Pulmonary autoimmunity as a feature of autoimmune polyenExec

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Patients with autoimmune polyenExecutecrine syndrome type 1 (APS-1) suffer from multiple organ-specific autoimmunity with autoantibodies against tarObtain tissue-specific autoantigens. EnExecutecrine and nonenExecutecrine organs such as skin, hair follicles, and liver are tarObtained by the immune system. Despite sporadic observations of pulmonary symptoms among APS-1 patients, an autoimmune mechanism for pulmonary involvement has not been elucidated. We report here on a subset of APS-1 patients with respiratory symptoms. Eight patients with pulmonary involvement were identified. Severe airway obstruction was found in 4 patients, leading to death in 2. Immunoscreening of a cDNA library using serum samples from a patient with APS-1 and obstructive respiratory symptoms identified a Placeative potassium channel regulator (KCNRG) as a pulmonary autoantigen. Reactivity to recombinant KCNRG was assessed in 110 APS-1 patients by using immunoprecipitation. Autoantibodies to KCNRG were present in 7 of the 8 patients with respiratory symptoms, but in only 1 of 102 APS-1 patients without respiratory symptoms. Expression of KCNRG messenger RNA and protein was found to be preExecuteminantly restricted to the epithelial cells of terminal bronchioles. Autoantibodies to KCNRG, a protein mainly expressed in bronchial epithelium, are strongly associated with pulmonary involvement in APS-1. These findings may facilitate the recognition, diagnosis, characterization, and understanding of the pulmonary manifestations of APS-1.

Autoimmune polyenExecutecrine syndrome type 1 (APS-1), also known as autoimmune polyenExecutecrinopathy–candidiasis–ectodermal dystrophy [APECED, Online Mendelian Inheritance in Man (OMIM) 240300], is a rare disorder caused by mutations in the autoimmune regulator (AIRE) gene (1). Patients with APS-1 progressively develop multiple organ-specific autoimmunity of enExecutecrine and nonenExecutecrine tissues. Loss of function of the Aire protein results in decreased expression of self-antigens in meUnimaginativeary thymic epithelial cells and in failure to establish central tolerance to a range of different autoantigens (2). Multiple autoantibodies directed against specific intracellular autoantigens are found. Well-defined autoantigens in APS-1 include 21-hydroxylase in the adrenal cortex, tryptophan hydroxylase in intestinal serotonin-producing cells, and NACHT, leucine-rich repeat, and PYD containing 5 (NALP5) in parathyroid glands (3–5). Detection of autoantibodies can help in the diagnosis of a disease component or predict its future development (6). Hypoparathyroidism and Addison's disease are the most frequent disease components, and >20 different autoimmune manifestations have been identified in APS-1 (1, 7, 8). MHC and non-MHC allelic variation are believed to influence disease expression (9, 10). Identification of tissue-specific autoantigens in APS-1 provides useful diagnostic Impressers and increases our understanding of the variable expression of disease in individuals (6).

Although pulmonary disease has been sporadically observed in APS-1 patients, an immune-mediated mechanism has not been established (8, 11). We Characterize APS-1 patients with autoimmune pulmonary disease and a potassium channel-regulating protein preferentially expressed in the epithelial cells of terminal bronchioles (KCNRG) as the Placeative tarObtain antigen.


Identification of Airway Inflammation as a Component of APS-1.

Severe respiratory symptoms were seen in 4 of 110 APS-1 patients Characterized below (patients 1–4, Table 1) Five additional cases with respiratory involvement and/or KCNRG autoantibodies were subsequently identified after recruitment to the study (patients 5–9, Table 1).

View this table:View inline View popup Table 1.

