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1.
Front Immunol ; 15: 1374581, 2024.
Article in English | MEDLINE | ID: mdl-38524140

ABSTRACT

Introduction: Psoriasis is a T-cell mediated autoimmune skin disease. HLA-C*06:02 is the main psoriasis-specific risk gene. Using a Vα3S1/Vß13S1 T-cell receptor (TCR) from a lesional psoriatic CD8+ T-cell clone we had discovered that, as an underlying pathomechanism, HLA-C*06:02 mediates an autoimmune response against melanocytes in psoriasis, and we had identified an epitope from ADAMTS-like protein 5 (ADAMTSL5) as a melanocyte autoantigen. The conditions activating the psoriatic autoimmune response in genetically predisposed individuals throughout life remain incompletely understood. Here, we aimed to identify environmental antigens that might trigger autoimmunity in psoriasis because of TCR polyspecificity. Methods: We screened databases with the peptide recognition motif of the Vα3S1/Vß13S1 TCR for environmental proteins containing peptides activating this TCR. We investigated the immunogenicity of these peptides for psoriasis patients and healthy controls by lymphocyte stimulation experiments and peptide-loaded HLA-C*06:02 tetramers. Results: We identified peptides from wheat, Saccharomyces cerevisiae, microbiota, tobacco, and pathogens that activated both the Vα3S1/Vß13S1 TCR and CD8+ T cells from psoriasis patients. Using fluorescent HLA-C*06:02 tetramers loaded with ADAMTSL5 or wheat peptides, we find that the same CD8+ T cells may recognize both autoantigen and environmental antigens. A wheat-free diet could alleviate psoriasis in several patients. Discussion: Our results show that due to TCR polyspecificity, several environmental antigens corresponding to previously suspected psoriasis risk conditions converge in the reactivity of a pathogenic psoriatic TCR and might thus be able to stimulate the psoriatic autoimmune response against melanocytes. Avoiding the corresponding environmental risk factors could contribute to the management of psoriasis.


Subject(s)
Autoimmunity , Psoriasis , Humans , CD8-Positive T-Lymphocytes , HLA-C Antigens , Autoantigens , Peptides , Receptors, Antigen, T-Cell , ADAMTS Proteins
2.
J Immunol ; 207(9): 2235-2244, 2021 11 01.
Article in English | MEDLINE | ID: mdl-34580106

ABSTRACT

Autoimmune diseases develop when autoantigens activate previously quiescent self-reactive lymphocytes. Gene-gene interaction between certain HLA class I risk alleles and variants of the endoplasmic reticulum aminopeptidase ERAP1 controls the risk for common immune-mediated diseases, including psoriasis, ankylosing spondylitis, and Behçet disease. The functional mechanisms underlying this statistical association are unknown. In psoriasis, HLA-C*06:02 mediates an autoimmune response against melanocytes by autoantigen presentation. Using various genetically modified cell lines together with an autoreactive psoriatic TCR in a TCR activation assay, we demonstrate in this study that in psoriasis, ERAP1 generates the causative melanocyte autoantigen through trimming N-terminal elongated peptide precursors to the appropriate length for presentation by HLA-C*06:02. An ERAP1 risk haplotype for psoriasis produced the autoantigen much more efficiently and increased HLA-C expression and stimulation of the psoriatic TCR by melanocytes significantly more than a protective haplotype. Compared with the overall HLA class I molecules, cell surface expression of HLA-C decreased significantly more upon ERAP1 knockout. The combined upregulation of ERAP1 and HLA-C on melanocytes in psoriasis lesions emphasizes the pathogenic relevance of their interaction in patients. We conclude that in psoriasis pathogenesis, the increased generation of an ERAP1-dependent autoantigen by an ERAP1 risk haplotype enhances the likelihood that autoantigen presentation by HLA-C*06:02 will exceed the threshold for activation of potentially autoreactive T cells, thereby triggering CD8+ T cell-mediated autoimmune disease. These data identify ERAP1 function as a central checkpoint and promising therapeutic target in psoriasis and possibly other HLA class I-associated diseases with a similar genetic predisposition.


