Characterization of the T Cell Response to Lactobacillus casei Cell Wall Extract in Children With Kawasaki Disease and Its Potential Role in Vascular Inflammation

KD is an acute febrile illness and systemic vasculitis of unknown etiology among young children, which can cause coronary artery abnormalities and aneurysms (CAA) and is the leading cause of acquired heart disease among children in the US. Lactobacillus casei cell wall extract (LCWE) induces in mice a vasculitis following intraperitoneal injection defined by the activation of macrophages, dendritic cells and CD8+ cytotoxic T cells leading to aortitis, coronary arteritis, aneurysms and myocarditis that strongly mimic the immunopathology and the cardiac lesions observed in children with Kawasaki disease (KD). To address a potential pathogenic role of LCWE-specific T cells in human vascular inflammation, we studied the activation of circulating CD4+ and CD8+ T cells ex vivo in response to LCWE in 3 cohorts: (1) KD children 2–3 weeks after fever onset, (2) age-similar healthy children controls, (3) healthy adult controls. In all subjects studied, pro-inflammatory CD4+ and CD8+T cells responded to LCWE with no significant differences. Peripherally-induced regulatory T cells (iTreg) also responded to LCWE and potentially reverted to Th17, as suggested by the detection of IL-17 in culture supernatants. Central memory T cells were also detectable and were more abundant in adults. The potential homing to the vessels of LCWE-specific T cells was suggested by the expression of CCR6 and CD31. In conclusion, a non-pathogenic, LCWE-specific T cell repertoire could lead to KD depending upon priming conditions, genetic factors and immune activation by other antigens.

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CD8+ T Cells Contribute to the Development of Coronary Arteritis in the Lactobacillus casei Cell Wall Extract-Induced Murine Model of Kawasaki Disease

Arthritis & Rheumatology ◽

10.1002/art.39939 ◽

2017 ◽

Vol 69 (2) ◽

pp. 410-421 ◽

Cited By ~ 16

Author(s):

Magali Noval Rivas ◽

Youngho Lee ◽

Daiko Wakita ◽

Norika Chiba ◽

Jargalsaikhan Dagvadorj ◽

...

Keyword(s):

T Cells ◽

Cell Wall ◽

Kawasaki Disease ◽

Cd8 T Cells ◽

Murine Model ◽

Lactobacillus Casei ◽

Coronary Arteritis ◽

Cell Wall Extract

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Superantigenic TCR Vbeta 21.3 signature in Multisystem Inflammatory Syndrome in Children

10.1101/2021.02.11.21251166 ◽

2021 ◽

Author(s):

