The Role of Immune and Inflammatory Cells in Idiopathic Pulmonary Fibrosis
Open accessAbstract
The contribution of the immune system to Idiopathic Pulmonary Fibrosis (IPF) remains poorly understood. While most sources agree that IPF does not result from a primary immunopathogenic mechanism, evidence gleaned from animal modeling and human studies suggests that innate and adaptive immune processes can orchestrate existing fibrotic responses. This review will synthesize the available data regarding the complex role of professional immune cells in IPF. The role of innate immune populations such as monocytes, macrophages, myeloid suppressor cells, and innate lymphoid cells will be discussed, as will the activation of these cells via pathogen associated molecular patterns derived from invading or commensural microbes, and danger associated molecular patterns derived from injured cells and tissues. The contribution of adaptive immune responses driven by T-helper cells and B cells will be reviewed as well. Each form of immune activation will be discussed in the context of its relationship to environmental and genetic factors, disease outcomes, and potential therapies. We conclude with discussion of unanswered questions and opportunities for future study in this area.
AI snapshot
Written from the paper’s full text.
TL;DR
This review argues that idiopathic pulmonary fibrosis (IPF) is not primarily an immunopathogenic disease, but that innate and adaptive immune cells can permit, promote, or suppress fibroblast-driven fibroproliferation. It synthesizes human and animal evidence on macrophages, neutrophils, fibrocytes, MDSCs, ILCs, T cells, and B cells, and highlights unresolved questions for future therapy.
Key findings
- IPF has mortality approaching 50% within 3–5 years after diagnosis, and classical immunosuppression—interferon gamma, TNFα neutralization, and low-dose prednisone/azathioprine—has failed or worsened outcomes, suggesting IPF is not a direct immune-cell dysfunction disease.
- Macrophages are central modulators: M1 macrophages are linked to epithelial death and acute exacerbation, while M2 macrophages promote dysregulated repair; macrophage-derived TGFβ1, efferocytosis, MMPs/TIMPs, and soluble mediators regulate fibroblast accumulation and ECM remodeling.
- Innate immune activation via PAMPs and DAMPs is implicated: viral and bacterial signals, TLR3 L412F polymorphism, TLR4 ligands, NALP3 inflammasome, uric acid, free ATP, and mitochondrial DNA are associated with IPF or experimental fibrosis.
- Adaptive immunity shows outcome-predictive abnormalities: reduced T-cell CTLA-4/CD28 signatures predict poor survival, Th2/Th17 cytokines are pro-fibrotic, Tregs can be harmful or protective depending on stage, and B-cell/autoantibody findings remain largely speculative.
Methods
- Narrative review synthesizing available data from animal modeling and human studies on professional immune cells in IPF.
- Discusses innate populations (monocytes, macrophages, MDSCs, ILCs), PAMP/DAMP activation, adaptive responses (T-helper cells, B cells), and therapeutic implications.
- No primary data collection or systematic review methodology is reported.
Limitations
- The paper does not state a formal limitations section; it acknowledges unanswered questions, including whether mouse models reflect human IPF, whether peripheral blood reflects lung events, and whether immune abnormalities represent immunosenescence.
- Evident from the text: many conclusions rely on animal models, and several immune cell roles—especially neutrophils, fibrocytes, MDSCs, ILCs, Tregs, and B cells—are described as unclear, controversial, speculative, or in need of further study.
- Evident from the text: this is a narrative review without stated systematic search, inclusion criteria, or quality assessment.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
0 of 69 cited sources checked · 0 supported · 0 flagged
- Premisecitation
An excess of M2 macrophages leads to aberrant and dysregulated repair responses that characterize progressive fibrosis.
“an excess of M2 macrophages leads to the aberrant and dysregulated repair responses that characterize progressive fibrosis (21)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [21] Zhou, 2014, Chitinase 3-like 1 suppresses injury and promotes fibroproliferative responses in Mammalian lung fibrosis, Sci Transl Med source
Not checked in the free run.
- Interpretationnone given
Immune and inflammatory cells can permit, promote, or suppress fibroproliferation driven by native lung fibroblasts.
“immune and inflammatory cells can permit, promote, or suppress fibroproliferation driven by native lung fibroblasts”
Quote in the paperSubstantial claim - Interpretationreasoning
IPF does not appear to be a direct result of immune cell dysfunction.
“IPF does not appear to be a direct result of immune cell dysfunction”
Quote in the paperSubstantial claim - Premisecitation
A relative excess of M1 macrophages leads to epithelial cell death and failure of repair such as that seen in acute exacerbation of IPF.
