Immune mechanisms in interstitial lung diseases (2000)

Several features have long suggested a strict relationship between the functional behavior of the host immune system and the pathobiology of interstitial lung diseases (ILDs). Most clinical manifestations of ILDs are secondary to the direct effect of the accumulation of activated immunocompetent cells in involved tissues, notably T cells, macrophages, or neutrophils. However, it is also believed that pathophysiologic events leading to the persistence and/or progression of the pulmonary disease are the same in most ILDs: the persistence of the causative agents and/or the imbalance of mechanisms for the removal of inflammatory cells favor a prolongation of inflammatory responses, the formation of pulmonary granulomas, and, in some cases, the development of irreversible fibrosis. Other characteristics which have captured the attention of immunologists are related to the fact that the development of some complications of ILDs, including the progression to fibrosis, are regulated by a complex cascade of interactions among T cells, accessory cells, and cytokines released by relevant immunocompetent cells. Recent data on the complex network of interactions between cells and biologic response modifiers which control the pulmonary immune system have dramatically expanded our knowledge of the pathogenesis of ILDs. Thanks to the cloning of cytokine genes, in situ hybridization methods, and cytokine receptor characterization, the cascade of interacting extracellular signaling molecules which orchestrate the trafficking of immune cells accounting for the alveolitis are beginning to be clarified. In this paper, we will mainly summarize the basic aspects of pathogenetic mechanisms leading to the recruitment, homing, and activity of inflammation in the respiratory tract of patients with ILDs. In the second part of the paper, we will comment on the role of the immunologic evaluations of pulmonary immunocompetence in specific ILDs. The development of alveolitis represents the immunologic hallmark of ILDs and is sustained by an ordered series of events that can be schematically divided into three phases: the triggering of CD4 T cells by local antigen-presenting cells (APCs) the release of cytokines with multiple and overlapping functions the intra-alveolar and interstitial accumulation of alveolar macrophages (AMs), CD4+ T cells, CD8+ T cells, or neutrophils, depending on the type of ILD ( 1, 2). The persistence of the antigenic stimulation and the consequent chronic inflammatory response lead to the organization of the local inflammatory process into a granuloma ( 3) or to the evolution toward fibrosis ( 4, 5) ( Fig. 1). In the next few paragraphs, we will describe the functional activities of cellular ( Table 1) and soluble factors that participate in the development of alveolitis. Pathogenesis of ILDs. Antigenic exposure triggers T cells and local APCs to release cytokines with multiple and overlapping functions. This favors intra-alveolar accumulation of macrophages and lymphocytes (alveolitis). After removal of antigenic exposure, alveolitis disappears. In contrast, persistence of antigenic stimulation leads to organization of local inflammatory process into granuloma and/or evolution toward tissue injury and fibrosis. The lymphoid tissue of the lung can be functionally subdivided into lymphoid cells arranged in organized aggregates or follicles, which, located throughout the bronchial tree, represent a site of secondary lymphoid differentiation the diffuse lymphoid tissue consisting of scattered lymphocytes which interact with AMs and dendritic cells in the induction of effector functions related to cellular and ( for in the knowledge of the pathophysiologic role of T cells in ILDs be to the to intra-alveolar this immunologic to the of inflammatory events in the lung a few lymphoid lymphocytes are in the of patients with ILDs ( 1, 2). In a of the cells the are macrophages, lymphocytes for of the lymphocytes are a are T cells which the receptor CD4+ and CD8+ T cells are in the same in In most patients with ILDs, lymphocytes dramatically in and in The of lymphocytes can be the of patients with and are T the cells in some a pathogenetic of mechanisms for the of lymphocytes the alveolar cellular the to the lung and in situ cytokines and can the of for molecules on cells ( it is that macrophages and accessory cells and favor of inflammation ( cytokines and are to in the of T cells in the lung of patients with molecules will be in in the next second for the accumulation of in ILDs is in situ have that and local factors for T cells in ILDs ( AMs ( The of to the of the in ILDs. factors with the to and of are involved in this the release of factors also the of the in ILDs. is a of the and alveolitis in most The in patients with be that alveolitis alveolitis represents the hallmark of the ILD which is with this that AMs are in ILDs ( In macrophages patients with ILDs and molecules involved in and/or inflammation and and and In a the development of the by the of and by the of AMs ( The fact that have accessory and can cytokines which the functional and activities of lung T cells in or pulmonary macrophages APCs ( accessory cells, release biologic of the immune and local effector functions ( The molecules that AMs to APCs are on the of including of the and some molecules of the and and the The of and by pulmonary macrophages of patients with ILDs is with that of APCs ( In AMs of molecules which macrophages with accessory including and in an that of interactions by lung inflammation and immune response in with a causative of ( can be in in the of patients with ILDs of lung and fibrosis ( of the of on the of with molecules by cells of the pulmonary tissue and ( and it can be and by which release factors for and ( activated are in to release cytokines and which the inflammatory are with a respiratory and which of of the extracellular is believed that participate in the or of lung tissue that can be in most patients with ILDs. In lung is with and an of can be in the of patients with ILDs and ( 4, and cells to immune events in ILDs with accessory cells in the of to pulmonary effector cells. also including and which are involved in the pathogenesis of ILDs. cells are also to and interact with of and cells the release of and, local inflammatory in the ( and are molecules