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

In This Article

Fibrosing Lung Diseases

Pulmonary fibrosis describes the repair process on which the lungs rely after injury. It is characterized by progressive, patchy diffuse thickening of the alveolar walls (fibrosing alveolitis) with connective tissue matrix and inflammatory cells. Fibrosing alveolitis can cause severe pulmonary impairment, and response to treatment is variable. [7,8] On computed tomography (CT), a predominantly reticular pattern indicates fibrosis whereas a ground-glass pattern is associated with an increased inflammatory cell content. [9-11] Figure 1A

Figure 1A.

CT scan of fibrosing alveolitis as a result of systemic sclerosis. Note dilated esophagus (closed arrow) and homogeneous pattern change consistent with fibrosis (open arrow).

Figure 1B. CT scan of patient with CFA. The pattern of fibrosis is coarser than for SSc (open arrow).

shows a typical CT scan of FA associated with systemic sclerosis and Figure 1B shows the coarser, less homogeneous reticular pattern associated with CFA.

Cryptogenic Fibrosing Alveolitis

CFA is a diffuse lung disease of unknown etiology with a relatively late age of onset, usually between the ages of 40 and 70 years.[4,12] Clinical manifestations of the disease commonly include breathlessness during exercise and a nonproductive cough, although other symptoms, such as weight loss, fever, and fatigue, may also be present.[13] CFA is a chronically progressive process, and the 5-year survival rate is approximately 50%.[7,14,15]

The pathogenesis of CFA involves the chronic accumulation of inflammatory and effector cells, predominantly macrophages and neutrophils, in the lower respiratory tract[16,17,18,19,20]; although other cells, including lymphocytes and mast cells, have also been shown to be important.[21,22,23,24] Triggers for the inflammatory process include initial injury and the subsequent formation of immune complexes that are chemotactic for neutrophils and capable of activating macrophages. The influx and activation of inflammatory cells are accompanied by the production of an array of inflammatory cytokines, which in turn stimulate the production of growth factors. Inflammation is, therefore, likely to be one of the key factors in the course of the disease.[7,25,26,27,28]

Biopsies taken from patients with fibrosing alveolitis appear similar to those seen in usual interstitial pneumonia (UIP). In some patients with the clinical and radiologic features of CFA, however, histopathology shows a desquamative interstitial pneumonia (DIP) pattern or nonspecific interstitial pneumonia (NSIP) pattern.[29] These differences are distinguishable by their distribution and pattern of cellularity and fibrosis as well as by their degree of homogeneity.

The identifiable risk factors for developing CFA include environmental exposure to dusts, chemicals, and cigarette smoking[4,12,30]; however, the odds of death are no higher for individuals in manual occupations when compared to the general population.[31] In industrialized areas, it appears that mortality is higher in men when the analysis is adjusted for age and sex.

Familial clustering of CFA does occur,[32] and it is thought that genetic factors play a role. Antigen processing and presentation are components of the immune response, and it is thought that the likely candidate genes predisposing patients to diffuse lung diseases are those of the major histocompatibility complex (MHC) (Figure 2). Human leukocyte antigen (HLA) molecules are cell-surface glycoproteins encoded by genes within the MHC region. The function of the HLA molecules is to present antigens to T lymphocytes (T-cells), which either recognize self antigens or stimulate an immune response. The genes within the MHC region are highly polymorphic and are associated with autoimmune diseases. T-cell receptor recognition of foreign peptides that are presented by the HLA molecules on the surface of antigen-presenting cells is the principal driving force of the immune response and results in T-cell activation, cytokine production, and antibody formation.

HSP = heat shock protein; TAP = transporter associated with antigen processing; TNF = tumor necrosis factor.

Immunoglobulin allotypes may also be involved in the development of diffuse interstitial lung disease.[33] CFA is characterized by inflammation, damage, and progressive fibrosis in the acinar regions of the lungs, which suggests that genes that influence the processes of inflammation (eg, pro-inflammatory cytokines), wound healing, and repair (eg, fibronectin and transforming growth factor-beta [TGF-beta]) may also play a role in the development and progression of this disease.

A substantial amount of research investigating the association between CFA and genes of the MHC complex has been done, but the results are inconsistent ( Table 1 ).[34,35,36]

Systemic Sclerosis

Scleroderma is a spectrum of relatively uncommon diseases ranging from localized skin disease to systemic sclerosis (SSc). It is characterized by the accumulation of extracellular matrix in the skin and internal organs, severe alterations in the microvasculature, and prominent inflammatory and immunologic alterations. Diffuse lung disease is one of the most common features of systemic sclerosis, and some degree of pulmonary fibrosis is found in the majority of patients postmortem.[37]

The etiology of SSc is unknown, but it almost certainly has a genetic basis. The female-to-male ratio is 9:1.

