| 1. |
- Abeler-Dörner, Lucie, et al.
(författare)
-
Butyrophilins: an emerging family of immune regulators
- 2012
-
Ingår i: Trends in immunology. - : Elsevier BV. - 1471-4906 .- 1471-4981. ; 33:1, s. 34-41
-
Forskningsöversikt (refereegranskat)abstract
- Butyrophilins (Btns) and butyrophilin-like (Btnl) molecules are emerging as novel regulators of immune responses in mice and humans. Several clues point to their probable importance: many of the genes are located within the MHC; they are structurally related to B7-co-stimulatory molecules; they are functionally implicated in T cell inhibition and in the modulation of epithelial cell-T cell interactions; and they are genetically associated with inflammatory diseases. Nonetheless, initial immersion into the current literature can uncover confusion over even basic information such as gene names and expression patterns, and seemingly conflicting data regarding the biological activities of different family members. This review addresses each of these issues, concluding with the attractive potential of Btn and Btnl molecules to act as specific attenuators of tissue-associated inflammatory responses.
|
|
| 2. |
- Bas, Anna, 1973, et al.
(författare)
-
Butyrophilin-like 1 encodes an enterocyte protein that selectively regulates functional interactions with T lymphocytes.
- 2011
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 108:11, s. 4376-81
-
Forskningsöversikt (refereegranskat)abstract
- Although local regulation of T-cell responses by epithelial cells is increasingly viewed as important, few molecules mediating such regulation have been identified. Skint1, a recently identified member of the Ig-supergene family expressed by thymic epithelial cells and keratinocytes, specifies the murine epidermal intraepithelial lymphocyte (IEL) repertoire. Investigating whether Skint1-related molecules might regulate IEL in other compartments, this study focuses on buytrophilin-like 1 (Btnl1), which is conspicuously similar to Skint1 and primarily restricted to small intestinal epithelium. Btnl1 protein is mostly cytoplasmic, but surface expression can be induced, and in vivo Btnl1 can be detected adjacent to the IEL. In a newly developed culture system, enforced epithelial cell expression of Btnl1 attenuated the cells' response to activated IEL, as evidenced by suppression of IL-6 and other inflammatory mediators. These findings offer a unique perspective on emerging genetic data that Btnl genes may comprise novel and important local regulators of gut inflammation.
|
|
| 3. |
- Bas, Anna, 1973-
(författare)
-
Extrathymic T cell receptor gene rearrangement in human alimentary tract
- 2003
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- T lymphocytes regulate the initiation, duration, and magnitude of adaptive immune responses and function as effector cells in cell mediated immunity. To become immunologically competent they must generate functional antigen receptors. This process takes place in the thymus and requires somatic recombination of T cell receptor (TCR) genes. It is mediated by the endonucleases recombination activating gene-1 (RAG1) and RAG2. Although the thymus regresses at puberty, T cells are present throughout life implying that other tissues must provide the proper milieu for T cell development. This thesis describes extrathymic T cell maturation in man. RAG1, RAG2, and the preTα-chain (pTα), which is exclusively utilized in developing T cells, were used as markers for TCR gene rearrangement. Two new exons (1A and 1B) encoding sequences in the 5’ untranslated region (5’UTR) of mRNA were discovered in the human RAG1 gene. The previously described 5’UTR exon (renamed 1C) was located between the new exons and exon 2, the latter containing the entire coding sequence. We found that small intestinal lymphocytes of the T cell lineage expressed the new exons in three different splice forms. RAG1 mRNA containing the 1C exon was not expressed in small intestinal lymphocytes. In contrast, splice forms containing the 1A exon were not expressed in thymocytes. RAG1 and pTα mRNA expressing lymphocytes were seen both within the epithelium and in lamina propria. Thymocyte-like