“a relative excess of M1 macrophages leads to epithelial cell death and failure of repair such as that seen in acute exacerbation of IPF (AE-IPF)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [21] Zhou, 2014, Chitinase 3-like 1 suppresses injury and promotes fibroproliferative responses in Mammalian lung fibrosis, Sci Transl Med source
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- Premisecitation
Myeloid-derived suppressor cells suppress T-cell activity.
“MDSCs play a role in the immune system through their suppressive action on T cells (116).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [116] Gabrilovich, 2009, Myeloid-derived suppressor cells as regulators of the immune system, Nat Rev Immunol source
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- Premisecitation
M2 macrophages promote fibroproliferation and uncontrolled repair.
“M1 macrophages suppress, and M2 macrophages promote, fibroproliferation and uncontrolled repair (17).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [17] Wynn, 2016, Macrophages in tissue repair, regeneration, and fibrosis, Immunity source
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- Premisecitation
In bleomycin-induced mice, preventing MDSC recruitment via CXCR2 neutralization normalized pulmonary pressure.
“preventing their recruitment via neutralization of CXCR2 normalized the pulmonary pressure (119).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [119] Bryant, 2017, Myeloid-derived suppressor cells are necessary for development of pulmonary hypertension, Am J Respir Cell Mol Biol source
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- Premisecitation
Alveolar macrophages obtained from patients with IPF stimulate fibroblast accumulation via a paracrine mechanism involving production of soluble mediators typically associated with alternative activation.
“alveolar macrophages obtained from patients with IPF were shown to stimulate fibroblast accumulation via a paracrine mechanism involving the production of soluble mediators typically associated with alternative activation (18)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [18] Bitterman, 1986, Modulation of alveolar macrophage-driven fibroblast proliferation by alternative macrophage mediators, J Clin Invest source
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- Premisecitation
M1 macrophages suppress fibroproliferation and uncontrolled repair.
“M1 macrophages suppress, and M2 macrophages promote, fibroproliferation and uncontrolled repair (17).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [17] Wynn, 2016, Macrophages in tissue repair, regeneration, and fibrosis, Immunity source
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- Premisecitation
In bleomycin-induced mice, MDSCs triggered vascular remodeling and pulmonary hypertension.
“Another experiment with bleomycin-induced mice showed that MDSCs triggered vascular remodeling and pulmonary hypertension”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [119] Bryant, 2017, Myeloid-derived suppressor cells are necessary for development of pulmonary hypertension, Am J Respir Cell Mol Biol source
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- Premisecitation
A relationship between total bacterial load and poor prognosis was observed in a study in which enriched detection of Haemophilus, Streptococcus, Neisseria and Veillonella was found in BAL fluid of IPF patients.
“a relationship between total bacterial load and poor prognosis was observed in a study in which enriched detection of organisms, such as Haemophilus, Streptococcus, Neisseria and Veillonella, was found in BAL fluid of IPF patients (59)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [59] Molyneaux, 2014, The role of bacteria in the pathogenesis and progression of idiopathic pulmonary fibrosis, Am J Respir Crit Care Med source
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- Premisecitation
Epstein-Barr virus is enriched in bronchoalveolar lavage fluid and lung biopsy tissue of IPF patients when compared with healthy controls.
“Epstein–Barr virus (EBV, a member of the Herpes family) is enriched in bronchoalveolar lavage (BAL) fluid and lung biopsy tissue of IPF patients when compared with healthy controls (52, 53)”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [52] Tang, 2001, Increased detection of herpesvirus DNA in idiopathic pulmonary fibrosis, Chest source
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- cites [53] Manika, 2007, Epstein-Barr virus DNA in bronchoalveolar lavage fluid from patients with idiopathic pulmonary fibrosis, Sarcoidosis Vasc Diffuse Lung Dis
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- Premisecitation
Elevated concentrations of peripheral blood MDSCs, defined by HLA-DR, CD33, CD11b, CD14, and CD66b, reflect poor lung function in patients with IPF.
“one recent study found that elevated concentrations of peripheral blood MDSCs, defined by the surface markers HLA-DR, CD33, CD11b, CD14, and CD66b, reflect poor lung function in patients with IPF (118).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [118] Fernandez, 2016, Peripheral blood myeloid-derived suppressor cells reflect disease status in idiopathic pulmonary fibrosis, Eur Respir J source
Not checked in the free run.
- Rests on an assumption: Myeloid-derived suppressor cells are associated with diseases characterized by fibrosis and pathologic remodeling.
- Premisecitation
Innate lymphoid cells in the lung interact with epithelial cells, natural killer T cells, and myeloid cells to form an immune system network.
