Actualités sur la sarcoïdose Tazi, Abdellatif
Revue de pneumologie clinique,
7/2005, Letnik:
61, Številka:
3
Journal Article
Depuis sa description il y a plus d’un siècle, la sarcoïdose continue à faire l’objet d’une recherche intense. Avec le recul, la sarcoïdose peut être considérée comme un syndrome immunitaire ...résultant de la combinaison variable de facteurs génétiques et ethniques prédisposants et de facteurs environnementaux, qui engendrent une expression clinique et un pronostic très variables de la maladie. Au cours des dernières années, plusieurs équipes dans le monde ont proposé un lien entre certains polymorphismes génétiques, en particulier du système HLA, et le risque de survenue ou le profil évolutif de la sarcoïdose. Parallèlement, les mécanismes pathogéniques impliqués dans la formation du granulome sarcoïdien sont mieux compris et sont à la base de l’utilisation de thérapeutiques nouvelles, comme les anti-TNF, dont l’efficacité doit cependant être évaluée au cours d’essais multicentriques.
Since the first description more than a century ago, intensive research continues to focus on sarcoidosis. Based on our current knowledge, sarcoidosis can be considered as an immune syndrome resulting from a variable combination of predisposing genetic, ethnic, and environmental factors. Over the last few years, several teams have proposed a link between certain genetic polymorphisms, particularly of the HLA system, and the risk of development or progression of sarcoidosis. Other pathogenic mechanisms involved in the formation of the sarcoid granuloma are becoming more clear and have led to the development of new therapeutic approaches such as anti-TNF currently being evaluated in multicentric trials.
Update on sarcoidosis Tazi, Abdellatif
Revue de pneumologie clinique
61, Številka:
3
Journal Article
Since the first description more than a century ago, intensive research continues to focus on sarcoidosis. Based on our current knowledge, sarcoidosis can be considered as an immune syndrome ...resulting from a variable combination of predisposing genetic, ethnic, and environmental factors. Over the last few years, several teams have proposed a link between certain genetic polymorphisms, particularly of the HLA system, and the risk of development or progression of sarcoidosis. Other pathogenic mechanisms involved in the formation of the sarcoid granuloma are becoming more clear and have led to the development of new therapeutic approaches such as anti-TNF currently being evaluated in multicentric trials.
We evaluated the repertoire of V beta segments used in forming the T-cell receptor of lavage and blood T lymphocytes from 11 sarcoid patients and 10 normal subjects using procedures based on ...quantitative polymerase chain reaction, permitting analysis of both the abundance of transcripts using each of 20 different V beta families and the diversity of the VDJC beta rearrangements within each V beta family. Blood and lung T cells from sarcoid patients had a very diverse V beta repertoire. For all V beta families but one, the abundance of the V beta transcripts fell within the mean +/- 2 SD of that observed for normal blood lymphocytes; no difference in the overall abundance was observed comparing lavage and blood T cells, and the length of VDJC beta rearrangements for a given V beta family in samples from sarcoid patients was usually quite heterogeneous. Despite the overall polyclonality, evidence for selective expansion of T cells was found, in that an increased abundance of V beta 19 transcripts was observed for sarcoid blood and/or lung T cells in eight out of 11 patients studied, and rearrangements of a single predominant length using certain (e.g., V beta 19, V beta 14), but not all, V beta families were present. Sequencing confirmed the presence of a single predominant VDJC beta rearrangement in these cases. These findings suggest that the alveolitis in sarcoidosis results from two distinct processes, a local clonal expansion of T cells associated with an apparently nonspecific accumulation of T cells with an extremely diverse V beta repertoire.
Heat shock proteins (HSP) are highly conserved molecules whose expression is induced in eukaryotic cells following a broad spectrum of environmental stresses. These proteins can also be expressed by ...virally transformed cells and cancer cells and are important targets for T lymphocytes. Little is known about the abundance and distribution of HSP in the normal lung, the effect of cigarette smoking on their expression, or their expression in human lung carcinomas. We have used monoclonal antibodies coupled with immunohistochemical and immunoelectrophoretic techniques to evaluate the distribution of four different HSP (HSP 90 kD, HSP 73 kD/constitutive, HSP 72 kD/inducible, and HSP 63 kD) in normal lung (n = 14) and lung cancers (n = 15). In lung tissue from nonsmokers (n = 7), bronchiolar epithelial cells were intensely positive for HSP 90 kD and HSP 72 kD/inducible and weakly reactive for HSP 63 kD. Most macrophages also expressed these HSP at low levels, but no other parenchymal or immune/inflammatory cells were positive. Cigarette smoking did not modify the distribution or the intensity of HSP in bronchiolar epithelial cells, and macrophages from smokers expressed similar or lower levels of these HSP. Tumor cells from 14 of 15 lung carcinomas expressed one or more of the HSP. Considerable heterogeneity in the expression of HSP by cells in a given tumor was observed, explained in part by differences in the differentiation of the cells. Detection of HSP by immunohistochemical and immunoelectrophoretic techniques gave similar results for HSP 72 kD/inducible and HSP 90 kD.
