The Immunome in Two Inherited Forms of Pulmonary Fibrosis

The immunome (immune cell phenotype, gene expression, and serum cytokines profiling) in pulmonary fibrosis is incompletely defined. Studies focusing on inherited forms of pulmonary fibrosis provide insights into mechanisms of fibrotic lung disease in general. To define the cellular and molecular immunologic phenotype in peripheral blood, high-dimensional flow cytometry and large-scale gene expression of peripheral blood mononuclear cells and serum proteomic multiplex analyses were performed and compared in a cohort with familial pulmonary fibrosis (FPF), an autosomal dominant disorder with incomplete penetrance; Hermansky–Pudlak syndrome pulmonary fibrosis (HPSPF), a rare autosomal recessive disorder; and their unaffected relatives. Our results showed high peripheral blood concentrations of activated central memory helper cells in patients with FPF. Proportions of CD38+ memory CD27− B-cells, IgA+ memory CD27+ B-cells, IgM+ and IgD+ B-cells, and CD39+ T helper cells were increased whereas those of CD39− T helper cells were reduced in patients affected with either familial or HPSPF. Gene expression and serum proteomic analyses revealed enrichment of upregulated genes associated with mitosis and cell cycle control in circulating mononuclear cells as well as altered levels of several analytes, including leptin, cytokines, and growth factors. In conclusion, dysregulation of the extra-pulmonary immunome is a phenotypic feature of FPF or HPSPF. Further studies investigating the blood immunome are indicated to determine the role of immune system dysregulation in the pathogenesis of pulmonary fibrosis. Clinical Trial Registration www.ClinicalTrials.gov, identifiers NCT00968084, NCT01200823, NCT00001456, and NCT00084305.

[1]  A. Dwyer,et al.  Hermansky-Pudlak syndrome: radiography and CT of the chest compared with pulmonary function tests and genetic studies. , 2002, AJR. American journal of roentgenology.

[2]  W. Gahl,et al.  Dysregulation of galectin-3. Implications for Hermansky-Pudlak syndrome pulmonary fibrosis. , 2014, American journal of respiratory cell and molecular biology.

[3]  George C Tseng,et al.  Peripheral Blood Mononuclear Cell Gene Expression Profiles Predict Poor Outcome in Idiopathic Pulmonary Fibrosis , 2013, Science Translational Medicine.

[4]  Shandra L. Protzko,et al.  An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis. An Update of the 2011 Clinical Practice Guideline. , 2015, American journal of respiratory and critical care medicine.

[5]  W. Gahl,et al.  Disorders of lysosome-related organelle biogenesis: clinical and molecular genetics. , 2008, Annual review of genomics and human genetics.

[6]  W. Gahl,et al.  Nonsense Mutations in ADTB3A Cause Complete Deficiency of the β3A Subunit of Adaptor Complex-3 and Severe Hermansky-Pudlak Syndrome Type 2 , 2002, Pediatric Research.

[7]  P L Molyneaux,et al.  Integrierte Analyse von Patienten-Genen und respiratorischem Mikrobiom , 2017, Pneumologie.

[8]  E. Kuehl,et al.  Genetic defects and clinical characteristics of patients with a form of oculocutaneous albinism (Hermansky-Pudlak syndrome). , 1998, The New England journal of medicine.

[9]  Leena Choi,et al.  A novel dyskerin (DKC1) mutation is associated with familial interstitial pneumonia. , 2014, Chest.

[10]  Yuri Kotliarov,et al.  Global Analyses of Human Immune Variation Reveal Baseline Predictors of Postvaccination Responses , 2014, Cell.

[11]  Sandra Romero-Steiner,et al.  Molecular signatures of antibody responses derived from a systems biology study of five human vaccines , 2022 .

[12]  J. Coligan,et al.  Natural killer cell activity and dysfunction in Hermansky‐Pudlak syndrome , 2017, British journal of haematology.

[13]  G. Edelman,et al.  Structure of a new nervous system glycoprotein, Nr-CAM, and its relationship to subgroups of neural cell adhesion molecules , 1991, The Journal of cell biology.

[14]  W. Travis,et al.  Early interstitial lung disease in familial pulmonary fibrosis. , 2007, American journal of respiratory and critical care medicine.

[15]  Athol U. Wells,et al.  Host‐Microbial Interactions in Idiopathic Pulmonary Fibrosis , 2017, American journal of respiratory and critical care medicine.

[16]  W. Gahl,et al.  Natural history of pulmonary fibrosis in two subjects with the same telomerase mutation. , 2011, Chest.

[17]  E. Matteson,et al.  B cell infiltration in systemic sclerosis-associated interstitial lung disease. , 2007, Arthritis and rheumatism.

[18]  Zhen-hua Li.  [The treatment of idiopathic pulmonary fibrosis]. , 2007, Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases.

[19]  F. Sciurba,et al.  Plasma B Lymphocyte Stimulator and B Cell Differentiation in Idiopathic Pulmonary Fibrosis Patients , 2013, The Journal of Immunology.