“ILCs in the lung interact with epithelial cells, natural killer T cells, and myeloid cells to form an immune system network (122).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [122] Lai, 2016, The origin and role of innate lymphoid cells in the lung, Mil Med Res source
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- Interpretationreasoning
Targeting the alternative activation state or specific function of macrophages, rather than the M1 phenotype or broadly active aspect such as recruitment, is more likely to be of benefit in a complex disease such as IPF.
“targeting the alternative activation state or specific function of macrophages, rather than the M1 phenotype or broadly active aspect such as recruitment, is more likely to be of benefit in a complex disease such as IPF”
Quote in the paperSubstantial claim - Interpretationnone given
Both arms of the immune system appear to be activated in IPF.
“Both arms of the immune system appear to be activated in IPF.”
Quote in the paperNot a substantial claim - Premisecitation
In silica-induced lung fibrosis, neutralization of IL-17A delayed T-cell-driven immune responses and slowed progression of lung inflammation and fibrosis.
“in silica-induced lung fibrosis, neutralization of IL-17A delayed T-cell-driven immune responses and consequently slowed the progression of lung inflammation and fibrosis (148).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [148] Chen, 2014, Neutralization of interleukin-17A delays progression of silica-induced lung inflammation and fibrosis in C57BL/6 mice, Toxicol Appl Pharmacol source
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- Premisecitation
Treatment with the lymphocyte-modulating agent azathioprine impairs function of molecules that function as immune checkpoints.
“treatment with the lymphocyte-modulating agent Azathioprine results in impaired function of molecules that function as immune checkpoints (131)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [131] Tiede, 2003, CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes, J Clin Invest source
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- Premisecitation
Innate lymphoid cells have been identified in the IPF lung.
“ILCs have been identified in the IPF lung (124)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [124] Monticelli, 2011, Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus, Nat Immunol source
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- Interpretationreasoning
Lymphocytes might participate in fibrosis via as yet undefined mechanisms.
“Thus, lymphocytes might participate in fibrosis via as yet undefined mechanisms.”
Quote in the paperNot a substantial claim- Rests on an assumption: IPF fails to improve in response to lymphocyte-modulating therapies.
- Premisecitation
In a bleomycin mouse study, IL-12 attenuated pulmonary fibrosis via modulation of IFNγ production, supporting a protective role of Th1-associated mediators in fibrosis.
“a bleomycin study in mice found that IL-12-attenuated pulmonary fibrosis via modulation of IFNγ production, thus presenting a protective role of Th1 associated mediators in fibrosis (135).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [135] Keane, 2001, IL-12 attenuates bleomycin-induced pulmonary fibrosis, Am J Physiol Lung Cell Mol Physiol source
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- Premisecitation
In an experimental model of hypersensitivity pneumonitis, neutrophils and monocytes/macrophages are a dominant source of IL-17A.
“one recent studying in an experimental model of HP found neutrophils and monocytes/macrophages to be a dominant source of IL-17A (149).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [149] Hasan, 2013, Role of IL-17A and neutrophils in fibrosis in experimental hypersensitivity pneumonitis, J Allergy Clin Immunol source
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- Premisecitation
In IPF lung tissue, lymphoid aggregates contain CD3+ T lymphocytes.
“In the tissue, these lymphoid aggregates contain CD3+ T lymphocytes (127)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [127] Nuovo, 2012, The distribution of immunomodulatory cells in the lungs of patients with idiopathic pulmonary fibrosis, Mod Pathol source
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- Premisecitation
A population of aberrantly activated Tregs identified by Semaphorin 7a+ expression was sufficient to engender TGF-β1-induced fibrosis in the adult mouse lung.
“a population of aberrantly activated Tregs identified by expression of the neuroimmune molecule Semaphorin 7a+ was sufficient to engender TGF-β1 induced fibrosis in the adult mouse lung (154)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [154] Reilkoff, 2013, Semaphorin 7a+ regulatory T cells are associated with progressive idiopathic pulmonary fibrosis and are implicated in transforming growth factor-beta1-induced pulmonary fibrosis, Am J Respir Crit Care Med source
Not checked in the free run.
- Premisecitation
BAL concentrations of IL-22 do not differ between IPF and control.
“BAL concentrations do not differ between IPF and control (151).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [151] Whittington, 2004, Interleukin-22: a potential immunomodulatory molecule in the lung, Am J Respir Cell Mol Biol source
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- Premisecitation
The association between the CTLA-4-related T cell regulatory gene signature and reduced event-free survival was recapitulated in six independent IPF cohorts from centers across the US and Europe.
