The role of Ro52 autoantibodies in congenital heart block
Author: Salomonsson, Stina
Date: 2004-05-28
Location: Föreläsningssalen Centrum för Molekylär Medicin (CMM), Karolinska Universitetssjukhuset
Time: 9.00
Department: Institutionen för medicin / Department of Medicine
View/ Open:
Thesis (1.575Mb)
Abstract
The presence of B cells producing autoantibodies is a common feature of many autoimmune conditions. The pathogenic role of the autoantibodies is often unclear, but they often serve as diagnostic markers and may be used as prognostic tools in some diseases. This thesis addresses the production of anti-Ro52 antibodies in patients with Sjögren's syndrome, and their pathogenic effect in the fetus after transplacental transport during pregnancy.
The autoimmune inflammation in Sjögren's syndrome targets exocrine organs. Lymphocytic infiltrates develop in the salivary glands, and within these infiltrates germinal center-like structures may develop. In the initial studies of this thesis the molecular requirements for lymphocyte recruitment to the salivary glands, as well as morphological and functional properties of the germinal center-like structures were investigated. Chronically inflamed salivary glands exhibited an increased expression of adhesion molecules (VCAM- 1, VLA-4, ICAM-1 and LFA- 1), detected on endothelium an infiltrating mononuclear cells. In addition, B and T cell-attracting chemokines (CXCL1 3, CCL21 and CXCL12) were expressed by epithelial cells in the glands, and the chemokine receptor (CXCR5) was detected on infiltrating lymphocytes.
Networks of follicular dendritic cells were demonstrated throughout the large infiltrates, while autoantibody-producing plasma cells and apoptotic cells were mainly localized to the margins of these infiltrates. The presented studies provide a molecular basis for lymphocyte-recruitment to the target organ and demonstrate functional ectopic germinal centers with local autoantibody production in the target organ. These structures might actively promote chronic inflammation, and differences in the microenvironment and structure compared to ordinary germinal centers might contribute to a disturbance in the selection process allowing autoreactive clones to develop more frequently.
During pregnancy Ro52 antibodies are tranfered to the fetus, which may lead to development of congenital heart block. Although rare, the condition is often fatal and the majority of live borns require a pacemaker at an early age. To elucidate the pathogenic importance of anti-Ro52 antibodies in the course of congenital heart block, their role was investigated in vivo in pregnant women and in a murine model for the disease, as well as in vitro in primary rat cardiomyocyte cultures. Seropositive pregnant women were prospectively followed and fetal progression monitored using Doppler echocardiography. One-third of the fetuses developed a transcient AV block 1, demonstrating that fetal affection is far more common than previously appreciated. The study also revealed congenital heart block develops gradually, a finding essential for therapeutic decisions and understanding of the underlying pathogenic mechanism.
Thorough epitope mapping of the humoral response in pregnant women with anti-Ro52 antibodies revealed a specific serologic marker associated with fetal heart block, a finding enabling risk assessment and increasing the chances for early detection of block and successful fetal outcome. The specific antibodies associated with block were cloned and demonstrated to bind to the cell surface of neonatal cardionryocytes in vitro, dysregulating Ca 21 homeostasis, leading to accumulating intracellular levels of Ca 2+ and eventually inducing apoptosis. The pathogenic effect of the antibodies was verified in a murine model for congenital heart block.
In conclusion, our results have led to the proposal of a mechanism for development of congenital heart block in which specific maternal anti-Ro52 antibodies have a central pathogenic role through interaction with fetal cardiomyocytes, affecting their function and resulting in a permanent cardiac insult.
The autoimmune inflammation in Sjögren's syndrome targets exocrine organs. Lymphocytic infiltrates develop in the salivary glands, and within these infiltrates germinal center-like structures may develop. In the initial studies of this thesis the molecular requirements for lymphocyte recruitment to the salivary glands, as well as morphological and functional properties of the germinal center-like structures were investigated. Chronically inflamed salivary glands exhibited an increased expression of adhesion molecules (VCAM- 1, VLA-4, ICAM-1 and LFA- 1), detected on endothelium an infiltrating mononuclear cells. In addition, B and T cell-attracting chemokines (CXCL1 3, CCL21 and CXCL12) were expressed by epithelial cells in the glands, and the chemokine receptor (CXCR5) was detected on infiltrating lymphocytes.
