Single cell analysis of T cells infiltrating labial salivary glands from patients with Sjögren's syndrome.

Matsumoto, Isao; Okada, Shunsuke; Kuroda, Keiko; Iwamoto, Itsuo; Saito, Yoshihiko; Tokuhisa, Takeshi; Nishioka, Kusuki; Sumida, Takayuki

doi:10.3892/ijmm.4.5.519

Cited by 10 publications

(10 citation statements)

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“…Early studies of the TCR repertoire of SS SG T cells provided evidence of clonal expansion and preferential gene segment usage but were limited by the use of bulk tissue, the separate evaluation of either TCRα or β gene usage, and/or the small numbers of cells analyzed (17, 19, 22, 23). We believe our work is the first to report the direct ex vivo analysis of large numbers (>3,000 CDR3 sequences) of defined, SG-localized memory CD4 + T cells and matched PB samples at the single-cell level from pSS subjects with extensive clinical data.…”

Section: Discussionmentioning

confidence: 99%

“…However, whether these TCR motifs occurred in expanded clones or CD4 + , CD8 + , or memory subsets is unknown. There is also little knowledge of the TCRα gene usage of T cells from SG tissue of pSS patients, with two studies evaluating fewer than 20 cells each (22, 23) and a third study evaluating only a portion of the known Vα gene families (20). Knowledge of paired TCRα and β sequences from SG clonal expansions is required for discovering the antigens driving T cell activation and expansion in SG tissue.…”

Section: Introductionmentioning

confidence: 99%

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Single-cell analysis of glandular T cell receptors in Sjögren’s syndrome

Joachims¹,

Leehan²,

Lawrence³

et al. 2016

JCI Insight

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CD4+ T cells predominate in salivary gland (SG) inflammatory lesions in Sjögren’s syndrome (SS). However, their antigen specificity, degree of clonal expansion, and relationship to clinical disease features remain unknown. We used multiplex reverse-transcriptase PCR to amplify paired T cell receptor α (TCRα) and β transcripts of single CD4+CD45RA− T cells from SG and peripheral blood (PB) of 10 individuals with primary SS, 9 of whom shared the HLA DR3/DQ2 risk haplotype. TCRα and β sequences were obtained from a median of 91 SG and 107 PB cells per subject. The degree of clonal expansion and frequency of cells expressing two productively rearranged α genes were increased in SG versus PB. Expanded clones from SG exhibited complementary-determining region 3 (CDR3) sequence similarity both within and among subjects, suggesting antigenic selection and shared antigen recognition. CDR3 similarities were shared among expanded clones from individuals discordant for canonical Ro and La autoantibodies, suggesting recognition of alternative SG antigen(s). The extent of SG clonal expansion correlated with reduced saliva production and increased SG fibrosis, linking expanded SG T cells with glandular dysfunction. Knowledge of paired TCRα and β sequences enables further work toward identification of target antigens and development of novel therapies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Single-cell analysis of glandular T cell receptors in Sjögren’s syndrome

Joachims¹,

Leehan²,

Lawrence³

et al. 2016

JCI Insight

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“…Scattered T cell clonotypes were found within different Vb families with a distinct pattern from patient to patient [24]. The TCR Vb2 of the infiltrating T cells recognizes restricted epitopes and functions in CD4+ Th0 type T cells [25]. Finally, SS patients producing autoantibodies often have a lower frequency of T cells expressing TCRs with Vb7.2 [26].…”

Section: Emergence Of Adaptive Immune Responsementioning

confidence: 99%

T Lymphocytes in Sjögren’s Syndrome: Contributors to and Regulators of Pathophysiology

Katsifis

Moutsopoulos

Wahl

2007

Clinic Rev Allerg Immunol

101

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Sjögren's syndrome is a chronic autoimmune disorder characterized by lymphocytic infiltration and malfunction of the exocrine glands, resulting in dry mouth and eyes. This multigenic and multifunctional disease can present as primary Sjögren's syndrome or secondary to an underlying connective tissue disease. Immune activation subsequent to activation or apoptosis of glandular epithelial cells in genetically predisposed individuals may expose autoantigens, which engage self-perpetuating T cell dependent autoimmune sequelae. The cellular and molecular context of this immune response may drive proinflammatory (Th1 and Th17) and restrain inhibitory (Treg) pathways. Inability to suppress the immune response results in persistent tissue damage and compromised function of salivary and lacrimal glands. Defining the contributions of participating T cells may unravel strategies for therapeutic intervention.

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“…A study in our laboratory using infiltrated salivary glands in the NOD (non-obese diabetic strain) mouse model of SS has confirmed the expression of E-cadherin on the entire range of infiltrating mononuclear cells (Esch et al, 2000). The only clue thus far as to possible functions for these adhesion molecules comes from a study in which CD8+ T-lymphocytes expressing the aE137 integrin were shown to localize around apoptotic acinar epithelial cells in samples from SS patients' salivary glands (Fujihara et a)., 1999 (1 C) T-CELL ANTIGEN RECEPTOR REPERTOIRES Previous work on restricted T-cell antigen receptor (TCR) usage among infiltrating T-cells in SS has been expanded to single-cell analysis of CDR3 regions (Matsumoto et al, 1999b). One-third of the TCR BV2+ cells isolated by cell sorting expressed one of two conserved CDR33 motifs, and three of these six also exhibited some conservation in the CDR33 region.…”

Section: Introductionmentioning

confidence: 99%

Pathogenetic Factors in Sjögren's Syndrome: Recent Developments

Esch¹

2001

Critical Reviews in Oral Biology & Medicine

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The study of pathogenetic factors in Sjogren's syndrome ISSI has been problematic, given the overall paucity of coherent data that integrate basic research with clinical findings. The presumed autoimmune nature of SS suggests T-cells, autoantibodies, and cytokines as possible immune factors in the initiation and progression of SS. Recent work on programmed cell death (apoptosis) in SS and its models suggests this as a fourth potential mechanism of disease. These four areas of SS research are reviewed with an emphasis on the most recent findings related to mechanisms of disease. New findings confirm the potential for antigen presentation to T-cells in the salivary glands, as well as involvement of other adhesion molecules with respect to T-cell functions. Restrictions on the receptor repertoires of infiltrating T-cells are discussed, as are new findings on antigenic specificities of these cells. New findings on the specificities of autoantibodies observed in SS are reviewed with an eye toward potential mechanisms for depression of exocrine secretory capacity. Stimulating new findings concerning cytokine production in salivary and lacrimal gland are noted.Particular points of interest with regard to apoptosis include the wide range of values obtained for apoptotic activity in SS and its models, and potential means of resolving discongruent results and the study of factors influencing apoptosis are discussed.

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Single cell analysis of T cells infiltrating labial salivary glands from patients with Sjögren's syndrome.

Cited by 10 publications

References 0 publications

Single-cell analysis of glandular T cell receptors in Sjögren’s syndrome

Single-cell analysis of glandular T cell receptors in Sjögren’s syndrome

T Lymphocytes in Sjögren’s Syndrome: Contributors to and Regulators of Pathophysiology

Pathogenetic Factors in Sjögren's Syndrome: Recent Developments

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