Infiltration of lymphocytes into the thyroid gland and formation of lymph node-like structures is a hallmark of Hashimoto's thyroiditis. Here we demonstrate that lymphatic vessels are present within these infiltrates. Mice overexpressing the chemokine CCL21 in the thyroid (TGCCL21 mice) developed similar lymphoid infiltrates and lymphatic vessels. TGCCL21 mice lacking mature T and B cells (RAGTGCCL21 mice) did not have cellular infiltrates or increased number of lymphatic vessels compared with controls. Transfer of CD3 ؉ CD4 ؉ T cells into RAGTGCCL21 mice promoted the development of LYVE-1 ؉ podoplanin ؉ Prox-1 ؉ vessels in the thyroid. Genetic deletion of lymphotoxin  receptor or lymphotoxin ␣ abrogated development of lymphatic vessels in the inflamed areas in the thyroid but did not affect development of neighboring lymphatics. These results define a model for the study of inflammatory lymphangiogenesis in the thyroid and implicate lymphotoxin  receptor signaling in this process.chemokine ͉ lymphatic vessels ͉ CCL21
Ectopic expression of CC chemokine ligand 21 (CCL21) in the thyroid leads to development of lymphoid structures that resemble those observed in Hashimoto thyroiditis. Deletion of the inhibitor of differentiation 2 (Id2) gene, essential for generation of CD3-CD4+ lymphoid tissue-inducer (LTi) cells and development of secondary lymphoid organs, did not affect formation of tertiary lymphoid structures. Rather, mature CD3+CD4+ T cells were critical for the development of tertiary lymphoid structures. The initial stages of this process involved interaction of CD3+CD4+ T cells with DCs, the appearance of peripheral-node addressin-positive (PNAd+) vessels, and production of chemokines that recruit lymphocytes and DCs. These findings indicate that the formation of tertiary lymphoid structures does not require Id2-dependent conventional LTis but depends on a program initiated by mature CD3+CD4+ T cells.
Ectopic expression of CC chemokine ligand 21 (CCL21) in the thyroid leads to development of lymphoid structures that resemble those observed in Hashimoto thyroiditis. Deletion of the inhibitor of differentiation 2 (Id2) gene, essential for generation of CD3 -CD4 + lymphoid tissue-inducer (LTi) cells and development of secondary lymphoid organs, did not affect formation of tertiary lymphoid structures. Rather, mature CD3 + CD4 + T cells were critical for the development of tertiary lymphoid structures. The initial stages of this process involved interaction of CD3 + CD4 + T cells with DCs, the appearance of peripheral-node addressin-positive (PNAd + ) vessels, and production of chemokines that recruit lymphocytes and DCs. These findings indicate that the formation of tertiary lymphoid structures does not require Id2-dependent conventional LTis but depends on a program initiated by mature CD3 + CD4 + T cells.
Key words: MYC; lymphomas; genomic instabilitySince the first description as the cellular homologue of the transforming sequences of the avian myelocytomatosis retrovirus, 1 many properties of the c-MYC (MYC) protooncogene have been described. The product of MYC oncogene is a bHLHZip transcription factor that is conserved from Xenopus to human. 2 Owing to the presence of the HLH and Zip motifs, MYC is able to participate in various protein-protein interactions. 3-7 The prototype MYC transcription factor forms a heterodimer with the related protein MAX. 8,9 It has been shown that both activation and repression of transcription could be mediated by MYC. 10 In general, MYC expression correlates tightly with the proliferative potential of a cell: in quiescent cells, expression is virtually undetectable, whereas upon mitogen stimulation, there is a rapid and transient burst in mRNA and protein levels. 11 It seems that MYC plays a role in cell cycle regulation, differentiation, apoptosis, metabolism, cell adhesion and regulation of hematopoietic homeostasis. [12][13][14][15][16] Expression of MYC is altered in a wide variety of human and animal tumors including breast, colon and cervical carcinomas, small cell lung carcinomas, osteosarcomas, glioblastomas, myeloid leukemias and lymphomas. 17 MYC is activated in these tumors by a variety of genetic alterations, e.g., chromosomal translocations, retroviral transduction, proviral insertion and gene amplification. Several transgenic models confirmed that MYC overexpression leads to tumorigenesis in different tissues. 18 -22 Results obtained with these transgenic models suggested that the effect of MYC on cell fate depends on cell type, stage of differentiation and physiological environment.Genomic instability is frequently observed in a diversity of tumors and correlates with the selection of the malignant phenotype. 23 Genome wide analysis techniques, such as chromosome painting, comparative genomic hybridization, representational difference analysis and restriction landmark genome scanning, have revealed that certain oncogenes might induce genome instability. 24,25 In vitro studies made on Rat1A, Ba/F3 and primary human fibroblast cells showed that MYC might also contribute to tumorigenesis by destabilizing the cellular genome. 26 -28 In order to study the effects of MYC activation in lymphoid tissues, we generated a conditional mouse model based on the tet-off system. These mice develop both T-and B-cell lymphomas. Upon transgene inactivation, tumor cells not only enter apoptosis but also show signs of differentiation. Furthermore, we demonstrate that overexpression of MYC alone can induce genomic instability. MATERIAL AND METHODS Generation of transgenic miceAn EcoRI-HindIII fragment that contained the human c-MYC cDNA (exons 2 and 3, provided by M. Eilers) was inserted into the bidirectional tetracycline-dependent expression vector pBI5, 29 creating tetO-MYC; E-tTA mice used in our study were previously described. 30 In both cases, founders were derived in the N...
CCR7 is involved in the initiation of immune responses and has been recently implicated in the control of tolerance. To analyze the role of CCR7 in autoimmunity, we backcrossed CCR7ko/ko mice (in which ko signifies deficient) onto the autoimmune-prone NOD background. Surprisingly, NODCCR7ko/ko mice never developed diabetes, but showed severe inflammation in multiple tissues including thyroid, lung, stomach, intestine, uterus, and testis. NODCCR7ko/ko mice had a marked enlargement of the thyroid gland (goiter) that was associated with circulating autoantibodies against thyroglobulin, and development of primary hypothyroidism (decreased levels of serum thyroxin, and augmented levels of thyroid-stimulating hormone in the pituitary gland), features found in Hashimoto’s thyroiditis. Cells isolated from diseased thyroids and activated splenocytes from NODCCR7ko/ko animals induced goiter in NOD.SCID recipients, demonstrating that autoreactive cells were generated in the absence of CCR7. Moreover, thyroid disease could be accelerated in young NODCCR7ko/ko mice by immunization with thyroglobulin. These results demonstrate the complexity in the generation of multiple autoimmune phenotypes in NOD mice and indicate that CCR7 is a key molecule in their development.
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