“these findings were recently recapitulated in a landmark study involving six independent IPF cohorts from centers across the US and Europe (129).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [129] Herazo-Maya, 2017, Validation of a 52-gene risk profile for outcome prediction in patients with idiopathic pulmonary fibrosis: an international, multicentre, cohort study, Lancet Respir Med source
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- Premisecitation
Lymphocytes are not required for the development of experimentally induced fibrosis in mice.
“lymphocytes are not required for the development of experimentally induced fibrosis in mice (125)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [125] Helene, 1999, T cell independence of bleomycin-induced pulmonary fibrosis, J Leukoc Biol source
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- Premisecitation
In murine studies, administration of IL-17A is sufficient to induce collagen accumulation and fibrotic lesions.
“murine studies in which administration of IL-17A is sufficient to induce collagen accumulation and fibrotic lesions (144, 145)”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [144] Wilson, 2010, Bleomycin and IL-1beta-mediated pulmonary fibrosis is IL-17A dependent, J Exp Med source
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- cites [145] Lei, 2016, Th17 cells and IL-17 promote the skin and lung inflammation and fibrosis process in a bleomycin-induced murine model of systemic sclerosis, Clin Exp Rheumatol
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- Premisecitation
Several studies have reported a relative reduction in IFNγ levels in the BAL or circulation of patients with IPF.
“several studies have reported a relative reduction in IFNγ levels in the BAL or circulation of patients with IPF (134).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [134] Prior, 1992, In vivo levels and in vitro production of interferon-gamma in fibrosing interstitial lung diseases, Clin Exp Immunol source
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- Premisecitation
Attenuation of Th1 differentiation via targeting the transcription factor T-bet increased bleomycin-induced lung injury.
“attenuation of Th1 differentiation via targeting of the transcription factor T-bet increased bleomycin-induced lung injury (136).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [136] Xu, 2006, Increased bleomycin-induced lung injury in mice deficient in the transcription factor T-bet, Am J Physiol Lung Cell Mol Physiol source
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- Interpretationcitation
The concept of the Th1/Th2 balance as a central mediator of IPF may require re-evaluation.
“Therefore, the concept of the Th1/Th2 balance as a central mediator of IPF may require re-evaluation”
Quote in the paperSubstantial claim - Premisecitation
A 2009 study reported marked suppression of functional CD4+, CD25high, FoxP3+ cells in the BAL and peripheral blood of IPF patients.
“a now seminal 2009 study reported marked suppression of functional CD4+, CD25high, FoxP3+ cells in the BAL and peripheral blood of IPF patients (152)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [152] Kotsianidis, 2009, Global impairment of CD4+CD25+FOXP3+ regulatory T cells in idiopathic pulmonary fibrosis, Am J Respir Crit Care Med source
Not checked in the free run.
- Interpretationreasoning
Tregs have the potential to both promote and suppress fibrosis depending on context, due to their ability to produce IL-10 and TGFβ1.
“Due to their ability to produce both IL-10 and TGFβ1, Tregs have the potential to both promote or suppress fibrosis depending on the context.”
Quote in the paperSubstantial claim - Interpretationcitation
Recruited or lung-resident Tregs might be fibrosis-suppressive or fibrosis-stimulatory depending on their interaction with the local milieu.
“A synthesis of this information suggests that recruited or lung resident Tregs might be fibrosis-suppressive or fibrosis-stimulatory depending on their interaction with the local milieu (155).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [155] Boveda-Ruiz, 2013, Differential role of regulatory T cells in early and late stages of pulmonary fibrosis, Immunobiology source
Not checked in the free run.
- Premisecitation
Increased detection of CD20+ B cells has been reported for IPF lungs.
“increased detection of CD20+ B cells has been reported for IPF lungs (158).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [158] Todd, 2013, Lymphocyte aggregates persist and accumulate in the lungs of patients with idiopathic pulmonary fibrosis, J Inflamm Res source
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- Premisecitation
Detection of Th2 cells and their secretory mediators is enhanced in the lungs and blood of patients with IPF.
“detection of Th2 cells and their secretory mediators appears to be enhanced in the lungs and blood of patients with IPF (137–140).”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [137] Saito, 2003, Potential action of IL-4 and IL-13 as fibrogenic factors on lung fibroblasts in vitro, Int Arch Allergy Immunol source
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- cites [138] Postlethwaite, 1992, Human fibroblasts synthesize elevated levels of extracellular matrix proteins in response to interleukin 4, J Clin Invest source
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- cites [139] Liu, 2002, Th2 cytokine regulation of type I collagen gel contraction mediated by human lung mesenchymal cells, Am J Physiol Lung Cell Mol Physiol source
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- cites [140] Kimura, 2006, Overexpression of the transcription factor GATA-3 enhances the development of pulmonary fibrosis, Am J Pathol source
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- Premisecitation
Patients with low-level titers of autoantibodies might have worsened clinical outcomes than those lacking these findings.