which can the of in cells ( role for cytokines and in the of immunologic and in the lung is suggested by the fact that type cells in and an of for and is in the alveolar cells of lung patients with pulmonary fibrosis ( represent type which in the cascade of interactions involved in the pathogenesis of cells release a of cytokines and into the tissue injury and data that lung be in of and in pulmonary inflammatory and that be in fibrosis ( the in the lung tissue a role in the release of or cytokines can lung to regulated on and or ( Recent have to our of the role of cytokine and cytokine in the of pulmonary inflammatory In the the of cytokines and of cytokine is complex biologic including and by the cytokines ( In most cases, for cytokines which are by pulmonary cells are of or that are with for the of the receptor is also a of the for and The system is a network of that to be in the few In the next few we will describe the most relevant cytokines involved in ILDs. 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In with also favors the between activated T cells and The between and the of ILDs. the role of in the development of pulmonary fibrosis. in the that role of AMs in the pathogenesis of pulmonary fibrosis is the of and the lung secondary to of including ( it is that and are part of the cytokine network that in the inflammatory the response to ( The of and in the development of pulmonary fibrosis by data in patients with pulmonary fibrosis ( is a cytokine by T cells, CD4 T cells, cells, and bronchial cells. This cytokine the response of CD4 cells, and and the of data a role for in the pathogenesis of ILDs. This which is involved in the pathogenesis of ( direct the into of inflammation and tissue injury in ILDs. 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In in patients with and ILDs and diseases with interstitial it is that an in T cells to of disease activity in ILDs. data the role of and molecules in the development of alveolitis. is that and interactions the local to the evolution toward fibrosis of with ILDs ( the in the of and the and/or of some have in pulmonary are to a of the of and in ILDs. the and of the it is to that a of the system in and diseases of the lung will to control of local immune in patients with ILDs. have the of alveolitis. the of the of the of T cells a in the clinical of this patients with ILDs are subdivided into patients with CD4 or alveolitis ( Table T cells which the pulmonary to the CD4 in patients with and an intra-alveolar accumulation of CD8+ T cells is the hallmark of ILDs with and host disease and In the paragraphs, we will summarize the immunologic characteristics of in some of However, it be that most data in for the of the of an of pulmonary CD4 or T cells in the be of with alveolitis the of the some patients with CD4 alveolitis the clinical of disease with to patients the alveolitis. a of the or of the clinical of the the of the alveolitis can In the of that of to a by or the of a in of be is an of by a immune response that leads to granuloma formation of disease activity ( with with and and The and are involved can be to be the of ILDs by CD4+ alveolitis. 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This that of be of in the clinical of The lung is an for the of is in the lung of and this site in the of the The of in the of immunocompetent cells in the lung and ( be in and is some patients lymphoid interstitial alveolitis is mainly secondary to the of CD8+ which are to and on the of cells ( In patients with respiratory the of cells is with the of the the and the of in the throughout the of the The of the of into the The persistence of alveolitis and activity is also in In contrast, the clinical of disease an of is the of is with the of the CD8+ the progression of pulmonary and the development of ( The in the is also in the of local The in the of cells in the and the of to pulmonary In cells are cells in immune mechanisms to the that the lung ( alveolitis is the of the of T cells the secondary lymphoid to the pulmonary in response to including and ( molecules the of with the cellular and extracellular and to the pulmonary In to of CD8+ T cells can be in the lung of most are T cells with activity and involved in the to ( in some T cells dramatically the pulmonary and alveolar an of host ( a of lung CD8+ T cells to be to and the and and is a between the in and the progression of disease the pulmonary ( are and of the pulmonary immune system in molecules and lung macrophages participate in the of pulmonary ( the of including and AMs release biologic relevant to the of effector mechanisms which ( in an immunocompetent an of tissue macrophages a immune response to or The and immunologic of cells also in ILDs by The of and the accumulation of in with in we have that the of patients with a of CD4 cells have a is to in patients with CD4 represent a of in most patients the CD4 is ( data are in with that the of of CD4 cells can CD4 with disease the of CD4 in the CD4+ in the a effect on are involved in and chronic of lung are an of specific to are by the local accumulation and of cells ( The the most of and among lung ( This process is sustained by the and of cells in the and and is an chronic However, the an for the development of it suggested that is an of lung ( to be of the and persistence of of ( The is by local and the consequent of the and of the of in in clinical of ( In a of a for the of immune lung cells in The of alveolitis in diseases by diffuse inflammatory including patients with tissue and ( In the in patients with and it suggested that a immune response in the of activated CD8+ T cells and cells ( The response is with of the local of and pulmonary the pulmonary inflammatory process to be of disease that the lung of patients with and the is alveolitis ( are by the of and/or alveolar is In and alveolitis a of respiratory in patients with and pulmonary ( an accumulation of CD8+ T cells is a in patients with ( the data the role of in ILDs in patients with it to be of cells the clinical of The of the role of immunologic mechanisms in the pathogenesis of lung for the clinical of ILDs. the of the cellular of our in the of pulmonary in the clinical of ILDs will on our to to local immunocompetence with or cytokines that the and activity of specific or In this be to the of in diffuse pulmonary The in this by the and and for in the of the