Artery Tertiary Lymphoid Organs Control Aorta Immunity and Protect against Atherosclerosis via Vascular Smooth Muscle Cell Lymphotoxin ? Receptors.
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SUBMITTER: Hu D
PROVIDER: S-EPMC4678289 | biostudies-literature | 2015 Jun
REPOSITORIES: biostudies-literature
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Artery Tertiary Lymphoid Organs Control Aorta Immunity and Protect against Atherosclerosis via Vascular Smooth Muscle Cell Lymphotoxin β Receptors.
Hu Desheng D Mohanta Sarajo K SK Yin Changjun C Peng Li L Ma Zhe Z Srikakulapu Prasad P Grassia Gianluca G MacRitchie Neil N Dever Gary G Gordon Peter P Burton Francis L FL Ialenti Armando A Sabir Suleman R SR McInnes Iain B IB Brewer James M JM Garside Paul P Weber Christian C Lehmann Thomas T Teupser Daniel D Habenicht Livia L Beer Michael M Grabner Rolf R Maffia Pasquale P Weih Falk F Habenicht Andreas J R AJ
Immunity 20150601 6
Tertiary lymphoid organs (TLOs) emerge during nonresolving peripheral inflammation, but their impact on disease progression remains unknown. We have found in aged Apoe(-/-) mice that artery TLOs (ATLOs) controlled highly territorialized aorta T cell responses. ATLOs promoted T cell recruitment, primed CD4(+) T cells, generated CD4(+), CD8(+), T regulatory (Treg) effector and central memory cells, converted naive CD4(+) T cells into induced Treg cells, and presented antigen by an unusual set of d ...[more]
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Project description:Tertiary lymphoid organs (TLOs) emerge in response to nonresolving inflammation but their roles in adaptive immunity remain unknown. Here, we explored artery TLOs (ATLOs) to delineate atherosclerosis T cell responses in apoe-/- mice during aging. Though the T cell repertoire showed systemic age-associated contractions in size and modifications in subtype composition and activation, wt and apoe-/- mice were equally affected. In contrast, ATLOs - but not wt aortae, apoe-/- aorta segments without ATLOs or atherosclerotic plaques - promoted T cell recruitment, altered characteristics of T cell motility, primed and imprinted T cells in situ, generated CD4+/FoxP3-, CD4+/FoxP3+, CD8+/FoxP3- effector and central memory cells, and converted naïve CD4+/FoxP3- T cells into induced Treg cells. ATLOs also showed substantially increased antigen presentation capability by conventional dendritic cells (DCs) and monocyte-derived DCs but not by plasmacytoid DCs. Thus, the senescent immune system specifically employs ATLOs to control dichotomic atherosclerosis T cell immune responses. We assembled transcriptome maps of wt and apoe-/- aortae and aorta-draining RLNs and identified ATLOs as major sites of atherosclerosis-specific T cell responses during aging: Transcriptome atlases of wt and apoe-/- abdominal aortae and associated draining RLNs were constructed from laser capture microdissection (LCM)-based whole genome mRNA expression microarrays yielding 6 maps: wt adventitia (tissue-1); wt RLN (tissue-2); apoe-/- ATLOs (tissue-3); apoe-/- RLN (tissue-4); apoe-/- adventitia without adjacent plaques (tissue-5), and plaques (tissue-6). Several two-tissue comparisons within the transcriptome atlases are noteworthy: Unexpectedly, transcriptomes of wt and apoe-/- RLNs were virtually identical; additonal data revealed that transcriptomes of RLNs were strikingly similar to those of inguinal LNs which do not drain the aorta adventitia (as shown of India ink injection experiments of surgically exposed aortae); in sharp contrast, wt adventitia versus ATLOs revealed 1405 differentially expressed transcripts many of which encoded members of GO terms immune response and inflammatory response; the ATLO-plaque comparison also showed > 1000 differentially expressed transcripts; however, wt adventitia versus apoe-/- adventitia without plaque showed few genes (< 5 % of differentially expressed transcripts of the wt adventitia-ATLO comparison). Thus, the aorta transcriptome atlases support the conclusion that neither aorta-draining apoe-/- RLNs nor ILNs participate in atherosclerosis-specific T cell responses. In addition, they demonstrate that T cell responses in the diseased aorta are highly territorialized. Finally, these data show that the immune responses carried out in ATLOs differ significantly from those carried