Impaired clearance of apoptotic cardiocytes is linked to anti-SSA/Ro and -SSB/La antibodies in the pathogenesis  of congenital heart block

Clancy, Robert M.; Neufing, Petra; Zheng, Ping; O’Mahony, Marguerita; Nimmerjahn, Falk; Gordon, Tom P.; Buyon, Jill P.

doi:10.1172/jci27803

Cited by 111 publications

(144 citation statements)

References 47 publications

(48 reference statements)

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“…Apoptosis induced translocation of SSA/Ro and SSB/La to the surface of fetal cardiomyocytes allows anti-SSA/Ro and anti-SSB/La antibodies to bind to the surface of the fetal cardiomyocytes [21]. Apoptotic cardiomyocytes are then phagocytosed by healthy fetal cardiomyocytes diverting these opsonized cardiomyocytes to uptake by macrophages [22], which release pro-inflammatory cytokines, initiating an inflammation-free physiologic remodelling of the human fetal heart and resulting in inflammation-induced tissue damage [23]. Tumor necrosis factor alpha and transforming growth factor beta may potentiate the inflammatory and fibrosis components respectively [24].…”

Section: Pathogenesismentioning

confidence: 99%

Neonatal Lupus Erythematosus

Nasef

Hafez²,

Bakr³

2014

NCP

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Neonatal lupus is a passively acquired autoimmune disease that occurs in offspring of mothers with anti-SSA/Ro and/or anti-SSB/La antibodies. The primary clinical features are a photosensitive rash that is usually found on the scalp and periorbital areas, congenital heart block with or without cardiomyopathy, cytopenias, disseminated intravascular coagulation, and neonatal cholestasis with or without elevated transaminases. The diagnosis is usually made in utero by detection of a slow fetal heart rate and subsequent fetal echocardiographic confirmation of heart block and/or cardiomyopathy. Prenatal treatment with fluorinated glucocorticoids beginning as soon after detection has favourable outcome for mothers of fetuses with second degree heart block, is of no value for mothers of fetuses with third degree heart block, and controversial for mothers of fetuses with first degree heart block. Prenatal glucocorticoids can be used also in presence of cardiomyopathy associated with neonatal lupus. Hydroxychloroquine has been used in pregnant women who have anti-SSA/Ro antibodies and who have previously given birth to a child with cardiac manifestations. First and second degree block, detected in utero or at birth, can progress to complete heart block. Infants with complete heart block usually require a pacemaker with an excellent prognosis, although development of heart failure may occur.

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Section: Pathogenesismentioning

confidence: 99%

Neonatal Lupus Erythematosus

Nasef

Hafez²,

Bakr³

2014

NCP

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“…The impact of apoptosis on immunity has been extensively investigated [2,13] and several reports suggest a correlation between apoptosis and autoimmunity through an impairment of apoptosis [14][15][16] or an ineffective removal of apoptotic cells [17][18][19][20]. Moreover, recent data have demonstrated that autoantigens are found within apoptotic bodies [21] and that apoptotic cells are critical in the presentation of antigens [22], activation of innate immunity and regulation of macrophage cytokine secretion [23].…”

Section: Introductionmentioning

confidence: 99%

The consequences of apoptosis in autoimmunity

Lleo

Selmi

Invernizzi

et al. 2008

Journal of Autoimmunity

124

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The clearance of apoptotic cells is a highly regulated mechanism, normally associated with antiinflammatory response. During early stages of apoptosis the cell is promptly recognized and engulfed by professional phagocytes or tissue cells to avoid the outflow of intracellular content and limit the immunological reaction against released antigens. However, increasing evidences suggest that impairment in the uptake of apoptotic cell debris is linked to the development of autoimmunity. In fact, autoantigens have been demonstrated to be content within apoptotic bodies and apoptotic cells seems to be critical in the presentation of antigens, activation of innate immunity and regulation of macrophage cytokine secretion.We herein review the known mechanisms for regulating the uptake of the products of apoptosis in the development of autoimmunity.

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“…The binding of AAs to apoptotic cells has been previously shown to inhibit clearance leading to the accumulation of apoptotic cells, which can promote inflammation and tissue damage (Clancy et al 2006;Gandhi et al 2006;Salomonsson et al 2005). Therefore, AAs induced by asbestos may exacerbate tissue damage in the lung, further promoting inflammation and fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Autoantibodies from mice exposed to Libby amphibole asbestos bind SSA/Ro52-enriched apoptotic blebs of murine macrophages

2008

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Asbestos exposure is associated with increased autoimmune responses in humans. For example, in Libby, MT where significant asbestos exposure has occurred due to an asbestos contaminated vermiculite mine near the community, residents have developed increased autoimmune responses compared to an unexposed population. However, the exact mechanism by which Libby amphibole asbestos generates autoimmune responses is unclear. A murine model of amphibole asbestos-induced autoimmunity was recently established, and one of the targets of the autoantibodies was the SSA/ Ro52 autoantigen. The purpose of this study was to determine whether the SSA/Ro52 autoantigen is exposed at the surface of cells as a result of asbestos exposure as a possible mechanism leading to antigenicity. Our results indicate that Libby asbestos induces apoptosis in murine macrophages as determined by phosphatidylserine exposure, cleavage of poly (ADP-ribose) polymerase and morphological changes such as nuclear condensation. Moreover, asbestos induced apoptosis results in the formation of apoptotic cell surface blebs enriched in SSA/Ro52 as determined by confocal microscopy. Most importantly, apoptotic cell surface blebs are recognized by autoantibodies from mice exposed to amphibole asbestos suggesting that these cell surface structures may be antigenic when presented in a pro-inflammatory context. This study supports the hypothesis that the induction of apoptosis plays a key role in environmentally-induced autoimmunity through cell surface exposure of a known autoantigen.

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Impaired clearance of apoptotic cardiocytes is linked to anti-SSA/Ro and -SSB/La antibodies in the pathogenesis of congenital heart block

Cited by 111 publications

References 47 publications

Neonatal Lupus Erythematosus

Neonatal Lupus Erythematosus

The consequences of apoptosis in autoimmunity

Autoantibodies from mice exposed to Libby amphibole asbestos bind SSA/Ro52-enriched apoptotic blebs of murine macrophages

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