Interstitial Lung Disease: Pathophysiology and Genetic Predisposition

Penelope A. Lympany, PhD, and Roland M. du Bois, MD, Imperial College of Science, Technology and Medicine, London, UK

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In This Article

Granulomatous Diseases

Immune granulomas are collections of inflammatory cells at disease sites that result from specific cell-mediated immune mechanisms, although the triggering event cannot always be clearly identified. It is generally thought that granulomas result from a specific T-cell-mediated response to an antigenic agent that has been processed by macrophages and presented to antigen-specific T cells. The T cell then directs the accumulation and differentiation of mononuclear phagocytes in the local microenvironment.[17,106,107]

Sarcoidosis

Sarcoidosis is a chronic, multi-organ granulomatous disorder of unknown etiology[108] that frequently affects the lungs. Sarcoidosis affects approximately 1 in 3000 of the UK population[109,110] and occurs with varying frequencies in other populations.[111] It is more aggressive in patients of Afro-Caribbean descent than in Caucasians[112,113,114,115,116] and occurs predominantly in the 30- to 40-year age range, although it may also be found in children.[117,118,119] There is a distinct geographic difference in sarcoidosis prevalence; it is low in the Spanish population[120] but high in Scandinavian countries.[107,121]

Sarcoidosis is characterized by the accumulation of activated T-cells and mononuclear cells at the sites of disease, resulting in the formation of noncaseating granulomas and in tissue damage.[17,107,122] Granulomas are identified in the airways in up to 55% of sarcoidosis patients[123] and severe lung fibrosis occurs in about 30%, resulting in high rates of morbidity and sometimes mortality.[107,124,125]

There is some evidence suggesting that sarcoid granulomas are formed in response to a persistent and poorly degraded antigenic stimulus (the persistent antigen hypothesis), although it is uncertain whether sarcoidosis is caused by a single agent, a relatively few closely related agents, or multiple factors.[126,127] Possible culprits are infectious agents including mycobacteria,[128,129,130] environmental agents including beryllium,[1,131,132,133] and autoantigens including heat-shock proteins.[134,135] The common factors among these agents are their low biodegradability and persistence within macrophages.[136] This suggests that antigenic processing and presentation are important and that there is likely some form of genetic predisposition to the disease that is related to antigen presentation.

Strong evidence of a genetic predisposition for sarcoidosis comes from the familial clustering of the disease.[137] For example, in a study of familial sarcoidosis in Ireland, 10% of individuals with sarcoidosis had siblings with the disease.[137] In studies of sarcoidosis in African-American and Caucasian families, Harrington and associates[138] demonstrated that the disease was more common in the former. In observations of sarcoidosis in twins, monozygotic twins are more concordant for disease than dizygotic twins, suggesting a significant genetic component to the disease in addition to any environmental influences.

Other Granulomatous Diseases

Chronic beryllium disease is an antigen-driven disease in which granulomas form in the lungs after inhalation of beryllium salts. It is clinically and histologically indistinguishable from sarcoidosis[1] and may, therefore, serve as a model for immune granuloma formation. Remarkably, exposure to similar amounts of beryllium does not induce disease in all individuals, suggesting genetic predisposition in the development of the disease. Richeldi and colleagues[132] found an association between HLA-DPB alleles with a glutamate residue at position 69 of the beta chain (Glu-69) and the development of chronic beryllium disease. This residue is situated within the binding cleft of the HLA-DPB molecule and is involved in antigen binding and presentation to the T-cell receptor. This suggests that the immune response seen in chronic beryllium disease, and by inference that seen in sarcoidosis, is at least partially controlled by the presentation and binding of the antigen within the HLA molecule.

Studies have been conducted into the association between sarcoidosis and genes of the MHC complex (Table 1), the most likely candidate genes, but often with disparate results.[139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162] The discrepancies are attributable to a number of factors, including differences in the ethnic origin of study participants and differences in disease diagnosis or staging.[162] It is interesting to note that some studies have reported associations between disease prognosis and specific HLA phenotypes.[163,164,165] In the study by Berlin and colleagues,[164] HLA-DR predicted disease prognosis; there was an increased frequency of HLA-DR17 in sarcoidosis patients with nonchronic disease compared with healthy controls, and patients with chronic disease had increased frequencies of HLA-DR14 and -DR15 compared with controls.

The MHC region contains genes that encode proteins resulting in antigen processing and presentation. Research investigating sarcoidosis and genes within or close to the MHC region (including the transport-associated peptide [TAP] genes) have indicated an association.[134,159,166,167,168,169,170,171,172]

The accumulation of activated T cells in target organs of patients with sarcoidosis, and the functional relationship between the MHC and the T-cell receptor, support the hypothesis that the genes encoding the T-cell receptor are good candidates to influence the development of sarcoidosis. Further support for the theory that sarcoidosis is the result of the presence of a specific antigen is provided by studies of the repertoire of T-cell antigen receptors at disease sites. Evidence from analysis of T-cell receptors in sarcoidosis points to the persistence antigen hypothesis. The T-cell receptor is heterodimeric, and its specificity is determined by variable (V) gene rearrangement during T-cell development. There have been several studies of the clonality of T-cell receptor V-chain families found in diffuse lung disease, and various T-cell receptor families have been shown to be preferentially expressed in sarcoidosis.[173,174,175,176,177,178,179,180,181]Although there is some disparity in the specific T-cell receptor family expansion reported in these studies, these studies support the hypothesis that T-cell activation is driven through an antigen-specific process. The discordance in the results of these studies may be due to variation in the MHC phenotype of the patients studied. Grunewald and coworkers[176] addressed this hypothesis in sarcoidosis using a combined MHC and T-cell receptor approach and showed a very strong concordance between HLA-DR3, DQ2, and the T-cell receptor V-alpha 2.3 chain.

Other genetic analyses focused on the genes encoding cytokines[182,183] and also those encoding the angiotensin-converting enzyme (ACE).[184,185,186,187,188,189,190,191] The ACE studies investigated the presence or absence of specific alleles (insertion or deletion). The deletion allele is associated with increased levels of ACE in sarcoidosis-affected and normal subjects. However, the contribution of genetic polymorphism to serum ACE levels in sarcoidosis remains unclear.

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