“patients with low level titers of autoantibodies might have worsened clinical outcomes than those patients lacking these findings (160).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [160] Lee, 2013, Prevalence and clinical significance of circulating autoantibodies in idiopathic pulmonary fibrosis, Respir Med source
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- Premisecitation
Reduced expression of the costimulatory molecule CD28 on circulating T cells predicts poor outcomes in IPF.
“reduced expression of the costimulatory molecule CD28 on circulating T cells was seen to be a predictor of poor outcomes (130).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [130] Gilani, 2010, CD28 down-regulation on circulating CD4 T-cells is associated with poor prognoses of patients with idiopathic pulmonary fibrosis, PLoS One source
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- Premisecitation
Lung tissue and BAL fluid from patients with IPF are enriched for several populations of T lymphocytes relative to normal individuals.
“Relative to samples obtained from normal individuals, lung tissue and BAL fluid from patients with IPF are enriched for several population of T lymphocytes (126).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [126] Fireman, 1998, Predictive value of response to treatment of T-lymphocyte subpopulations in idiopathic pulmonary fibrosis, Eur Respir J source
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- Premisecitation
IL-22 appears protective in the bleomycin model.
“IL-22, another product of Th17 cells, appears to be protective in the bleomycin model (150)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [150] Liang, 2006, Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides, J Exp Med source
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- Premisecitation
A PBMC transcriptional signature characterized by reduced expression of T cell regulatory genes related to the immune checkpoint CTLA-4 is associated with reduced event-free survival in IPF.
“transcriptional profiling of PBMCs found that a signature characterized by reduced expression of T cell regulatory genes related to the immune checkpoint CTLA-4 was associated with reduced event free survival (128)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [128] Herazo-Maya, 2013, Peripheral blood mononuclear cell gene expression profiles predict poor outcome in idiopathic pulmonary fibrosis, Sci Transl Med source
Not checked in the free run.
- Premisecitation
In a silicosis model, Tregs promote fibroblast activation via production of PDGFβ.
“but promote fibroblast activation via production of PDGFβ in a model of silicosis (157).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [157] Lo Re, 2011, Platelet-derived growth factor-producing CD4+ Foxp3+ regulatory T lymphocytes promote lung fibrosis, Am J Respir Crit Care Med source
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- Premisecitation
Neutralization of IL-17 can reduce fibrosis in several animal models.
“neutralization of IL-17 can reduce fibrosis in several animal models (146, 147).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [146] Mi, 2011, Blocking IL-17A promotes the resolution of pulmonary inflammation and fibrosis via TGF-beta1-dependent and -independent mechanisms, J Immunol source
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- cites [147] Dong, 2015, IL-27 alleviates the bleomycin-induced pulmonary fibrosis by regulating the Th17 cell differentiation, BMC Pulm Med source
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- Premisecitation
In an LPS model of lung injury, Tregs suppress fibrocyte recruitment and fibrosis via interruption of the CXCL4/SDF1 axis.
“data from an LPS model of lung injury showing that Tregs suppress fibrocyte recruitment and fibrosis via interruption of the chemokine C-X-C motif ligand 4/stromal cell-derived factor 1 (CXCL4/SDF1) axis (156)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [156] Garibaldi, 2013, Regulatory T cells reduce acute lung injury fibroproliferation by decreasing fibrocyte recruitment, Am J Respir Cell Mol Biol source
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- Premisecitation
High levels of anti-vimentin are associated with worsened pulmonary function and prognosis in IPF.
“high levels of anti-vimentin were associated with worsened pulmonary function and prognosis (165).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [165] Li, 2017, Autoimmunity to vimentin is associated with outcomes of patients with idiopathic pulmonary fibrosis, J Immunol source
Not checked in the free run.
- Interpretationreasoning
The cells of the immune system show a rich and multifaceted contribution to IPF.
“As can be seen, the cells of the immune system show a rich and multifaceted contribution to IPF.”
Quote in the paperSubstantial claim- Rests on an assumption: Myeloid-derived suppressor cells are associated with diseases characterized by fibrosis and pathologic remodeling.
- Rests on an assumption: IPF fails to improve in response to lymphocyte-modulating therapies.
- Interpretationnone given
Currently available data suggest that innate mechanisms may dominate in IPF.
“Currently available data suggest that innate mechanisms may dominate.”
