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 Table of Contents  
Year : 2021  |  Volume : 16  |  Issue : 5  |  Page : 29-38

Genetics and pathogenesis of connective tissue disease-associated interstitial lung disease

OPTIMA Arthritis and Rheumatology Clinics, Bengaluru, Karnataka, India

Date of Submission08-Sep-2021
Date of Acceptance24-Oct-2021
Date of Web Publication21-Dec-2021

Correspondence Address:
Dr. Sharath Kumar
185, 1st Main Road, Mahalaxmi Layout, Behind Mahalaxmi Metro Station, Next to Abaran Showroom, Bengaluru - 560 086, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-3698.332976

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Connective tissue diseases (CTD) are a broad category of diseases with autoimmune etiology and multi-system involvement. The lung seems to be involved in some form in most CTDs. Interstitial lung disease (ILD) is the prototypic lung manifestation and is seen in 2%–50% of patients with CTDs.[1] It leads to significant morbidity and mortality. Unfortunately, the ubiquitous involvement across CTDs, along with the possible benefit of treating this manifestation, has not translated into a good understanding of its pathogenesis or treatment. We must aim for a better understanding of the genetic determinants of this manifestation (to help identify those who are at risk) as well as its pathogenesis (to help identify therapeutic targets). This review aims to provide a summary of the key genetic determinants of CTD-ILD as well as the key players of the pathogenic pathway of this manifestation.

Keywords: Autoimmune diseases, connective tissue diseases, genetics, immunology, interstitial, lung diseases, physiopathology

How to cite this article:
Kumar S. Genetics and pathogenesis of connective tissue disease-associated interstitial lung disease. Indian J Rheumatol 2021;16, Suppl S1:29-38

How to cite this URL:
Kumar S. Genetics and pathogenesis of connective tissue disease-associated interstitial lung disease. Indian J Rheumatol [serial online] 2021 [cited 2023 Feb 1];16, Suppl S1:29-38. Available from:

  Introduction Top

There have been relatively few studies dedicated to deciphering the pathogenic process as well as determining predispositions to interstitial lung disease (ILD) in patients with Connective tissue diseases (CTDs). This is unfortunate as it is quite probable that insights gained by such research are likely to translate into a new therapeutic arsenal to help mitigate this potentially devastating complication. An understanding of the genetics of the condition will also lead to the detection of new pathogenic pathways and help identify which patients are more likely to benefit from which therapeutic interventions.

For matters of convenience, and given that many studies have grouped different CTD-ILDs, most discussion in the rest of the article will refer to CTD-ILDs together as one group. In reality, they are a heterogeneous group and better understanding is likely to further highlight major differences between individual CTD-ILDs. For example, the INBUILD study[2] grouped all CTD-ILD patients demonstrating a progressive fibrosing phenotype together. When the same criteria were applied to the CTD-ILD cohorts in other studies, the percentage of patients fulfilling the “progressive fibrosing phenotype” was ~ 33% in Systemic Sclerosis-related ILD Systemic Sclerosis-related ILD (SSc-ILD) but only around 8% of patients with rheumatoid arthritis-ILD (RA-ILD).[3] Most CTD-ILDs commonly show a nonspecific interstitial pneumonitis or nonspecific interstitial pneumonia (NSIP) pattern but RA-ILD more frequently demonstrates a usual interstitial pneumonitis or usual interstitial pneumonia (UIP) pattern [Table 1] and [Table 2].[4]
Table 1: Histopathological patterns of connective tissue diseases-interstitial lung disease and their characteristics

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Table 2: Frequency of different Interstitial lung disease patterns among the connective tissue diseases

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Before delving into the genetics and pathogenesis of the condition we need to make note of some of the characteristics of the histopathological patterns being discussed [Table 1] and their representation across different CTDs [Table 2].[4]

  Overview of Pathogenic Process Top

As with most autoimmune diseases, a genetic predisposition with an environmental trigger has been considered as the cause of CTD-ILDs. The current understanding of the genetics of CTD-ILDs has been summarized below as well as in [Table 3]. A detailed discussion of environmental triggers is outside the purview of this review. These triggers lead to an injury to lung tissue leading to the recruitment of cells of the immune system which produces an inflammatory milieu of cytokines causing dysregulated fibrosis. The resulting injury from fibrosis helps set up a self-perpetuating cycle [Figure 1].
Table 3: Genetic associations with connective tissue diseases-interstitial lung disease

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Figure 1: Overview of the pathogenic process of fibrosis in connective tissue disease-related interstitial lung disease

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The initial step of pathogenesis is a predisposition. This has been the main focus of research on genetics in CTD-ILD.

