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Antibodies to fibroblasts in idiopathic and scleroderma-associated pulmonary hypertension

Posted Dec 07 2009 12:00am

By M. C. Tamby and Colleague

The aim of the present study was to investigate the presence of anti-fibroblast antibodies in patients with idiopathic or scleroderma-associated pulmonary arterial hypertension (PAH) and healthy controls.

PAH was documented by right-heart catheterisation (mean pulmonary artery pressure at rest >25 mmHg). Serum immunoglobulin (Ig)G and IgM reactivities of patients with idiopathic PAH (n = 35), scleroderma-associated PAH (n = 10), diffuse (n = 10) or limited cutaneous (n = 10) scleroderma without PAH and age- and sex-matched healthy individuals (n = 65) were analysed by cell-based ELISA and immunoblotting on normal human fibroblasts.

As assessed by ELISA, 14 out of 35 (40%) patients with idiopathic PAH and three out of 10 (30%) patients with scleroderma-associated PAH expressed anti-fibroblast IgG antibodies. IgG from all individuals bound to one major 40-kDa protein band. IgG from patients with idiopathic PAH bound to two 25- and 60-kDa bands with a higher intensity than IgG from other individuals.

In conclusion, immunoglobulin G anti-fibroblast antibodies are present in the serum of patients with pulmonary arterial hypertension. Immunoglobulin G from patients with idiopathic pulmonary arterial hypertension or scleroderma-associated pulmonary arterial hypertension express distinct reactivity profiles with fibroblasts antigens, suggesting distinct target antigens.

Pulmonary arterial hypertension (PAH) is a rare clinical condition leading to progressive right-heart failure and death 1. PAH is defined by a mean pulmonary artery pressure >25 mmHg at rest or >30 mmHg with exercise in the absence of a post-capillary process as assessed by right-heart catheterisation 2. PAH occurs as a consequence of chronic obstruction of small pulmonary arteries secondary to dysfunctions and proliferation of endothelial cells, vascular smooth muscle cells and fibroblasts 3.

According to the World Health Organization classification established in Venice in 2003 4, PAH is classified as idiopathic (IPAH), familial or related to other conditions: dexfenfluramine therapy 1, HIV infection 5, portal hypertension, congenital heart disease, and connective tissue diseases such as systemic sclerosis (SSc). Thus, 10–14% of SSc patients develop PAH 6, which is responsible for a high mortality rate.

The formation of a layer of myofibroblasts and extracellular matrix between the endothelium and the internal elastic lamina, termed neointima, is a hallmark of severe PAH. In hypoxia models, adventitial fibroblasts appear to be first cells activated to proliferate and to synthesise matrix proteins in response to pulmonary hypertensive stimulus 7.

To date, very few studies have been conducted to identify autoantibodies in the serum of PAH patients. A recent study identified anti-endothelial cell immunoglobulin (Ig)G antibodies in patients with IPAH or SSc-associated PAH 8. Since fibroblast dysfunctions have been identified in both SSc and IPAH, and since anti-fibroblast antibodies that are able to activate and induce collagen synthesis have been detected in the serum of SSc patients 9, the current authors analysed the reactivity profiles of anti-fibroblast antibodies in patients with IPAH or SSc-associated PAH and in healthy individuals.

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