Anti-Type V Collagen Humoral Immunity in Lung Transplant Primary Graft Dysfunction

Iwata, Takekazu; Philipovskiy, Alexander; Fisher, Amanda; Presson, Robert G.; Chiyo, Masako; Lee, Jae; Mickler, Elizabeth A.; Smith, Gerald N.; Petrache, Irina; Brand, David B.; Burlingham, William J.; Bulusu, Gopalakrishnan; Greenspan, Daniel S.; Christie, Jason D.; Wilkes, David S.

doi:10.4049/jimmunol.181.8.5738

Cited by 103 publications

(116 citation statements)

References 34 publications

(76 reference statements)

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“…found on the apical surface of airway epithelium, it is not secreted by such cells into the extracellular milieu (26). We observed robust expression of ␣1(V) in response to IL-17 and TGF-␤ treatment, which is the same ␣-chain recognized as the antigen.…”

Section: L409 Il-17 Mediated Col(v) Overexpression and Emtmentioning

confidence: 59%

“…Col(V), which can be considered a cryptic antigen, is normally intercalated within fibrils of col(I) (34). As such, col(V) is expressed at low levels in perivascular interstitial spaces and on the apical, but not basolateral, surfaces of airway epithelial cells (26). We have previously reported de novo generation of antibodies to col(V) in patients with lung transplants with OB (49) and that this was IL-17 dependent (14).…”

Section: Discussionmentioning

confidence: 99%

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IL-17 induces type V collagen overexpression and EMT via TGF-β-dependent pathways in obliterative bronchiolitis

Vittal¹,

Fan²,

Greenspan³

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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erative bronchiolitis (OB), a fibrotic airway lesion, is the leading cause of death after lung transplantation. Type V collagen [col(V)] overexpression and IL-17-mediated anti-col(V) immunity are key contributors to OB pathogenesis. Here, we report a previously undefined role of IL-17 in inducing col(V) overexpression, leading to epithelial mesenchymal transition (EMT) and subsequent OB. We observed IL-17-mediated induction of col(V) ␣1 chains [␣1 (V)] in normal airway epithelial cells in vitro and detected ␣1 (V)-specific antibodies in bronchoalveolar lavage fluid of lung transplant patients. Overexpression of IL-17 and col(V) was detected in OB lesions in patient lung biopsies and in a murine OB model. IL-17 is shown to induce EMT, TGF-␤ mRNA expression, and SMAD3 activation, whereas downregulating SMAD7 expression in vitro. Pharmacological inhibition of TGF-␤RI tyrosine kinase, p38 MAPK, or focal adhesion kinase prevented col(V) overexpression and EMT. In murine orthotopic lung transplants, neutralizing IL-17 significantly decreased TGF-␤ mRNA and protein expression and prevented epithelial repair/ OB. Our findings highlight a feed-forward loop between IL-17 and TGF-␤, leading to induction of col(V) and associated epithelial repair, thus providing one possible link between autoimmunity and OB after lung transplantation. autoimmunity; p38 MAPK; focal adhesion kinase; small-airway epithelial cells; RLE-6TN; mouse transplant model; epithelial-mesenchymal transition OBLITERATIVE BRONCHIOLITIS (OB) is characterized by extensive peribronchiolar fibrosis with plugs of granulation tissues (fibroblasts and collagen) that occlude small airways. OB is the key reason that the 5-yr survival of lung transplant recipients is only 50%, the worst of all major solid organ transplants (42,48).Aberrant epithelial repair is a key event in the transplanted lung (1, 9) in which bronchioles lose resident epithelial cells and become occluded by granulation tissue. Abnormal epithelial repair eventually causes an epithelial-to-mesenchymal transition (EMT), a functional and phenotypic change of epithelial cells into spindle-shaped, migratory (43) and matrix-component-secreting mesenchymal cells (10, 41), and a process associated with lung fibrosis (15,27). However, the direct connection between EMT and the in vivo phenomena of fibrosis and fibro-obliterative disease remains controversial.We and others previously reported that OB is associated with dysregulation of two types of collagen: 1) marked increase in type V collagen [col(V)], a quantitatively minor lung collagen (8,14,40), and 2) a decrease in the major lung collagen type I [col(I)] (2, 53). We have shown that prospective monitoring of patients with human lung transplant revealed a critical role of col(V)-specific cellular immunity in OB pathogenesis (14,40). Although overexpression of col(V), an otherwise quantitatively minor collagen, is involved in OB pathology, mechanisms leading to col(V) overexpression are unknown. Thus a mechanistic understanding of the triggers of col(V)...

