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1.
Transplant Direct ; 6(10): e607, 2020 Oct.
Article in English | MEDLINE | ID: mdl-33062840

ABSTRACT

Individuals harbor preexisting HLA-DR/DQ-restricted responses to collagen type V (ColV) mediated by Th17 cells under Treg control, both specific to peptides that bind to inherited HLA class II antigens. Yet after transplant, the donor-DR type somehow influences graft outcome. We hypothesized that, long after a lung or heart allograft, the particular HLA-DR type of the mismatched transplant donor transforms the specificity of the "anti-self" response. This could explain why, over long term, certain donor DRs could be more immunogenic than others. METHODS: We analyzed 7 HLA-DR15neg patients who had received a lung allograft from a DR15+ donor. To determine the mechanism of acquired specificity in self-reactivity, we analyzed the kinetics of DR1 (host) and DR15 (donor) peptide restriction in a heart transplant model using DR-transgenic mice. RESULTS: Beyond 1.5 years post-lung transplant, all patients tested had acquired DR15-restricted immune responses to ColV peptides. These responses were either unrestrained Th17 type (n = 4) or Th17 controlled by Treg arising early (<5 y) or late (>7 y) after transplant (n = 4). Treg suppression via conventional (transforming growth factor-ß [TGF-ß]) and extracellular vesicle-associated (IL-35) cytokines correlated with superior outcomes. Naïve DR1 and DR15 transgenic mice had preexisting DR-restricted responses, exclusively to ColV fragments containing DR1- or DR15-binding peptides. When HLA-DR1 transgenic recipients of a HLA-DR15 heart developed ColV reactivity post-transplant, mice that acutely rejected (20-25 d) responded only to the DR1-restricted ColV peptide epitope. In animals whose grafts survived long term, we could detect acquisition of DR from the transplant donor onto the surface of recipient dendritic cells, and immune responses against a donor DR15-restricted ColV peptide. CONCLUSIONS: These results might explain how certain donor HLA-DR types redirect host immune responses to novel peptides of critical self-antigens. Unless regulated, such responses may predispose the allograft to chronic rejection.

2.
J Immunol ; 201(2): 772-781, 2018 07 15.
Article in English | MEDLINE | ID: mdl-29884698

ABSTRACT

Leukocyte-associated Ig-like receptor 1 (LAIR1) is an ITIM-bearing collagen receptor expressed by leukocytes and is implicated in immune suppression. However, using a divalent soluble LAIR1/Fc recombinant protein to block interaction of cell surface LAIR1 with matrix collagen, we found that whereas Th1 responses were enhanced as predicted, Th17 responses were strongly inhibited. Indeed, LAIR1 on both T cells and monocytes was required for optimal Th17 responses to collagen type (Col)V. For pre-existing "natural" Th17 response to ColV, the LAIR1 requirement was absolute, whereas adaptive Th17 and Th1/17 immune responses in both mice and humans were profoundly reduced in the absence of LAIR1. Furthermore, the addition of C1q, a natural LAIR1 ligand, decreased Th1 responses in a dose-dependent manner, but it had no effect on Th17 responses. In IL-17-dependent murine organ transplant models of chronic rejection, LAIR1+/+ but not LAIR1-/- littermates mounted strong fibroproliferative responses. Surface LAIR1 expression was higher on human Th17 cells as compared with Th1 cells, ruling out a receptor deficiency that could account for the differences. We conclude that LAIR1 ligation by its natural ligands favors Th17 cell development, allowing for preferential activity of these cells in collagen-rich environments. The emergence of cryptic self-antigens such as the LAIR1 ligand ColV during ischemia/reperfusion injury and early acute rejection, as well as the tendency of macrophages/monocytes to accumulate in the allograft during chronic rejection, favors Th17 over Th1 development, posing a risk to long-term graft survival.


Subject(s)
Graft Rejection/immunology , Receptors, Immunologic/metabolism , Th1 Cells/physiology , Th17 Cells/immunology , Animals , Autoantigens/immunology , Cells, Cultured , Collagen/metabolism , Humans , Immunity, Cellular , Immunomodulation , Interleukin-17/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Monocytes/immunology , Organ Transplantation , Protein Binding , Receptors, Immunologic/genetics
3.
Curr Transplant Rep ; 2(3): 211-221, 2015 Sep.
Article in English | MEDLINE | ID: mdl-29057202

ABSTRACT

Organ transplantation is the only viable treatment for several end-stage organ failures. However chronic rejection prevents long-term graft survival. Traditionally this rejection was attributed to the development of alloimmunity in transplant patients. However recent evidence suggests that autoimmunity plays a larger role in chronic rejection of certain organ transplants, than alloimmunity. In this review we will focus on the history of autoimmunity in solid-organ transplantation and at look the Collagen Type V, K-α-tubulin, Vimentin, Cardiac myosin and Heat Shock Proteins as classical examples of auto-antigens in organ transplantation. We will also look at some of the recent reports looking at the mechanisms of autoimmunity and try to provide answers to some of the age-old questions in autoimmunity.

4.
PLoS One ; 8(11): e79601, 2013.
Article in English | MEDLINE | ID: mdl-24265781

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.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Collagen Type V/immunology , Epitope Mapping , HLA-DRB1 Chains/immunology , Lung Transplantation , Tissue Donors , Amino Acid Sequence , Animals , Autoimmunity , Cattle , Female , Gene Expression Regulation/immunology , HLA-DRB1 Chains/chemistry , Humans , Lung Diseases/immunology , Lung Diseases/surgery , Male , Mice , Molecular Sequence Data
5.
Autoimmunity ; 45(3): 199-209, 2012 May.
Article in English | MEDLINE | ID: mdl-21985327

ABSTRACT

Previous studies characterized B cell-dependent and B cell-independent models of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. To further characterize the B cell response generated in these two models, the serum antibody response and the B cell surface immunoglobulin (Ig) repertoire were analyzed following immunization of wild-type C57BL/6 mice with either recombinant myelin oligodendrocyte glycoprotein (MOG; B cell-dependent EAE) or the encephalitogenic MOG(35-55) peptide (B cell-independent EAE). Plasma ELISA revealed responses to unique linear epitopes of MOG following immunization with recombinant MOG that were absent in MOG(35-55)-immunized animals. B cell repertoire analysis by RT-PCR identified a unique response restricted to 7183 Ig heavy chain variable gene family in mice immunized with recombinant MOG that was not observed in MOG(35-55)-immunized mice. These insights could aid in the identification of the relevant B cell populations important to the pathogenesis of B cell-dependent EAE and in the mechanisms by which these B cell populations contribute to disease.


Subject(s)
B-Lymphocytes/immunology , Encephalomyelitis, Autoimmune, Experimental/immunology , Amino Acid Sequence , Animals , B-Lymphocytes/metabolism , Central Nervous System/immunology , Encephalomyelitis, Autoimmune, Experimental/genetics , Female , Gene Rearrangement, B-Lymphocyte , Immunoglobulin G/blood , Immunoglobulin G/immunology , Immunoglobulin M/blood , Immunoglobulin M/immunology , Immunoglobulin Variable Region/immunology , Lymph Nodes/immunology , Mice , Mice, Inbred C57BL , Myelin Proteins/chemistry , Myelin Proteins/immunology , Myelin-Oligodendrocyte Glycoprotein , Peptides/chemistry , Peptides/immunology
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