CD2+CD7+CD3-, CD4+CD8+, CD1a+, and IL7-R+ lymphocytes were identified in the small intestinal mucosa. CD2+CD7+CD3- cells had the highest expression levels of mRNA for RAG1 and pTα, suggesting that the small intestinal mucosa is indeed a site for T cell maturation. Small intestinal T lymphocytes were also shown to kill via the Fas/FasL pathway in a TCR/CD3 independent manner and via the perforin/granzyme pathway in a TCR/CD3 dependent manner. The Fas/FasL-mediated cytotoxicity may reflect an ongoing selection process of extrathymically maturated T cells.The nasopharyngeal tonsil is the major inductive site for immune reactions against inhaled antigens. Previous demonstration of RAG1 expression in tonsillar B cells was interpreted as antigen driven receptor revision. The present study confirms the expression of RAG1 in B cells. We also found that RAG1, RAG2, and pTa mRNAs were expressed in lymphocytes of the T cell lineage. A small population of cells with the immature phenotype CD2+CD7+CD3- was demonstrated. This population had the highest expression levels of mRNA for RAG1, RAG2, pTα and terminal deoxynucleotidyl transferase. All four splice-forms of RAG1 mRNA were expressed. RAG1 and pTα mRNA expressing cells were mainly located in the proximity of the surface epithelium and in the outer rim of the follicles. These results suggest that the nasopharyngeal tonsil is a site where extrathymic T cell development and antigen driven TCR revision are occurring in parallel.Celiac disease (CD) is a small intestinal enteropathy characterized by permanent intolerance to gluten. Gluten reactive intestinal T cells are central in the pathogenesis and CD can be regarded as a failure to maintain tolerance to this food antigen. Expression of the RAG1 1A/2 splice form was significantly decreased in small intestinal T cell subsets of CD patients suggesting that impaired TCR gene rearrangement could contribute to failure of maintain tolerance in CD.Together, these findings show that both small intestinal and nasopharyngeal tonsillar lymphocytes of T cell lineage have the molecular machinery for antigen receptor rearrangement and that thymocyte-like lymphocytes are present in both tissues. Thus these organs are likely sites of T lymphocyte ontogeny as well as for secondary T cell receptor rearrangement in man.
|
|
| 4. |
|
|
| 5. |
- Suzuki, Toshiyasu, et al.
(författare)
-
b-Catenin Drives Butyrophilin-like Molecule Loss and gd T-cell Exclusion in Colon Cancer
- 2023
-
Ingår i: CANCER IMMUNOLOGY RESEARCH. - : AMER ASSOC CANCER RESEARCH. - 2326-6066. ; 11:8, s. 1137-1155
-
Tidskriftsartikel (refereegranskat)abstract
- Intraepithelial lymphocytes (IEL) expressing y8 T-cell receptors (y8TCR) play key roles in elimination of colon cancer. However, the precise mechanisms by which progressing cancer cells evade immu-nosurveillance by these innate T cells are unknown. Here, we investigated how loss of the Apc tumor suppressor in gut tissue could enable nascent cancer cells to escape immunosurveillance by cytotoxic y8IELs. In contrast with healthy intestinal or colonic tissue, we found that y8IELs were largely absent from the micro-environment of both mouse and human tumors, and that butyr-ophilin-like (BTNL) molecules, which can critically regulate y8IEL through direct y8TCR interactions, were also downregulated in tumors. We then demonstrated that 13-catenin activation through loss of Apc rapidly suppressed expression of the mRNA encoding the HNF4A and HNF4G transcription factors, preventing their binding to promoter regions of Btnl genes. Reexpression of BTNL1 and BTNL6 in cancer cells increased y8IEL survival and activation in coculture assays but failed to augment their cancer-killing ability in vitro or their recruitment to orthotopic tumors. However, inhibition of 13-catenin signaling via genetic deletion of Bcl9/Bcl9L in either Apc-deficient or mutant 13-catenin mouse models restored Hnf4a, Hnf4g, and Btnl gene expression and y8 T-cell infiltration into tumors. These observations highlight an immune-evasion mechanism specific to WNT-driven colon cancer cells that disrupts y8IEL immunosurveillance and furthers cancer progression.
|
|
| 6. |
- Van Hemelrijck, Mieke, et al.
