Autoimmunity in Idiopathic Pulmonary Fibrosis - ATS Journals

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Are Circulating Autoantibodies Pathogenic or Epiphenomena? The role of ... cific antinuclear antibody (ANA) staining pattern by immu- nofluorescence on Hep-2 ...
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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE

influenza, where the severity of illness could be greater. With bacterial pathogens such as Haemophilus influenzae and Pseudomonas aeruginosa, airway inflammation is more intense and potentially damaging, and chronic infections can develop, as can complications such as pneumonia and bacteremia. Mallia and colleagues have performed a novel and unique study that, in spite of its limitations, will provide insight in to the mechanisms of exacerbations of COPD and responses to treatment, and enhance our understanding and lead to better therapy of these episodes. Author Disclosure: S.S. has received sponsored grants from the National Institutes of Health and the Veterans’ Administration (each over $100,000). W.M. has received consultancy fees from Pfizer ($1,001–$5,000). He has received advisory board fees from GSK and Pfizer (each $1,001–$5,000). He has received lecture fees from GSK ($5,001–$10,000) and AZ ($5,001–$10,000). He has received industry-sponsored grants from GSK and Pfizer (each over $100,000).

Sanjay Sethi, M.D. Department of Medicine University at Buffalo, SUNY Buffalo, New York and VA WNY Healthcare system Buffalo, New York William MacNee, M.B.Ch.B., M.D. MRC/UoE Centre for Inflammation Research Queen’s Medical Research Institute Edinburgh, Scotland, United Kingdom

VOL 183

2011

References 1. Sethi S, Murphy TF. Infection in the pathogenesis and course of chronic obstructive pulmonary disease. N Engl J Med 2008;359:2355–2365. 2. Drost EM, Skwarski KM, Sauleda J, Soler N, Roca J, Agusti A, MacNee W. Oxidative stress and airway inflammation in severe exacerbations of COPD. Thorax 2005;60:293–300. 3. Papi A, Bellettato CM, Braccioni F, Romagnoli M, Casolari P, Caramori G, Fabbri LM, Johnston SL. Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations. Am J Respir Crit Care Med 2006;173:1114–1121. 4. Sethi S, Wrona C, Eschberger K, Lobbins P, Cai X, Murphy TF. Inflammatory profile of new bacterial strain exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008;177: 491–497. 5. Gaschler GJ, Skrtic M, Zavitz CC, Lindahl M, Onnervik PO, Murphy TF, Sethi S, Stampfli MR. Bacteria challenge in smoke-exposed mice exacerbates inflammation and skews the inflammatory profile. Am J Respir Crit Care Med 2009;179:666–675. 6. Mallia P, Message SD, Gielen V, Contoli M, Gray K, Kebadze T, Aniscenko J, Laza-Stanca V, Edwards MR, Slater L, et al. Experimental rhinovirus infection as a human model of chronic obstructive pulmonary disease exacerbation. Am J Respir Crit Care Med 2011;183:734–742. 7. Saetta M, Di Stefano A, Maestrelli JP, Turato G, Ruggieri MP, Roggeri A, Calcagni PG, Mapp CE, Ciaccia A, Fabbri LM. Airway eiosinophilia in chronic bronchitis during exacerbations. Am J Respir Crit Care Med 1994;150:1646–1652. 8. Cohen S, Tyrrell DA, Russell MA, Jarvis MJ, Smith AP. Smoking, alcohol consumption, and susceptibility to the common cold. Am J Public Health 1993;83:1277–1283.

DOI: 10.1164/rccm.201009-1498ED

Autoimmunity in Idiopathic Pulmonary Fibrosis Are Circulating Autoantibodies Pathogenic or Epiphenomena? The role of autoimmunity in the pathogenesis of idiopathic pulmonary fibrosis (IPF) has been the subject of active discussions and investigations. Circulating antibodies to self antigens have been reported by several groups, without any definitive evidence of causality (1–8). In fact, very early studies attempting to examine IPF pathogenesis reported the presence of circulating immune complexes (9). In this issue of the Journal (pp. 759–766), Taille´ and coworkers elegantly demonstrate the presence of autoantibodies to another self antigen, periplakin, in 40% of patients with IPF, and show that these antibodies correlate with disease severity but not survival (10). Furthermore, the authors demonstrate using recombinant periplakin the specificity of these autoantibodies. They extend their findings to detecting the presence of these autoantibodies in bronchoalveolar lavage of patients with IPF. They further localize periplakin to bronchial and alveolar epithelial cells with a clear difference in intracellular compartmentalization in normal and IPF lung tissues. Periplakin is an intracellular component of adhesion junctions that mediates keratin organization and epithelial cell migration. It is cleaved by caspase 6 during apoptosis (11). Although not investigated in the article by Taille´ and colleagues, it is plausible that caspase-mediated cleavage of periplakin during epithelial cell apoptosis can result in the The authors are supported by NIH RO1 AR050840 and RO1 HL096845.

