RESUMEN
OBJECTIVE: It has previously been shown that the adhesion of lymphocytes to microvascular endothelium mediates lymphocyte extravasation within inflamed synovium. After passing the endothelial barrier, binding of lymphocytes to matrix proteins and synovial lining cells may further lead to synovial membrane hyperplasia and subsequent cartilage destruction. Thus, we have explored the molecular basis of T cell-synovial lining cell interaction in the synovial membrane of patients with rheumatoid arthritis (RA). METHODS: Using an immunohistochemical staining technique and an in vitro frozen section assay we studied the expression and the role of several adhesion molecules in T lymphocyte-synovial lining cell interaction in the inflamed synovial membrane. RESULTS: In RA the macrophage-like (type A) synovial lining cells express high levels of intercellular adhesion molecule 1 [ICAM-1 (CD54)], whereas the fibroblast-like (type B) synovial lining cells predominantly express vascular cell adhesion molecule 1 (VCAM-1), in addition to moderate levels of ICAM-1. Both cell types express low levels of fibronectin. Unstimulated and anti-CD3 stimulated peripheral blood T cells bear the respective ligands lymphocyte function associated antigen 1 [LFA-1 (CD18/11a)], and very late antigen 4 and 5 [VLA-4 (CD29/49d) and VLA-5 (CD29/49e)]. T lymphocytes predominantly bound to type B synovial lining cells. Inhibition studies with monoclonal antibodies revealed that this binding involves the VLA-4/VCAM-1 and VLA-5/fibronectin (FN), but not the VLA-4/CS1 pathway. LFA-1 is also involved in this interaction via its ligand ICAM-1. CONCLUSION: These results show that the molecular basis of T lymphocyte binding to rheumatoid synovial lining cells is different from that described for T lymphocyte binding to synovial membrane vascular endothelium which involves the VLA-4/VCAM-1 and VLA-4/CS-1 pathways, but not the LFA-1/ICAM-1 pathway.
Asunto(s)
Artritis Reumatoide/patología , Moléculas de Adhesión Celular/análisis , Membrana Sinovial/química , Linfocitos T/fisiología , Anticuerpos Monoclonales , Artritis Reumatoide/inmunología , Adhesión Celular , Moléculas de Adhesión Celular/inmunología , Moléculas de Adhesión Celular/fisiología , Línea Celular , Endotelio Vascular/inmunología , Endotelio Vascular/patología , Humanos , Inmunohistoquímica , Molécula 1 de Adhesión Intercelular/análisis , Molécula 1 de Adhesión Intercelular/inmunología , Molécula 1 de Adhesión Intercelular/fisiología , Péptidos y Proteínas de Señalización Intercelular , Antígeno-1 Asociado a Función de Linfocito/análisis , Antígeno-1 Asociado a Función de Linfocito/inmunología , Antígeno-1 Asociado a Función de Linfocito/fisiología , Péptidos/farmacología , Receptores de Antígeno muy Tardío/análisis , Receptores de Antígeno muy Tardío/inmunología , Receptores de Antígeno muy Tardío/fisiología , Membrana Sinovial/irrigación sanguínea , Membrana Sinovial/inmunología , Membrana Sinovial/patología , Linfocitos T/inmunología , Molécula 1 de Adhesión Celular VascularRESUMEN
OBJECTIVES: It has previously been shown that the very late antigen-4/vascular cell adhesion molecule-1 (VLA-4/VCAM-1) pathway functions as a receptor/ligand interaction system mediating the recruitment of activated lymphocytes to inflamed synovium of patients with rheumatoid arthritis. This study was performed to determine whether VLA-4 also affects lymphocyte adhesion to inflamed synovium through interaction with the alternatively spliced CS1 domain of fibronectin. METHODS: The effect of the synthetic peptide CS1 on lymphocyte binding to human synovial and peripheral lymph node high endothelial venules (HEVs) was measured in an in vitro frozen section assay. RESULTS: In the presence of the CS1 peptide or antibody to fibronectin, significant inhibition of binding was observed (54 and 51% respectively). Blocking with antibody to VCAM-1 yielded inhibition of binding to 46% of the control value. Maximum inhibition of binding was obtained with a combination of antibody to VCAM-1 and CS1 (65%) and with antibody to VLA-4 alpha (68%). Blocking the classical fibronectin receptor with antibody to VLA-5 alpha gave a slightly lower inhibition at 42%. In normal peripheral lymph nodes, the synthetic peptide CS1 and antibodies to fibronectin and VLA-5 also partially inhibited T cell binding to HEVs (45, 47, and 52% respectively). CONCLUSION: These results show that fibronectin mediates lymphocyte-HEV interactions not only through its classical VLA-5 receptor, but also through its CS1 adhesion motif in inflamed synovium and peripheral lymph nodes.