  Genetics Top

The two main subtypes of CTD-ILD which have been studied individually are RA-ILD and SSc-ILD:

Rheumatoid arthritis interstitial lung disease

Significant interest in the genetics of CTD-ILD has concentrated on the mucin 5B (MUC5B) gene known to predispose to idiopathic pulmonary fibrosis (IPF).[5] The results of this gene in CTD-ILDs were generally disappointing except for the UIP type of RA-ILD. In one study which included 620 patients with RA-ILD, the MUC5B gene promoter variant rs35705950 revealed an association with RA-ILD with an odds ratio (OR) of 4.7 versus 5448 unaffected controls. The OR on comparison to 614 patients who had RA without ILD was 3.4 and this increased to 6.1 when only UIP type RA-ILD were compared to RA without ILD. The associations which were tested in a French population were validated in multi-ethnic populations from six countries.[6] The polymorphism leads to a gain of function leading to increased production of mucin glycoprotein which hampers mucociliary clearance and interferes with alveolar repair postinjury. Lung tissue in RA-ILD patients showed increased MUC5B expression in the distal airways as well as in areas of microscopic honeycombing.[6]

Research has also focused on telomeres,[7] which are distal regions of the chromosomes and guard them against degradation. As we age, the length of telomeres tends to shorten. Shortened telomeres may hamper healing and/or turnover of the alveolar epithelial cells after an initial insult. Mutations in telomere-related genes (TERT, TERC, RTEL1, PARN, TINF2, NAF1, and DKC1) are strongly associated with RA-ILD (OR-3.17) in the study among the French population.[8]

A recent meta-analysis of genome-wide association studies of two large Japanese cohorts of RA patients identified RPA3-UMAD1 at 7p21 as an association with RA-ILD. (OR = 2.04) RPA plays a role in DNA replication and responds to damage. It has also been reported to be involved in the modulation of telomerase activity.[9]

Given the autoimmune nature of the disease, it is not surprising that many genetic associations involving the short arm of chromosome 6 (i.e., MHC loci) have been elucidated [Table 3]. One of the strongest genetic risk factors for RA has been the shared epitope (SE) encoded by human leukocyte antigen (HLA) DRB1 alleles such as DRB1 × 04 allele group. They are strongly associated with anti-cyclic citrullinated peptide (anti-CCP) antibodies and smoking.[10] The association between HLA-DRB1 alleles and RA-ILD, on the other hand, has not been so straightforward. Despite anti-CCP strongly correlating with RA-ILD (see next section), the SE alleles were protective against the development of ILD in RA in a Japanese cohort (OR 0.66). HLA DR-2 serological group alleles (DRB1 × 15 and × 16 alleles) carried a higher risk of RA-ILD in the same cohort (OR 1.75) as did HLA-DQB1 × 06 (OR 1.57).[11] In another Japanese cohort as well as in a cohort in the UK, the SE alleles were equally distributed between RA patients with ILD and those without.[10] We can, therefore, conclude that there is a lot to be done to elucidate the nature and full extent of association between different HLA alleles and ILD in RA.

SSc-interstitial lung disease

Several MHC associations are seen with SSc-ILD as well [Table 3]. A study in the UK on SSc patients revealed HLA-DRB1 × 11 as having a strong association with ILD (RR = 2.7). A similar study among native population in South Africa reaffirmed the association with an OR of 4.69. Genetic association studies in the Chinese population showed an association with DPB1 × 0301(OR-3.56) and DPB1 × 1301(OR-2.25). A report from a couple of Japanese cohorts showed an association with DRB5 × 105(OR-8.07–17.39). HLA-DRB1 × 0301 was found to be associated with SSc-ILD in another Chinese cohort. It was also found to be associated with SSc-ILD in the previously mentioned UK cohort (RR = 7.5), but only in patients who were negative for anti-topoisomerase antibody.[12]

The transcription factor interferon regulatory factor 5 (IRF5) is a transcription factor that induces inflammatory cytokines and interferons and is needed for antiviral immunity. The IRF5 rs2004640: G > T variant was significantly associated with SSc-ILD when compared to healthy controls in French and Han Chinese cohorts (OR = 1.38 in both). However, the same was found to not be significantly different between SSc with ILD and those without in metanalysis from five European populations.[12]