Networks of follicular dendritic cells were demonstrated throughout the large infiltrates, while autoantibody-producing plasma cells and apoptotic cells were mainly localized to the margins of these infiltrates. The presented studies provide a molecular basis for lymphocyte-recruitment to the target organ and demonstrate functional ectopic germinal centers with local autoantibody production in the target organ. These structures might actively promote chronic inflammation, and differences in the microenvironment and structure compared to ordinary germinal centers might contribute to a disturbance in the selection process allowing autoreactive clones to develop more frequently.
During pregnancy Ro52 antibodies are tranfered to the fetus, which may lead to development of congenital heart block. Although rare, the condition is often fatal and the majority of live borns require a pacemaker at an early age. To elucidate the pathogenic importance of anti-Ro52 antibodies in the course of congenital heart block, their role was investigated in vivo in pregnant women and in a murine model for the disease, as well as in vitro in primary rat cardiomyocyte cultures. Seropositive pregnant women were prospectively followed and fetal progression monitored using Doppler echocardiography. One-third of the fetuses developed a transcient AV block 1, demonstrating that fetal affection is far more common than previously appreciated. The study also revealed congenital heart block develops gradually, a finding essential for therapeutic decisions and understanding of the underlying pathogenic mechanism.
Thorough epitope mapping of the humoral response in pregnant women with anti-Ro52 antibodies revealed a specific serologic marker associated with fetal heart block, a finding enabling risk assessment and increasing the chances for early detection of block and successful fetal outcome. The specific antibodies associated with block were cloned and demonstrated to bind to the cell surface of neonatal cardionryocytes in vitro, dysregulating Ca 21 homeostasis, leading to accumulating intracellular levels of Ca 2+ and eventually inducing apoptosis. The pathogenic effect of the antibodies was verified in a murine model for congenital heart block.
In conclusion, our results have led to the proposal of a mechanism for development of congenital heart block in which specific maternal anti-Ro52 antibodies have a central pathogenic role through interaction with fetal cardiomyocytes, affecting their function and resulting in a permanent cardiac insult.
List of papers:
I. Salomonsson S, Larsson P, Tengner P, Mellquist E, Hjelmstrom P, Wahren-Herlenius M (2002). Expression of the B cell-attracting chemokine CXCL13 in the target organ and autoantibody production in ectopic lymphoid tissue in the chronic inflammatory disease Sjogrens syndrome. Scand J Immunol. 55(4): 336-42.
Pubmed
II. Salomonsson S, Jonsson MV, Skarstein K, Brokstad KA, Hjelmstrom P, Wahren-Herlenius M, Jonsson R (2003). Cellular basis of ectopic germinal center formation and autoantibody production in the target organ of patients with Sjogrens syndrome. Arthritis Rheum. 48(11): 3187-201.
Pubmed
III. Salomonsson S, Wahren-Herlenius M (2003). Local production of Ro/SSA and La/SSB autoantibodies in the target organ coincides with high levels of circulating antibodies in sera of patients with Sjogrens syndrome. Scand J Rheumatol. 32(2): 79-82.
Pubmed
IV. Theander E, Brucato A, Gudmundsson S, Salomonsson S, Wahren-Herlenius M, Manthorpe R (2001). Primary Sjogrens syndrome--treatment of fetal incomplete atrioventricular block with dexamethasone. J Rheumatol. 28(2): 373-6.
Pubmed
V. Salomonsson S, Dorner T, Theander E, Bremme K, Larsson P, Wahren-Herlenius M (2002). A serologic marker for fetal risk of congenital heart block. Arthritis Rheum. 46(5): 1233-41.
Pubmed
VI. Horvath L, Salomonsson S, Sonesson SE, Bremme K, Wahren-Herlenius M (2004). Ro/SSA and La/SSB autoantibody level variation before, during and after pregnancy in women with systemic rheumatic diseases biving birth to children with and without neonatal lupus. [Submitted]
VII. Sonesson SE, Salomonsson S, Jacobsson LA, Bremme K, Wahren-Herlenius M (2004). Signs of first-degree heart block occur in one-third of fetuses of pregnant women with anti-SSA/Ro 52-kd antibodies. Arthritis Rheum. 50(4): 1253-61.
