Reflux-Induced Collagen Type V Sensitization: Potential Mediator of Bronchiolitis Obliterans Syndrome

doi:10.1378/chest.09-2610

Chest

Volume 138, Issue 2, August 2010, Pages 363-370

https://doi.org/10.1378/chest.09-2610 Get rights and content

Background

Lung transplantation continues to have poor long-term survival partly because of the high incidence of bronchiolitis obliterans syndrome (BOS). Gastroesophageal reflux disease (GERD) has been implicated in BOS pathogenesis. We investigated the role of collagen type V [col(V)] sensitization in this process.

Methods

Only primary lung transplant recipients were included. Reflux status was assessed with pH monitoring, impedance plethysmography, and esophagogastroduodenoscopy. Sensitivity to col(V) was determined with trans vivo delayed-type hypersensitivity reaction (DTH). Kaplan-Meier analyses were performed.

Results

Of the 54 recipients, 26 had proven GERD. There were no significant between-group differences in diagnosis; donor and recipient age; sex; ischemic time; single vs bilateral; human leukocyte antigen A, B, and DR matching cytomegalovirus status; acute rejections; or mean follow-up period. The mean DTH response in the GERD group was 25.7 × 10⁻⁴ inches vs 18.3 × 10⁻⁴ inches in the non-GERD group (P = .023). There was a significant reduction in BOS-free survival in the GERD group for both BOS-I (GERD+, 28.3%; GERD−, 86.6%; P = .0001) and BOS-II/III (GERD+, 66.2%; GERD−, 91.7%; P = .0374). A second cohort of 53 patients awaiting lung transplantation also was assayed. The mean DTH response in the GERD group was 24.0 × 10⁻⁴ inches vs 13.1 × 10⁻⁴ inches in the non-GERD group (P = .003). There were no differences in age or sex.

Conclusions

GERD is strongly associated with the development of BOS after primary lung transplantation. Col(V) sensitization is associated with reflux and BOS and may play an intermediary role in the pathogenesis of BOS. Trials using col(V) reactivity to assess the impact of antireflux procedures in patients with lung transplantation and idiopathic pulmonary fibrosis are warranted.

Section snippets

Trans Vivo Delayed-Type Hypersensitivity Assay

The trans vivo delayed-type hypersensitivity (TV-DTH) assay was used to detect antigen-specific memory responses as previously described.19, 20, 21 Briefly, 7 × 10⁶ to 9 × 10⁶ mononuclear cells derived from peripheral blood were injected along with antigen into the footpads of CB.17 severe combined immunodeficiency mice. Animals were housed and treated in accordance with Association for Assessment and Accreditation of Laboratory Animal Care International and National Institutes of Health

Results

During a 9-year period from May 1998 to May 2007, 107 patients donated blood for measurement of TV-DTH responses to col(V), 54 of whom had already undergone lung transplantation. A second cohort of 53 patients was assayed while on the lung transplant wait-list as a confirmatory cohort. All 54 patients with primary lung transplants were monitored prospectively from the time of transplantation to the onset of BOS. Among these 54 patients, 26 had an objectively documented history of GERD by

Discussion

Long-term survival in lung transplantation recipients continues to be limited despite a substantial increase in the 1-year survival rate.²³ BOS, which is characterized by fibrous obliteration of the small airways, is the most common cause of death 6 months after transplantation.² The syndrome affects 50% to 60% of patients by 5 years posttransplantation. Survival at 5 years posttransplantation is 20% to 40% lower than that in patients who do not develop BOS.²⁴ Once BOS ensues, it continues to

Acknowledgments

Author contributions: Dr Bobadilla: contributed to the experimental design, statistical analysis, critical review, and manuscript review.

Ms Jankowska-Gan: contributed to the experimental design and execution and patient enrollment.

Dr Xu: contributed to the experimental design and execution and patient enrollment.

Ms Haynes: contributed to the experimental design and execution and patient enrollment.

Dr Munoz del Rio: contributed to the statistical analysis.