Asunto(s)
Artritis Reumatoide/metabolismo , Fibronectinas/fisiología , Péptidos/fisiología , Membrana Sinovial/metabolismo , Linfocitos T/fisiología , Artritis Reumatoide/inmunología , Unión Competitiva/fisiología , Adhesión Celular/fisiología , Técnicas de Cultivo , Endotelio Linfático/metabolismo , Humanos , Técnicas para Inmunoenzimas , Péptidos y Proteínas de Señalización IntercelularRESUMEN
Extravasation of leucocytes in tissues is mediated by leucocyte-endothelial cell interactions in which adhesion molecules play an important role. Until now, two pathways have been unravelled, i.e., the LFA-1/ICAM-1 and the VLA-4/VCAM-1 pathways. ELAM-1 has been shown to be involved in granulocyte accumulation and recently also in lymphocyte migration. The role of HECA-452 is under investigation. In this study we have investigated the expression of the above-mentioned adhesion molecules in lung tissue of patients with pulmonary sarcoidosis and usual interstitial pneumonitis (UIP), and in mediastinal lymph nodes of patients with sarcoidosis. ICAM-1 (CD54) was broadly distributed on the endothelium of all the vessels found in sarcoidosis and UIP. VCAM-1 was present on the endothelium of the venules, capillaries, and arterioles in both sarcoidosis and UIP. ELAM-1 reacted with endothelial cells lining venules and capillaries in chronic progressive sarcoidosis and in the active phase of UIP but not in the stationary phases of both diseases. HECA-452 activity could be detected only on high endothelial venules within sarcoid lymph nodes. In lung tissues, macrophages bearing the ICAM-1 antigen were present in sarcoid tissue but not in the interstitium and alveolar space of UIP. LFA-1 (CD11a/CD18) and VLA-4 (CD49d/CD29) were present on all leucocytes found but seemed to be more highly expressed on lymphocytes in sarcoidosis. These findings suggest that the LFA-1/ICAM-1 and VLA-4/VCAM-1 pathways are involved in leucocyte migration in both types of lung disease, while in the active phases of sarcoidosis and UIP, ELAM-1 is also involved.
Asunto(s)
Moléculas de Adhesión Celular/análisis , Pulmón/química , Fibrosis Pulmonar/metabolismo , Sarcoidosis/metabolismo , Adulto , Selectina E , Femenino , Humanos , Molécula 1 de Adhesión Intercelular , Ganglios Linfáticos/química , Masculino , Persona de Mediana Edad , Molécula 1 de Adhesión Celular VascularRESUMEN
Six patients with rheumatoid factor positive rheumatoid arthritis who had shown a marked symptomatic improvement during four weeks of hypoallergic, artificial diet were studied in greater detail. Placebo controlled rechallenges showed intolerance for specific foodstuffs in four patients. In three of these patients biopsies of both the synovial membrane and of the proximal small intestine were carried out before and during allergen free feeding. In two patients, both with raised serum IgE concentrations and specific IgE antibodies to certain foods, a marked reduction of mast cells in the synovial membrane and proximal small intestine was demonstrated. Although the number of food intolerant patients with RA remains limited and markers of allergic activity are scanty, our observations suggest an underlying immunoallergological mechanism.
