Autoimmune Disease Research

Immunosequencing enables incredible insight into the adaptive immune system and its role in numerous disease states by identifying biomarkers of disease, response, or inflammation, and establishing mechanism of action of therapeutics through assessment of repertoire dynamics. With a few clicks, the immunoSEQ® Analyzer allows you to easily correlate repertoire characteristics with disease, flare ups, and mechanism of action, along with other important analyses.

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  • SEQdiscovery Autoimmune Webinar
    Applications of Immunosequencing in Autoimmunity

    This webinar describes how researchers have applied the immunoSEQ® Technology in the context of autoimmune research including applications in diseases such as Crohn's disease, multiple sclerosis, psoriasis, narcolepsy, and alopecia, as well as treatment-induced autoimmunity. Learn how immunosequencing can be used to understand autoimmune disease pathology, response to different treatment modalities, and duration of treatment response.

NEW AND KEY PUBLICATIONS

Kelkka et al. Front Immunol. 2020

Adult-Onset Anti-Citrullinated Peptide Antibody-Negative Destructive Rheumatoid Arthritis Is Characterized by a Disease-Specific CD8+ T Lymphocyte Signature

Rheumatoid arthritis (RA) is a complex autoimmune disease targeting synovial joints. Traditionally, RA is divided into seropositive (SP) and seronegative (SN) disease forms, the latter consisting of an array of unrelated diseases with joint involvement. Recently, we described a severe form of SN-RA that associates with characteristic joint destruction. Here, we sought biological characteristics to differentiate this rare but aggressive anti-citrullinated peptide antibody-negative destructive RA (CND-RA) from early seropositive (SP-RA) and seronegative rheumatoid arthritis (SN-RA). We also aimed to study cytotoxic CD8+ lymphocytes in autoimmune arthritis. CND-RA, SP-RA and SN-RA were compared to healthy controls to reveal differences in T-cell receptor beta (TCRβ) repertoire, cytokine levels and autoantibody repertoires. Whole-exome sequencing (WES) followed by single-cell RNA-sequencing (sc-RNA-seq) was performed to study somatic mutations in a clonally expanded CD8+ lymphocyte population in an index patient. A unique TCRβ signature was detected in CND-RA patients. In addition, CND-RA patients expressed higher levels of the bone destruction-associated TNFSF14 cytokine. Blood IgG repertoire from CND-RA patients recognized fewer endogenous proteins than SP-RA patients’ repertoires. Using WES, we detected a stable mutation profile in the clonally expanded CD8+ T-cell population characterized by cytotoxic gene expression signature discovered by sc-RNA-sequencing. Our results identify CND-RA as an independent RA subset and reveal a CND-RA specific TCR signature in the CD8+ lymphocytes. Improved classification of seronegative RA patients underlines the heterogeneity of RA and also, facilitates development of improved therapeutic options for the treatment resistant patients.

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Khosravi-Maharlooei et al. Journal of Autoimmunity, 2021

Role of the thymus in spontaneous development of a multi-organ autoimmune disease in human immune system mice

We evaluated the role of the thymus in development of multi-organ autoimmunity in human immune system (HIS) mice. T cells were essential for disease development and the same T cell clones with varying phenotypes infiltrated multiple tissues. De novo-generated hematopoietic stem cell (HSC)-derived T cells were the major disease drivers, though thymocytes pre-existing in grafted human thymi contributed if not first depleted. HIS mice with a native mouse thymus developed disease earlier than thymectomized mice with a thymocyte-depleted human thymus graft. Defective structure in the native mouse thymus was associated with impaired negative selection of thymocytes expressing a transgenic TCR recognizing a self-antigen. Disease developed without direct recognition of antigens on recipient mouse MHC. While human thymus grafts had normal structure and negative selection, failure to tolerize human T cells recognizing mouse antigens presented on HLA molecules may explain eventual disease development. These new insights have implications for human autoimmunity and suggest methods of avoiding autoimmunity in next-generation HIS mice.

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Keymeulen et al, Diabetologia, 2021

randomised, single-blind, placebo-controlled, dose-finding safety and tolerability study of the anti-CD3 monoclonal antibody otelixizumab in new-onset type 1 diabetes

Numerous clinical studies have investigated the anti-CD3ɛ monoclonal antibody otelixizumab in individuals with type 1 diabetes, but limited progress has been made in identifying the optimal clinical dose with acceptable tolerability and safety. The aim of this study was to evaluate the association between dose-response, safety and tolerability, beta cell function preservation and the immunological effects of otelixizumab in new-onset type 1 diabetes.

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Jiang et al. Proc Natl Acad Sci USA, 2020

Thymus-derived B cell clones persist in the circulation after thymectomy in myasthenia gravis

Myasthenia gravis (MG) is a neuromuscular, autoimmune disease caused by autoantibodies that target postsynaptic proteins, primarily the acetylcholine receptor (AChR) and inhibit signaling at the neuromuscular junction. The majority of patients under 50 y with AChR autoantibody MG have thymic lymphofollicular hyperplasia. The MG thymus is a reservoir of plasma cells that secrete disease-causing AChR autoantibodies and although thymectomy improves clinical scores, many patients fail to achieve complete stable remission without additional immunosuppressive treatments. We speculate that thymus-associated B cells and plasma cells persist in the circulation after thymectomy and that their persistence could explain incomplete responses to resection. We studied patients enrolled in a randomized clinical trial and used complementary modalities of B cell repertoire sequencing to characterize the thymus B cell repertoire and identify B cell clones that resided in the thymus and circulation before and 12 mo after thymectomy. Thymus-associated B cell clones were detected in the circulation by both mRNA-based and genomic DNA-based sequencing. These antigen-experienced B cells persisted in the circulation after thymectomy. Many circulating thymus-associated B cell clones were inferred to have originated and initially matured in the thymus before emigration from the thymus to the circulation. The persistence of thymus-associated B cells correlated with less favorable changes in clinical symptom measures, steroid dose required to manage symptoms, and marginal changes in AChR autoantibody titer. This investigation indicates that the diminished clinical response to thymectomy is related to persistent circulating thymus-associated B cell clones.

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ACCESS OUR LATEST CONTENT

T-cell repertoire dynamics during pregnancy in multiple sclerosis

Read this case study to learn how Ramien et al. characterized repertoire changes at high-level and single-clone level by sequencing the T-cell repertoire in female Multiple Sclerosis patients and healthy women over the course of pregnancy, and post-partum relapse.

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High-throughput T-cell receptor sequencing identifies clonally expanded CD8+ T cell populations in alopecia areata

Learn how de Jong et al. used TCR sequencing to analyze TCR diversity and dynamics of effector T-cell populations and to monitor pathogenic T cells duing alopecia areata onset and during treatment

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COVID-19 Applications

Learn how immunoSEQ® T-MAP™ COVID can help uncover the T-cell immune response in COVID-19.

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