Philippe Guilpain

Churg-Strauss syndrome.

Purpose of reviewChurg–Strauss syndrome is a small-vessel necrotizing vasculitis typically characterized by asthma, lung infiltrates, extravascular necrotizing granulomas and hypereosinophilia. The most recent clinical studies on its pathogenesis and therapeutic management are reviewed here. Recent findingsFrench and Italian clinical studies found that the clinical characteristics of patients with Churg–Strauss syndrome differed according to their antineutrophil cytoplasmic autoantibody status: cardiomyopathy predominated in antineutrophil cytoplasmic autoantibody-negative patients while necrotizing glomerulonephritis was more often observed in antineutrophil cytoplasmic autoantibody-positive patients. These histologically documented findings suggest the existence of different Churg–Strauss syndrome subtypes, characterized by the predominance of distinct pathogenetic mechanisms. To date, following the therapeutic recommendations for Churg–Strauss syndrome (i.e. corticosteroids and, when required, immunosuppressants), patient outcomes are good, with 5-year survival exceeding 90%, but often with the need to continue low-dose corticosteroids to control residual asthma. SummaryThe precise pathogenetic mechanisms of Churg–Strauss syndrome are only partly elucidated. Recent results suggest that antineutrophil cytoplasmic autoantibodies are probably more involved in the vasculitic manifestations of Churg–Strauss syndrome (e.g. glomerulonephritis) whereas eosinophil tissue infiltration and associated cytotoxicity would be responsible for cardiomyopathy. If confirmed, these results could support individual therapeutic stratification according to the clinical pattern. Furthermore, some patients may benefit from new biologic therapies under development, for example antiinterleukin-5 or antiimmunoglobulin E monoclonal antibodies.

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 (nu200a=u200a35), patients with PAH associated with SSc (nu200a=u200a10), patients with diffuse (nu200a=u200a10) or limited cutaneous (nu200a=u200a10) 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.

Selective Oxidation of DNA Topoisomerase 1 Induces Systemic Sclerosis in the Mouse

Systemic sclerosis (SSc) is a connective tissue disorder of great clinical heterogeneity. Its pathophysiology remains unclear. Our aim was to evaluate the relative roles of reactive oxygen species (ROS) and of the immune system using an original model of SSc. BALB/c and immunodeficient BALB/c SCID mice were injected s.c. with prooxidative agents (hydroxyl radicals, hypochlorous acid, peroxynitrites, superoxide anions), bleomycin, or PBS everyday for 6 wk. Skin and lung fibrosis were assessed by histological and biochemical methods. Autoantibodies were detected by ELISA. The effects of mouse sera on H2O2 production by endothelial cells and on fibroblast proliferation, and serum concentrations in advanced oxidation protein products (AOPP) were compared with sera from patients with limited or diffuse SSc. We observed that s.c. peroxynitrites induced skin fibrosis and serum anti-CENP-B Abs that characterize limited SSc, whereas hypochlorite or hydroxyl radicals induced cutaneous and lung fibrosis and anti-DNA topoisomerase 1 autoantibodies that characterize human diffuse SSc. Sera from hypochlorite- or hydroxyl radical-treated mice and of patients with diffuse SSc contained high levels of AOPP that triggered endothelial production of H2O2 and fibroblast hyperproliferation. Oxidized topoisomerase 1 recapitulated the effects of whole serum AOPP. SCID mice developed an attenuated form of SSc, demonstrating the synergistic role of the immune system with AOPP in disease propagation. We demonstrate a direct role for ROS in SSc and show that the nature of the ROS dictates the form of SSc. Moreover, this demonstration is the first that shows the specific oxidation of an autoantigen directly participates in the pathogenesis of an autoimmune disease.

Antibodies to fibroblasts in idiopathic and scleroderma-associated pulmonary hypertension

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 >25u2005mmHg). Serum immunoglobulin (Ig)G and IgM reactivities of patients with idiopathic PAH (nu200a=u200a35), scleroderma-associated PAH (nu200a=u200a10), diffuse (nu200a=u200a10) or limited cutaneous (nu200a=u200a10) scleroderma without PAH and age- and sex-matched healthy individuals (nu200a=u200a65) 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.