out in plaques. We next identified three major clusters within the transcriptome atlases through ANOVA analyses and application of strict filters: An adventitia cluster, a plaque/ATLO cluster, and a LN/plaque cluster. The total number of differentially expressed genes in each cluster were examined for GO terms immune response, inflammatory response, T cell activation, positive regulation of T cell response, and T cell proliferation. Within the adventitia cluster, similarities of transcriptomes of wt adventitia and apoe-/- adventitia without associated plaque versus ATLOs indicate that a robust number of immune response-regulating genes are selectively expressed in ATLOs which are located within a distance of few µm of the adventitia without associated plaques indicating a very high degree of territoriality of the atherosclerosis T cell response. Furthermore, unlike the total number of differentially regulated transcripts, the majority of transcripts among GO terms immune response and inflammatory response, was up-regulated. Inspection of the plaque/ATLO cluster provided further information: The majority of immune response regulating genes where expressed at a higher level in ATLOs when compared to plaques though plaques also contained a significant number of immune response regulating genes; the reverse is true for genes regulating inflammation. Finally, the lymph node cluster revealed that though the majority of immune response regulating genes resides in both wt and apoe-/- RLNs (with little differences between them) ATLOs express a selected set of immune response regulating genes at a higher level when compared to LNs. In addition, the inflammatory component of ATLOs when compared to LNs is documented by the finding that many more genes regulating inflammation reside in ATLOs even when compared to those of plaques. Key words: T cell response in atherosclerosis; Laser capture microdissection; transcriptome atlas of atherosclerosis. Citations: Gräbner R. et al. Lymphotoxin beta receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE-/- mice. J Exp Med 2009 Jan 16;206(1):233-48. PMID: 19139167; Moos M. et al. The lamina adventitia is the major site of immune cell accumulation in standard chow-fed apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 2005 Nov;25(11):2386-91. Epub 2005 Sep 22. PMID: 16179593; Beer M. et al. Laser-capture microdissection of hyperlipidemic/ApoE-/- mouse aorta atherosclerosis. Methods Mol Biol. 2011;755:417-28. PMID: 21761324; Weih F. et al. Control of Dichotomic Innate and Adaptive Immune Responses by Artery Tertiary Lymphoid Organs in Atherosclerosis. Front Physiol. 2012;3:226. Epub 2012 Jul 6. PMID: 22783198. Wild-type and apoE-deficient mice on the C57BL/6J genetic background were maintained on a standard mouse chow. Total aortae were removed at the age of 6 (n=3), 32 (n=3), or 78 (n=3) w and microarrays were prepared from total RNA extracts or extracts of atherosclerotic lesions and adventitiae obtained by the use of a laser dissection microscope. In addition, aorta associated LNs or distant LNs were prepared from both mouse genotypes.
2013-10-30 | E-GEOD-40156 | biostudies-arrayexpress
Project description:Tertiary lymphoid organs (TLOs) emerge in response to nonresolving inflammation but their roles in adaptive immunity remain unknown. Here, we explored artery TLOs (ATLOs) to delineate atherosclerosis T cell responses in apoe-/- mice during aging. Though the T cell repertoire showed systemic age-associated contractions in size and modifications in subtype composition and activation, wt and apoe-/- mice were equally affected. In contrast, ATLOs - but not wt aortae, apoe-/- aorta segments without ATLOs or atherosclerotic plaques - promoted T cell recruitment, altered characteristics of T cell motility, primed and imprinted T cells in situ, generated CD4+/FoxP3-, CD4+/FoxP3+, CD8+/FoxP3- effector and central memory cells, and converted naïve CD4+/FoxP3- T cells into induced Treg cells. ATLOs also showed substantially increased antigen presentation capability by conventional dendritic cells (DCs) and monocyte-derived DCs but not by plasmacytoid DCs. Thus, the senescent immune system specifically employs ATLOs to control dichotomic atherosclerosis T cell immune responses. We assembled transcriptome maps of wt and apoe-/- aortae and aorta-draining RLNs