Dr Meyer: contributed to the

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Chronic lung allograft dysfunction is associated with an increased number of non-HLA antibodies
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Chronic lung allograft dysfunction (CLAD) is the major cause of adverse outcomes in lung transplant recipients. Multiple factors, such as infection, alloimmunity, and autoimmunity, may lead to CLAD. Here, we aim to examine the role of non-human leukocytes antigen (HLA) antibodies in CLAD in a large retrospective cohort.
We analyzed non-HLA antibodies in the pre- and post-transplant sera of 226 (100 CLAD, 126 stable) lung transplant recipients from 5 centers, and we used a separate cohort to confirm our findings.
A panel of 18 non-HLA antibodies was selected for analysis based on their significantly higher positive rates in CLAD vs stable groups. The panel-18 non-HLA antibodies (n > 3) may be positive pre- or post-transplant; the risk for CLAD is higher in the latter. The presence of both non-HLA antibody and HLA donor-specific antibody (DSA) was associated with an augmented risk of CLAD (HR = 25.09 [5.52-14.04], p < 0.001), which was higher than that for single-positive patients. In the independent confirmatory cohort of 61 (20 CLAD, 41 stable) lung transplant recipients, the risk for CLAD remained elevated in double-positive patients (HR = 10.67 [0.98-115.68], p = 0.052). After adjusting for nonstandard immunosuppression, patients with double-positive DSA/Non-HLA antibodies had an elevated risk for graft loss (HR = 2.53 [1.29-4.96], p = 0.007).
Circulating non-HLA antibodies (n > 3) were independently associated with a higher risk for CLAD. Furthermore, when non-HLA antibodies and DSA were detected concomitantly, the risk for CLAD and graft loss was significantly increased. These results show that humoral immunity to HLA and non-HLA antigens may contribute to CLAD development.
A potential mechanism by which aspiration of duodenogastric fluid augments the risk for bronchiolitis obliterans syndrome after lung transplantation
2023, Journal of Thoracic and Cardiovascular Surgery
Citation Excerpt :
Even in a murine model of syngeneic LTx, Subramanian and colleagues4 determined that in the absence of alloimmunity, antibodies to lung SAgs can lead to airway inflammation and fibrogenesis associated with the accumulation of Kα1T- and Col–V-specific interleukin 17+ T cells. Another theory, particularly related to acid reflux, suggests that autoreactivity against Col-V may be induced by acid-related alteration, which has been implicated in the progression of OB in clinical and basic science investigations.27,28 In the present study, we developed a robust murine model to investigate how transplant status and acute aspiration influence autoimmune responses to lung SAgs (Figure 8 and Video Abstract).
Aspiration of duodenogastric refluxate may damage the respiratory epithelium of lung allografts in transplant recipients. We sought to define a mechanism by which aspiration of duodenogastric fluid augments the risk of bronchiolitis obliterans syndrome after lung transplant in a murine model.
We analyzed the immunological effects of acute aspiration of duodenogastric fluid (0.5 mL/kg) on transplant naive (strain DBA/2J) and transplanted mice (strain B6D2F1/J to strain DBA/2J). Serum antibodies to the lung self-antigens (SAgs) K-alpha1 tubulin and collagen-V were determined by enzyme-linked immunosorbent assay. Exosomes were isolated from serum, and immunoblot membranes were probed for antibodies to lung SAgs. Lung sections were assessed for fibrotic burden and obliterative bronchiolitis lesions by histologic and immunohistochemical analyses, including trichrome staining.
Transplanted mice that received duodenogastric fluid developed higher levels of antibodies to the lung SAgs K-alpha1 tubulin and collagen-V and exosomes with lung SAgs on posttransplant days 14 and 28 than transplanted mice with sham aspiration or transplant naive mice (with and without aspiration). All lung allografts demonstrated severe grade A4 rejection on posttransplant day 14, with the highest mean fibrotic burden and mean number of obliterative bronchiolitis-like lesions per microscopic field on day 28 in recipients with aspiration.
This study links aspiration of duodenogastric fluid after lung transplant to higher autoimmune responses to lung SAgs and the release of circulating exosomes with lung SAgs, which together promote sustained immune responses leading to extensive lung parenchymal damage and, ultimately, severe obliterative bronchiolitis—the histologic hallmark of bronchiolitis obliterans syndrome.
Clinical relevance of lung-restricted antibodies in lung transplantation
2019, Human Immunology
Citation Excerpt :
Clinical studies demonstrated that therapy directed against alloimmunity only reduced the incidence of chronic rejection if autoantibodies were depleted and abrogation of alloimmunity alone was not associated with amelioration of chronic rejection [39,40]. Similarly, gastroesophageal reflux which has been associated with chronic rejection is now known to induce de novo lung-restricted autoimmunity [19,41]. Intriguingly, LRA, especially Col-V, are structural proteins located predominantly in the peri-capillary and peri-bronchiolar tissue where BO lesions are observed [42].
Lung transplant is a definitive treatment for several end-stage lung diseases. However, the high incidence of allograft rejection limits the overall survival following lung transplantation. Traditionally, alloimmunity directed against human leukocyte antigens (HLA) has been implicated in transplant rejection. Recently, the clinical impact of non-HLA lung-restricted antibodies (LRA) has been recognized and extensive research has demonstrated that they may play a dominant role in the development of lung allograft rejection. The immunogenic lung-restricted antigens that have been identified include amongst others, collagen type I, collagen type V, and k-alpha 1 tubulin. Pre-existing antibodies against these lung-restricted antigens are prevalent in patients undergoing lung transplantation and have emerged as one of the predominant risk factors for primary graft dysfunction which limits short-term survival following lung transplantation. Additionally, LRA have been shown to predispose to chronic lung allograft rejection, the predominant cause of poor long-term survival. This review will discuss ongoing research into the mechanisms of development of LRA as well as the pathogenesis of associated lung allograft injury.
