but not nonopsonized) dramatically increased expression of the myofibroblast marker a-smooth muscle actin (SMAc). The "opsonized" supernatant reversed an inhibitory effect of the "nonopsonized" supernatant on proliferation of fibroblasts (120 vs 69%, p < 0.05). Parallel experiments examined the effects of two cytokines and their neutralizing Abs on fibroblasts. TGFbeta1 increased SMAc staining but decreased proliferation. TNF-alpha did not affect either readout. Addition of anti-TGFbeta1 Abs to the "opsonized" supernatant blocked SMAc expression but increased proliferation, while anti-TNF-alpha blocking Abs had no effects. These data suggest that transdifferentiation of cardiac fibroblasts to a scarring phenotype is a pathologic process initiated by maternal Abs.
引用
收藏
页码:2156 / 2163
页数:8
相关论文
共 31 条
[1]   Differences between scar and dermal cultured fibroblasts derived from a patient with recurrent abdominal incision wound herniation [J].
Boemi, L ;
Allison, GM ;
Graham, WP ;
Krummel, TM ;
Ehrlich, HP .
PLASTIC AND RECONSTRUCTIVE SURGERY, 1999, 104 (05) :1397-1405
[2]  
Brucato A, 2001, ARTHRITIS RHEUM-US, V44, P1832, DOI 10.1002/1529-0131(200108)44:8<1832::AID-ART320>3.0.CO
[3]  
2-C
[4]  
BUYON JP, 1999, SYSTEMIC LUPUS ERYTH, P337
[5]  
CARTER JB, 1974, ARCH PATHOL, V97, P51
[6]   Cleavage by granzyme B is strongly predictive of autoantigen status: Implications for initiation of autoimmunity [J].
Casciola-Rosen, L ;
Andrade, F ;
Ulanet, D ;
Wong, WB ;
Rosen, A .
JOURNAL OF EXPERIMENTAL MEDICINE, 1999, 190 (06) :815-825
[7]   AUTOANTIGENS TARGETED IN SYSTEMIC LUPUS-ERYTHEMATOSUS ARE CLUSTERED IN 2 POPULATIONS OF SURFACE-STRUCTURES ON APOPTOTIC KERATINOCYTES [J].
CASCIOLAROSEN, LA ;
ANHALT, G ;
ROSEN, A .
JOURNAL OF EXPERIMENTAL MEDICINE, 1994, 179 (04) :1317-1330
[8]  
Chen KM, 2000, J LEUKOCYTE BIOL, V68, P828
[9]   CARDIOVASCULAR MANIFESTATIONS OF LYME-DISEASE [J].
COX, J ;
KRAJDEN, M .
AMERICAN HEART JOURNAL, 1991, 122 (05) :1449-1455
[10]   TRANSFORMING GROWTH-FACTOR-BETA-1 INDUCES ALPHA-SMOOTH MUSCLE ACTIN EXPRESSION IN GRANULATION-TISSUE MYOFIBROBLASTS AND IN QUIESCENT AND GROWING CULTURED FIBROBLASTS [J].
DESMOULIERE, A ;
GEINOZ, A ;
GABBIANI, F ;
GABBIANI, G .
JOURNAL OF CELL BIOLOGY, 1993, 122 (01) :103-111