Subject(s)
Aminopeptidases/metabolism , CD8-Positive T-Lymphocytes/immunology , HLA-C Antigens/metabolism , Melanocytes/immunology , Minor Histocompatibility Antigens/metabolism , Psoriasis/immunology , Aminopeptidases/genetics , Antigen Presentation , Autoantigens/immunology , Autoimmunity , Gene Knockdown Techniques , Genetic Predisposition to Disease , HEK293 Cells , HLA-C Antigens/genetics , Humans , Minor Histocompatibility Antigens/genetics , Molecular Targeted Therapy , Psoriasis/genetics , Receptors, Antigen, T-Cell/metabolism , Risk
3.
Front Immunol ; 10: 1336, 2019.
Article in English | MEDLINE | ID: mdl-31275310

ABSTRACT

Recognition of cancer antigens drives the clonal expansion of cancer-reactive T cells, which is thought to contribute to restricted T-cell receptor (TCR) repertoires in tumor-infiltrating lymphocytes (TILs). To understand how tumors escape anti-tumor immunity, we investigated tumor-associated T-cell repertoires of patients with advanced melanoma and after blockade of the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1 (PD-1). TCR Vß-gene spectratyping allowed us to quantify restrictions of T-cell repertoires and, further, diversities of T-cell clones. In this study, we show that the blood TCR repertoires were variably restricted in CD4+ and extensively restricted in CD8+ T cells of patients with advanced melanoma, and contained clones in both T-cell fractions prior to the start of immunotherapy. A greater diversification especially of CD4+ blood T-cell clones before immunotherapy showed statistically significant correlations with long-term survival upon CTLA4 or PD-1 inhibition. Analysis of TILs and corresponding blood available in one patient indicated that blood clonality may at least partially be related to the clonal expansion in the tumor microenvironment. In patients who developed severe immune-related adverse events (IrAEs), CD4+ and CD8+ TCR spectratypes became more restricted during anti-CTLA4 treatment, suggesting that newly expanded oligoclonal T-cell responses may contribute to IrAEs. This study reveals diverse T-cell clones in the blood of melanoma patients prior to immunotherapy, which may reflect the extent to which T cells are able to react against melanoma and potentially control melanoma progression. Therefore, the T-cell clonality in the circulation may have predictive value for antitumor responses from checkpoint inhibition.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CTLA-4 Antigen/immunology , Melanoma/immunology , Programmed Cell Death 1 Receptor/immunology , Adult , Aged , CD8-Positive T-Lymphocytes/immunology , Female , Humans , Immunotherapy/methods , Lymphocytes, Tumor-Infiltrating/immunology , Male , Middle Aged , Tumor Microenvironment/immunology
4.
J Invest Dermatol ; 138(6): 1338-1347, 2018 06.
Article in English | MEDLINE | ID: mdl-29288651

ABSTRACT

Generalized pustular psoriasis (GPP) is the most severe psoriasis variant. Mutations in the IL-36 antagonist IL36RN, in CARD14 or AP1S3 provide genetic evidence for autoinflammatory etiology but cannot explain its pathogenesis completely. Here we demonstrate that unopposed IL-36 signaling promotes antigen-driven and likely pathogenic T-helper type 17 (Th17) responses in GPP. We observed that CD4+ T cells in blood and skin lesions of GPP patients were characterized by intense hyperproliferation, production of the GPP key mediator, IL-17A, and highly restricted TCR repertoires with identical T-cell clones in blood and skin lesions, indicating antigen-driven T-cell expansions. The clonally expanded CD4+ T cells were major producers of IL-17A. IL-36 signaling substantially enhanced TCR-mediated proliferation of CD4+ T cells. Moreover, GPP patients showed preferences for HLA-DRB1∗14, HLA-DQB1∗05, and HLA-DQB1∗03. We conclude that in GPP unopposed IL-36 signaling and certain HLA-class II alleles may cooperate in promoting antigen-driven Th17 responses, which in the obvious absence of exogenous triggers may reflect autoimmune reactions. This study reveals a pathogenic pathway where innate immune dysregulation promotes T-cell-mediated inflammation in GPP.


Subject(s)
Autoimmunity , Interleukin-17/metabolism , Interleukin-1/metabolism , Psoriasis/immunology , Th17 Cells/immunology , Adult , Aged , Autoantigens/immunology , Female , Histocompatibility Antigens Class II/immunology , Histocompatibility Antigens Class II/metabolism , Humans , Interleukin-1/immunology , Interleukin-17/immunology , Interleukins/genetics , Interleukins/immunology , Male , Middle Aged , Psoriasis/genetics , Psoriasis/pathology , Receptors, Antigen, T-Cell/immunology , Receptors, Antigen, T-Cell/metabolism , Skin/immunology , Skin/metabolism , Skin/pathology , Th17 Cells/metabolism , Young Adult
5.
J Exp Med ; 212(13): 2203-12, 2015 Dec 14.
Article in English | MEDLINE | ID: mdl-26621454

