Somatic mutations in clonally expanded cytotoxic T lymphocytes in patients with newly diagnosed rheumatoid arthritis

Savola, Paula; Kelkka, Tiina; Rajala, Hanna; Kuuliala, Antti; Kuuliala, Krista; Eldfors, Samuli; Ellonen, Pekka; Lagström, Sonja; Lepistö, Maija; Hannunen, Tiina; Andersson, Emma; Khajuria, Rajiv K.; Jaatinen, Taina; Koivuniemi, Riitta; Repo, Heikki; Saarela, Janna; Porkka, Kimmo; Leirisalo‐Repo, Marjatta; Mustjoki, Satu

doi:10.1038/ncomms15869

Cited by 101 publications

(114 citation statements)

References 54 publications

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“…As the number of mixed repertoire data of TCRs of unkown-specifities in clinical settings is highly increasing (Emerson et al, 2017;Savola et al, 2017;Tumeh et al, 2014), we expect that computational models like ours can be applied to a variety of research questions where exhaustive ex vivo pMHC-multimer assays are not feasible. Applications where our model can prove to be useful includes diagnosis of infectious diseases, linking antiviral immunity to initiation of autoimmune disorders and cancer immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

Determining epitope specificity of T cell receptors with TCRGP

Jokinen

Huuhtanen

Mustjoki

et al. 2019

Preprint

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T cell receptors (TCRs) can recognize various pathogens and consequently start immune responses. TCRs can be sequenced from individuals and methods that can analyze the specificity of the TCRs can help us better understand the individual's immune status in different diseases. We have developed TCRGP, a novel Gaussian process (GP) method that can predict if TCRs recognize certain epitopes. This method can utilize different CDR sequences from both TCRα and TCRβ chains from single-cell data and learn which CDRs are important in recognizing the different epitopes. We have experimented with one previously presented and one new data set and show that TCRGP outperforms other state-of-the-art methods in predicting the epitope specificity of TCRs on both data sets. The software implementation and data sets are available at https://github.com/emmijokinen/TCRGP.

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Section: Discussionmentioning

confidence: 99%

Determining epitope specificity of T cell receptors with TCRGP

Jokinen

Huuhtanen

Mustjoki

et al. 2019

Preprint

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“…Additionally, smaller clonal expansions (Vβ5.1 11.8%, Vβ7.1 21.0%, Vβ17 12.1%, and Vβ23 12.2%) were detected among CD8+ T cells (Figure 1B). To assess the clonality in more detail, FACS-sorted CD4+ Vβ20+, CD4+ Vβ20- and CD8+ T cells, obtained in 2015, were further analyzed by a TCRβ deep-sequencing assay( 6 ), which confirmed the TCRBV30-01 clone expansion (corresponding to the Vβ20+ expansion observed by flow cytometry) in the CD4+Vβ20+ fraction (66.2% of sorted cells) (Figure 1C). TCRβ sequencing of CD8+ T cells revealed two relatively large clones, TCRBV07-09 (16.1%) and TCRBV28-01 (17.9%).…”

Section: Resultsmentioning

confidence: 77%

“…To screen for somatic mutations, a customized immunity and inflammation-related gene sequencing panel (immunogene panel)( 6 ) was applied to immunomagnetic bead-separated blood CD4+ and CD8+ T cells, that were obtained from the index patient in 2013. The median target gene coverage for the panel was 152 in CD4+ and 160 for CD8+ T cells.…”

Section: Resultsmentioning

confidence: 99%

Somatic Mutations in Clonally Expanded T-lymphocytes in Patients with Chronic Graft-Versus-Host Disease