Quote in the paperSubstantial claim - Premisecitation
Detection of B lymphocyte stimulator, also known as B-cell-activating factor (BAFF), is enriched in the lungs and blood of patients with IPF.
“detection of B lymphocyte stimulator, which is also known as B-cell-activating factor (BAFF), is enriched in the lungs and blood of patients with IPF (168).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [168] Francois, 2015, B cell activating factor is central to bleomycin- and IL-17-mediated experimental pulmonary fibrosis, J Autoimmun source
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- Premisecitation
Stable outpatients with end-stage ILD who received CD20-targeted therapy showed a trend toward improved lung function.
“a retrospective study in which stable outpatients with end stage ILD who received CD20 targeted therapy (which removes B cells) showed a trend toward improved lung function (169).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [169] Keir, 2014, Rituximab in severe, treatment-refractory interstitial lung disease, Respirology source
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- Interpretationreasoning
The heterogeneous contribution of the innate and adaptive immune systems is nuanced and unlikely to respond to a single intervention.
“the more heterogeneous contribution of the innate and adaptive immune systems shown in Figure 4 is nuanced and unlikely to respond to a single intervention.”
Quote in the paperNot a substantial claim - Interpretationreasoning
The redundancy and opposing effects of immune functions likely account for the failure of IPF to respond to classical forms of immunosuppression.
“The redundancy and opposing effects of these functions likely accounts for the failure of IPF to respond to classical forms of immunosuppression.”
Quote in the paperSubstantial claim - Premisecitation
Presence of anti-HSP70 autoantibodies in patients with IPF is associated with similar findings.
“Similar findings were observed with the presence of anti-HSP70 autoantibodies in patients with IPF (166).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [166] Kahloon, 2013, Patients with idiopathic pulmonary fibrosis with antibodies to heat shock protein 70 have poor prognoses, Am J Respir Crit Care Med source
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- Premisecitation
Data from other models show that B cells may suppress fibrotic response.
“data gleaned in other models show that B cells may actually suppress fibrotic response (171)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [171] Arras, 2006, B lymphocytes are critical for lung fibrosis control and prostaglandin E2 regulation in IL-9 transgenic mice, Am J Respir Cell Mol Biol source
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- Premisecitation
In animal modeling, neutralization or genetic ablation of BAFF attenuates pulmonary fibrosis.
“animal modeling in which neutralization or genetic ablation of BAFF attenuates pulmonary fibrosis (168).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [168] Francois, 2015, B cell activating factor is central to bleomycin- and IL-17-mediated experimental pulmonary fibrosis, J Autoimmun source
Not checked in the free run.
- Premisecitation
Patients with respiratory failure due to AE-IPF showed clinical improvement after combined plasmapheresis and anti-CD20 therapy.
“patients with respiratory failure due to an AE-IPF showed clinical improvement after undergoing combined plasmapheresis (which would be presumed to remove offending antibodies) and anti-CD20 therapy (170).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [170] Donahoe, 2015, Autoantibody-targeted treatments for acute exacerbations of idiopathic pulmonary fibrosis, PLoS One source
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- May combine two claims. 12
- Classified as probably not a substantial claim. 3
May combine two claims.
PremisecitationRemoval or repolarizing of interstitial macrophages is both preventative and therapeutic in several mouse models of IPF.
“removal (27, 28) or repolarizing (27) of interstitial macrophages is both preventative and therapeutic in several mouse models of IPF”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [27] Murray, 2011, TGF-beta driven lung fibrosis is macrophage dependent and blocked by Serum amyloid P, Int J Biochem Cell Biol source
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- cites [28] Gibbons, 2011, Ly6Chi monocytes direct alternatively activated profibrotic macrophage regulation of lung fibrosis, Am J Respir Crit Care Med source
Not checked in the free run.
May combine two claims.
PremisecitationMyeloid-derived suppressor cells promote regulatory T cell expansion and restrain T-cell activation.
“They promote regulatory T cell (Treg) expansion and restrain T-cell activation (117)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [117] Zoso, 2014, Human fibrocytic myeloid-derived suppressor cells express IDO and promote tolerance via Treg-cell expansion, Eur J Immunol source
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May combine two claims.
PremisecitationSystemic recombinant IFNγ and monoclonal antibody-mediated neutralization of IL-13 failed to demonstrate efficacy in randomized, placebo-controlled trials of patients with IPF.