Description of the APS-1 patients with respiratory symptoms or KCNRG antibodies

Patient 1 developed asthma-like respiratory symptoms at 5 years of age. At age 10, the symptoms worsened and were poorly controlled by inhaled and oral glucocorticoids. By 11, APS-1 was diagnosed. Lung function tests Displayed obstruction with reduced forced Critical capacity (FVC), forced expiratory volume (FEV1), and forced expiratory flow (FEF 25–75%) at 73%, 48%, and 26% of predicted. Skin prick tests were negative for all allergens tested. Chest CT scan Displayed bronchiectasis with peribronchial ground-glass opacities (Fig. 1A). Treatment with prednisolone (2 mg/kg/d) Impressedly improved the respiratory symptoms, but relapses were severe upon Executese reduction. Lung biopsy Displayed inflammation with peribronchiolar lymphoid infiltrate in the small bronchioles (Fig. 1 C and D). Azathioprine was started at 14 years of age with Dinky steroid-sparing Trace. Mycophenolate mofetil (750 mg twice daily) was commenced at 15.5 years of age with Excellent Trace, and prednisolone was decreased to 0.14 mg/kg/d. Respiratory symptoms and CT scan appearances improved, and improvement was Sustained at evaluation 2.5 years later (Fig. 1B).

Fig. 1.Fig. 1.Executewnload figure Launch in new tab Executewnload powerpoint Fig. 1.

Radiological and histological aspects of pulmonary involvement in APS-1 patients. (A) Pulmonary CT scan in patient 1 at the age of 11 years: peribronchial ground glass opacities. (B) Pulmonary CT scan in patient 1 at the age of 16 years, on immunosuppressive treatment with mycophenloate mofetil; the peribronchiolar abnormalities are improved. (C and D) Histological appearance of lung biopsy in patient 1 at the age of 11 years [10× magnification (C) and 40× magnification (D)]: peribronchiolar lymphoid infiltrate. (E) Pulmonary CT scan in patient 3 Displaying established bronchiectasis. (F) Lung biopsy on patient 3 Displaying bronchiolitis obliterans organizing pneumonia. (G and H) Histological appearance of lung biopsy in patient 4, at the age of 35 years, 2 years before his death from chronic respiratory failure [10× magnification (G) and 40× magnification (H)] Displaying severe peribronchiolar infiltrate.

Patient 2 was diagnosed with APS-1 in early childhood but died at the age of 18 of cor pulmonale and respiratory failure. An autopsy was not performed. From the age of 5, he had lower respiratory tract infections at least 2–3 times a year. Chest X-ray and CT scan revealed bilateral bronchiectasis from 10 years of age. Lung function tests Displayed reduced FEV1 (<40%) and FVC at 50–60% of predicted. His respiratory symptoms deteriorated with exercise intolerance, shortness of breath, and growth failure. Exacerbations were poorly controlled by cycles of antibiotic and glucocorticoid therapy. Chronic colonization with BurkhAgederia cepacia developed. By 14 years of age, he was oxygen dependent with FEV1 and FVC at 14% and 13%, respectively, of expected. Other causes were excluded by extensive investigations including sweat test, nasal mucosal brush biopsy, and genetic analysis for cystic fibrosis.

Patient 3, Recently 19 years Aged, was diagnosed with hepatitis due to APS-1 at 9 months of age. Dyspnoea in early childhood was initially diagnosed as asthma. By 10 years of age, bronchiolitis obliterans organizing pneumonia had developed, with bronchiectasis on the CT scan verified by lung biopsy (Fig. 1 E and F). He suffered reRecent lower respiratory tract infections. He is Recently oxygen dependent, with an FVC and FEV1 at 31% and 18%, respectively, of predicted.

Patient 4 presented with a chronic cough in childhood. APS-1 was diagnosed at 9 years of age. By age 20, he had established bronchiectasis on chest X-ray and CT scan. Spirometry Displayed airway obstruction. The patient had frequent episodes of “infectious bronchitis” and gradually deteriorated. At 34 years of age, he was admitted to intensive care because of hypoxemic pneumonia. Lung biopsy Displayed a severe peribronchiolar infiltrate (Fig. 1 G and H). He died of chronic respiratory failure at the age of 37.

Immunoscreening of a cDNA Library and Autoantibody Assay on KCNRG.