Pubmed
VIII. Salomonsson S, Ottosson L, Safsten P, Hof D, Brauner H, Sunnerhagen M, Raats J, Wahren-Herlenius M (2004). Cloning and characterization of two human Ro52-specific monoclonal autoantibodies directed towards a domain associated with congenital heart block. J Autoimmun. 22(2): 167-77.
Pubmed
IX. Ottosson L, Salomonsson S, Hennig J, Sonesson SE, Dorner T, Raats J, Kuchroo VK, Sunnerhagen M, Wahren-Herlenius M (2004). Structurally derived mutations define congenital heart block-related epitopes within the 200-239 amino acid stretch of the Ro52 protein. [Submitted]
View record in Web of Science®
X. Salomonsson S, Sonesson SE, Ottosson L, Muhallab S, Olsson T, Sunnerhagen M, Kuchroo VK, Thorén P; Herlenius E, Wahren-Herlenius M (2004). Ro/SSA autoantibodies direvtly bind cardiomyocytes, disturb calcium homeostasis and mediate congenital heart block. [Submitted]
View record in Web of Science®
I. Salomonsson S, Larsson P, Tengner P, Mellquist E, Hjelmstrom P, Wahren-Herlenius M (2002). Expression of the B cell-attracting chemokine CXCL13 in the target organ and autoantibody production in ectopic lymphoid tissue in the chronic inflammatory disease Sjogrens syndrome. Scand J Immunol. 55(4): 336-42.
Pubmed
II. Salomonsson S, Jonsson MV, Skarstein K, Brokstad KA, Hjelmstrom P, Wahren-Herlenius M, Jonsson R (2003). Cellular basis of ectopic germinal center formation and autoantibody production in the target organ of patients with Sjogrens syndrome. Arthritis Rheum. 48(11): 3187-201.
Pubmed
III. Salomonsson S, Wahren-Herlenius M (2003). Local production of Ro/SSA and La/SSB autoantibodies in the target organ coincides with high levels of circulating antibodies in sera of patients with Sjogrens syndrome. Scand J Rheumatol. 32(2): 79-82.
Pubmed
IV. Theander E, Brucato A, Gudmundsson S, Salomonsson S, Wahren-Herlenius M, Manthorpe R (2001). Primary Sjogrens syndrome--treatment of fetal incomplete atrioventricular block with dexamethasone. J Rheumatol. 28(2): 373-6.
Pubmed
V. Salomonsson S, Dorner T, Theander E, Bremme K, Larsson P, Wahren-Herlenius M (2002). A serologic marker for fetal risk of congenital heart block. Arthritis Rheum. 46(5): 1233-41.
Pubmed
VI. Horvath L, Salomonsson S, Sonesson SE, Bremme K, Wahren-Herlenius M (2004). Ro/SSA and La/SSB autoantibody level variation before, during and after pregnancy in women with systemic rheumatic diseases biving birth to children with and without neonatal lupus. [Submitted]
VII. Sonesson SE, Salomonsson S, Jacobsson LA, Bremme K, Wahren-Herlenius M (2004). Signs of first-degree heart block occur in one-third of fetuses of pregnant women with anti-SSA/Ro 52-kd antibodies. Arthritis Rheum. 50(4): 1253-61.
Pubmed
VIII. Salomonsson S, Ottosson L, Safsten P, Hof D, Brauner H, Sunnerhagen M, Raats J, Wahren-Herlenius M (2004). Cloning and characterization of two human Ro52-specific monoclonal autoantibodies directed towards a domain associated with congenital heart block. J Autoimmun. 22(2): 167-77.
Pubmed
IX. Ottosson L, Salomonsson S, Hennig J, Sonesson SE, Dorner T, Raats J, Kuchroo VK, Sunnerhagen M, Wahren-Herlenius M (2004). Structurally derived mutations define congenital heart block-related epitopes within the 200-239 amino acid stretch of the Ro52 protein. [Submitted]
View record in Web of Science®
X. Salomonsson S, Sonesson SE, Ottosson L, Muhallab S, Olsson T, Sunnerhagen M, Kuchroo VK, Thorén P; Herlenius E, Wahren-Herlenius M (2004). Ro/SSA autoantibodies direvtly bind cardiomyocytes, disturb calcium homeostasis and mediate congenital heart block. [Submitted]
View record in Web of Science®
Issue date: 2004-05-07
Rights:
Publication year: 2004
ISBN: 91-7349-842-4
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