Studies in experimental animals have suggested that gamma/delta T-cells play an important role in the immune response against mycobacteria, but evidence for the participation of these cells in the ...course of human tuberculosis remains fragmentary. We have evaluated the number and state of activation of gamma/delta T-cells in the peripheral blood of patients with active tuberculosis using two-color cytofluorometry, and we have sought evidence that these cells might play a role in the impaired responses to recall antigens seen in some patients by comparing the proliferation of blood T-lymphocytes before and after removing gamma/delta T-cells by panning. Results were compared with those obtained for cells from normal subjects and from patients with sarcoidosis. The proportion and absolute number of circulating CD3+ gamma/delta T-cells were not significantly different comparing blood from patients with tuberculosis and that from control subjects 54.6 +/- 39.9 (n = 17) and 59.1 +/- 30.2 cells/microliters (n = 10), respectively, p > 0.2, and the proportion of cells expressing receptors using the V delta 1 variable region remained unchanged in patients with tuberculosis. Few gamma/delta T-cells from patients with tuberculosis expressed surface antigens associated with activation (IL-2R, < 1%; HLA-DR, 2.6 +/- 3.4%). Four of 15 patients with sarcoidosis had a proportion of gamma/delta T-cells that was outside the range observed in normal subjects, but the absolute number of CD3+ gamma/delta T-lymphocytes was not different comparing the two groups (p > 0.2).
The phenotypic and functional properties of T cells recovered from the lung indicate that many of these cells have been recently activated. Because such recently activated cells are often more ...susceptible to death through apoptotic mechanisms, the viability of lung T cells recovered from bronchoalveolar lavage and those isolated from peripheral blood was compared. The progressive loss of viable cells following in vitro culture was considerably greater for lavage T cells than blood T cells, and was observed for cells from both patients with sarcoidosis and control subjects. Following 4 days of culture, 76 +/- 14% of blood cells, but only 31 +/- 13% of lavage cells from sarcoid patients were viable. The evaluation of morphologic features and flow cytometric profiles, as well as the demonstration of typical oligonucleosomal fragmentation of DNA extracted from these cells indicated that lavage T cells were dying by apoptotic mechanisms. CD4+ T cells appeared to be particularly sensitive to apoptosis. Most lavage T cells from controls and sarcoid patients expressed Fas (CD95) antigen. Although some lavage T Cells were sensitive to Fas-induced apoptosis, the viability of lavage T cells was not improved by incubation in the presence of a monoclonal antibody that inhibits Fas-induced apoptosis. Culture in the presence of interleukin 2 did prevent, at least in part, the progressive death of lavage T cells, suggesting that the viability of T cells in the lung may depend on the presence of locally delivered trophic signals. These studies emphasize that T cells on the alveolar surface are in a different state of activation and differentiation compared with that of circulating T cells, and offer a possible explanation for the impaired functional capacities observed for lavage T cells in some in vitro studies.
BACKGROUND--Several chest radiographic abnormalities have been described in pulmonary sarcoidosis, but a diffuse ground glass pattern is extremely rare. METHODS--The chest radiographs of more than ...1600 patients with sarcoidosis evaluated in our service between 1976 and 1991 were reviewed to determine the prevalence of this pattern on chest radiography at presentation, and to assess the clinical characteristics of these patients. RESULTS--Ten patients (0.6%) were identified with diffuse ground glass abnormalities on the chest radiography (eight men); all had associated hilar or mediastinal adenopathy. All patients were white and nine were smokers or former smokers. Nine patients were symptomatic and six had inspiratory crackles on physical examination. As a group these patients were remarkable for the frequency and severity of physiological abnormalities and the presence of various findings typically associated with "active" disease. Nine patients were followed for more than three years. All were treated with oral corticosteroids because of significant symptoms or physiological abnormalities, or both. Symptoms and radiological abnormalities disappeared or improved in all patients, but recurred in a high proportion when steroids were tapered or discontinued. By December 1992 only three patients had been withdrawn from treatment. CONCLUSIONS--A diffuse ground glass pattern on the chest radiograph is unusual in patients with sarcoidosis and may occur more commonly in white subjects and cigarette smokers. Its presence suggests the existence of active disease of recent onset likely to require long term treatment with corticosteroids.
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