and identified ATLOs as major sites of atherosclerosis-specific T cell responses during aging: Transcriptome atlases of wt and apoe-/- abdominal aortae and associated draining RLNs were constructed from laser capture microdissection (LCM)-based whole genome mRNA expression microarrays yielding 6 maps: wt adventitia (tissue-1); wt RLN (tissue-2); apoe-/- ATLOs (tissue-3); apoe-/- RLN (tissue-4); apoe-/- adventitia without adjacent plaques (tissue-5), and plaques (tissue-6). Several two-tissue comparisons within the transcriptome atlases are noteworthy: Unexpectedly, transcriptomes of wt and apoe-/- RLNs were virtually identical; additonal data revealed that transcriptomes of RLNs were strikingly similar to those of inguinal LNs which do not drain the aorta adventitia (as shown of India ink injection experiments of surgically exposed aortae); in sharp contrast, wt adventitia versus ATLOs revealed 1405 differentially expressed transcripts many of which encoded members of GO terms immune response and inflammatory response; the ATLO-plaque comparison also showed > 1000 differentially expressed transcripts; however, wt adventitia versus apoe-/- adventitia without plaque showed few genes (< 5 % of differentially expressed transcripts of the wt adventitia-ATLO comparison). Thus, the aorta transcriptome atlases support the conclusion that neither aorta-draining apoe-/- RLNs nor ILNs participate in atherosclerosis-specific T cell responses. In addition, they demonstrate that T cell responses in the diseased aorta are highly territorialized. Finally, these data show that the immune responses carried out in ATLOs differ significantly from those carried out in plaques. We next identified three major clusters within the transcriptome atlases through ANOVA analyses and application of strict filters: An adventitia cluster, a plaque/ATLO cluster, and a LN/plaque cluster. The total number of differentially expressed genes in each cluster were examined for GO terms immune response, inflammatory response, T cell activation, positive regulation of T cell response, and T cell proliferation. Within the adventitia cluster, similarities of transcriptomes of wt adventitia and apoe-/- adventitia without associated plaque versus ATLOs indicate that a robust number of immune response-regulating genes are selectively expressed in ATLOs which are located within a distance of few µm of the adventitia without associated plaques indicating a very high degree of territoriality of the atherosclerosis T cell response. Furthermore, unlike the total number of differentially regulated transcripts, the majority of transcripts among GO terms immune response and inflammatory response, was up-regulated. Inspection of the plaque/ATLO cluster provided further information: The majority of immune response regulating genes where expressed at a higher level in ATLOs when compared to plaques though plaques also contained a significant number of immune response regulating genes; the reverse is true for genes regulating inflammation. Finally, the lymph node cluster revealed that though the majority of immune response regulating genes resides in both wt and apoe-/- RLNs (with little differences between them) ATLOs express a selected set of immune response regulating genes at a higher level when compared to LNs. In addition, the inflammatory component of ATLOs when compared to LNs is documented by the finding that many more genes regulating inflammation reside in ATLOs even when compared to those of plaques. Key words: T cell response in atherosclerosis; Laser capture microdissection; transcriptome atlas of atherosclerosis. Citations: Gräbner R. et al. Lymphotoxin beta receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE-/- mice. J Exp Med 2009 Jan 16;206(1):233-48. PMID: 19139167; Moos M. et al. The lamina adventitia is the major site of immune cell accumulation in standard chow-fed apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 2005 Nov;25(11):2386-91. Epub 2005 Sep 22. PMID: 16179593; Beer M. et al. Laser-capture microdissection of hyperlipidemic/ApoE-/- mouse aorta atherosclerosis. Methods Mol Biol. 2011;755:417-28. PMID: 21761324; Weih F. et al. Control of Dichotomic Innate and Adaptive Immune Responses by Artery Tertiary Lymphoid Organs in Atherosclerosis. Front Physiol. 2012;3:226. Epub 2012 Jul 6. PMID: 22783198.