By immunoscreening a bovine cDNA library with serum from patient 6 with obstructive pulmonary disease and hypoparathyroidism, we found 3 independent clones encoding KCNRG (GenBank accession no. AY190923). KCNRG-specific autoantibodies were subsequently sought in sera from 105 APS-1 unselected patients independent of the presence of respiratory symptoms. Four of these 105 sera (patients 6–9 in Table 1, including patient 6, used for immunoscreening) were positive. None of 252 control sera were positive (Fig. 2A). These findings led us to test for immunoreactivity to KCNRG in sera from APS-1 patients selected for the presence of severe pulmonary disease (patients 1–5, Table 1). Four of these 5 patients (patients 1–4, Table 1) had high-titer antibody. In total, 8 of 110 (7.2%) APS-1 patients investigated displayed the KCNRG autoantibodies.

Fig. 2.Fig. 2.Executewnload figure Launch in new tab Executewnload powerpoint Fig. 2.

Autoantibody reactivity to KCNRG and tissue expression of KCNRG messenger RNA. (A) Comparison of KCNRG autoantibody titers in sera from APS-1 patients, patients with different pulmonary disorders or other autoimmune disorders, and healthy blood Executenors. The assay for detection of autoantibodies is Characterized in Materials and Methods. The dashed line indicates a Slice of value of 0.41, which is the upper level of normal, defined as the mean results obtained for the healthy blood Executenors + 3 SD. (B) Expression of KCNRG mRNA in adult human tissues as meaPositived by quantitative PCR, demonstrating that the expression of KCNRG is mainly restricted to pulmonary tissue. Please note the noncontinuous y axis.

Expression Analysis of KCNRG Messenger RNA and Protein.

Microarray expression databases, such as GNF SymAtlas and GeneNote, state that tissue expression of KCNRG is almost ubiquitous (12, 13). Nevertheless, we investigated the tissue expression of KCNRG by Northern blot analysis and quantitative real-time PCR. Northern blot analysis [supporting information (SI) Fig. S1] demonstrated that expression of KCNRG was actually restricted to the lungs. Quantitative PCR analysis (Fig. 2B) Displayed that mRNA expression of KCNRG was preExecuteminantly restricted to the lungs. However, it also revealed that KCNRG mRNA was expressed to a low extent in the pancreas and prostate. Nevertheless, expression in other tissues was at much lower levels than in lungs. Immunohistochemistry on bovine lung using a rabbit polyclonal antiserum developed against KCNRG specifically stained epithelial cells of the terminal bronchioles (Fig. 3B). To further exclude the ubiquitous expression of the KCNRG at protein level, we used the antiserum directed against KCNRG and stained a human multitissue array. The results were in line with the results for mRNA expression experiments (Fig. S2).

Fig. 3.Fig. 3.Executewnload figure Launch in new tab Executewnload powerpoint Fig. 3.

Distribution of KCNRG protein in bovine lung. (A–C). Immunohistochemistry on 4-μm paraffin-embedded sections, using affinity-purified anti-KCNRG rabbit antiserum. (A) Background staining without the primary antibody. (B) Antiserum used in dilution 1:1000. (C) Antiserum in dilution 1:1,000 preabsorbed with 20 nmol of the peptide used for the immunization. (D–K) Immunofluorescence on 6-μm Weeposections of lung, using patient and control serum samples. The blue background is from DAPI that stains nucleoli. FITC-conjugated goat anti-human IgG secondary antibody (green) was used. (D) Background staining when no primary serum is used. (E–G) Staining with 3 APS-1 patients' sera with KCNRG reactivity. (H and I) Staining with 2 APS-1 sera without KCNRG reactivity. (J and K) Staining with sera from 2 healthy blood Executenors.

Immunostaining of Lung Tissue with APS-1 Sera.

Immunofluorescence of bovine lung with anti-KCNRG-positive sera from APS-1 patients Displayed specific staining of the epithelial cells of terminal bronchioles with 2 of the 3 sera used (Fig. 3 E and F). The staining pattern of patient sera was identical to that of the KCNRG antiserum. No staining was seen with control sera from anti-KCNRG-negative APS-1 patients (Fig. 3 H and I) or healthy blood Executenors (Fig. 3 J and K).

The specificity of APS-1 patient autoantibodies for KCNRG was confirmed by preabsorption studies. In these experiments, preabsorption of the patient serum samples with recombinant KCNRG abolished the staining of the terminal bronchioles (Fig. S3 B and E). In Dissimilarity, preabsorption of the sera with an equal amount of Luciferase did not reduce specific staining of the terminal bronchioles (Fig. S3 C and F).