Signal transducer and activator of transcription 4 (STAT4) another transcription factor whose gene polymorphism (i.e., STAT4 rs7574865: T > G) has been associated with SLE and RA has also been shown to be associated with SSc-ILD compared to controls in a French cohort (OR-1.44) as well as Han Chinese population study (OR-1.38). STAT 4 is needed for the secretion of type 1 interferons, interleukins (IL)-12, and IL-23.[12] The STAT4 polymorphism and the IRF5 polymorphism described above seem to show an additive risk for the development of SSc-ILD in a French cohort (OR = 1.79). Interferons are known to be essential for anti-viral defense. The association of these genes with ILD in SSc raises the question of whether the Epstein-Barr virus infection (apart from other viruses and bacteria) is an important environmental trigger for the development of ILD in these patients.[12]

GG genotype of Connective tissue growth factor (CTGF) rs6918698: G > C was significantly associated with SSc-ILD in comparison to controls in a British cohort (OR-3.1) and a Japanese cohort (OR-2.0). The association was not replicated in a study on the Thai population or in a study of seven populations of European ancestry. CTGF plays a significant role in myofibroblast differentiation and extracellular matrix production.[12]

A few studies have reported on myositis-ILD as well in which the HLA associations have been the main focus [Table 3]. A study in Caucasian patients from the UK who had anti synthetase antibodies showed a significant association with HLA-DRB1 × 03-DQA1 × 05-DQB1 × 02 haplotypes (OR 5.5).[13] No separate studies exist on the genetics of Sjogren-ILD, lupus-related ILD or mixed connective tissue disease-related ILD (MCTD-ILD). Patients with these diseases are generally grouped with patients with RA, SSc, and myositis in many studies. One such study from China included 280 patients with IPF, 774 patients with CTD-ILD, and 109 controls who had pneumonia. The authors showed a significant association of the p. G1205R variant of the ATP-binding cassette (ABC) transporter gene ABCA3 with only CTD-ILD and not with IPF or controls. The ABC transporter is an essential membrane protein and is highly expressed in alveolar epithelial type 2 cells and plays an essential role in surfactant synthesis.[14]

  Transcriptional Assays and Epigenetics Top

The other type of genetic research is on gene expression profiling. The latter helps determine which genes are actively involved at a particular phase of the disease. Thus, they provide clues of pathogenic processes or pathways. In SSc, during early disease gene expression profiling shows association with genes related to antigen presentation, IL-17 signaling, and chemokine pathways. In contrast, in end-stage SSc-ILD lung disease profiling studies show a lot of similarities with IPF (i.e., genes related to epithelial injury and proliferation-the Wnt/b-catenin pathway, epithelial cell plasticity, and epithelial-mesenchymal transition [EMT]).[15]

The timing of gene activation and suppression thus seems to be important in the pathogenesis of CTD-ILDs. DNA methylation pattern influences which genes get activated and which get silenced during a particular phase of the disease. This is one of the important epigenetic mechanisms thought to play a role in CTD-ILD based on data from IPF and mouse models. Other important epigenetic mechanisms include posttranslational histone modification and noncoding RNA. Histone deacetylase inhibitors can prevent myofibroblast differentiation and make them and fibroblasts sensitive to Fas-mediated apoptosis. The noncoding RNAs (microRNA or miRNAs) can inhibit certain mRNAs and prevent them from leading to protein production. For example, miR-21 downregulates Smad 7 which is an inhibitor of tissue growth factor-b (TGF-b) and has been shown to lead to lung fibrosis in mouse models.[4]

However, most genes associated with CTD-ILD do not explain the initial insult or injury initiating the immune cascade. The significant HLA associations lead one to suspect that the initial injury or insult is immunological. This is where autoantibodies are hypothesized to play a role.

  Antibodies Top

Among a particular CTD, the presence of certain autoantibodies carries a much higher risk of ILD in comparison to patients without those antibodies. For example, the presence of anti-CCP was significantly associated with RA-ILD with an OR of 2.1. Patients with RA-ILD generally had higher anti-CCP titers and the prevalence of ILD also increased as the titer of anti-CCP increased.[16] This was seen despite the protective effect of SE in RA-ILD. Another example would be the presence of anti-topoisomerase-1/anti Scl-70 which carries a high risk for the development of progressive ILD in scleroderma. The strongest risk factor for ILD among patients with SSc was a combination of auto-antibodies with two other independent factors; i.e., diffuse disease and HLA-DRB1 × 11 (RR-21.19).[12] Thus, antibodies seem to have an association with the development of ILD which is either independent or complementary to genetic predisposition. Antibodies could be the initial triggering event in CTD-ILD causing cell damage. However, there has been scant evidence for a direct pathogenic role for autoantibodies leading to speculation that they may be mere associations.