Park

Kim

Huuhtanen

et al. 2019

Preprint

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38Graft-versus-host-disease (GvHD) is the main complication of allogeneic hematopoietic stem cell 39 transplantation. GvHD patients have aberrant T cell expansions, which are thought to drive pathological 40 immune activation. Here we report mechanistic insights that somatic mutations may account for persistent 41 clonal T cell expansions in chronic GvHD (cGvHD). In an index patient suffering from cGVHD, we discovered 42 persisting somatic MTOR, NFKB2, and TLR2 mutations in an expanded CD4+ T clone. In the screening 43 cohort (n=135), the MTOR P2229R kinase domain mutation was detected in two additional cGvHD patients, 44but not in controls. Functional analysis of the discovered MTOR mutation indicated a gain-of-function 45 alteration in translational regulation yielding in up-regulation of phosphorylated S6K1, S6, and AKT. Paired 46 single-cell RNA and T cell receptor alpha and beta sequencing strongly supported cytotoxicity and 47 54 55Graft-versus host disease (GvHD) is the main complication of allogeneic hematopoietic stem cell 56 transplantation (allo-HSCT).(1) Chronic GvHD (cGvHD), that occurs more than 100 days after the 57 transplantation, develops in 30-70 % of allo-HSCT recipients. Affected patients frequently need 58 immunosuppressive treatment for years or even for a lifetime, and in many patients the condition is 59 fatal.(2) The genesis of cGvHD is multifactorial, but donor alloreactive lymphocytes are believed to be the 60 key pathogenetic drivers that target host tissues such as skin, soft tissues, oral mucosa, and eyes. In 61 particular, CD4+ T cells contribute to the early inflammation and tissue injury, to subsequent chronic 62 inflammation, and late aberrant tissue repair and fibrosis.(3) 63 During normal immune response, naïve T cells encounter their cognate antigen, get activated and 64 undergo a rapid clonal expansion.(4) The activation and proliferation of T cells are usually tightly regulated 65 processes, in which effector cells undergo apoptosis upon proper immune response. In many immune-66 system-mediated disorders, such as cGvHD, the immune homeostasis is disturbed, and the enormous 67 variability of different T cell clones is diminished. In some patients, the T cell receptor (TCR) repertoire is 68 heavily skewed, and clones comprising up to 20-40% of all T cells can exist.(5) The underlying mechanisms 69 for this phenomenon remain unknown. 70Here, we hypothesized that in cGvHD antigen-encountered T cells may acquire somatic mutations 71 due to constant immune-system activation and proliferation. Such mutations might lead to functional and 72 survival advantages of T cells that result in clonal expansion and aberrant immune responses. To explore 73 this theory, we sequenced purified CD4+ and CD8+ lymphocytes from an index patient suffering from 74 cGVHD with a custom deep-sequencing panel consisting of immunity and inflammation-related genes. 75 Mutation findings were confirmed in a validation cohort of 135 GVHD patients. Subsequently, the 76 functional consequences of the discovered...

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“…Estudos sugerem que células inflamatórias como os linfócitos T, presentes no líquido sinovial em articulações acometidas pela AR, constituem a principal fonte de RANKL nesta doença 22,23,24 .…”

Section: Perda óSsea Inflamatória Na Artrite Reumatoide E Na Periodonunclassified

Efeito Da Terapia Periodontal Não Cirúrgica Na Redução Da Severidade Da Artrite Reumatoide

Sousa¹,

Figueiredo²,

Guimarães³

2017

RevBahianaOdonto

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A remodelação óssea é um processo contínuo que depende da atuação equilibrada entre osteoclastos e osteoblastos, responsáveis pela reabsorção e formação óssea, respectivamente. Situações inflamatórias persistentes podem alterar este processo, como a artrite reumatoide (AR) e a periodontite crônica. A patogênese destas duas doenças está associada às alterações nos níveis de mediadores inflamatórios que leva a um desequilíbrio imunológico associado à perda óssea. Estudos têm sugerido que tais doenças são bidirecionais, onde a presença de uma influencia a evolução da outra. Esse trabalho revisa os resultados de estudos de pesquisas científicas sobre o efeito da terapia periodontal não cirúrgica (TP) na redução da gravidade da AR. Para tanto, foi realizada uma busca por artigos científicos publicados a partir do ano 2006, no banco de dados PubMed, utilizando-se as palavras chaves: artrite reumatoide, periodontite e tratamento periodontal, nos idiomas inglês/português. Foram selecionados nove estudos com metodologia de pesquisa semelhante e que compuseram amostras de pacientes acometidos pelas duas doenças. Parâmetros como índice de sangramento gengival, profundidade de sondagem, sangramento à sondagem ou nível clínico de inserção avaliaram a condição periodontal de cada paciente, enquanto que questionários averiguando a qualidade de vida dos pacientes e os testes laboratoriais relacionados à atividade inflamatória sistêmica foram considerados parâmetros associados à severidade da artrite reumatoide. Em oito estudos, a TP reduziu significamente severidade inflamatória da AR. Assim, os últimos dados científicos indicam o benefício da realização do TP ao reduzir a gravidade da AR, considerando, ainda a facilidade e baixo custo deste tipo de terapia.

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Somatic mutations in clonally expanded cytotoxic T lymphocytes in patients with newly diagnosed rheumatoid arthritis

Cited by 101 publications

References 54 publications

Determining epitope specificity of T cell receptors with TCRGP

Determining epitope specificity of T cell receptors with TCRGP

Somatic Mutations in Clonally Expanded T-lymphocytes in Patients with Chronic Graft-Versus-Host Disease

Efeito Da Terapia Periodontal Não Cirúrgica Na Redução Da Severidade Da Artrite Reumatoide

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