Lymphotoxin Plays a Crucial Role in the Development and Function of Nasal-Associated Lymphoid Tissue through Regulation of Chemokines and Peripheral Node Addressin

Ying, Xiaoyan; Chan, Kee; Shenoy, Priti; Hill, Myriam; Ruddle, Nancy H.

doi:10.1016/s0002-9440(10)62239-0

Cited by 35 publications

(42 citation statements)

References 31 publications

(34 reference statements)

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“…It is induced soon after birth and rapidly increases to the adult level in PLN HEV (data not shown), consistent with the switch from MAdCAM-1 to PNAd expression (26). HEV development in NALT is considerably slower than that in LN, requiring Ϸ5-6 weeks to attain mature HEV status as we have previously reported (25). We thus analyzed LacZ expression in NALT during postnatal development.…”

Section: Transgenic Lacz Expression On Hev Mimics That Of Hec-6st In supporting

confidence: 80%

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Transgenic LacZ under control of Hec-6st regulatory sequences recapitulates endogenous gene expression on high endothelial venules

Liao

Bentley

Lebrun

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Hec-6st is a highly specific high endothelial venule (HEV) gene that is crucial for regulating lymphocyte homing to lymph nodes (LN). The enzyme is also expressed in HEV-like vessels in tertiary lymphoid organs that form in chronic inflammation in autoimmunity, graft rejection, and microbial infection. Understanding the molecular nature of Hec-6st regulation is crucial for elucidating its function in development and disease. However, studies of HEV are limited because of the difficulties in isolating and maintaining the unique characteristics of these vessels in vitro. The novel pClasper yeast homologous recombination technique was used to isolate from a BAC clone a 60-kb DNA fragment that included the Hec-6st (Chst4) gene with flanking sequences. Transgenic mice were generated with the ␤-galactosidase (LacZ) reporter gene inserted in-frame in the exon II of Hec-6st within the isolated BAC DNA fragment. LacZ was expressed specifically on HEV in LN, as indicated by its colocalization with peripheral node vascular addressin. LacZ was increased in nasal-associated lymphoid tissue during development and was reduced in LN and nasal-associated lymphoid tissue by LT␤R-Ig (lymphotoxin-␤ receptor human Ig fusion protein) treatment in a manner identical to the endogenous gene.The transgene was expressed at high levels in lymphoid accumulations with characteristics of tertiary lymphoid organs in the salivary glands of aged mice. Thus, the Hec-6st-LacZ construct faithfully reproduces Hec-6st tissue-specific expression and can be used in further studies to drive expression of reporter or effector genes, which could visualize or inhibit HEV in autoimmunity.lymphoid organ ͉ pClasper ͉ peripheral node vascular addressin ͉ sulfotransferase ͉ lymphotoxin H igh endothelial venules (HEV) are the site of entry of naïve lymphocytes into the lymph node (LN) parenchyma from the blood stream. Lymphocyte tethering along HEV in LN is mediated by the interaction of L-selectin expressed on the surface of lymphocytes and L-selectin ligands expressed on HEV.

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Section: Transgenic Lacz Expression On Hev Mimics That Of Hec-6st In supporting

confidence: 80%

“…As a mature HEV marker, HEC-6ST expression is regulated during development (25,26). It is induced soon after birth and rapidly increases to the adult level in PLN HEV (data not shown), consistent with the switch from MAdCAM-1 to PNAd expression (26).…”

Section: Transgenic Lacz Expression On Hev Mimics That Of Hec-6st In supporting

confidence: 54%

Transgenic LacZ under control of Hec-6st regulatory sequences recapitulates endogenous gene expression on high endothelial venules

Liao

Bentley

Lebrun

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…However, we did not observe LTα expression on B cells in follicles, possibly due to the low level of LT expression on B cells (44) and the limited sensitivity of immunofluorescence. LT is also important for the differentiation of HEVs and for the expression of PNAd (43,45,46,60). In the samples of human lungs studied here, LTα-producing cells were located around the B cell follicles in areas where we found vessels that expressed PNAd.…”

Section: Figurementioning

confidence: 63%

“…LT is also crucial for the expression of the enzymes that regulate PNAd expression and the development of HEVs (45,46). Therefore, we determined whether LTα-producing cells could be found in areas of iBALT.…”