2013-10-30 | GSE40156 | GEO
Project description:Explore aorta B-cell immunity in aged apolipoprotein E-deficient (ApoE(-/-)) mice.Transcript maps, fluorescence-activated cell sorting, immunofluorescence analyses, cell transfers, and Ig-ELISPOT (enzyme-linked immunospot) assays showed multilayered atherosclerosis B-cell responses in artery tertiary lymphoid organs (ATLOs). Aging-associated aorta B-cell-related transcriptomes were identified, and transcript atlases revealed highly territorialized B-cell responses in ATLOs versus atherosclerotic lesions: ATLOs showed upregulation of bona fide B-cell genes, including Cd19, Ms4a1 (Cd20), Cd79a/b, and Ighm although intima plaques preferentially expressed molecules involved in non-B effector responses toward B-cell-derived mediators, that is, Fcgr3 (Cd16), Fcer1g (Cd23), and the C1q family. ATLOs promoted B-cell recruitment. ATLO B-2 B cells included naive, transitional, follicular, germinal center, switched IgG1(+), IgA(+), and IgE(+) memory cells, plasmablasts, and long-lived plasma cells. ATLOs recruited large numbers of B-1 cells whose subtypes were skewed toward interleukin-10(+) B-1b cells versus interleukin-10(-) B-1a cells. ATLO B-1 cells and plasma cells constitutively produced IgM and IgG and a fraction of plasma cells expressed interleukin-10. Moreover, ApoE(-/-) mice showed increased germinal center B cells in renal lymph nodes, IgM-producing plasma cells in the bone marrow, and higher IgM and anti-MDA-LDL (malondialdehyde-modified low-density lipoprotein) IgG serum titers.ATLOs orchestrate dichotomic, territorialized, and multilayered B-cell responses in the diseased aorta; germinal center reactions indicate generation of autoimmune B cells within the diseased arterial wall during aging.
| S-EPMC4894775 | biostudies-literature
Project description:Giant cell arteritis (GCA) can be classified into Cranial(C)-GCA and Large Vessel(LV)-GCA. Based on analysis of temporal arteries, GCA is postulated to be T-cell-mediated. Recently, a disturbed B-cell homeostasis was documented in newly diagnosed GCA patients. In the current study, we assessed the presence of B-cells and their level of ectopic organization in the aorta of LV-GCA patients. Aorta tissue samples of 9 histologically-proven LV-GCA patients and 22 age- and sex-matched atherosclerosis patients who underwent aortic aneurysm surgery were studied by immunohistochemistry. Sections were stained for B-cells, T-cells, follicular dendritic cells, high endothelial venules, germinal center B-cells, proliferating B-cells, macrophages, and plasma cells. Aortas of LV-GCA patients showed massive infiltration of B-cells, which clearly outnumbered T-cells, as opposed to C-GCA patients where, as previously reported, T-cells outnumber B-cells. B-cells were mainly found in the adventitia of the vessel wall and were organized into artery tertiary lymphoid organs. These tertiary lymphoid organs had germinal centers, proliferating B-cells and plasma cell niches. In conclusion, we found massive and organized B-cell infiltrates in the aorta of LV-GCA patients, which is in line with the previously documented decrease of circulating B-cells in active GCA. Our data indicate a role for B-cells in the pathogenesis of GCA and thus evoke further investigation into the factors determining the tissue tropism and organization of B-cells in GCA.
| S-EPMC6361817 | biostudies-literature
Project description:Atherosclerosis involves a macrophage-rich inflammation in the aortic intima. It is increasingly recognized that this intimal inflammation is paralleled over time by a distinct inflammatory reaction in adjacent adventitia. Though cross talk between the coordinated inflammatory foci in the intima and the adventitia seems implicit, the mechanism(s) underlying their communication is unclear. Here, using detailed imaging analysis, microarray analyses, laser-capture microdissection, adoptive lymphocyte transfers, and functional blocking studies, we undertook to identify this mechanism. We show that in aged apoE(-/-) mice, medial smooth muscle cells (SMCs) beneath intimal plaques in abdominal aortae become activated through lymphotoxin beta receptor (LTbetaR) to express the lymphorganogenic chemokines CXCL13 and CCL21. These signals in turn trigger the development of elaborate bona fide adventitial aortic tertiary lymphoid organs (ATLOs) containing functional conduit meshworks, germinal centers within B cell follicles, clusters of plasma cells, high endothelial venules (HEVs) in T cell areas, and a high proportion of T regulatory cells. Treatment of apoE(-/-) mice with LTbetaR-Ig to interrupt LTbetaR signaling in SMCs strongly reduced HEV abundance, CXCL13, and CCL21 expression, and disrupted the structure and maintenance of ATLOs. Thus, the LTbetaR pathway has a major role in shaping the immunological characteristics and overall integrity of the arterial wall.
