Youri Chanseaud

Anti-endothelial cell antibodies in idiopathic and systemic sclerosis associated pulmonary arterial hypertension

Background: It has previously been shown that IgG antibodies from patients with limited cutaneous systemic sclerosis (SSc) bind to specific microvascular endothelial cell antigens. Since patients with limited cutaneous SSc are prone to develop pulmonary arterial hypertension (PAH), and since endothelial cell activation is involved in the pathogenesis of idiopathic PAH (IPAH), a study was undertaken to examine the presence of anti-endothelial cell antibodies in patients with idiopathic or SSc associated PAH. Methods: PAH was confirmed by right heart catheterisation (mean pulmonary artery pressure at rest >25 mm Hg). Serum IgG and IgM reactivities were analysed by immunoblotting on human macrovascular and microvascular lung and dermal endothelial cells from patients with IPAH (n = 35), patients with PAH associated with SSc (n = 10), patients with diffuse (n = 10) or limited cutaneous (n = 10) SSc without PAH, and 65 age and sex matched healthy individuals. Results: IgG antibodies from patients with IPAH bound to a 36 kDa band in macrovascular endothelial cell extracts with a higher intensity than IgG from other patient groups and controls. IgG antibodies from patients with IPAH bound more strongly to a 58 kDa band in microvascular dermal endothelial cells and to a 53 kDa band in microvascular lung endothelial cells than IgG antibodies from other patients and controls. IgG antibodies from patients with limited cutaneous SSc with or without PAH, but not from other groups or from healthy controls, bound to two major bands (75 kDa and 85 kDa) in microvascular endothelial cells. Conclusion: IgG antibodies from patients with idiopathic or SSc associated PAH express distinct reactivity profiles with macrovascular and microvascular endothelial cell antigens.

New insights into the pathogenesis of systemic sclerosis.

Systemic sclerosis (SSc) is a connective tissue disorder characterized by vascular abnormalities and excessive collagen synthesis. Extracellular matrix overproduction by fibroblasts results from abnormal interactions among endothelial cells, mononuclear cells (lymphocytes and monocytes) and fibroblasts, in a setting of vascular hyperreactivity and tissue hypoxia. Many autoantibodies have been identified in the sera of SSc patients; some of them are specific to the disease, such as anti-centromere antibodies in limited SSc, anti-topoisomerase 1 and anti-RNA polymerase I/III antibodies in diffuse SSc. Their pathogenetic role(s) remains uncertain. However, genetic, environmental and possibly alloreactive factors might also contribute to disease susceptibility.

Mechanisms of Intravenous Immunoglobulin Action in the Treatment of Autoimmune Disorders

Intravenous immunoglobulins (IVIg) are therapeutic preparations of normal human immunoglobulin (Ig) G obtained from pools of blood from more than 1000 healthy donors, and exert immunomodulatory effects in autoantibody-mediated and T-cell-mediated autoimmune disorders and systemic inflammatory diseases. IVIg mechanisms of action in autoimmune diseases have been extensively analysed during the last 15 years and include the following: (i) interaction of the IgG Fc fragment with Fc receptors on leucocytes and endothelial cells; (ii) interaction of infused IgG with complement proteins; (iii) monocyte and lymphocyte modulation of synthesis and release of cytokines and cytokine antagonists; (iv) modulation of cell proliferation and reparation; (v) neutralisation of circulating autoantibodies; (vi) selection of immune repertoires; and (vii) interaction with other cell-surface molecules on T and B lymphocytes.

Effets immunomodulateurs des immunoglobulines intraveineuses

Resume Utilisation therapeutique Les immunoglobulines intraveineuses (IgIV) sont des preparations therapeutiques d’IgG humaines normales obtenues a partir d’un pool de plasmas provenant de plus de 1 000 individus sains. Elles sont utilisees dans le traitement d’un grand nombre de maladies auto-immunes, qu’elles soient associees a la mise en evidence d’auto-anticorps ou de lymphocytes T autoreactifs, ainsi que dans le traitement de maladies inflammatoires systemiques. Des mecanismes d’action multiples et intriques Depuis 20 ans, de nombreux mecanismes d’action des IgIV au cours de ces maladies ont ete identifies. Ils comprennent : la modulation de l’expression des recepteurs Fc a la surface des leucocytes et des cellules endotheliales ; la modulation du systeme du complement ; la modulation de la synthese et de la liberation des cytokines et des chemokines ; la modulation de la proliferation cellulaire et de l’apoptose ; la remyelinisation ; la neutralisation des auto-anticorps circulants ; la selection des repertoires des lymphocytes B et des lymphocytes T ; l’interaction avec d’autres molecules a la surface des lymphocytes et des monocytes ; l’epargne cortisonique. Ces mecanismes d’action sont multiples et souvent intriques. Ils ne sont cependant pas encore completement elucides et le champ des investigations a effectuer reste large dans ce domaine.