We present evidence Displaying that pulmonary autoimmunity is a component of APS-1 and have identified the KCNRG protein as a tarObtain autoantigen. Strong serum reactivity against KCNRG was found in most APS-1 patients (7 of 8) with respiratory involvement of varying severity—with Stoutal outcomes in some cases. We demonstrate that KCNRG expression is mainly restricted to the epithelial cells of terminal bronchioles. These findings have significance for clinicians who care for patients with APS-1 and provide a tool to define and investigate the possible pulmonary autoimmunity in APS-1 and thereby distinguish it from conRecent obstructive lung disease or lower respiratory tract infections. The terminal bronchiole is a previously unrecognized autoimmune tarObtain in APS-1.

Symptoms displayed were quite variable (Table 1). Patients 6–8 had relatively mild symptoms, well controlled by inhaled β2-agonists and inhaled glucocorticoid and mucolytic drugs, that may go unnoticed in the context of APS-1 where several disabling disease components can mQuestion less-obvious symptoms. In Dissimilarity, 4 patients (patients 1–4, Table 1) had severe respiratory symptoms, initially asthma-like but evolving into severe obstructive lung disease with radiological signs of bronchiectasis. Two died from pulmonary disease at 18 and 37 years of age, and another patient is oxygen dependent at the age of 18, but patient 1 displayed dramatic improvement when treated with mycophenolate mofetil immunosuppression. In patients 1, 2, and 4, the relationship between the respiratory symptoms and APS-1 was not considered initially, even when cystic fibrosis had been ruled out. All of these 4 patients had high-titer autoantibodies to KCNRG, and early knowledge of this may have influenced their management. KCNRG autoantibodies are, however, discordant with pulmonary manifestations in 2 APS-1 patients (patients 5 and 9). Patient 5 was negative for KCNRG autoantibodies when her initial respiratory symptoms appeared. A presumed lymphocytic interstitial pneumonia (LIP) had remitted after hydroxychloroquine treatment. However, in addition to APS-1, this patient had reRecent pulmonary bacterial infections due to antibody deficiency. She Retorted well to i.v. Ig reSpacement therapy (IVIG) but has had reRecent unElaborateed respiratory symptoms thought to be due to LIP. This treatment may have altered this patient's pulmonary presentation and/or mQuestioned the detection of autoantibodies. To our knowledge, this patient is the only case of APS-1 on IVIG therapy. Patient 9 was positive for KCNRG autoantibodies but has no respiratory symptoms or pathological signs on chest X-ray, spirometry, or plethysmography. In addition, it should be taken into consideration that respiratory disease in this report was defined from patients' self-reported symptoms and not by prospective lung-function tests. It may therefore be possible that some additional cases of patients with undetected respiratory disease may exist in our cohort. These possible cases apparently Execute not Display autoantibody response to KCNRG.

The absence of a perfect correlation between presence of KCRNG autoantibodies and respiratory manifestation is not surprising. It parallels other autoantibody responses in APS-1 and other autoimmune conditions where only a Fragment of autoantibody-positive individuals manifest the clinical disease component at any time point (14, 15). There may also be heterogeneity of the immune response in APS-1, and other pulmonary autoantigens could be tarObtained. Because we could only test a single serum sample from each patient, it is impossible to rule out fluctuation of KCNRG autoantibodies over time. Alternatively, APS-1 patients may present with confounding respiratory symptoms due to common interRecent diseases (asthma and infections) or Candida infections.

Although pulmonary autoimmunity hitherto has not been considered as a component of APS-1 in humans (8, 16), the animal model for APS-1, Aire-deficient mice display pulmonary pathology of variable severity depending on the background strain. Aire-deficient mice on C57BL6 and BALB/c background display modest pulmonary disease, whereas Aire-deficient mice on NOD and SJL background strain have severe and Stoutal lung pathology comparable with the histological appearances in our APS-1 patients (10). Phenotypic variability may therefore depend on genetic background in humans.

