Shared αβ TCR Usage in Lungs of Sarcoidosis Patients with Löfgren’s Syndrome

Mitchell, Angela M.; Kaiser, Ylva; Falta, Michael T.; Munson, Daniel J.; Landry, Laurie G.; Eklúnd, Anders; Nakayama, Maki; Slansky, Jill E.; Grünewald, Johan; Fontenot, Andrew P.

doi:10.4049/jimmunol.1700570

Cited by 19 publications

(22 citation statements)

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“…Neither IgG nor IgA for any of the investigated vimentin substrates showed any consistent relationship between the AVA levels in BALF and serum. This observation is complementary to studies demonstrating a much higher diversity of TCR repertoires in peripheral blood compared to the lung compartment ( 30 ) and suggests that adaptive immunity in the sarcoid lung is local, restricted, and self-contained.…”

Section: Discussionsupporting

confidence: 66%

In Situ Humoral Immunity to Vimentin in HLA-DRB1*03+ Patients With Pulmonary Sarcoidosis

et al. 2018

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Vimentin has been implicated in pulmonary sarcoidosis as a T-cell autoantigen, particularly in the context of HLA-DRB1*03, the Vα2.3/Vβ22 T-cell receptor (TCR), and Löfgren’s syndrome. As vimentin is a known antigenic target in B-cell-mediated autoimmunity, we investigated in situ humoral anti-vimentin responses in pulmonary sarcoidosis and their relationship with HLA-DRB1*03. Sarcoid and healthy control (HC) lung biopsies were analyzed by multi-color confocal microscopy for B-cells, T-cells, proliferation, and vimentin, and compared to tonsillectomy tissue. Bronchoalveolar lavage fluid (BALF) and serum from 48 sarcoidosis patients and 15 healthy volunteers were typed for HLA-DRB1*03 and titrated for antibodies to full-length vimentin, vimentin truncations, and total IgG and IgA by ELISA. Presence of extracellular vimentin in BALF was determined by mass spectrometry and T-cell populations measured by flow cytometry. Sarcoid lung samples, especially from HLA-DRB1*03+ patients, contained vimentin-rich tertiary lymphoid structures and corresponding BALF was highly enriched for both IgG and IgA anti-vimentin antibody (AVA) titers. Furthermore, sarcoidosis patient BALF AVA concentrations (expressed as arbitrary units per milligram of total immunoglobulin isotype) correlated with the percentage of CD4+ T-cells expressing the Vα2.3/Vβ22 TCR. BALF antibody reactivity to the vimentin N-terminus was most prominent in HCs, whereas reactivity to the C-terminus (VimC-term) was enriched in the sarcoid lung. Specifically, HLA-DRB1*03+ patient BALF contained higher concentrations of anti-VimC-term antibodies than BALF from both HCs and HLA-DRB1*03− patients. Consistent with the lung as a site of AVA production, the concentration of AVAs in BALF was dramatically higher than in matched serum samples. Overall, there was a poor correlation between BALF and serum AVA concentrations. Together, these studies reveal the presence of linked in situ recognition of vimentin by both T- and B-cells in HLA-DRB1*03+ sarcoidosis patients, associated with a selective humoral immune response to the vimentin C-terminus.

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Section: Discussionsupporting

confidence: 66%

In Situ Humoral Immunity to Vimentin in HLA-DRB1*03+ Patients With Pulmonary Sarcoidosis

et al. 2018

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“…Importantly, this expansion of TRAV12-1+ CD4+ T cells is only seen in patients with active disease, and upon disease resolution, these cells are greatly reduced, highlighting their importance in disease pathogenesis (80). Using deep sequencing approaches, our group recently demonstrated that TRAV12-1 preferentially pairs with TCRβ variable region (TRBV) 2 in BAL CD4+ T cells from Löfgren's syndrome patients and that TRAV12-1 and TRBV2 are the most expanded variable regions relative to control subjects (81). Additionally, there are specific TRAV12-1/TRBV2 CDR3 motifs expressed on BAL CD4+ T cells of multiple Löfgren's syndrome patients, indicating that these T cells are trafficking to and expanding in the lung in response to the same antigen.…”

Section: Public T Cells In Bal Of Cbd and Sarcoidosis Driving Diseasementioning

confidence: 99%

Adaptive Immunity in Pulmonary Sarcoidosis and Chronic Beryllium Disease

2020

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Pulmonary sarcoidosis and chronic beryllium disease (CBD) are inflammatory granulomatous lung diseases defined by the presence of non-caseating granulomas in the lung. CBD results from beryllium exposure in the workplace, while the cause of sarcoidosis remains unknown. CBD and sarcoidosis are both immune-mediated diseases that involve Th1-polarized inflammation in the lung. Beryllium exposure induces trafficking of dendritic cells to the lung in a mechanism dependent on MyD88 and IL-1α. B cells are also recruited to the lung in a MyD88 dependent manner after beryllium exposure in order to protect the lung from beryllium-induced injury. Similar to most immune-mediated diseases, disease susceptibility in CBD and sarcoidosis is driven by the expression of certain MHCII molecules, primarily HLA-DPB1 in CBD and several HLA-DRB1 alleles in sarcoidosis. One of the defining features of both CBD and sarcoidosis is an infiltration of activated CD4+ T cells in the lung. CD4+ T cells in the bronchoalveolar lavage (BAL) of CBD and sarcoidosis patients are highly Th1 polarized, and there is a significant increase in inflammatory Th1 cytokines present in the BAL fluid. In sarcoidosis, there is also a significant population of Th17 cells in the lungs that is not present in CBD. Due to persistent antigen exposure and chronic inflammation in the lung, these activated CD4+ T cells often display either an exhausted or anergic phenotype. Evidence suggests that these T cells are responding to common antigens in the lung. In CBD there is an expansion of beryllium-responsive TRBV5.1+ TCRs expressed on pathogenic CD4+ T cells derived from the BAL of CBD patients that react with endogenous human peptides derived from the plexin A protein.In an acute form of sarcoidosis, there are expansions of specific TRAV12-1/TRBV2 T cell receptors expressed on BAL CD4+ T cells, indicating that these T cells are trafficking to and expanding in the lung in response to common antigens. The specificity of these pathogenic CD4+T cells in sarcoidosis are currently unknown.