Identification of Target Antigens of Antifibroblast Antibodies in Pulmonary Arterial Hypertension

RATIONALEnPulmonary arterial hypertension (PAH) may be classified as idiopathic (IPAH) or familial (FPAH) or associated with various conditions and exposures such as dexfenfluramine intake (Dex-PAH) or systemic sclerosis (SSc-PAH). Because fibroblast dysfunction has been identified in SSc and IPAH and antifibroblast antibodies (AFAs) with a pathogenic role have been detected in the serum of SSc patients, we used a proteomic approach combining two-dimensional electrophoresis and immunoblotting to identify the target antigens of AFAs in such patients.nnnOBJECTIVESnTo identify target antigens of antifibroblast antibodies in pulmonary arterial hypertension.nnnMETHODSnSera from 24 patients with IPAH, 6 with FPAH, 6 with Dex-PAH, and 12 with SSc-PAH were collected. We pooled sera from sets of three patients with PAH classification and SSc-PAH based on autoantibody profile. Sera from 14 healthy blood donors were also pooled and used as a control.nnnMEASUREMENTS AND MAIN RESULTSnSerum IgG antibodies in the pools of patients with IPAH (n = 8), FPAH (n = 2), Dex-PAH (n = 2), and SSc-PAH (n = 4) recognized 103 +/- 31, 63 +/- 20, 78 +/- 11, and 81 +/- 12 protein spots, respectively, whereas serum IgG antibodies from healthy control subjects recognized 43 +/- 22 protein spots. Twenty-one protein spots were specifically recognized by the serum IgG antibodies from patients with PAH. We identified 16 of the protein spots as vimentin, calumenin, tropomyosin 1, heat shock proteins 27 and 70, glucose-6-phosphate-dehydrogenase, phosphatidylinositol 3-kinase, DAP kinase, and others. These proteins are involved in regulation of cytoskeletal function, cell contraction, oxidative stress, cell energy metabolism, and other key cellular pathways.nnnCONCLUSIONSnAFAs detected in patients with PAH recognize cellular targets playing key roles in cell biology and maintenance of homeostasis.

Pulmonary Hypertension Associated with Myeloproliferative Disorders: A Retrospective Study of Ten Cases

Background: Pulmonary hypertension (PH) is a severe hemodynamic disorder in which the pulmonary artery pressure is persistently elevated, leading to right-sided heart failure. Some studies have suggested an association between PH and myeloproliferative diseases (MPD). Objectives: This study describes clinical, hematological and hemodynamic characteristics of PH associated with MPD. Methods: We retrospectively reviewed 10 cases of PH associated with MPD: polycythemia vera (8 patients) and essential thrombocythemia (2 patients), followed between 1993 and 2002. The baseline evaluation was established by right-sided heart catheterization, ventilation/perfusion lung scan and pulmonary angiography if required. Results: Six patients had confirmed chronic thromboembolic pulmonary hypertension (CTEPH) and 4 had pulmonary arterial hypertension (PAH) associated with MPD without other risk factors for PAH. The hemodynamic characteristics of CTEPH and PAH associated with MPD were similar. The diagnosis of CTEPH was concomitant to that of MPD in all cases (5 polycythemia vera and 1 essential thrombocythemia). The PAH associated with MPD occurred later in the evolution of the MPD (3 polycythemia vera and 1 essential thrombocythemia) with a median of 162 months after the diagnosis of MPD, and it was associated with myeloid metaplasia (p < 0.01). Conclusion: We describe 2 distinct forms of PH in the context of MPD: CTEPH, which is diagnosed at an early stage of the MPD, and PAH, which occurs later in the course of the MPD and is associated with myeloid metaplasia. Progressively increasing dyspnea in a patient with an MPD warrants further investigation to rule out PAH and CTEPH, while a diagnosis of CTEPH warrants ruling out MPD.

Churg-strauss syndrome.