unmasking of a novel epitope in patients with IPF, thus triggering the initiation of an immune response. In fact, similarly to the findings of Taille´ and colleagues, IgG and IgA antibodies to periplakin are detected in patients with paraneoplastic pemphigus and severe alveolitis (12). The authors also detected antiperiplakin antibodies in one of two (50%) patients with dermatomyositis and interstitial lung disease (ILD). Recently, antibodies against an autoantigen of molecular weight similar to that of periplakin were described in patients with necrotizing myopathy (13). HeLa cells were used as an antigen source for the immunoprecipitation assay in the latter study, whereas A549 cells were used for the detection of antiperiplakin antibodies in patients with IPF. Thus the antigen source may generate variability in the detection of antibodies against self antigens. To rule out the presence of antiperiplakin antibodies in connective tissue disease (CTD)-associated ILD, different cell sources and a larger number of patients with CTD should have been included. The rationale for increasing the number of CTD patients is that these patients can have different autoantibodies depending on their disease subtype. As an example, nine SSc-associated autoantibodies that are mostly mutually exclusive have been described in patients with SSc. Each of these antibodies associates with specific internal organ involvement (14). Thus, the presence of antiperiplakin antibodies in CTD patients may have been missed due to the small number of patients representative of each disease.

Editorials

Autoantibodies associated with the presence of interstitial lung involvement in connective tissue diseases have been extensively reported and include anti-tRNA synthetases in myositis-associated ILD (15), anti-Scl70 (topoisomerase I), anti-U1 RNP, anti-U11/U12 RNP, and anti-Th/To in systemic sclerosis-associated ILD (14). Some of these result in a specific antinuclear antibody (ANA) staining pattern by immunofluorescence on Hep-2 substrate, while others are reported as ANA negative since the corresponding proteins localize to the cytoplasm. It is not surprising that Taille´ and coworkers did not detect the presence of antinuclear antibodies (ANA) in the sera of their patients. Proteins such as periplakin are found in the cytoplasmic compartment in close proximity to the plasma membrane, rather than in the nucleus. Thus the pattern on immunofluorescence is likely to be anticytoplasmic rather than antinuclear, and such a pattern is not reported by clinical laboratories. This is also consistent with the authors’ immunofluorescence data showing that periplakin is localized to the cytoplasm and apex of alveolar epithelial cells. Similarly to other groups, the authors detected multiple antigenic targets following immunoblotting of A549 cellular lysates. The significance of antibodies recognizing multiple autoantigens is not known. In the case of antigens exhibiting homology, a role for epitope spreading can be postulated. Alternatively, modification of the antigens through cleavage or post-translational modifications may result in new epitopes that exhibit molecular mimicry and/or result in crossreactivity. Since T cells provide help for B cells to produce antibodies, the data in the current study are consistent with a previous report of autoantigen-induced T cell proliferation in IPF (1). Under normal conditions, regulatory T cells (Tregs) have key roles in suppressing T cell–mediated autoreactivity. A recent study from Kotsianidis and colleagues reporting defective Treg function in IPF could help to explain the mechanism leading to IPF-associated autoimmunity (15). Although the role of Tregs in suppressing autoantibody production remains unclear, impaired Treg function could also help to explain the presence of anti–type V collagen reactive T cells and antibodies in IPF (16). Clinically, the identification of immunodominant antigens could suggest their role as potential immunotherapeutics to treat this devastating disease (17). In summary, whether autoantibodies in patients with ILD are disease triggers, contribute to disease pathogenesis, or are simply epiphenomena and disease or prognostic biomarkers remains to be determined. Identification of novel circulating autoantibodies to self antigens in IPF and other lung diseases significantly impacts our understanding of ILD and clearly implicates the immune system in disease development and/or perpetuation. Author Disclosure: C.A.F.-B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. D.S.W. has received consultancy fees, industry-sponsored grants, and patents from ImmuneWorks. He holds stock in ImmuneWorks.

