High endothelial venules associated with T cell subsets in the inflamed gut of newly diagnosed inflammatory bowel disease patients

Horje, Carmen S. Horjus Talabur; Smids, Carolijn; Meijer, Jos W. R.; Groenen, Marcel; Rijnders, M K; Lochem, Ellen G. van; Wahab, Peter J.

doi:10.1111/cei.12918

Cited by 20 publications

(25 citation statements)

References 35 publications

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“…Our findings of PNAd + venules being present in the colonic mucosa during inflammation of UC are in line with two earlier studies performed in a small patient group [14,15]. However, these studies did not take MAdCAM-1 positivity into account, and were cross-sectional in design providing no information during the follow-up of the disease.…”

Section: Discussionsupporting

confidence: 91%

“…Results from the previous studies using different methods (flowcytometry versus immunohistochemistry) suggest the recruitment of L-selectin-expressing naive T cells through these PNAd + HEVs [14,15]. Categorizing patients into groups based on the relative number of PNAd + venules (HEV high and HEV low ), a correlation was found between the presence of more lymphoid follicles and higher percentages of Tn and Tcm lymphocytes in the HEV high group [14]. In the present study, we demonstrated a statistically significant correlation between the proportion of PNAd + venules and the number of lymphoid follicles.…”

Section: Discussionmentioning

confidence: 95%

“…Expression of PNAd on mucosal HEVs in active disease enables the recruitment of T cells to TLOs [11]. Results from the previous studies using different methods (flowcytometry versus immunohistochemistry) suggest the recruitment of L-selectin-expressing naive T cells through these PNAd + HEVs [14,15]. Categorizing patients into groups based on the relative number of PNAd + venules (HEV high and HEV low ), a correlation was found between the presence of more lymphoid follicles and higher percentages of Tn and Tcm lymphocytes in the HEV high group [14].…”

Section: Discussionmentioning

confidence: 98%

“…Currently, little is known about the presence of PNAd + and MAdCAM-1 + venules in the colon of UC patients and their role in the pathogenesis and disease course of UC [13]. During active disease in UC patients, the induction of colonic PNAd + HEVs was associated with a greater influx of T n and T cm cells and correlated with the intensity of inflammation based on Ulcerative Colitis Disease Activity Index (UCDAI) scores in a small group of patients [14,15]. In another small cohort of patients, MAdCAM-1 + venules were suggested to be upregulated in active UC compared to HC, with no differences in numbers of MAdCAM-1 + venules between patients with active disease and remission [16].…”

Section: Introductionmentioning

confidence: 99%

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Development of Mucosal PNAd+ and MAdCAM-1+ Venules during Disease Course in Ulcerative Colitis

Roosenboom

Lochem

Meijer

et al. 2020

Cells

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PNAd and MAdCAM-1 addressins on venules are of importance in T-cell homing and potential therapeutic targets in ulcerative colitis (UC). Normally, PNAd+ high endothelial venules (HEVs) are only present in lymphoid organs, whereas small numbers of MAdCAM-1+ venules can be seen in non-lymphoid tissue. We aimed to study their presence in the intestinal mucosa of UC patients at diagnosis and during follow-up, and their correlation with disease activity. Colonic biopsy specimens of 378 UC patients were analyzed by immunohistochemistry for CD3, CD20, ERG, MECA-79 (PNAd) and MECA-376 (MAdCAM-1) and compared to healthy controls (HC). The proportion of PNAd+HEVs in UC at diagnosis was 4.9% (IQR 2.0%–8.3%), while none were detected in HC. During follow-up, PNAd+HEVs completely disappeared in remission (n = 93), whereas the proportion in active disease was similar to baseline (n = 285, p = 0.39). The proportion of MAdCAM-1+venules in UC at baseline was 5.8% (IQR 2.6–10.0). During follow-up, the proportion in remission was comparable to diagnosis, but upregulated (7.5% (IQR 4.4–10.9), p = 0.001) in active disease. In conclusion, PNAd+HEVs appear in UC during active inflammation which could thus serve as a marker for disease activity, whereas MAdCAM-1+venules remain present after inflammation is resolved and increase after subsequent flares, reflecting chronicity and potentially serving as a therapeutic target.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Development of Mucosal PNAd+ and MAdCAM-1+ Venules during Disease Course in Ulcerative Colitis

Roosenboom

Lochem

Meijer

et al. 2020

Cells

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“…34 Lymphoid follicles were also associated with high endothelial venules, facilitating homing of immune cells. 35…”