| S-EPMC2626665 | biostudies-literature
Project description:ObjectiveMouse aorta smooth muscle cells (SMC) express tumor necrosis factor receptor superfamily member 1A (TNFR-1) and lymphotoxin beta-receptor (LTbetaR). Circumstantial evidence has linked the SMC LTbetaR to tertiary lymphoid organogenesis in hyperlipidemic mice. Here, we explored TNFR-1 and LTbetaR signaling in cultured SMC.Methods and resultsTNFR-1 signaling activated the classical RelA NF-kappaB pathway, whereas LTbetaR signaling activated the classical RelA and alternative RelB NF-kappaB pathways, and both signaling pathways synergized to enhance p100 inhibitor processing to the p52 subunit of NF-kappaB. Microarrays showed that simultaneous TNFR-1/LTbetaR activation resulted in elevated mRNA encoding leukocyte homeostatic chemokines CCL2, CCL5, CXCL1, and CX3CL1. Importantly, SMC acquired features of lymphoid tissue organizers, which control tertiary lymphoid organogenesis in autoimmune diseases through hyperinduction of CCL7, CCL9, CXCL13, CCL19, CXCL16, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1. TNFR-1/LTbetaR cross-talk resulted in augmented secretion of lymphorganogenic chemokine proteins. Supernatants of TNFR-1/LTbetaR-activated SMC markedly supported migration of splenic T cells, B cells, and macrophages/dendritic cells. Experiments with ltbr(-/-) SMC indicated that LTbetaR-RelB activation was obligatory to generate the lymphoid tissue organizer phenotype.ConclusionsSMC may participate in the formation of tertiary lymphoid tissue in atherosclerosis by upregulation of lymphorganogenic chemokines involved in T-lymphocyte, B-lymphocyte, and macrophage/dendritic cell attraction.
| S-EPMC2874749 | biostudies-literature
Project description:Atherosclerosis is a leading cause of mortality worldwide. Artery tertiary lymphoid organ (ATLO) neogenesis is affected by abdominal aorta atherosclerosis, which may lead to an immune response. The present study obtained microarray data to investigate the gene expression differences underlying the potential pathogenesis of atherosclerosis and to elucidate the mechanisms underlying ATLO development. Microarray studies of the aorta, plaques, adventitia, blood, spleen, renal lymph nodes and ATLO were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified in aorta clusters and ATLO clusters. Kyoto Encyclopedia of Genes and Genomes enrichment and Gene Ontology (GO) analyses were conducted to predict the biological functions of DEGs. The results demonstrated that interleukin 7 receptor (Il7r), C‑X‑C motif chemokine ligand (Cxcl)16, Cxcl13, Cxcl12, C‑C motif chemokine receptor 2, C‑C motif chemokine ligand (Ccl)8, Ccl5 and Ccl12 may function through pathways associated with 'cytokine‑cytokine receptor interaction' and 'chemokine signaling pathway' in ATLO. Gene expression alterations were validated by reverse transcription‑quantitative polymerase chain reaction. Il7r appeared to be the central gene involved in these events, and chemokines and/or chemokine receptors were visualized by GO enrichment. A protein‑protein interaction network was constructed, which suggested that Il7r had a core function in all clusters. Taken together, the results indicated that Il7r upregulation may serve an important role in ATLO development via 'cytokine‑cytokine receptor interaction' and 'chemokine signaling pathway'. This may provide novel perspectives for understanding ATLO development and the regulation of the immune response in atherosclerosis.
| S-EPMC6423582 | biostudies-literature
Project description:Our aim is to complement observer-dependent approaches of immune cell evaluation in microscopy images with reproducible measures for spatial composition of lymphocytic infiltrates. Analyzing such patterns of inflammation is becoming increasingly important for therapeutic decisions, for example in transplantation medicine or cancer immunology. We developed a graph-based assessment of lymphocyte clustering in full whole slide images. Based on cell coordinates detected in the full image, a Delaunay triangulation and distance criteria are used to build neighborhood graphs. The composition of nodes and edges are used for classification, e.g. using a support vector machine. We describe the variability of these infiltrates on CD3/CD20 duplex staining in renal biopsies of long-term functioning allografts, in breast cancer cases, and in lung tissue of cystic fibrosis patients. The assessment includes automated cell detection, identification of regions of interest, and classification of lymphocytic clusters according to their degree of organization. We propose a neighborhood feature which considers the occurrence of edges with a certain type in the graph to distinguish between phenotypically different immune infiltrates. Our work addresses a medical need and provides a scalable framework that can be easily adjusted to the requirements of different research questions.