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Section: L409 Il-17 Mediated Col(v) Overexpression and Emtmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

IL-17 induces type V collagen overexpression and EMT via TGF-β-dependent pathways in obliterative bronchiolitis

Vittal¹,

Fan²,

Greenspan³

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Thus, mutations in the genes encoding either ␣1(V) or ␣2(V) chains result in the human connective tissue disorder classic Ehlers-Danlos syndrome, characterized by collagen I fibrils of abnormal shapes and diameters and deficient tensile strength (7,8). More recently, it has been demonstrated that anti-col(V) autoimmune responses can underlie chronic lung transplant rejection in both humans (9) and animal models (10) and that pre-transplant col(V)-specific autoimmunity is also a significant risk factor for primary graft dysfunction, the leading cause of early morbidity and mortality after lung transplantation (11,12). Col(V) autoimmunity has also been identified as a consistent feature in both late stage human coronary artery disease and a mouse model of atherosclerosis (13).…”

Section: Collagen Type V (Col(v))mentioning

confidence: 99%

Comprehensive Mass Spectrometric Mapping of the Hydroxylated Amino Acid residues of the α1(V) Collagen Chain

Yang

Park

Davis

et al. 2012

Journal of Biological Chemistry

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Background: ␣1(V) is an extensively modified collagen chain important in disease. Results: Comprehensive mapping of ␣1(V) post-translational modifications reveals unexpectedly large numbers of X-position hydroxyprolines in Gly-X-Y amino acid triplets. Conclusion:The unexpected abundance of X-position hydroxyprolines suggests a mechanism for differential modification of collagen properties. Significance: Positions, numbers, and occupancy of modified sites can provide insights into ␣1(V) biological properties.

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“…Antibodies to col(V) were detected in patients' plasma using a patented flow cytometry bead assay (ImmuneWorks, Indianapolis, IN, USA) [18]. A floating cut-off was determined by using serum from 66 adult, nonsmoking normal volunteers, following an immunogenicity white paper [19].…”

Section: Anti-col(v) Ab Detectionmentioning

confidence: 99%

Oral immunotherapy with type V collagen in idiopathic pulmonary fibrosis

et al. 2015

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Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis. IPF appears to be heterogeneous in pathobiology with ∼40% of IPF patients found to have elevated levels of circulating antibodies to the autoantigen type V collagen (col(V)).Following a targeted, precision medicine approach, we conducted a phase 1 study to test the safety and explore potential efficacy of IW001, a col(V) oral immunotherapeutic developed to treat antibody-positive IPF patients. We divided 30 antibody-positive IPF patients into three cohorts for daily dosing over a 24-week period.All patients completed treatment without serious adverse events, acute exacerbations or IPF-related hospitalisations. A decline in lung function occurred in the lowest-dose cohort that was comparable to that reported in placebo arms of published IPF trials. In contrast, the highest-dose cohort showed a trend toward stabilisation of forced vital capacity and matrix metalloproteinase 7, and a reduction in binding of C1q to anti-col(V) antibodies.IW001 may modulate the immune response to col(V) and may represent a new therapeutic for col(V)-reactive IPF patients. @ERSpublications IW001 is safe, and improves biomarkers and lung function in IPF patients with type V collagen antibodies http://ow.ly/LirbO

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Anti-Type V Collagen Humoral Immunity in Lung Transplant Primary Graft Dysfunction

Cited by 103 publications

References 34 publications

IL-17 induces type V collagen overexpression and EMT via TGF-β-dependent pathways in obliterative bronchiolitis

IL-17 induces type V collagen overexpression and EMT via TGF-β-dependent pathways in obliterative bronchiolitis

Comprehensive Mass Spectrometric Mapping of the Hydroxylated Amino Acid residues of the α1(V) Collagen Chain

Oral immunotherapy with type V collagen in idiopathic pulmonary fibrosis

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