“However, systemic administration of recombinant IFNγ (which would simulate the presence of Th1 biology) and monoclonal antibody-mediated neutralization of IL-13 (which would specifically target Th2 responses) failed to demonstrate efficacy in randomized, placebo-controlled trials of patients with IPF (141, 142).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [141] Raghu, 2004, A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis, N Engl J Med source
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- cites [142] Parker, 2017, A phase 2 randomized controlled study of tralokinumab in subjects with idiopathic pulmonary fibrosis, Am J Respir Crit Care Med source
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May combine two claims.
PremisecitationMore recent studies have shown an increase in Tregs and an imbalance of the Treg/Th17 axis in IPF patients.
“more recent studies in this area have actually shown an increase in Tregs, and an imbalance of the Treg/Th17 axis in IPF patients (153).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [153] Galati, 2014, Peripheral depletion of NK cells and imbalance of the Treg/Th17 axis in idiopathic pulmonary fibrosis patients, Cytokine source
Not checked in the free run.
May combine two claims.
PremisecitationThe Th2 cytokines IL-4 and IL-13 stimulate fibroblast proliferation, collagen production, and fibroblast-to-myofibroblast differentiation, rendering Th2 cells fibrogenic.
“studies that focused on the Th2 cytokines IL-4 and IL-13 showed them to stimulate fibroblast proliferation, collagen production, and fibroblast to myofibroblast differentiation—thereby rendering Th2 cells fibrogenic (137).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [137] Saito, 2003, Potential action of IL-4 and IL-13 as fibrogenic factors on lung fibroblasts in vitro, Int Arch Allergy Immunol source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCheckpoint inhibitors used as cancer immunotherapy can cause inflammatory interstitial lung disease.
“checkpoint inhibitors used as cancer immunotherapy can cause inflammatory ILD (132)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [132] Delaunay, 2017, Immune-checkpoint inhibitors associated with interstitial lung disease in cancer patients, Eur Respir J source
Not checked in the free run.
May combine two claims.
InterpretationreasoningTregs play a controversial role in pulmonary fibrosis and, depending on the stage of fibrosis, can be both harmful and protective.
“In summary, Tregs play a controversial role in pulmonary fibrosis and depending on the stage of fibrosis, they can be both harmful as well as protective.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationTh17 cells produce IL-17 and IL-22, which are host-defensive in many infectious conditions but also promote inflammatory pathology in diseases such as autoimmune conditions.
“Th17 cells produce cytokines, such as IL-17 and IL-22, which are host-defensive cytokine in many infectious conditions but also promote inflammatory pathology in various diseases such as autoimmune conditions (143).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [143] Onishi, 2010, Interleukin-17 and its target genes: mechanisms of interleukin-17 function in disease, Immunology source
Not checked in the free run.
May combine two claims.
PremisecitationIn a bleomycin model, Tregs may stimulate TGFβ1 production and collagen accumulation when present during the injury phase, but might reduce these endpoints when present during later stages.
“experimental data from a bleomycin model showing that Tregs may stimulate TGFβ1 production and collagen accumulation when present during the injury phase, but might reduce these endpoints when present during the later stages of the model (155).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [155] Boveda-Ruiz, 2013, Differential role of regulatory T cells in early and late stages of pulmonary fibrosis, Immunobiology source
Not checked in the free run.
May combine two claims.
PremisecitationILC2 are activated quickly by environmental antigens and pathogens to release large quantities of IL-13, suggesting a potential role in pulmonary fibrosis.
“ILC2 are activated quickly by environmental antigens and pathogens to release large quantities of IL-13, thereby suggesting a potential role in pulmonary fibrosis (123).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [123] Peebles, 2015, At the bedside: the emergence of group 2 innate lymphoid cells in human disease, J Leukoc Biol source
Not checked in the free run.
May combine two claims.
PremisecitationTh1 cells and their secretory products are anti-fibrotic, whereas Th2 cells and their mediators are pro-fibrotic.
“Here, Th1 cells and their secretory products are thought of as being anti-fibrotic and Th2 cells and their mediators are considered pro-fibrotic (133).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [133] Luzina, 2008, Roles of T lymphocytes in pulmonary fibrosis, J Leukoc Biol source
Not checked in the free run.
May combine two claims.
PremisecitationIL-17 stimulates extracellular matrix production, collagen disposition, and mediates TGF-β signaling.
“the functions of IL-17 include stimulation of ECM production, collagen disposition, and mediation of TGF-β signaling (144).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [144] Wilson, 2010, Bleomycin and IL-1beta-mediated pulmonary fibrosis is IL-17A dependent, J Exp Med source
Not checked in the free run.
May combine two claims.
PremisecitationA variety of novel autoantibodies targeting neoepitopes have been reported in IPF, with many targets being structural cell proteins such as desmoplakin and periplakin.