PURPOSE OF REVIEWnChurg-Strauss syndrome is a small-vessel necrotizing vasculitis typically characterized by asthma, lung infiltrates, extravascular necrotizing granulomas and hypereosinophilia. The most recent clinical studies on its pathogenesis and therapeutic management are reviewed here.nnnRECENT FINDINGSnFrench and Italian clinical studies found that the clinical characteristics of patients with Churg-Strauss syndrome differed according to their antineutrophil cytoplasmic autoantibody status: cardiomyopathy predominated in antineutrophil cytoplasmic autoantibody-negative patients while necrotizing glomerulonephritis was more often observed in antineutrophil cytoplasmic autoantibody-positive patients. These histologically documented findings suggest the existence of different Churg-Strauss syndrome subtypes, characterized by the predominance of distinct pathogenetic mechanisms. To date, following the therapeutic recommendations for Churg-Strauss syndrome (i.e. corticosteroids and, when required, immunosuppressants), patient outcomes are good, with 5-year survival exceeding 90%, but often with the need to continue low-dose corticosteroids to control residual asthma.nnnSUMMARYnThe precise pathogenetic mechanisms of Churg-Strauss syndrome are only partly elucidated. Recent results suggest that antineutrophil cytoplasmic autoantibodies are probably more involved in the vasculitic manifestations of Churg-Strauss syndrome (e.g. glomerulonephritis) whereas eosinophil tissue infiltration and associated cytotoxicity would be responsible for cardiomyopathy. If confirmed, these results could support individual therapeutic stratification according to the clinical pattern. Furthermore, some patients may benefit from new biologic therapies under development, for example antiinterleukin-5 or antiimmunoglobulin E monoclonal antibodies.

Impact of autoantibody glycosylation in autoimmune diseases

OBJECTIVEnRecent outcomes enhanced the critical role of glycosylation pattern of autoantibodies in the pathophysiology of antibody-mediated autoimmune diseases. In this review, we discuss the critical role of immunoglobulin (Ig) glycosylation on skewing immune response towards a pro- or anti-inflammatory pathway.nnnMETHODSnA comprehensive search of Pubmed references was completed by hand searching of selected articles.nnnRESULTSnWe first described the impact of glycosylation on Ig immune effector functions: antibody-dependent cell-mediated cytotoxicity, complement activation, dendritic cell, macrophage or B-cell activation and maturation, neoantigen formation, or Ig-receptor binding. We then reviewed autoimmune diseases with abnormal Ig glycosylation, trying to understand its role in the pathogenic process. We then discussed the usefulness of monitoring Ig glycosylation as a biomarker of disease activity, as demonstrated in proteinase-3 anti-neutrophil cytoplasmic autoantibodies associated vasculitis. After reporting environmental and immune factors known to affect Ig glycosylation process, we finally evoked therapeutic strategies currently being developed in order to modulate Ig glycosylation pattern and autoimmune disease evolution.nnnCONCLUSIONnThis overview on Ig glycosylation mechanisms and impact on immune system modulation is necessary to face new therapeutic approaches of autoimmune diseases.

IgM and IgG autoantibodies from microscopic polyangiitis patients but not those with other small- and medium-sized vessel vasculitides recognize multiple endothelial cell antigens

Using a quantitative immunoblotting technique on extracts of macrovascular and microvascular endothelial cells (EC), we analyzed serum IgM and IgG reactivities of patients with active disease fulfilling the ACR and Chapel Hill criteria for the diagnosis of polyarteritis nodosa (PAN) (n = 8), PAN related to hepatitis B virus (HBV) infection (HBV-PAN) (n = 5), Wegeners granulomatosis (n = 6), microscopic polyangiitis (MPA) (n = 18), Churg-Strauss syndrome (n = 8), and patients with chronic HBV infection without PAN (n = 5) and age- and gender-matched healthy individuals (n = 45). MPA patients IgM bound to 200-, 105-, 80-, 65-, 45-, 35-, and 33-kDa major bands, whereas IgM from controls and other patients bound predominantly to the 65-kDa band in EC extracts. MPA patients IgG reacted mainly with 105-, 70-, 55-, and 38-kDa protein bands, whereas IgG from controls and other patients did not. Our results provide evidence that IgM and to a lesser degree IgG from MPA patients specifically recognize multiple EC antigens.

Brief Report: Childhood-Onset Systemic Necrotizing Vasculitides: Long-Term Data From the French Vasculitis Study Group Registry.

To describe the initial features and long‐term outcomes of childhood‐onset small vessel and medium vessel systemic necrotizing vasculitides (SNVs), including antineutrophil cytoplasmic antibody–associated vasculitides (AAVs) and polyarteritis nodosa (PAN).