Section: Homeostatic Chemokines and Lt Are Expressed In Areas Of Ibalmentioning

confidence: 99%

Inducible bronchus-associated lymphoid tissue (iBALT) in patients with pulmonary complications of rheumatoid arthritis

Rangel-Moreno¹,

Hartson²,

Navarro³

et al. 2006

J. Clin. Invest.

408

359

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Bronchus-associated lymphoid tissue (BALT) was originally described as a mucosal lymphoid organ in the lungs of some species. However, while the lungs of naive mice and humans typically lack BALT, pulmonary infection in mice leads to the development of inducible BALT (iBALT), which is located in peribronchial, perivascular, and interstitial areas throughout the lung. Here we investigated whether iBALT forms in patients with a variety of interstitial lung diseases. We show that while iBALT can be found in the lungs of patients suffering from multiple diseases, well-developed iBALT is most prevalent in patients with pulmonary complications of RA and Sjögren syndrome. In these patients, iBALT consisted of numerous B cell follicles containing germinal centers and follicular dendritic cells. A loosely defined T cell area surrounded the B cell follicles while lymphatics and high endothelial venules were found at the B cell/T cell interface. Increased expression of lymphoid-organizing chemokines, such as CXCL13 and CCL21, as well as molecules involved in the immunopathology of RA, such as B cell-activating factor of the TNF family (BAFF), ICOS ligand, and lymphotoxin, correlated with more well-developed iBALT. Finally, the presence of iBALT correlated with tissue damage in the lungs of RA patients, suggesting that iBALT participates in local RA pathogenesis.

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“…For example, although NALT and Peyer's patches share an architectural similarity, the development of these organs is very different. The organogenesis of NALT occurs during the first week or two after birth (21,112), which is significantly later than that of Peyer's patches. As in Peyer's patch development, CD4 + CD3 − LTi cells are among the first to appear in the developing NALT anlagen (21,113).…”

Section: Exceptions To the Paradigm Of Secondary Lymphoid Organ Develmentioning

confidence: 99%

Development of Secondary Lymphoid Organs

Randall

Carragher²,

Rangel-Moreno³

2008

Annu. Rev. Immunol.

271

258

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Secondary lymphoid organs develop during embryogenesis or in the first few weeks after birth according to a highly coordinated series of interactions between newly emerging hematopoietic cells and immature mesenchymal or stromal cells. These interactions are orchestrated by homeostatic chemokines, cytokines and growth factors that attract hematopoietic cells to sites of future lymphoid organ development and promote their survival and differentiation. In turn, lymphotoxin-expressing hematopoietic cells trigger the differentiation of stromal and endothelial cells that make up the scaffolding of secondary lymphoid organs. Lymphotoxin signaling also maintains the expression of adhesion molecules and chemokines that govern the ultimate structure and function of secondary lymphoid organs. Here we describe the current paradigm of secondary lymphoid organ development and discuss the subtle differences in the timing, molecular interactions and cell types involved in the development of each secondary lymphoid organ. 2. The development of LTi cells from precursors in the fetal liver and their local differentiation into LTαβ-expressing cells requires the activities of cytokines, such as TRANCE or IL-7. IL-7 seems to be most important for the differentiation of LTi cells at mucosal sites, such as the Peyer's patches, while TRANCE is most important at sites of peripheral lymph node development.3. LTi cells are attracted to sites of lymphoid organ development by homeostatic chemokines, including CXCL13, CCL19 and CCL21. Like TRANCE and IL-7, these chemokines also maintain surface LTαβ expression on LTi cells. 4.The lymphotoxin signalling pathway plays a central role in the development of secondary lymphoid organs due to its ability to trigger mesenchymal cell differentiation, elicit homeostatic chemokine expression and to promote the differentiation of HEVs, stromal cells and dendritic cells.

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Lymphotoxin Plays a Crucial Role in the Development and Function of Nasal-Associated Lymphoid Tissue through Regulation of Chemokines and Peripheral Node Addressin

Cited by 35 publications

References 31 publications

Transgenic LacZ under control of Hec-6st regulatory sequences recapitulates endogenous gene expression on high endothelial venules

Transgenic LacZ under control of Hec-6st regulatory sequences recapitulates endogenous gene expression on high endothelial venules

Inducible bronchus-associated lymphoid tissue (iBALT) in patients with pulmonary complications of rheumatoid arthritis

Development of Secondary Lymphoid Organs

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