Ssc is considered an autoimmune disease and, therefore, the candidate genes are those encoded by the MHC (Table 1). Initial studies of the association between genes of the MHC and SSc found an increased frequency of specific MHC class I and class II alleles.[38,39,40,41,42,43,44,45,46,47,48,49,50,51,52] Some of these studies demonstrated a stronger association with HLA-DQ than with HLA-DR alleles, indicating that HLA-DR associations were due to linkage disequilibrium. This lack of concordance between studies is attributable to study population heterogeneity. Geographic and environmental variability, ethnic variability, or clinical heterogeneity cause disparate results. Environmental variability suggests that different causal agents are involved; geographic variability may be associated with differences in both environmental triggers and the gene pools of specific populations.

A further complicating factor may be heterogeneity of disease diagnosis, resulting in a lack of consistency in the definition of disease subsets. A prominent feature of SSc is the presence of serum antinuclear antibodies. It is estimated that up to 90% of patients with SSc have such antibodies.[53] Although a pathogenic role has yet to be established for any scleroderma-specific autoantibody, these autoantibodies are clearly associated with different clinical subsets of the disease[54]; the anti-topoisomerase autoantibody (ATA) is associated with pulmonary fibrosis[52]; the anti-centromere autoantibody (ACA) is linked to limited disease[55]; anti-RNA polymerase I and III autoantibodies are associated with diffuse disease and a higher incidence of heart and kidney involvement[56]; and autoantibodies against the nucleolar ribonucleoprotein U3 are linked to a high incidence of pulmonary hypertension.[57] Interestingly, these antibodies are mutually exclusive,[58] although it is unknown how this relates to the development of the clinical syndromes with which they are associated.

Autoantibody formation is an antigen-driven process requiring the presentation of processed antigen in association with class II MHC molecules to helper T-cells, resulting in activation, proliferation, and induction of an antigen-specific immune response.[59] For example, in a subset of patients with SSc in association with pulmonary fibrosis, it was demonstrated that the presence of the HLA-DR3/DR52a alleles and/or the anti-Scl70 autoantibody was a risk factor for the development of pulmonary fibrosis.[52] A subsequent study reported an association between anti-Scl70-positive patients with systemic sclerosis and HLA-DPB1*1301,[60] and this was confirmed in a study by Gilchrist and colleagues.[61] They demonstrated a strong association between the presence of HLA-DPB1*1301 and ATA in patients with SSc (P = 1 × 10-7).

Marguerie and coworkers[62] found that all subjects with PM-Scl antibody were positive for HLA-DR3. Increased frequencies of HLA-DR1, -DR4, -DR8, and HLA-DQB with a polar glycine or tyrosine residue at position 26 of the beta chain have been reported to be associated with the ACA.[63,64]In addition, anti-ATA autoantibody has been shown to be associated with HLA-DR15, -11, and -7.[65,66,67,68] Kuwana and associates[65,69]found that anti-HLA-DPB antibodies did not affect topoisomerase-induced T-cell proliferation, whereas anti-HLA-DR and, to a lesser extent, anti-HLA-DQ antibodies inhibited proliferation. It is possible that HLA-DPB1*1301-positive subjects with ATA form a subpopulation with a distinct clinical phenotype compared with other ATA-positive populations. However, the associations between other autoantibodies and HLA alleles are less clear, possibly because of differences in susceptibility alleles among ethnic groups or to differences in disease subsets.[52,61,70,71,72,73,74,75,76,77,78,79,80,81,82]

Fibrosing alveolitis in association with systemic sclerosis (FASSc), like CFA, is characterized by inflammation, damage, and progressive fibrosis of the lungs. As mentioned previously, research on the association between the genes of the MHC and FASSc has produced interesting, although disparate, results. It is therefore likely that there are other genetic influences on the development of the disease. Genes that influence the processes of inflammation, wound healing, and repair (eg, fibronectin and TGF) are likely candidates. Avila and coworkers[83] demonstrated that polymorphism within the fibronectin gene is associated with fibrosis. This study suggested that heterozygosity of the fibronectin gene may be important in the development of FASSc ( Table 2 ). It is also suggested that there is a gene polymorphism within the TGF-beta 1 gene that plays a role in the development of fibrosis in FASSc.[84]


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