ABSTRACT

Psoriasis vulgaris is a common T cell-mediated inflammatory skin disease with a suspected autoimmune pathogenesis. The human leukocyte antigen (HLA) class I allele, HLA-C*06:02, is the main psoriasis risk gene. Epidermal CD8(+) T cells are essential for psoriasis development. Functional implications of HLA-C*06:02 and mechanisms of lesional T cell activation in psoriasis, however, remained elusive. Here we identify melanocytes as skin-specific target cells of an HLA-C*06:02-restricted psoriatic T cell response. We found that a Vα3S1/Vß13S1 T cell receptor (TCR), which we had reconstituted from an epidermal CD8(+) T cell clone of an HLA-C*06:02-positive psoriasis patient specifically recognizes HLA-C*06:02-positive melanocytes. Through peptide library screening, we identified ADAMTS-like protein 5 (ADAMTSL5) as an HLA-C*06:02-presented melanocytic autoantigen of the Vα3S1/Vß13S1 TCR. Consistent with the Vα3S1/Vß13S1-TCR reactivity, we observed numerous CD8(+) T cells in psoriasis lesions attacking melanocytes, the only epidermal cells expressing ADAMTSL5. Furthermore, ADAMTSL5 stimulation induced the psoriasis signature cytokine, IL-17A, in CD8(+) T cells from psoriasis patients only, supporting a role as psoriatic autoantigen. This unbiased analysis of a TCR obtained directly from tissue-infiltrating CD8(+) T cells reveals that in psoriasis HLA-C*06:02 directs an autoimmune response against melanocytes through autoantigen presentation. We propose that HLA-C*06:02 may predispose to psoriasis via this newly identified autoimmune pathway.


Subject(s)
Autoantigens/immunology , Autoimmunity/immunology , Melanocytes/metabolism , Psoriasis/immunology , ADAM Proteins/metabolism , ADAMTS Proteins , Adult , Amino Acid Sequence , CD8-Positive T-Lymphocytes/immunology , Cell Line , Epidermis/metabolism , Epidermis/pathology , Epitopes/chemistry , Epitopes/immunology , Female , HLA-C Antigens/immunology , Humans , Male , Molecular Sequence Data , Peptides/chemistry , Receptors, Antigen, T-Cell, alpha-beta/metabolism
6.
PLoS One ; 7(5): e37338, 2012.
Article in English | MEDLINE | ID: mdl-22649519

ABSTRACT

Analysis of the paired i.e. matching TCR α- and ß-chain rearrangements of single human T cells is required for a precise investigation of clonal diversity, tissue distribution and specificity of protective and pathologic T-cell mediated immune responses. Here we describe a multiplex RT-PCR based technology, which for the first time allows for an unbiased analysis of the complete sequences of both α- and ß-chains of TCR from single T cells. We validated our technology by the analysis of the pathologic T-cell infiltrates from tissue lesions of two T-cell mediated autoimmune diseases, psoriasis vulgaris (PV) and multiple sclerosis (MS). In both disorders we could detect various T cell clones as defined by multiple T cells with identical α- and ß-chain rearrangements distributed across the tissue lesions. In PV, single cell TCR analysis of lesional T cells identified clonal CD8(+) T cell expansions that predominated in the epidermis of psoriatic plaques. An MS brain lesion contained two dominant CD8(+) T-cell clones that extended over the white and grey matter and meninges. In both diseases several clonally expanded T cells carried dual TCRs composed of one Vß and two different Vα-chain rearrangements. These results show that our technology is an efficient instrument to analyse αß-T cell responses with single cell resolution in man. It should facilitate essential new insights into the mechanisms of protective and pathologic immunity in many human T-cell mediated conditions and allow for resurrecting functional TCRs from any αß-T cell of choice that can be used for investigating their specificity.


Subject(s)
Genes, T-Cell Receptor alpha/genetics , Genes, T-Cell Receptor beta/genetics , Multiplex Polymerase Chain Reaction/methods , Reverse Transcriptase Polymerase Chain Reaction/methods , T-Lymphocytes/metabolism , Antigen-Presenting Cells/immunology , DNA Primers/genetics , Flow Cytometry , Humans , Multiple Sclerosis/immunology , Psoriasis/immunology , Skin/immunology
7.
J Immunol ; 184(9): 5392-402, 2010 May 01.
Article in English | MEDLINE | ID: mdl-20363977

ABSTRACT

Psoriasis is an HLA-Cw6-associated T cell-mediated autoimmune disease of the skin that is often triggered by streptococcal angina. To identify keratinocyte proteins, which may become psoriatic autoantigens as the result of an immune response against streptococci, rabbits were immunized with heat-killed Streptococcus pyogenes. Streptococcal immunization induced Ab formation against various human keratinocyte proteins. Sera from psoriasis patients reacted against several of these proteins as well. Common serologic reactivities of rabbits and patients included the proteins ezrin, maspin, peroxiredoxin 2 (PRDX2), heat shock protein (hsp)27, and keratin 6. When used for stimulation of blood lymphocytes, ezrin, maspin, PRDX2, and hsp27 induced increased T cell activation in psoriasis patients, which was particularly evident for HLA-Cw6(+) individuals. Ag-specific T cell lines generated with these proteins consisted predominantly of CD8(+) T cells and used TCR beta-chain rearrangements, which were highly homologous to those expanded within the corresponding skin lesion. Several immunodominant epitopes on the different proteins could be defined according to sequence alignments with the whole genome of S. pyogenes. Our data indicate that maspin, ezrin, PRDX2, hsp27, and potentially keratin 6 could act as autoantigens of a streptococcal-induced autoimmune response and represent targets of the exaggerated T cell response in psoriasis. Additionally, ezrin and hsp27 might constitute antigenic links between psoriasis and inflammatory bowel disease, uveitis, or arteriosclerosis, which are clinically associated.


