Autoimmunity is intrinsically driven by memory T and B cell clones inappropriately targeted at self-antigens. Selective depletion or suppression of self-reactive T cells remains a holy grail of autoimmune therapy, but disease-associated T cell receptors (TCRs) and cognate antigenic epitopes remained elusive. A TRBV9-containing CD8+ TCR motif was recently associated with the pathogenesis of ankylosing spondylitis, psoriatic arthritis and acute anterior uveitis, and cognate HLA-B*27-presented epitopes were identified. Following successful testing in nonhuman primate models, here we report human TRBV9+ T cell elimination in ankylosing spondylitis. The patient achieved remission within 3 months and ceased anti-TNF therapy after 5 years of continuous use. Complete remission has now persisted for 4 years, with three doses of anti-TRBV9 administered per year. We also observed a profound improvement in spinal mobility metrics and the Bath Ankylosing Spondylitis Metrology Index (BASMI). This represents a possibly curative therapy of an autoimmune disease via selective depletion of a TRBV-defined group of T cells. The anti-TRBV9 therapy could potentially be applicable to other HLA-B*27-associated spondyloarthropathies. Such targeted elimination of the underlying cause of the disease without systemic immunosuppression could offer a new generation of safe and efficient therapies for autoimmunity.

• MeSH
• Spondylitis, Ankylosing * drug therapy   MeSH
• Epitopes MeSH
• HLA-B Antigens MeSH
• Immunotherapy MeSH
• Tumor Necrosis Factor Inhibitors therapeutic use   MeSH
• Humans MeSH
• Receptors, Antigen, T-Cell genetics   therapeutic use   MeSH
• T-Lymphocytes MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Names of Substances
• Epitopes MeSH
• HLA-B Antigens MeSH
• Tumor Necrosis Factor Inhibitors MeSH
• Receptors, Antigen, T-Cell MeSH

BACKGROUND AND AIMS: Intestinal inflammation in inflammatory bowel diseases [IBD] is thought to be T cell mediated and therefore dependent on the interaction between the T cell receptor [TCR] and human leukocyte antigen [HLA] proteins expressed on antigen presenting cells. The collection of all TCRs in one individual, known as the TCR repertoire, is characterised by enormous diversity and inter-individual variability. It was shown that healthy monozygotic [MZ] twins are more similar in their TCR repertoire than unrelated individuals. Therefore MZ twins, concordant or discordant for IBD, may be useful to identify disease-related and non-genetic factors in the TCR repertoire which could potentially be used as disease biomarkers. METHODS: Employing unique molecular barcoding that can distinguish between polymerase chain reaction [PCR] artefacts and true sequence variation, we performed deep TCRα and TCRβ repertoire profiling of the peripheral blood of 28 MZ twin pairs from Denmark and Germany, 24 of whom were discordant and four concordant for IBD. RESULTS: We observed disease- and smoking-associated traits such as sharing, diversity and abundance of specific clonotypes in the TCR repertoire of IBD patients, and particularly in patients with active disease, compared with their healthy twins. CONCLUSIONS: Our findings identified TCR repertoire features specific for smokers and IBD patients, particularly when signs of disease activity were present. These findings are a first step towards the application of TCR repertoire analyses as a valuable tool to characterise inflammatory bowel diseases and to identify potential biomarkers and true disease causes.

• Keywords
• T cell receptor [TCR] repertoire, inflammatory bowel diseases [IBD], monozygotic twins,
• MeSH
• C-Reactive Protein analysis   MeSH
• Crohn Disease * diagnosis   immunology   physiopathology   MeSH
• Adult MeSH
• Twins, Monozygotic MeSH
• Feces MeSH
• Genes, T-Cell Receptor alpha * MeSH
• Genes, T-Cell Receptor beta * MeSH
• Smoking immunology   MeSH
• Leukocyte L1 Antigen Complex analysis   MeSH
• Humans MeSH
• Patient Acuity MeSH
• Receptors, Antigen, T-Cell, alpha-beta blood   MeSH
• Sequence Analysis, DNA MeSH
• Colitis, Ulcerative * diagnosis   immunology   physiopathology   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Twin Study MeSH
• Geographicals
• Denmark MeSH
• Germany MeSH
• Names of Substances
• C-Reactive Protein MeSH
• Leukocyte L1 Antigen Complex MeSH
• Receptors, Antigen, T-Cell, alpha-beta MeSH

Hypervariable T cell receptors (TCRs) play a key role in adaptive immunity, recognizing a vast diversity of pathogen-derived antigens. Our ability to extract clinically relevant information from large high-throughput sequencing of TCR repertoires (RepSeq) data is limited, because little is known about TCR-disease associations. We present Antigen-specific Lymphocyte Identification by Clustering of Expanded sequences (ALICE), a statistical approach that identifies TCR sequences actively involved in current immune responses from a single RepSeq sample and apply it to repertoires of patients with a variety of disorders - patients with autoimmune disease (ankylosing spondylitis [AS]), under cancer immunotherapy, or subject to an acute infection (live yellow fever [YF] vaccine). We validate the method with independent assays. ALICE requires no longitudinal data collection nor large cohorts, and it is directly applicable to most RepSeq datasets. Its results facilitate the identification of TCR variants associated with diseases and conditions, which can be used for diagnostics and rational vaccine design.

• MeSH
• Adaptive Immunity genetics   MeSH
• Antigens, Viral MeSH
• Antigens MeSH
• Complementarity Determining Regions genetics   physiology   MeSH
• Immunotherapy MeSH
• Humans MeSH
• Receptors, Antigen, T-Cell immunology   metabolism   physiology   MeSH
• Sequence Analysis, DNA methods   MeSH
• Cluster Analysis MeSH
• High-Throughput Nucleotide Sequencing methods   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Antigens, Viral MeSH
• Antigens MeSH
• Complementarity Determining Regions MeSH
• Receptors, Antigen, T-Cell MeSH