What is clear is that there is an insult and the resultant injury leads to recruitment of the cells which are then involved in further development of the disease process. These cellular players and their contribution to the pathogenic process are discussed below.

  Cells Involved Top

The pathogenic pathway in pulmonary fibrosis is triggered by damage to the alveolar epithelial cell or endothelial cell with enhanced permeability following the destruction of the alveolar-capillary barrier. There is an infiltration of inflammatory cells which interact with fibrocytes and thus promote fibrocyte infiltration and formation of fibrotic foci. Fibrocytes differentiate into myofibroblasts which play an active role in architectural disruption. The normal resolution of this infiltration of activated cells by apoptosis is dysregulated [Figure 1]. The role of the different cells involved in these steps of the pathogenic pathway is summarized individually below.

Alveolar epithelial cell damage

This seems to be the initial triggering event and a key process in the development of ILD.[17] Endothelial cell damage may be the initial event in patients with SSc.[11] The initiating pathway for the cell damage remains uncertain. Early growth response 1, lysophosphatidic acid receptor 1, the Wnt/-catenin pathway, oxidative stress, and the unfolded protein response/endoplasmic reticulum stress have all been considered as possible pathways.[18] The importance of this step is highlighted by the fact that the levels of proteins that are released by epithelial injuries such as SP-D, KL-6, and YKL-40 reflect disease progression and severity.[19] This damage is the trigger for the next step in the pathogenic pathway which is inflammatory cell infiltration.

Infiltration of inflammatory cells

Alveolar epithelial cell damage seems to be followed by an infiltration of the lung tissue by cells of the immune system mediating inflammation. This feature is an evident differentiating factor between CTD-ILD and IPF. Research has shown a role for almost every part of the cellular immune system-both innate and adaptive. The role of individual cells of the immune system is summarized below as well as in [Table 4].
Table 4: Immune cells, cytokines and chemokines involved in connective tissue diseases-interstitial lung disease

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Analysis of the bronchoalveolar lavage fluid (BALF) has shown an accumulation of neutrophils and the same has been associated with poorer outcomes.[20] Macrophages can generally be divided into two main contrasting phenotypes, i.e., M1 (classically activated, depending on stimulation by Th1 cytokines) and M2 (alternatively activated, depending on stimulation by Th2 cytokines). Pechkovsky et al. demonstrated that cells in BALF from patients with systemic sclerosis were found to release much higher amounts of M2 marker proteins such as IL-1RA, CCL17, CCL18, and CCL22 compared to cells from healthy donors.[21] B cell infiltration in varying degrees is common in pulmonary tissue of patients with SSc-ILD[22] and RA-ILD.[23]

Overall, the role of T-cells in ILD seems to be complex. Work on bleomycin-induced lung injury model in mice has shown that there is an accumulation of T-cells in the lungs in the first few days (day 3–5) after which the numbers die down[24] However, the role of individual types of T-cells tend to vary. There has been a lot of interest in the Th1/Th2 cell balance in the pathogenesis of fibrotic lung disease with Th2 considered to be “pro-fibrogenic.” T-regulatory cells have been shown to have a differential effect on fibrogenesis depending on the stage of the disease.[25] The immune cell infiltration and resultant cytokine release help in the activation and proliferation of fibroblasts in the lung tissue which seems to be the next essential step in the pathogenesis of CTD-ILD.

Fibrocyte infiltration and differentiation into myofibroblasts

Fibrocytes are circulating myeloid-derived cells that migrate to tissues and can differentiate into myofibroblasts. Circulating fibrocytes are elevated in patients with IPF for whom they are an independent predictor of mortality.[26] RA-ILD patients have also been shown to have increased levels of circulating fibrocytes compared to healthy controls.[27] Residential fibroblasts and the fibrocytes which migrate from circulation differentiate to myofibroblasts. Myofibroblasts can also be derived from epithelial cells as well by trans differentiation- [EMT].[17]

Myofibroblasts are the main effector cells of fibrosis. They synthesize extracellular matrix components and contain microfilaments in their cytoplasm similar to those of smooth muscle cells conferring contractile function to them. These functions lead to structural remodeling and are thus the key mediators of the loss of alveolar function. The persistence and self-perpetuation of this process lead to pathology. An important requirement for the persistence of this process is the myofibroblasts in CTD-ILD seem to be resistant to apoptosis.