Subject(s)
Autoimmune Diseases/immunology , Autoimmune Diseases/microbiology , Cytoskeletal Proteins/immunology , HSP27 Heat-Shock Proteins/immunology , Peroxiredoxins/immunology , Psoriasis/immunology , Serpins/immunology , Streptococcal Infections/immunology , Amino Acid Sequence , Animals , Autoantigens/immunology , Autoimmune Diseases/blood , Cell Line, Transformed , Cell Line, Tumor , Cells, Cultured , Cytoskeletal Proteins/blood , Epitopes, T-Lymphocyte/immunology , HSP27 Heat-Shock Proteins/blood , Humans , Keratinocytes/immunology , Keratinocytes/metabolism , Keratinocytes/pathology , Molecular Sequence Data , Peroxiredoxins/blood , Psoriasis/blood , Psoriasis/microbiology , Rabbits , Serpins/blood , Streptococcal Infections/blood , Streptococcal Vaccines/administration & dosage , Streptococcal Vaccines/immunology , Streptococcus pyogenes/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/microbiology
8.
J Immunol ; 176(11): 7104-11, 2006 Jun 01.
Article in English | MEDLINE | ID: mdl-16709873

ABSTRACT

Tonsillar infection with Streptococcus pyogenes may induce several nonsuppurative autoimmune sequelae. The precise pathogenetic mechanisms behind this clinically well-established association are still unresolved. Using TCR analysis, we sought to identify a link between streptococcal tonsillitis and the T cell-mediated autoimmune response in psoriasis. Three patients with streptococcal-induced psoriasis underwent tonsillectomy. Using size spectratyping and sequencing of TCR beta-chain variable region gene (TCRBV) rearrangements, we compared the TCR usage of psoriatic skin lesions, blood, tonsils, and tonsillar T cells fractionated according to the expression of the skin address in "cutaneous lymphocyte-associated Ag" (CLA). TCRBV-size spectratype analysis of the blood lymphocytes, tonsils, and the CLA-negative tonsillar T cells revealed largely unselected T cell populations. Instead, TCRBV gene families of the psoriatic lesions and skin-homing CLA-positive tonsillar T cells displayed highly restricted spectratypes. Sequencing of TCRBV cDNA identified various clonal TCRBV rearrangements within the psoriatic lesions that indicated Ag-driven T cell expansion. Several of these clonotypes were also detected within the tonsils and, in one of the patients, within the small subset of CLA-positive tonsillar T cells, suggesting that T cells from the same T cell clones were simultaneously present within skin and tonsillar tissue. Because after tonsillectomy psoriasis cleared in all three patients our observations indicate that T cells may connect psoriatic inflammation to streptococcal angina. They suggest that the chronic streptococcal immune stimulus within the tonsils could act as a source for pathogenic T cells in poststreptococcal disorders, and they may help to explain why eliminating this source with tonsillectomy may improve streptococcal-induced sequelae.


Subject(s)
Gene Rearrangement, beta-Chain T-Cell Antigen Receptor , Psoriasis/immunology , Psoriasis/pathology , Receptors, Antigen, T-Cell, alpha-beta/biosynthesis , Receptors, Antigen, T-Cell, alpha-beta/isolation & purification , Rheumatic Heart Disease/immunology , Streptococcal Infections/immunology , T-Lymphocyte Subsets/metabolism , Adult , Amino Acid Sequence , Antigens, Differentiation, T-Lymphocyte , Antigens, Neoplasm/genetics , Base Sequence , Clone Cells , Humans , Membrane Glycoproteins/genetics , Molecular Sequence Data , Multigene Family , Palatine Tonsil/immunology , Palatine Tonsil/metabolism , Palatine Tonsil/pathology , Psoriasis/surgery , Receptors, Antigen, T-Cell, alpha-beta/genetics , Receptors, Lymphocyte Homing/genetics , Remission Induction , Rheumatic Heart Disease/pathology , Rheumatic Heart Disease/surgery , Severity of Illness Index , Streptococcal Infections/pathology , Streptococcal Infections/surgery , Streptococcus pyogenes/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/pathology , Tonsillectomy , Tonsillitis/immunology , Tonsillitis/pathology , Tonsillitis/surgery
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