Asunto(s)
Artritis Reumatoide/dietoterapia , Hipersensibilidad a los Alimentos/dietoterapia , Anciano , Artritis Reumatoide/inmunología , Artritis Reumatoide/patología , Biopsia , Femenino , Hipersensibilidad a los Alimentos/inmunología , Humanos , Inmunoglobulina E/análisis , Inmunoglobulina G/análisis , Intestino Delgado/inmunología , Masculino , Persona de Mediana Edad , Membrana Sinovial/inmunologíaRESUMEN
Lymphocyte migration and recirculation of lymphocytes between the lymphoid organs and other tissues is thought to be essential for effective immunologic surveillance and dissemination of the immune response. In addition, lymphocyte recirculation may also be important in the segregation of lymphocytes with particular functions in the different lymphoid tissues. Furthermore, insight in the molecular basis of these processes may help us to understand lymphoma spreading and metastatic invasion of carcinoma cells.
Asunto(s)
Movimiento Celular , Linfocitos/fisiología , Linfoma/patología , Neoplasias/inmunología , Neoplasias/patología , Receptores Mensajeros de Linfocitos/fisiología , Humanos , Vigilancia Inmunológica , Tejido Linfoide/inmunología , Linfoma/inmunología , Invasividad Neoplásica , Metástasis de la Neoplasia , Receptores Mensajeros de Linfocitos/clasificación , Receptores Mensajeros de Linfocitos/inmunologíaRESUMEN
Lymphocyte migration to inflammatory sites is an essential factor in the pathogenesis of chronic inflammation. An ensemble of adhesion receptors mediating lymphocyte-endothelial cell recognition and binding are thought to play a crucial role in this process. In the present study, we have explored the molecular basis of lymphocyte adhesion to endothelium in the synovial membrane of patients with rheumatoid arthritis. We established that the very late antigen-4 [VLA-4 (CD49d)] and the vascular cell adhesion molecule-1 (VCAM-1) are important mediators of binding to synovial endothelium of resting and, to a greater extent, of activated T lymphocytes, whereas the leukocyte-function associated antigen-1 [LFA-1 (CD11a/18)]/intercellular adhesion molecule-1 [ICAM-1 (CD54)] pathway is less important in this interaction. In contrast to its prominent role in lymphocyte interaction with endothelium in rheumatoid synovium, the VLA-4/VCAM-1 pathway does not significantly contribute to lymphocyte adhesion to peripheral lymph node high endothelial venule. Thus, the VLA-4/VCAM-1 pathway may be of primary importance in mediating lymphocyte adhesion to inflamed endothelium and in lymphocyte homing to rheumatoid synovium.
Asunto(s)
Artritis Reumatoide/inmunología , Moléculas de Adhesión Celular/fisiología , Endotelio Vascular/fisiología , Linfocitos/fisiología , Receptores de Antígeno muy Tardío/fisiología , Membrana Sinovial/inmunología , Anticuerpos Monoclonales/inmunología , Adhesión Celular , Humanos , Técnicas In Vitro , Molécula 1 de Adhesión Celular VascularRESUMEN
Since dendritic cells are believed to play a crucial role in the pathogenesis of rheumatoid arthritis (RA) we studied the microenvironmental relationship of these cells with endothelial cells, lymphocytes and macrophages in the rheumatoid synovial membrane. With the monoclonal antibodies OKIa (MHC Class II determinants), RFD1 and L25 (both specific for "active" human dendritic cells) we identified large numbers of dendritic cells. With the monoclonal antibody HECA 452 [specific for a putative adhesion molecule notably present on high endothelial venules (HEV)], a subset of dendritic cells could be detected. HECA-452 positive dendritic cells were found in 2 basic patterns: (1) associated with small lymphoid cell clusters in the neighborhood of vessels with flat, HECA-452 negative endothelium, (2) at the periphery of dense organoid lymphoid infiltrates, surrounding HECA-452 positive HEV-like vessels. Our data suggest that the influx of HECA-452, L25, RFD1 and MHC Class II positive dendritic cells is an early event in the development of the inflammatory infiltrate found in the rheumatoid synovial membrane. The formation of organoid lymphoplasmacellular infiltrates with high endothelial venules would be secondary to this event.
