Epitope analysis of the collagen type V-specific T cell response in lung transplantation reveals an HLA-DRB1*15 bias in both recipient and donor.

Abstract

BACKGROUND:

IL-17-dependent cellular immune responses to the α1 chain of collagen type V are associated with development of bronchiolitis obliterans syndrome after lung transplantation, and with idiopathic pulmonary fibrosis and coronary artery disease, primary indications for lung or heart transplantation, respectively.

METHODOLOGY/PRINCIPAL FINDINGS:

We found that 30% of the patients awaiting lung transplantation exhibited a strong cell-mediated immune response to col(V). Of these, 53% expressed HLA-DR15, compared to a 28% HLA-DR15 frequency in col(V) low-responders (p=0.02). After transplantation, patients with HLA-DR1 and -DR17, not -DR15, developed anti-col(V) responses most frequently (p=0.04 and 0.01 vs. controls, respectively). However, recipients of a lung from an HLA-DR15(+)donor were at significantly elevated risk of developing anti-col(V) responses (p=0.02) and BOS (p=0.03). To determine the molecular basis of this unusual pattern of DR allele bias, a peptide library comprising the collagenous region of the α1(V) protein was screened for binding to HLA-DR0101, -DR1501, -DR0301 (DR17) or to HLA-DQ2 (DQA1*0501: DQB1*0201; in linkage disequilibrium with -DR17) and -DQ6 (DQA1*0102: DQB1*0602; linked to -DR15). Eight 15-mer peptides, six DR-binding and two DQ-binding, were identified. HLA-DR15 binding to two peptides yielded the highest binding scores: 650 (where 100 = positive control) for p799 (GIRGLKGTKGEKGED), and 193 for p1439 (LRGIPGPVGEQGLPG). These peptides, which also bound weakly to HLA-DR1, elicited responses in both HLA-DR1(+) and -DR15(+) col(V) reactive hosts, whereas binding and immunoreactivity of p1049 (KDGPPGLRGFPGDRG) was DR15-specific. Remarkably, a col(V)-reactive HLA-DR1(+)DR15(neg) lung transplant patient, whose donor was HLA-DR15(+), responded not only to p799 and p1439, but also to p1049.

CONCLUSIONS/SIGNIFICANCE:

HLA-DR15 and IPF disease were independently associated with pre-transplant col(V) autoimmunity. The increased risk of de novo immunity to col(V) and BOS, associated with receiving a lung transplant from an HLA-DR15(+) donor, may result from presentation by donor-derived HLA- DR15, of novel self-peptides to recipient T cells.

• Authors: Melissa R Keller, Lynn D Haynes, Ewa Jankowska-Gan, Jeremy A Sullivan, Vrushali V Agashe, Scott R Burlingham, William J Burlingham
• Journal: PloS one (PLoS One) Vol. 8 Issue 11 Pg. e79601 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24265781 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Collagen Type V
• HLA-DRB1 Chains
• HLA-DRB1*15 antigen

Topics

• Amino Acid Sequence
• Animals
• Autoimmunity
• CD4-Positive T-Lymphocytes (immunology)
• Cattle
• Collagen Type V (immunology)
• Epitope Mapping
• Female
• Gene Expression Regulation (immunology)
• HLA-DRB1 Chains (chemistry, immunology)
• Humans
• Lung Diseases (immunology, surgery)
• Lung Transplantation
• Male
• Mice
• Molecular Sequence Data
• Tissue Donors