[20]  W. Travis,et al.  Progressive preclinical interstitial lung disease in rheumatoid arthritis. , 2008, Archives of internal medicine.

[21]  Neil A. Miller,et al.  Exome sequencing reveals a pallidin mutation in a Hermansky-Pudlak-like primary immunodeficiency syndrome. , 2012, Blood.

[22]  P. Lansdorp,et al.  Telomerase mutations in families with idiopathic pulmonary fibrosis. , 2007, The New England journal of medicine.

[23]  Chao Xing,et al.  Adult-onset pulmonary fibrosis caused by mutations in telomerase , 2007, Proceedings of the National Academy of Sciences.

[24]  F. Martinez,et al.  The Clinical Course of Patients with Idiopathic Pulmonary Fibrosis , 2005, Annals of Internal Medicine.

[25]  Jonathan Haines,et al.  Heterozygosity for a surfactant protein C gene mutation associated with usual interstitial pneumonitis and cellular nonspecific interstitial pneumonitis in one kindred. , 2002, American journal of respiratory and critical care medicine.

[26]  W. Gahl,et al.  Hermansky-Pudlak syndrome type 4 (HPS-4): clinical and molecular characteristics , 2001, Human Genetics.

[27]  W. Gahl,et al.  Interstitial Lung Disease and Pulmonary Fibrosis in Hermansky-Pudlak Syndrome Type 2, an Adaptor Protein-3 Complex Disease , 2012, Molecular medicine.

[28]  D. Malide,et al.  Abnormal lymphangiogenesis in idiopathic pulmonary fibrosis with insights into cellular and molecular mechanisms , 2009, Proceedings of the National Academy of Sciences.

[29]  D. Wallace,et al.  Telomere diseases. , 2010, The New England journal of medicine.

[30]  P. Kincade,et al.  Leptin signaling maintains B-cell homeostasis via induction of Bcl-2 and Cyclin D1 , 2010, Proceedings of the National Academy of Sciences.

[31]  N. Grishin,et al.  Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer. , 2009, American journal of human genetics.

[32]  S. Mane,et al.  Exome Sequencing Links Mutations in PARN and RTEL1 with Familial Pulmonary Fibrosis and Telomere Shortening , 2015, Nature Genetics.

[33]  W. Gahl,et al.  Pulmonary function and high-resolution CT findings in patients with an inherited form of pulmonary fibrosis, Hermansky-Pudlak syndrome, due to mutations in HPS-1. , 2000, Chest.

[34]  J. P. McCoy,et al.  High dimensional flow cytometry for comprehensive leukocyte immunophenotyping (CLIP) in translational research. , 2011, Journal of immunological methods.

[35]  Teresa Domaszewska,et al.  tmod: an R package for general and multivariate enrichment analysis , 2016 .

[36]  N. Müller,et al.  High Resolution CT and Pathologic Findings , 2005 .

[37]  V. Sánchez-Margalet,et al.  Human leptin enhances activation and proliferation of human circulating T lymphocytes. , 2000, Cellular immunology.

[38]  M. Munakata,et al.  Pulmonary fibrosis in dyskeratosis congenita with TINF2 gene mutation , 2013, European Respiratory Journal.

[39]  Sudhir Gupta,et al.  Leptin Activates Human B Cells to Secrete TNF-α, IL-6, and IL-10 via JAK2/STAT3 and p38MAPK/ERK1/2 Signaling Pathway , 2011, Journal of Clinical Immunology.

[40]  V. Pinto-Plata,et al.  Mononuclear Phagocytes and Airway Epithelial Cells: Novel Sources of Matrix Metalloproteinase-8 (MMP-8) in Patients with Idiopathic Pulmonary Fibrosis , 2014, PloS one.

[41]  J. P. McCoy,et al.  Studying the human immunome: the complexity of comprehensive leukocyte immunophenotyping. , 2014, Current topics in microbiology and immunology.

[42]  G. Bandara,et al.  Immunophenotypic and Ultrastructural Analysis of Mast Cells in Hermansky-Pudlak Syndrome Type-1: A Possible Connection to Pulmonary Fibrosis , 2016, PLoS ONE.

[43]  K. S. Lee,et al.  Nonspecific interstitial pneumonia with fibrosis: high-resolution CT and pathologic findings. , 1998, AJR. American journal of roentgenology.

[44]  W. Gahl,et al.  Alveolar macrophage dysregulation in Hermansky-Pudlak syndrome type 1. , 2009, American journal of respiratory and critical care medicine.

[45]  S. Rosselot.  Idiopathic pulmonary fibrosis. , 2014, Nursing standard (Royal College of Nursing (Great Britain) : 1987).

[46]  K. Batra,et al.  Telomere-related lung fibrosis is diagnostically heterogeneous but uniformly progressive , 2016, European Respiratory Journal.

[47]  A. Schulz,et al.  Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome. , 2016, Blood.