Carol A. Feghali-Bostwick, Ph.D. Division of Pulmonary, Allergy, and Critical Care Medicine University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania David S. Wilkes, M.D. Center for Immunobiology Indiana University School of Medicine Indianapolis, Indiana

693 References 1. Feghali-Bostwick CA, Tsai CG, Valentine VG, Kantrow S, Stoner MW, Pilewski JM, Gadgil A, George MP, Gibson KF, Choi AM, et al. Cellular and humoral autoreactivity in idiopathic pulmonary fibrosis. J Immunol 2007;179:2592–2599. 2. Wallace WA, Roberts SN, Caldwell H, Thornton E, Greening AP, Lamb D, Howie SE. Circulating antibodies to lung protein(s) in patients with cryptogenic fibrosing alveolitis. Thorax 1994;49: 218–224. 3. Wallace WA, Schofield JA, Lamb D, Howie SE. Localisation of a pulmonary autoantigen in cryptogenic fibrosing alveolitis. Thorax 1994;49:1139–1145. 4. Yang Y, Fujita J, Bandoh S, Ohtsuki Y, Yamadori I, Yoshinouchi T, Ishida T. Detection of antivimentin antibody in sera of patients with idiopathic pulmonary fibrosis and non-specific interstitial pneumonia. Clin Exp Immunol 2002;128:169–174. 5. Dobashi N, Fujita J, Ohtsuki Y, Yamadori I, Yoshinouchi T, Kamei T, Tokuda M, Hojo S, Okada H, Takahara J. Detection of anticytokerain 8 antibody in the serum of patients with cryptogenic fibrosing alveolitis and pulmonary fibrosis associated with collagen vascular disorders. Thorax 1998;53:969–974. 6. Fujita J, Dobashi N, Ohtsuki Y, Yamadori I, Yoshinouchi T, Kamei T, Tokuda M, Hojo S, Okada H, Takahara J. Elevation of anticytokeratin 19 antibody in sera of the patients with idiopathic pulmonary fibrosis and pulmonary fibrosis associated with collagen vascular disorders. Lung 1999;177:311:319. 7. Kurosu K, Takiguchi Y, Okada O, Yumoto N, Sakao S, Tada Y, Kasahara Y, Tanabe N, Tatsumi K, Weiden M, et al. Identification of annexin 1 as a novel autoantigen in acute exacerbation of idiopathic pulmonary fibrosis. J Immunol 2008;181:756–767. 8. Nakos G, Adams A, Andriopoulos N. Antibodies to collagen in patients with idiopathic pulmonary fibrosis. Chest 1993;103:1051–1058. 9. Nagaya H, Elmore M, Ford CD. Idiopathic interstitial pulmonary fibrosis: an immune complex disease? Am Rev Respir Dis 1973;107: 826–830. 10. Taille´ C, Grootenboer-Mignot S, Boursier C, Michel L, Debray M-P, Fagart J, Barrientos L, Mailleux A, Cigna N, Tubach F, et al. Identification of Periplakin as a New Target for Autoreactivity in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 2011;183: 759–766. 11. Aho S. Plakin proteins are coordinately cleaved during apoptosis but preferentially through the action of different caspases. Exp Dermatol 2004;13:700–707. 12. Preisz K, Horvath A, Sardy M, Somlai B, Harsing J, Amagai M, Hashimoto T, Nagata Y, Fekete S, Karpati S. Exacerbation of paraneoplastic pemphigus by cyclophosphamide treatment: detection of novel autoantigens and bronchial autoantibodies. Br J Dermatol 2004;150:1018–1024. 13. Christopher-Stine L, Casciola-Rosen LA, Hong G, Chung T, Corse AM, Mammen AL. A novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing myopathy. Arthritis Rheum 2010;62:2757–2766. 14. Fertig N, Domsic RT, Rodriguez-Reyna T, Kuwana M, Lucas M, Medsger TA Jr, Feghali-Bostwick CA. Anti-U11/U12 RNP antibodies in systemic sclerosis: a new serologic marker associated with pulmonary fibrosis. Arthritis Rheum 2009;61:958–965. 15. Labirua A, Lundberg IE. Interstitial lung disease and idiopathic inflammatory myopathies: progress and pitfalls. Curr Opin Rheumatol 2010;22:633–638. 16. Kotsianidis I, Nakou E, Bouchliou I, Tzouvelekis A, Spanoudakis E, Steiropoulos P, Sotiriou I, Aidinis V, Margaritis D, Tsatalas C, et al. Global impairment of CD41CD251FOXP31 regulatory T cells in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2009;179: 1121–1130. 17. Bobadilla JL, Love RB, Jankowska-Gan E, Xu Q, Haynes LD, Braun RK, Hayney MS, Munoz dl Rio A, Meyer K, Greenspan DS, et al. Th-17, monokines, collagen type V, and primary graft dysfunction in lung transplantation. Am J Respir Crit Care Med 2008;177:660– 668. 18. Braun RK, Martin A, Shah S, Iwashima M, Medina M, Byrne K, Sethupathi P, Wigfield CH, Brand DD, Love RB. Inhibition of bleomycin-induced pulmonary fibrosis through pre-treatment with collagen type V. J Heart Lung Transplant 2010;29:873–880.

DOI: 10.1164/rccm.201010-1727ED