Asunto(s)
Artritis Reumatoide/inmunología , Células Dendríticas/inmunología , Membrana Sinovial/inmunología , Anticuerpos Monoclonales/inmunología , Artritis Reumatoide/patología , Endotelio/irrigación sanguínea , Endotelio/inmunología , Endotelio/patología , Humanos , Linfocitos/inmunología , Macrófagos/inmunología , Membrana Sinovial/irrigación sanguínea , Membrana Sinovial/patología , VénulasRESUMEN
Specificity of plasmacellular infiltration was studied using a guinea pig peritoneal inflammation model. Acute and chronic inflammations were induced by repeated injections of either of two non-crossreacting antigens (DNP-BSA and PPD). With an enzyme-immunohistochemical sandwich procedure allowing quantitation of DNP-BSA-specific plasma cells, specificity of plasmacellular infiltration could be demonstrated. DNP-BSA-specific antibody-forming cells were found not to enter inflammatory reactions elicited by PPD. Our data support the hypothesis that virtually all plasma cells in a chronic inflammatory exudate release antibodies specific for antigens that are locally available, and that such antigens are likely to play a central role in the perpetuation of chronicity.
Asunto(s)
Células Productoras de Anticuerpos/inmunología , Inflamación/inmunología , Cavidad Peritoneal/inmunología , Células Plasmáticas/inmunología , Animales , Especificidad de Anticuerpos , Movimiento Celular , Enfermedad Crónica , Dinitrobencenos/inmunología , Femenino , Cobayas , Albúmina Sérica Bovina/inmunología , Tuberculina/inmunologíaAsunto(s)
Dermatitis por Contacto/inmunología , Epítopos/inmunología , Haptenos/inmunología , Linfocitos T/inmunología , Animales , Movimiento Celular , Células Cultivadas , Dermatitis por Contacto/fisiopatología , Dinitroclorobenceno/inmunología , Femenino , Cobayas , Ganglios Linfáticos/citología , Masculino , Linfocitos T/fisiologíaRESUMEN
Homing of 51Cr-labelled spleen and lymph node-derived T- and B-cell subpopulations into inflammatory sites in the skin, as well as into lymphoid and non-lymphoid organs, was studied in outbred and inbred guinea-pigs. The early progeny of activated T cells were demonstrated in immunologically-mediated inflammation of the skin, for example a cell-mediated immune reaction and a reversed passive Arthus reaction. In contrast, spleen and lymph node-derived B cells were virtually unable to enter inflammatory sites. Organ-specific homing of T and B cells was detected. The significance of these observations for the interpretation of results of lymphoid cell transfers in guinea-pigs is discussed.
Asunto(s)
Linfocitos B/fisiología , Dermatitis por Contacto/fisiopatología , Linfocitos T/fisiología , Animales , Linfocitos B/inmunología , Movimiento Celular , Dermatitis por Contacto/inmunología , Femenino , Cobayas , Ganglios Linfáticos/inmunología , Especificidad de Órganos , Piel/inmunología , Bazo/inmunología , Linfocitos T/inmunologíaRESUMEN
Guinea pig T lymphocytes were labelled with various concentrations of 111In-oxine. The capacity of these cells to migrate into a skin inflammatory site was compared with that of 51Cr-labelled cells. The results show that even with low dosages of 111In-oxine which did not impair lymph node localization (1-10 microCi/10(8) cells/ml), migration into an inflammatory site was markedly reduced. Moreover, using this isotope, a significant contribution to the radioactivity recovered from an inflammatory site is made by the local accumulation of non-cell-bound label. These results stress the limited use of 111 In-oxine as a radiolabel in lymphocyte migration studies.