Lack of apoptosis

All the above processes can be normally found in the physiological response to tissue injury such as wound healing. However, aberrant persistence of these processes in an abnormally large magnitude is what ultimately contributes to fibrotic diseases. Fibroblasts from patients with SSc show reduced sensitivity to Fas ligand-mediated apoptosis as they express less pro-apoptotic BCL2-associated X protein.[28] In addition, stiff ECM itself can contribute to evasion of apoptosis by myofibroblast via Rho and Rho-associated kinase. Studies in cultured fibroblasts from SSc patients show that TGF b1 and ET-1 can also mediate resistance to apoptosis via increased activation of focal adhesion kinase-protein kinase B pathway.[29] The latter two processes can trigger off a positive feedback loop leading to unbridled fibrosis.

As shown above, the pathogenic process seems to be a complex symphony with several players of the immune system as well as resident lung tissue being involved. The migration of immune cells as well as circulating fibrocytes into the lung cannot happen without the help of chemokines. In addition, the cells use various cytokines for communication with each other.

  Cytokines and Chemokines Top

Several cytokines and chemokines have been studied and shown to play a role in the pathogenesis of pulmonary fibrosis. TGF b-1 is the prototypical, most well studied, and most potent fibrogenic mediator in pulmonary fibrosis. Platelet-derived growth factor is another important mediator of fibrosis. Interleukins such as IL-1, IL-17, IL-6, and IL-13 are important mediators of inflammation and fibrosis. Aiding in the process are chemokines such as CCL2, CCL17, CCL18, and CXCL12. The roles of these key cytokines and chemokines which could serve as therapeutic targets for CTD-ILD are highlighted in [Table 4].

  Clinical Implications Top

A better understanding of the above key players is likely to lead to a breakthrough in therapeutics. A case in point is the approval of anti-IL-6 biological, tocilizumab, for the treatment of SSc-ILD by the FDA. Pirfenidone can suppress CCL18 expression by alveolar macrophages in IPF.[19] It has also been shown to retard ECM synthesis and inhibit the proliferation of fibroblasts and myofibroblasts.[30] Indeed, pirfenidone has shown promising results in a couple of phase 2 trials among patients with progressive fibrosing lung disease which included CTD-ILD[3] Similar basic research for other medications can help discover potentially useful therapeutic interventions. Telomerase length was assessed among patients with IPF who responded to pirfenidone in the ASCEND and CAPACITY trial. The results showed that pirfenidone slowed forced vital capacity decline among patients with both short telomeres as well as those with long telomeres.[31] Although this analysis was not fruitful, it is quite likely that similar analysis in other future trials including CTD-ILD patients could reveal specific subsets of patients based on genetic makeup who would be more likely to respond to a particular medication.

The approval of nintedanib for the treatment of all progressive fibrosing ILDs,[2] whether IPF or CTD-ILD, seems to suggest a common pathogenic pathway, at least partially. However, there are several differences between CTD-ILDs and IPF which are summarized in [Table 5]. Thus, we must understand the apparent dichotomy, in some parts, and a degree of synchrony, in other parts, that the pathogenic mechanisms of CTD-ILDs seem to have in comparison to IPF. This will help us understand the ideal place and timing of immunomodulation and anti-fibrotic agents. Hence, dedicated research on CTD-ILDs in general and specific CTDs, in particular, is required. CTD-ILDs need to be brought out from under the shadow of IPF and we should no longer depend on paradigms or research generated from IPF.
Table 5: Differences between connective tissue diseases-interstitial lung disease and idiopathic pulmonary fibrosis

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  Conclusion Top

CTD-ILDs generally demonstrate an NSIP phenotype (except for RA-ILD in which UIP is more common). Although each CTD-ILD is likely to have individual characteristics, several key common pathogenic processes are seen across the different CTDs. A better understanding of these processes will open the doors to new therapeutic targets. Genetic signatures of pathological tissues are likely to reveal secrets of undiscovered pathogenic pathways. Understanding the genes involved in the development of CTD-ILD will lead to early detection and specific targeting of any new therapeutic target to the population to which it is likely to have the highest impact.

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Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Figure 1]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]


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