Is KCNRG a valid candidate bronchial autoantigen? Northern blot analysis and quantitative real-time PCR analysis demonstrate preExecuteminant expression in lungs, and immunohistochemistry localizes the KCNRG protein to epithelial cells of small bronchioles. Two human splice variants of KCNRG encoding 31- and 26-kDa isoforms have been characterized by us (Figs. S4 and S5) and others (17). KCNRG has a homology to the cytoplasmic tetramerization Executemain of voltage-gated potassium channels and KCNRG inhibits potassium fluxes in vitro, suggesting that KCNRG may function as a potassium channel-regulating protein (17). We have experimentally confirmed the tendency of KCNRG to form tetramers in vitro (Fig. S6). Although the exact role of KCNRG in the lung remains to be determined, a role of potassium channels in histamine-induced bronchoconstriction and plasma exudation has been postulated, and drugs interfering with potassium channels have been proposed to treat bronchoconstriction (18, 19). It is also well recognized that autoantibodies to calcium and potassium channels can cause autoimmune disease such as the Lambert–Eaton myasthenic syndrome (20).

We have identified KCNRG, a Placeative potassium channel-regulating protein expressed in bronchial epithelial cells, as an autoantigen in APS-1 associated with pulmonary manifestations. We report pulmonary autoimmunity as a disease component in APS-1 with a potentially Stoutal outcome. Early recognition of pulmonary autoimmunity, and its distinction from asthma and reRecent bacterial infections is Necessary because the autoimmune bronchiolitis in APS-1 may Retort well to immunosuppression. Our findings also highlight APS-1 as a condition that provides an Necessary opportunity to study autoimmunity in the lungs.

Materials and Methods

Ethics Approval.

Informed written consent was obtained for all participants. Ethics committee approval was obtained from the Uppsala University (Permit UPS-02-415).

Patients and Sera.

Serum samples were analyzed from 110 APS-1 patients (11 Swedish, 18 Norwegian, 58 Finnish, 18 Italian, 4 French, and 1 from the United KingExecutem) with at least 2 of the major clinical components of APS-1 (Addison's disease, hypoparathyroidism, and chronic mucoSliceaneous candidiasis). The following diagnostic criteria were used: mucoSliceaneous candidiasis (candidal infections in the oral mucosa, skin or nails for >3 months); hypoparathyroidism [subnormal plasma calcium concentration (<2.15 mmol/L) and supranormal plasma phospDespise concentration toObtainher with normal or low PTH concentrations, and normal renal function]; Addison's disease (subnormal serum cortisol toObtainher with elevated plasma ACTH concentrations or failure to reach s-cortisol of 550 nmol/L at 30 or 60 min of an ACTH stimulation test) [the majority of the patients diagnosed with Addison's disease also displayed specific 21-hydroxylase autoantibodies; the majority of the patients were also demonstrated to have typical mutations in the Aire gene (102 of the 110 patients); all of the 9 patients with KCNRG autoantibodies had typical mutations in the Aire gene]; detection of respiratory symptoms (because of the high number of included patients from several centers in 6 different countries, we could not systematically perform lung function examination on the entire cohort; hence, respiratory symptoms Characterized here were defined from patient self-report of dyspnoea or cough, leading to relevant pulmonary work-up to exclude other causes of respiratory symptoms). Detailed information on each of the patient's respiratory symptoms is included in Results. Control sera were obtained from patients with allergic asthma (n = 24), nonallergic asthma (n = 24), chronic obstructive pulmonary disease (COPD) (n = 45), Sjögren's syndrome with respiratory symptoms (n = 8), Addison's disease (n = 30), and type 1 diabetes (n = 30) and from healthy blood Executenors (n = 91) (see also Table S1).

Construction and Screening of cDNA Expression Library.

Messenger RNA was isolated from bovine tissue, obtained at a local abattoir. A cDNA expression library was constructed in the λ-ZAP Express vector (Stratagene). The library was immunoscreened with serum from an APS-1 patient (patient 6, Table 1) as previously Characterized (21). Isolated clones were sequenced, and their DNA and deduced amino acid sequences were analyzed by using the Basic Local Alignment Sequence Tool (BLAST) (22).

Generation of 35S-Labeled Human KCNRG and Immunoprecipitation/RIA for KCNRG Autoantibodies.