| S-EPMC7055921 | biostudies-literature
Project description:BACKGROUND:Programmed cell death 1 inhibitors have revolutionized therapy for cancer by their outstanding effectiveness. However, they may cause adverse effects, among which inflammatory myopathy is one of the most disabling. To elucidate its mechanism, we analysed muscle biopsies and compared them with other inflammatory myopathies. METHODS:Muscle biopsies from three patients with inflammatory myopathy after treatment with PD-1 inhibitors for cancer were subjected to immunohistochemical and ultrastructural analyses to localize CD8+ cytotoxic cells and markers of lymphoid follicles. For comparison, two cases of polymyositis and one of juvenile dermatomyositis were examined. RESULTS:Nearly identical pathological features were observed in the three cases. In the island-like foci of inflammation, muscle fibers were undergoing degeneration. CD8+ cytotoxic T cells, macrophages, CD4+ cells, and B cells were observed in the foci. CD8+ cells were seen outside and inside the basal lamina of non-necrotic muscle fibers. Lymphoid follicle-like structures with CD21+ follicular dendritic cells were present. The blood vessels in the foci showed features consistent with the high endothelial venules, on which their markers, PNAd and CCL21, were expressed. In polymyositis, blood vessels stained only faintly for PNAd and CCL21, while in juvenile dermatomyositis, in which tertiary lymphoid follicle-like structure was reported in the past, they stained positively. CONCLUSIONS:In inflammatory myopathy associated with PD-1 inhibitors, CD8+ cells appear to predominantly destruct muscle fibers. The presence of lymphoid follicle-like structures and expression of PNAd and CCL21 on the endothelial cells suggest the tertiary lymphoid organs are formed, and involved in the leakage of lymphocytes. Thus, in the three cases examined, formation of the tertiary lymphoid organs is likely to play an important role in genesis of the PD-1 myopathy.
| S-EPMC6751882 | biostudies-other
Project description:Aims/hypothesisWe and others previously reported the presence of tertiary lymphoid organs (TLOs) in the pancreas of NOD mice, where they play a role in the development of type 1 diabetes. Our aims here are to investigate whether TLOs are present in the pancreas of individuals with type 1 diabetes and to characterise their distinctive features, in comparison with TLOs present in NOD mouse pancreases, in order to interpret their functional significance.MethodsUsing immunofluorescence confocal microscopy, we examined the extracellular matrix (ECM) and cellular constituents of pancreatic TLOs from individuals with ongoing islet autoimmunity in three distinct clinical settings of type 1 diabetes: at risk of diabetes; at/after diagnosis; and in the transplanted pancreas with recurrent diabetes. Comparisons were made with TLOs from 14-week-old NOD mice, which contain islets exhibiting mild to heavy leucocyte infiltration. We determined the frequency of the TLOs in human type 1diabetes with insulitis and investigated the presence of TLOs in relation to age of onset, disease duration and disease severity.ResultsTLOs were identified in preclinical and clinical settings of human type 1 diabetes. The main characteristics of these TLOs, including the cellular and ECM composition of reticular fibres (RFs), the presence of high endothelial venules and immune cell subtypes detected, were similar to those observed for TLOs from NOD mouse pancreases. Among 21 donors with clinical type 1 diabetes who exhibited insulitis, 12 had TLOs and had developed disease at younger age compared with those lacking TLOs. Compartmentalised TLOs with distinct T cell and B cell zones were detected in donors with short disease duration. Overall, TLOs were mainly associated with insulin-containing islets and their frequency decreased with increasing severity of beta cell loss. Parallel studies in NOD mice further revealed some differences in so far as regulatory T cells were essentially absent from human pancreatic TLOs and CCL21 was not associated with RFs.Conclusions/interpretationWe demonstrate a novel feature of pancreas pathology in type 1 diabetes. TLOs represent a potential site of autoreactive effector T cell generation in islet autoimmunity and our data from mouse and human tissues suggest that they disappear once the destructive process has run its course. Thus, TLOs may be important for type 1 diabetes progression.
| S-EPMC8187221 | biostudies-literature