“A variety of novel autoantibodies targeting neoepitopes have been reported in IPF (159–163), with many of the targets being structural cell proteins, such as desmoplakin (164) and periplakin (159).”
Quote in the paperNot a substantial claim0 of 6 sources checked- cites [159] Taille, 2011, Identification of periplakin as a new target for autoreactivity in idiopathic pulmonary fibrosis, Am J Respir Crit Care Med source
Not checked in the free run.
- cites [160] Lee, 2013, Prevalence and clinical significance of circulating autoantibodies in idiopathic pulmonary fibrosis, Respir Med source
Not checked in the free run.
- cites [161] Wallace, 1994, Circulating antibodies to lung protein(s) in patients with cryptogenic fibrosing alveolitis, Thorax source
Not checked in the free run.
- cites [162] Yang, 2002, Detection of antivimentin antibody in sera of patients with idiopathic pulmonary fibrosis and non-specific interstitial pneumonia, Clin Exp Immunol source
Not checked in the free run.
- cites [163] Fujita, 1999, Elevation of anti-cytokeratin 19 antibody in sera of the patients with idiopathic pulmonary fibrosis and pulmonary fibrosis associated with collagen vascular disorders, Lung source
Not checked in the free run.
- cites [164] Mathai, 2016, Desmoplakin variants are associated with idiopathic pulmonary fibrosis, Am J Respir Crit Care Med source
Not checked in the free run.
Classified as probably not a substantial claim.
InterpretationreasoningThe relative ease of isolating immune cells and substances from BAL and circulation renders the immune system an attractive area for developing immunopathogenesis-based personalized therapies based on easily accessible biomarkers.
“This aspect, combined with the relative ease of isolating immune cells and substances from the BAL and circulation renders the immune system an attractive area for the development of immunopathogenesis-based personalized therapies based on easily accessible biomarkers.”
Quote in the paperSubstantial claim
The paper relies on this without support.
Myeloid-derived suppressor cells are associated with diseases characterized by fibrosis and pathologic remodeling.
“They promote regulatory T cell (Treg) expansion and restrain T-cell activation (117) and are associated with a number of diseases characterized by fibrosis and pathologic remodeling.”
The paper relies on this without support.
IPF fails to improve in response to lymphocyte-modulating therapies.
“The failure of IPF to improve in response to lymphocyte-modulating therapies, and the observation that lymphocytes are not required for the development of experimentally induced fibrosis in mice (125), has contributed to this situation.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
B cells accumulate in the IPF lung and produce antibodies against self-antigens, suggesting autoimmunity may be a feature and play a role in the disease.
“B cells have also been found to accumulate in the IPF lung and produce antibodies against selfantigens, suggesting that autoimmunity may be a feature and also play a role in the disease (Desai et al., 2018).”
From Pulmonary fibrosis: Emerging diagnostic and therapeutic strategies (2023) · cites this paper as Desai et al., 2018
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Figure 1 places the newer model on both the right and the left
MinorThe caption says the refined model is shown on the right, but then identifies a panel in that newer model as being on the left.
“In this newer model, the stimuli affecting the lung epithelium leads to fibroblast activation and ECM accumulation that can occur without a primary immunopathogenic component (second panel on left).”
“Observations gleaned from clinical trials and experimental modeling have refined this paradigm, however, to result in the scheme shown on the right.”
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- Authors
- Desai, O., Winkler, J., Minasyan, M., & Herzog, E. L.
- Affiliations
- Yale University (US)
- Corresponding author
- Herzog, Erica L.
- Venue
- Frontiers in Medicine
- Publisher
- Frontiers Media SA
- Published
- 2018-03-20
- Volume
- 5
- Pages
- 43-43
- ISSN
- 2296-858X (ISSN-L)
- PMC
- PMC5869935
- OpenAlex
- W2791214769
- Cited by
- 314
- References
- 165
- Citations by year
- 2026: 23 · 2025: 31 · 2024: 43 · 2023: 48 · 2022: 55 · 2021: 47 · 2020: 41 · 2019: 19 · 2018: 6 · 2014: 1
- FWCI
- 5.18
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Frontiers in Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Institutes of Health (HL109233, HL125250)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Occupational and environmental lung diseases
- Health Sciences › Medicine › Surgery › Transplantation: Methods and Outcomes
- Keywords
- idiopathic pulmonary fibrosis, immune cells, inflammation, innate immunity, adaptive immunity, monocytes, macrophages, myeloid-derived suppressor cells, innate lymphoid cells, pathogen-associated molecular patterns, damage-associated molecular patterns, T helper cells, B cells, genetic and environmental factors, fibrosis treatment
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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