Aspiration Pneumonia and Related Syndromes
2018, Mayo Clinic Proceedings
Citation Excerpt :
In fact, assuming that many aspiration events are not related to pill or food matter, such foreign body reactions may not be present at all, making the precise role of lung biopsy as the confirmatory procedure for diagnosing aspiration-related lung disease questionable. Multiple series have reported the increased prevalence of GER among lung transplant recipients,48-50 including the importance of nonacid reflux and esophageal dysmotility related to aspiration and development of bronchiolitis obliterans syndrome.49,51,52 Aspiration in lung transplant recipients has been defined primarily by the detection of pepsin and bile in BALF.
Aspiration is a syndrome with variable respiratory manifestations that span acute, life-threatening illnesses, such as acute respiratory distress syndrome, to chronic, sometimes insidious, respiratory disorders such as aspiration bronchiolitis. Diagnostic testing is limited by the insensitivity of histologic testing, and although gastric biomarkers for aspiration are increasingly available, none have been clinically validated. The leading mechanism for microaspiration is thought to be gastroesophageal reflux disease, largely driven by the increased prevalence of gastroesophageal reflux across a variety of respiratory disorders, including chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis, and chronic cough. Failure of therapies targeting gastric acidity in clinical trials, in addition to increasing concerns about both the overuse of and adverse events associated with proton pump inhibitors, raise questions about the precise mechanism and causal link between gastroesophageal reflux and respiratory disease. Our review summarizes key aspiration syndromes with a focus on reflux-mediated aspiration and highlights the need for additional mechanistic studies to find more effective therapies for aspiration syndromes.
Early fundoplication is associated with slower decline in lung function after lung transplantation in patients with gastroesophageal reflux disease
2018, Journal of Thoracic and Cardiovascular Surgery
Gastroesophageal reflux disease (GERD) is prevalent after lung transplantation. Fundoplication slows lung function decline in patients with GERD, but the optimal timing of fundoplication is unknown.
We retrospectively reviewed patients who underwent fundoplication after lung transplantion at our center from April 2007 to July 2014. Patients were divided into 2 groups: early fundoplication (<6 months after lung transplantation) and late fundoplication (≥6 months after lung transplantation). Annual decline in percent predicted forced expiratory volume in 1 second (FEV₁) was analyzed.
Of the 251 patients who underwent lung transplantation during the study period with available pH data, 86 (34.3%) underwent post-transplantation fundoplication for GERD. Thirty of 86 (34.9%) had early fundoplication and 56 of 86 (65.1%) had late fundoplication. Median time from lung transplantation to fundoplication was 4.6 months (interquartile range, 2.0-5.2) and 13.8 months (interquartile range, 9.0-16.1) for the early and late groups, respectively. The median DeMeester score was comparable between groups. One-, 3-, and 5-year actuarial survival rates in the early group were 90%, 70%, and 70%, respectively; in the late group, these rates were 91%, 66%, and 66% (log rank P = .60). Three- and 5-year percent predicted FEV₁ was lower in the late group by 8.9% (95% confidence interval, −30.2 to 12.38; P = .46) and 40.7% (95% confidence interval, −73.66 to −7.69; P = .019). A linear mixed model showed a 5.7% lower percent predicted FEV₁ over time in the late fundoplication group (P < .001).
In this study, patients with early fundoplication had a higher FEV₁ 5 years after lung transplantation. Early fundoplication might protect against GERD-induced lung damage in lung transplant recipients with GERD.
Distal airway microbiome is associated with immunoregulatory myeloid cell responses in lung transplant recipients
2018, Journal of Heart and Lung Transplantation
Long-term survival of lung transplant recipients (LTRs) is limited by the occurrence of bronchiolitis obliterans syndrome (BOS). Recent evidence suggests a role for microbiome alterations in the occurrence of BOS, although the precise mechanisms are unclear. In this study we evaluated the relationship between the airway microbiome and distinct subsets of immunoregulatory myeloid-derived suppressor cells (MDSCs) in LTRs.
Bronchoalveolar lavage (BAL) and simultaneous oral wash and nasal swab samples were collected from adult LTRs. Microbial genomic DNA was isolated, 16S rRNA genes amplified using V4 primers, and polymerase chain reaction (PCR) products sequenced and analyzed. BAL MDSC subsets were enumerated using flow cytometry.
The oral microbiome signature differs from that of the nasal, proximal and distal airway microbiomes, whereas the nasal microbiome is closer to the airway microbiome. Proximal and distal airway microbiome signatures of individual subjects are distinct. We identified phenotypic subsets of MDSCs in BAL, with a higher proportion of immunosuppressive MDSCs in the proximal airways, in contrast to a preponderance of pro-inflammatory MDSCs in distal airways. Relative abundance of distinct bacterial phyla in proximal and distal airways correlated with particular airway MDSCs. Expression of CCAAT/enhancer binding protein (C/EBP)-homologous protein (CHOP), an endoplasmic (ER) stress sensor, was increased in immunosuppressive MDSCs when compared with pro-inflammatory MDSCs.
The nasal microbiome closely resembles the microbiome of the proximal and distal airways in LTRs. The association of distinct microbial communities with airway MDSCs suggests a functional relationship between the local microbiome and MDSC phenotype, which may contribute to the pathogenesis of BOS.