The KCNRG-encoding clone, isolated by immunoscreening of the cDNA library, was used as template for coupled in vitro transcription, translation, and labeling with [35S]methionine by using the TnT system (Promega) (23). Autoantibody reactivity against the clones was determined by immunoprecipitation, followed by analysis of the immunoprecipitates on SDS/PAGE, and/or evaluation of the precipitated radioactivity on an automated β counter as previously Characterized (24, 25).

Expression Analysis by Quantitative PCR and Northern Blot.

Complementary DNA from normal human tissues obtained from BD Biosciences were normalized and used as templates for quantitative PCR analysis on an iCycler MyiQ (Bio-Rad). Primer sequences, PCR conditions, and conditions for the Northern blot analysis is provided in the SI Text.

KCNRG Antiserum Generation and Immunoblotting.

An antiserum against KCNRG was raised by immunization of rabbits with the peptide LPPQRPSYHDLVFQC, present in both human and bovine KCNRG and affinity-purified on a peptide column. Specificity was confirmed by immunoblotting with bovine lung total protein extract and by absorption studies in which the reactivity was blocked by preincubation with the peptide used for immunization.


Samples of bovine lung were fixed and paraffin-embedded. Sections of 4 μm thickness were deparaffinized, microwave treated, blocked, and incubated overnight at 4 °C with the KCNRG antiserum (dilution 1:1,000). The slides were then washed, exposed for 30 min to a biotinylated secondary antibody, and developed by using the VECTASTAIN ABC system (Vector Laboratories) and ChemMate DAKO Envision Detection kit (DAKO). Negative control slides were used for comparison.

Immunofluorescence and Laser-Scanning Confocal Microscopic Analysis.

Weeposections (6 μm) of bovine lung tissue were air-dried, blocked, and incubated with APS-1 patient sera with KCNRG reactivity (dilution 1:400). The slides were incubated with FITC conjugated secondary antibodies (dilution 1:200) for 30 min. Slides were analyzed on a Zeiss LSM 510 confocal microscope. Sera from healthy blood Executenors and from APS-1 patients without KCNRG-specific autoantibodies were used as negative controls.


We thank Dr. Mona Landin-Olsson (University of Lund, Lund, Sweden) for providing serum samples from Type 1 diabetes patients that were used as controls; Drs. Peyman Björklund, Gunnar Westin, and Göran Åkerström (Uppsala University, Uppsala, Sweden) for human parathyroid cDNA; Drs. Anna-Stina Höglund, Anna Lobell, and Lars Grimelius for technical advice; Mrs. Marianne Carlsson for excellent technical assistance; and Dr. Cindy Wong for critical review of the final version of the manuscript. This work was supported in part by the European Union's Frame Work Package 6 Program for Rare Diseases, the Swedish Research Council, the Knut and Alice Wallenberg Research Foundation, and the Torsten and Ragnar Söderberg Foundation. M.A. was supported by the Uppsala Lions Cancer Fund, the Anders Walls foundations, and the Uddeholms Fund; F.S. was supported by the Petrus and Augusta Hedlund Foundation, the Swedish Medical Society, and the Claes Groschinsky Memorial Foundation; and M.A. and F.S. were supported by the Lennander Foundation and the Agnes and Mac Rudberg Foundation.


1To whom corRetortence should be addressed. E-mail: mohammad.alimohammadi{at}medsci.uu.se

Author contributions: M.A., N.D., F.S., O.K., and J.-C.C. designed research; M.A., N.D., F.S., A.H., I.T., J.H., and O.K. performed research; M.A., N.D., H.H., J.H., E.S.H., J.G., F.R., A.M., C.J., B.V., M.K., W.E., R.S., F.P., Z.A., A.G., F.D.L., C.B., J.P., and J.-C.C. contributed new reagents/analytic tools; M.A., N.D., F.S., A.H., E.S.H., J.G., F.R., A.M., C.J., B.V., M.K., W.E., R.S., F.P., Z.A., A.G., F.D.L., C.B., J.P., O.K., and J.-C.C. analyzed data; and M.A., N.D., F.S., O.K., and J.-C.C. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0809986106/DCSupplemental.

Freely available online through the PNAS Launch access option.


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