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“…The discrete Gamma-GPD spliced threshold model 68 Our goal is to model the clone size distribution of a sample immune repertoire. Fig 1A 69 shows a typical distribution plotted using the repertoire of a Sarcoidosis patient in [16]. 70 If the data are truly Pareto distributed, this plot would appear linear [17,18].…”

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confidence: 99%

“…This notion is convenient for studying factors such as 119 CDR3 (complementarity-determining region 3) amino acid motifs or specific V, D, and 120 J genes important for combating certain antigens, which are typically determined based 121 on a heuristic abundance cutoff. For example, [21] studies the 1,000 most abundant 122 CDR3 amino acid motifs across all sampled peripheral blood mononuclear cell (PBMC) 123 libraries, while [16] determines CDR3 amino acid motifs from clones that are present 124 with 10 or more reads in a sampled repertoire. The threshold u estimated with our 125 model, however, introduces a means to select motifs that does not rely on heuristics and 126 automatically scales with sequencing depth.…”

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confidence: 99%

“…cells, which is expected to significantly alter the entire landscape of the TCR repertoire. 228 We applied our method to TCR repertoire data of LS and non-LS Sarcoidosis 229 patients [29], originally described in [16]. In this study, bronchoscopy with the 230 bronchoalveolar lavage was performed on a cohort of 9 LS and 4 non-LS individuals and 231 prepared for TCR α− and β−chain sequencing.…”

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confidence: 99%

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powerTCR: a model-based approach to comparative analysis of the clone size distribution of the T cell receptor repertoire

Koch

Starenki

Cooper

et al. 2018

Preprint

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Sequencing of the T cell receptor repertoire is a powerful tool for deeper study of immune response, but the unique structure of this type of data makes its meaningful quantification challenging. We introduce a new method, the Gamma-GPD spliced threshold model, to address this difficulty. This biologically interpretable model captures the distribution of the TCR repertoire, demonstrates stability across varying sequencing depths, and permits comparative analysis across any number of sampled individuals. We apply our method to several datasets and obtain insights regarding the differentiating features in the T cell receptor repertoire among sampled individuals across conditions. We have implemented our method in the open-source R package powerTCR. Author summaryA more detailed understanding of the immune response can unlock critical information concerning diagnosis and treatment of disease. Here, in particular, we study T cells through T cell receptor sequencing, as T cells play a vital role in immune response. One important feature of T cell receptor sequencing data is the frequencies of each receptor in a given sample. These frequencies harbor global information about the landscape of the immune response. We introduce a flexible method that extracts this information by modeling the distribution of these frequencies, and show that it can be used to quantify differences in samples from individuals of different biological conditions. Recent advances in high-throughput sequencing of the T cell receptor (TCR) repertoire 2 provide a new, detailed characterization of the immune system. T cells, each displaying 3 a unique TCR, are capable of responding to presented antigens and initiating an 4 adaptive immune response. An immune response is described by rapid proliferation of T 5 cell clonotypes whose TCRs are specific to the antigen. In humans, it is estimated that 6 the body is capable of producing more than 10 18 different TCRs [1,2], where high 7 diversity of the TCR repertoire implies a greater range of pathogens that can be fought 8 off. A variety of studies have been published demonstrating the value in characterizing 9 this immune response for purposes such as describing tumor cell origin [3] and 10 predicting response to cancer therapy and infection [4]. The applications of TCR 11 1 sequencing are many, but this type of data presents new needs for analysis techniques 12 not met by existing tools for other kinds of genomic experiments. 13Several groups have identified that the distribution of larger clone sizes in a sample 14 can be approximated by a power law [5][6][7][8], which means that the number of clones of a 15 given size decays approximately as a power of the clone size. This heavy-tailed 16 distribution comes as a consequence of extensively proliferated clones actively 17 participating in an ongoing immune response. More recent work has aimed to quantify 18 statistically the diversity of the TCR repertoire, initially through the use of various 19 estimators borrowed from ecology, such as species richne...

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Shared αβ TCR Usage in Lungs of Sarcoidosis Patients with Löfgren’s Syndrome

Cited by 19 publications

References 34 publications

In Situ Humoral Immunity to Vimentin in HLA-DRB1*03+ Patients With Pulmonary Sarcoidosis

In Situ Humoral Immunity to Vimentin in HLA-DRB1*03+ Patients With Pulmonary Sarcoidosis

Adaptive Immunity in Pulmonary Sarcoidosis and Chronic Beryllium Disease

powerTCR: a model-based approach to comparative analysis of the clone size distribution of the T cell receptor repertoire

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