Marion Moreews ◽

Kenz Le Gouge ◽

Alicia Bellomo ◽

Christophe Malcus ◽

Rémi Pescarmona ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

Kawasaki Disease ◽

T Cell Activation ◽

Toxic Shock Syndrome ◽

Healthy Children ◽

Toxic Shock ◽

Hla Dr ◽

Inflammatory Syndrome

AbstractObjectivesMultiple Inflammatory Syndrome in Children (MIS-C) is the most severe pediatric form of COVID-19 and occurs in previously healthy children. MIS-C combines features of Kawasaki disease and Toxic Shock Syndrome (TSS).MethodsChildren with suspected MIS-C were included within the first week of diagnosis and a large scale immunoassay was performed to determein the immunologic signature of these patients.ResultsWe characterized the immunological profile of 27 MIS-C cases in comparison with 4 KD and 4 TSS cases. Similarly to TSS, an increase of serum inflammatory cytokines (IL-6, TNF-a, CD25s) was observed in MIS-C contrasting with low expression of HLA-DR monocytes, a feature often associated with immune paralysis. Expansions of T cells expressing the Vβ21.3 T cell receptor β chain variable region were detected in both CD4 and CD8 subsets in almost 50% of patients and Vβ21.3-positive T cells expressed high level of HLA-DR highlighting their specific activation. TCR sequencing uncovered the polyclonal nature of the Vβ 21.3+ population. SARS-CoV2 antigene-specific production of interferon gamma in T cells was not increased in MIS-C T cells compared to COVID-19 patients suggesting the antigen-specific immune response in MIS-C patients is not pivotal to the manifestation.ConclusionsOur findings argue in favor of a strong activation of the immune system related to a superantigenic immune response in MIS-C with a specific polyclonal Vβ21.3 T cell expansion.Key messagesWhat is already known about this subject ?MIS-C occurs 3-5 weeks after acute SARS-CoV2 infection and overlap features of Toxic Shock syndrome and Kawasaki disease.MIS-C appears different in term of cytokine and autoantibodies generation from KD with subtle signs of T cells activationWhat does this study add?This study demonstrates that Vβ21.3+ CD4 and CD8 T cells are highly increased in about 50% of MIS-C and distinctive of the Vβ2+ expansion observed in toxic shock syndrome in This reflects a specific T cell activation and cytokine release syndrome similar to toxic shock syndromeHow mich this impact on clinical practice or future developments?Vβ21.3+ signature can be available on a short term basis by flowcytometry and represents a signature of the MIS-C.As for TSS, immunomodulating therapies may revert the superantigenic activation and resolve this life threatening pediatric condition.

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Dectin-1/Syk signaling is involved in Lactobacillus casei cell wall extract-induced mouse model of Kawasaki disease

Immunobiology ◽

10.1016/j.imbio.2012.04.004 ◽

2013 ◽

Vol 218 (2) ◽

pp. 201-212 ◽

Cited By ~ 16

Author(s):

I-Chun Lin ◽

Jau-Ling Suen ◽

Shau-Ku Huang ◽

Shun-Chen Huang ◽

Hsin-Chun Huang ◽

...

Keyword(s):

Cell Wall ◽

Kawasaki Disease ◽

Mouse Model ◽

Lactobacillus Casei ◽

Cell Wall Extract

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Notch4 signaling pathway in a Kawasaki disease mouse model induced by Lactobacillus casei cell wall extract

Experimental and Therapeutic Medicine ◽

10.3892/etm.2017.4434 ◽

2017 ◽

Vol 13 (6) ◽

pp. 3438-3442

Author(s):

Lichao Gao ◽

Songling Fu ◽

Wei Wang ◽

Chunhong Xie ◽

Yiying Zhang ◽

...

Keyword(s):

Cell Wall ◽

Kawasaki Disease ◽

Mouse Model ◽

Signaling Pathway ◽

Lactobacillus Casei ◽

Cell Wall Extract

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Characterization of T cell repertoire changes in acute Kawasaki disease.

Journal of Experimental Medicine ◽

10.1084/jem.177.3.791 ◽

1993 ◽

Vol 177 (3) ◽

pp. 791-796 ◽

Cited By ~ 142

Author(s):

J Abe ◽

B L Kotzin ◽

C Meissner ◽

M E Melish ◽

M Takahashi ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Kawasaki Disease ◽

Quantitative Polymerase Chain Reaction ◽

Cell Subset ◽

Cell Receptor ◽

Unknown Etiology ◽

Cell Repertoire ◽

Beta 2 ◽

Beta Chain Genes

Kawasaki disease (KD) is an acute multisystem vasculitis of unknown etiology that is associated with marked activation of T cells and monocyte/macrophages. Using a quantitative polymerase chain reaction (PCR) technique, we recently found that the acute phase of KD is associated with the expansion of T cells expressing the V beta 2 and V beta 8.1 gene segments. In the present work, we used a newly developed anti-V beta 2 monoclonal antibody (mAb) and studied a new group of KD patients to extend our previous PCR results. Immunofluorescence analysis confirmed that V beta 2-bearing T cells are selectively increased in patients with acute KD. The increase occurred primarily in the CD4 T cell subset. The percentages of V beta 2+ T cells as determined by mAb reactivity and flow cytometry correlated linearly with V beta expression as quantitated by PCR. However, T cells from acute KD patients appeared to express proportionately higher levels of V beta 2 transcripts per cell as compared with healthy controls or convalescent KD patients. Sequence analysis of T cell receptor beta chain genes of V beta 2 and V beta 8.1 expressing T cells from acute KD patients showed extensive junctional region diversity. These data showing polyclonal expansion of V beta 2+ and V beta 8+ T cells in acute KD provide additional insight into the immunopathogenesis of this disease.