Section: Discussionmentioning

confidence: 99%

The EBI2-oxysterol axis promotes the development of intestinal lymphoid structures and colitis

Wyss

Raselli

Schmelczer

et al. 2018

Preprint

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The gene encoding for Epstein-Barr virus-induced G-protein coupled receptor 2 (EBI2) is a risk gene for inflammatory bowel disease (IBD). Together with its oxysterol ligand 7α,25-dihydroxycholesterol, EBI2 mediates migration and differentiation of immune cells. However, the role of EBI2 in the colonic immune system remains insufficiently studied.We found increased mRNA expression of EBI2 and oxysterol synthesizing enzymes (CH25H, CYP7B1) in the inflamed colon of patients with ulcerative colitis and mice with acute or chronic dextran sulfate sodium (DSS) colitis. Accordingly, we detected elevated extraintestinal levels of 25-hydroxylated oxysterols, including 7α,25-dihydroxycholesterol in mice with acute colonic inflammation. Knockout of EBI2 or CH25H did not affect severity of DSS colitis; however, inflammation was decreased in male EBI2-/- mice in the IL-10 colitis model.The colonic immune system comprises mucosal lymphoid structures, which accumulate upon chronic inflammation in IL-10-deficient mice and in chronic DSS colitis. However, EBI2-/- mice formed significantly less colonic lymphoid structures at baseline and showed defects in inflammation-induced accumulation of lymphoid structures.In summary, we report induction of the EBI2-7α,25-dihydroxycholesterol axis in colitis and a role of EBI2 for the accumulation of lymphoid tissue during homeostasis and inflammation. These data implicate the EBI2-7α,25-dihydroxycholesterol axis in IBD pathogenesis.

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High endothelial venules in intracranial germinomas: Implications for lymphocytes infiltration

Chen

Cui

et al. 2022

Cancer Medicine

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BackgroundReactive lymphocytes are substantial components of germinoma, which are believed to be related to the favorable prognosis of this intracranial tumor and better response to immunotherapy. However, the mechanisms managing the recruitment of lymphocytes are poorly understood. High endothelial venules (HEVs) are specialized blood vessels that play key roles in lymphocyte tra cking in Lymph nodes. These vessels are associated with lymphocytes in ltration in chronic in ammatory diseases and various malignant tumors, but their distribution and implications in germinoma are unknown. MethodsThis study investigated the presence and distribution of HEVs in 42 germinomas by immunohistochemical staining of peripheral node addressin (PNAd) and transmission electron microscopic examination. The correlation of the densities of HEVs with the extent of T and B lymphocytes in ltration and several clinicopathological characteristics were also analyzed to determine whether HEVs are responsible for lymphocytes recruitment and their roles in anti-tumor immunity in germinoma. ResultsPNAd-positive HEVs were detected in 31% (13/42) of germinomas, and their presence correlated with abundant in ltrating CD3 + T cells, CD20 + B cells and CD8 + Cytotoxic T Lymphocytes (p = 0.0410, 0.0023, 0.0061, respectively). Higher HEVs density was also correlated with several clinicopathological parameters, which are recognized indicators for favorable prognosis in germinomas, including typical tumor location (p = 0.0093), lower tumor cell content (P = 0.0428), and younger age at diagnosis (p = 0.0121). Furthermore, bioinformatics analysis showed HEVs-associated genes mainly enriched in immune-related Gene Ontology terms, including innate immune response, in ammatory response, and B cell receptor signaling pathway. The xCell analysis revealed that germinomas with higher HEVs enrichment scores had increased levels of the immune score, microenvironment score, dendritic cells, CD8 + central memory T-cells, CD4 + memory T-cells, and B-cells. ConclusionOur ndings indicate that HEVs could contribute to lymphocytes recruitment in germinomas, thus may serve as a predictor of favorable prognosis and better response to immunotherapy in this intracranial tumor.

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High endothelial venules associated with T cell subsets in the inflamed gut of newly diagnosed inflammatory bowel disease patients

Cited by 20 publications

References 35 publications

Development of Mucosal PNAd+ and MAdCAM-1+ Venules during Disease Course in Ulcerative Colitis

Development of Mucosal PNAd+ and MAdCAM-1+ Venules during Disease Course in Ulcerative Colitis

The EBI2-oxysterol axis promotes the development of intestinal lymphoid structures and colitis

High endothelial venules in intracranial germinomas: Implications for lymphocytes infiltration

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