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Funding/Support: This study was supported by the National Institutes of Health [Grants R01 AI48624 (Drs Bobadilla and Meyer and Mss Jankowska-Gan and Haynes), R21 A1049900 (Dr Bobadilla and Mss Haynes and Jankowska-Gan), and R01 AR47746 (Dr Greenspan)]. Dr Maloney is supported by a CHEST Foundation award for clinical investigation in lung transplantation.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).

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Chest

Original ResearchBronchiolitis Obliterans SyndromeReflux-Induced Collagen Type V Sensitization: Potential Mediator of Bronchiolitis Obliterans Syndrome

Background

Methods

Results

Conclusions

Section snippets

Trans Vivo Delayed-Type Hypersensitivity Assay

Results

Discussion

Acknowledgments

Chest

Ann Thorac Surg

Chest

J Thorac Cardiovasc Surg

Int J Biochem Cell Biol

Am J Transplant

J Heart Lung Transplant

J Heart Lung Transplant

Ann Thorac Surg

Chest

Chest

J Thorac Cardiovasc Surg

Ann Thorac Surg

Chronic rejection—an undefined conundrum

Transplantation

Mechanisms of airway obliteration after lung transplantation

Proc Am Thorac Soc

Severity of lymphocytic bronchiolitis predicts long-term outcome after lung transplantation

Am J Respir Crit Care Med

Graft ischemic time and outcome of lung transplantation: a multicenter analysis

Am J Respir Crit Care Med

Original Research
Bronchiolitis Obliterans Syndrome
Reflux-Induced Collagen Type V Sensitization: Potential Mediator of Bronchiolitis Obliterans Syndrome