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A novel mouse model of coronary stenosis mimicking Kawasaki disease induced by Lactobacillus casei cell wall extract

Experimental Animals ◽

10.1538/expanim.19-0124 ◽

2020 ◽

Vol 69 (2) ◽

pp. 233-241

Author(s):

Eisuke Suganuma ◽

Satoshi Sato ◽

Satoko Honda ◽

Atsuko Nakazawa

Keyword(s):

Cell Wall ◽

Kawasaki Disease ◽

Mouse Model ◽

Coronary Stenosis ◽

Lactobacillus Casei ◽

Cell Wall Extract

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Abstract 593: Vascular Inflammation and Hypertension are Attenuated with T Cell Deletion of Serum and Glucocorticoid-regulated Kinase 1 (SGK1)

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.593 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Author(s):

Allison E Norlander ◽

Mohamed A Saleh ◽

Arvind Pandey ◽

Hana A Itani ◽

Jing Wu ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Angiotensin Ii ◽

Cd8 T Cells ◽

Vascular Dysfunction ◽

Vascular Inflammation ◽

Mesenteric Arteries ◽

Dependent Manner ◽

Salt Treatment ◽

Cell Deletion

We have previously shown that the T cell-derived pro-inflammatory cytokine, interleukin 17A (IL-17A), is upregulated by and promotes angiotensin II-induced hypertension and contributes to vascular dysfunction. It was recently demonstrated that an excess of 40 mM of sodium chloride in culture enhances IL-17A production from CD4+ T cells in a Serum and Glucocorticoid-Regulated Kinase 1 (SGK1) dependent manner. We confirmed the effect of salt on CD4+ T cell differentiation and extended this finding to CD8+ T cells in which 40mM of excess salt increased the expression of IL-17A (4.7 fold, p=0.0003) and the salt-sensing kinase SGK1 (2.2 fold, p=.001) in naive CD8+ T cells cultured under Th17 polarizing conditions. Since dietary salt intake is associated with hypertension, we hypothesized that T cell SGK1 promotes hypertension and contributes to vascular dysfunction. To test this hypothesis, we crossed SGK1 fl/fl mice with CD4cre mice to delete SGK1 in most T lymphocytes. Loss of T cell SGK1 resulted in a blunted blood pressure response to angiotensin II infusion (24.8 mmHg reduction, p=0.01) and DOCA-salt treatment (15.51 mmHg reduction, p<0.05). Moreover, vascular inflammation in response to angiotensin II infusion and/or DOCA-salt treatment was abrogated in these mice compared to SGK1 fl/fl control mice. Angiotensin II increased total (CD45+) leukocytes in the aorta from 5.7 to 52.4x10 3 (p<0.01) in SGK1 fl/fl mice compared to no increase in mice with T cell deletion of SGK1 (16.1 to 10.1x10 3 , p=ns). DOCA-salt induction increased total (CD45+) leukocytes in the aorta in SGK1 fl/fl mice from 7.4 to 20.6x10 3 (p<0.05) compared to no increase in mice with T cell deletion of SGK1 (8.7 to 10.8x10 3 , p=ns). Furthermore, preliminary data show that angiotensin II infusion impairs vascular relaxation in mesenteric arteries isolated from SGK1 fl/fl control mice, while this effect is blunted in angiotensin II treated mice with T cell deletion of SGK1. These studies demonstrate that T cell SGK1 may be a novel therapeutic target for hypertension and its associated vascular dysfunction.

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