Research group Marie Wahren-Herlenius
Aim
Prevention, diagnostics and therapy of the autoimmune diseases Sjögren's syndrome and congenital heart block
Description of the project
Sjögren's syndrome
The autoimmune inflammation in Sjögren's syndrome targets the exocrine organs, in particular involving the salivary and lacrymal glands where large infiltrates of mononuclear cells are observed. Systemic manifestations include severe tiredness, muscle and joint pain. Patients with Sjögren's syndrome have a defective B cell differentiation, and serologically hypergammaglobulinemia with autoantibodies to the Ro/SSA autoantigen are characteristic features.
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| The panel of figures shows normal human salivary gland tissue (a), initiated development of lymhocytic infiltration in a patient with Sjögren's syndrome typically around excretory ducts (b) and (c) a salivary gland biopsy from a patient with Sjögren's syndrome where the infiltrating cells have destroyed and replaced large portions of the gland. |
The lymphocytic infiltrates that develop in the salivary glands of patients with Sjögren's syndrome consist of B cells, T cell and plasma cells. When extensive, the infiltrates may replace large portions of the glands and in some patients formation of germinal center-like structures can be observed. Such lymphoid neogenesis has also been observed in target organs in other autoimmune diseases, and proposed to contribute to the chronicity of the conditions. We focus on understanding the molecular basis for the lymphoid neogensis and how the germinal center-like structures promote formation of autoreactive clones, including formation of Ro/SSA autoantibody producing plasma cells.
Congenital heart block
During pregnancy, the Ro/SSA autoantibodies formed in the mother are transported across the placenta and affect the fetus, which may develop a neonatal lupus syndrome. The neonatal lupus syndrome includes dermatologic, liver and hematopoetic manifestations which are all transient and disappear in parallel to clearence of the maternal autoantibodies from the circulation of the child. More seriously, a permanent congenital heart block may affect the child.
The heart block develops during 18-24th week of gestation, and inflammation with deposition of autoantibodies and complement is observed around the conduction system. The mortality of fetuses diagnosed with complete congenital heart block is high, 10-30%, and around two thirds of live born children require lifelong use of pacemaker. To date, a complete block is irreversible, while AV block I and II have been successfully treated with high dose steroids, stressing the importance of early detection and prognostic markers.
The identification and cloning of the heart block inducing antibodies in addition to animal models we have developed and close clinical collaborations allows us to address questions of mechanisms in heart block development; on a molecular level including why the heart is targeted and why development occurs during a specific time in development, as well as develop clinical predictive tests and preventive measures.
Overall aim
We study the role of B lymphocytes in autoimmune rheumatic diseases with the aim to understand pathogenic processes and identify targets for therapeutic intervention. The conditions we take specific interest in are Sjögren's syndrome and congenital heart block.
Work plan and methods
Our research has a translational approach and involves both basic molecular studies, analysis in experimental models and clinical investigations.
The research group
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| Picture of some members of the group when sailing and discussing science in the inspiring Stockholm archipelago. From left: Linn Strandberg (former PhD student, now PhD), Alexander Espinosa, XXX, Stina Salomonsson, Robert Klauninger, Susanna Brauner, Karin Popovic (former PhD student, now PhD), Monika Ek (former post doc), XXX. |
Marie Wahren-Herlenius, group supervisor
Stina Salomonsson, PhD, associated scientist
Åse Elfving, biomedical scientist, engineer
Vijole Dzikatité, PhD, laboratory manager
Aurélie Ambrosi, PhD student
Marika Kvarnström, PhD student
Robert Klauninger, PhD student
Susanna Brauner, PhD student
Vilija Oke, PhD student
Alexander Espinosa, post doc
Five selected publications
Search Pubmed for Wahren-Herlenius M
or Wahren M
The Sjogren's syndrome-associated autoantigen Ro52 is an E3 ligase that regulates proliferation and cell death.
J. Immunol. 2006 May;176(10):6277-85
Mutations in the gene encoding fibroblast growth factor 10 are associated with aplasia of lacrimal and salivary glands.
Nat. Genet. 2005 Feb;37(2):125-7
Ro/SSA autoantibodies directly bind cardiomyocytes, disturb calcium homeostasis, and mediate congenital heart block.
J. Exp. Med. 2005 Jan;201(1):11-7
Signs of first-degree heart block occur in one-third of fetuses of pregnant women with anti-SSA/Ro 52-kd antibodies.
Arthritis Rheum. 2004 Apr;50(4):1253-61
Killers come to the rescue.
Nat. Biotechnol. 2002 Dec;20(12):1205-6