(författare)
-
Immunoglobulin E and cancer : a meta-analysis and a large Swedish cohort study
- 2010
-
Ingår i: Cancer Causes and Control. - : Springer Science and Business Media LLC. - 0957-5243 .- 1573-7225. ; 21:10, s. 1657-1667
-
Tidskriftsartikel (refereegranskat)abstract
- We quantified associations between IgE and cancer in a meta-analysis and cohort study. Pubmed and Embase were searched to extract information using predefined inclusion criteria. In the Apolipoprotein MOrtality RISk (AMORIS) database, 24,820 persons had IgE measurements. Multivariate Cox proportional hazard models were used to analyze associations between IgE and cancer. Twenty-seven studies were reviewed from which seven case-control studies were included for analysis. The pooled relative risk (random effects model) was 0.97 (95% CI 0.86-1.09). Cell types of tumor origin (mesenchymal tissue or cells of the nervous system, lymphatic or hematopoietic tissue, and epithelium) modified the effect. In the AMORIS cohort, 862 persons developed cancer. Hazard ratios comparing quartiles of IgE were similar to the findings in the meta-analysis (HR 0.87 (95% CI 0.72-1.06); 0.94 (0.78-1.14); 0.90 (0.74-1.10) for the 2nd, 3rd, and 4th quartile compared to the 1st quartile), but there was no pattern by tumor origin. Both studies showed a weak inverse association between IgE and cancer, but a pattern by cancer type was only seen in the meta-analysis. Our findings suggest the need for prospective studies studying IgE and cancer. Measurements of IgE should be combined with other information, e.g., bio-banked samples containing other key immunological discriminators.
|
|
| 7. |
- Van Hemelrijck, Mieke, et al.
(författare)
-
Low levels of apolipoprotein A-I and HDL are associated with risk of prostate cancer in the Swedish AMORIS study
- 2011
-
Ingår i: Cancer Causes and Control. - : Springer Science and Business Media LLC. - 0957-5243 .- 1573-7225. ; 22:7, s. 1011-1019
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A detailed analysis of lipid profiles, using apolipoproteins, has not yet been conducted for prostate cancer (PCa). Since several etiological pathways have been proposed for PCa and lipids, we aimed to study this in a large Swedish cohort with 1,469 primary prostate cancers. METHODS: A cohort (n = 69,735) of all men aged 35 years or older, whose levels of triglycerides (TG) (mmol/L), total cholesterol (mmol/L), glucose (mmol/L), LDL (mmol/L), HDL (mmol/L), apoB (g/L), and apoA-I (g/L) were measured at baseline, was selected from the Apolipoprotein MOrtality RISk (AMORIS) database. About 2,008 men developed PCa. Multivariate Cox proportional hazard models were used to analyze associations between lipid components and PCa. RESULTS: ApoA-I and HDL were inversely associated with PCa risk (e.g., HR for HDL: 0.93 (95% CI: 0.81-1.07), 0.88 (0.76-1.01), 0.81 (0.70-0.94), for second, third, and fourth quartiles compared with the first quartile; with p for trend: 0.004; HR for apoA-I: 1.00 (0.88-1.13), 0.93 (0.82-1.05), 0.88 (0.77-0.99),), for second, third, and fourth quartiles compared with the first quartile; with p for trend: 0.022). ApoB, LDL, and non-HDL were not associated with PCa risk. CONCLUSIONS: Our results show that low HDL and ApoA-I as well as increased lipid ratios are related to increased PCa risk. Experimental studies are required to tease out the underlying biological mechanisms linking these lipid components to PCa.
|
|
| 8. |
- Van Hemelrijck, Mieke, et al.
(författare)
-
Risk of prostate cancer is not associated with levels of C-reactive protein and other commonly used markers of inflammation
- 2011
-
Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 10:2, s. 207-207
-
Tidskriftsartikel (refereegranskat)abstract
- Most population-based studies studied the association between inflammation and prostate cancer (PCa) by assessing C-reactive protein (CRP). Since these findings have shown inconsistent results, we aimed to also study different markers that have been commonly taken as indications of inflammation.A cohort based on four groups of men (n=34,891), according to age at cohort entry (45, 55, 65, and 75 years), with measurements of glucose, triglycerides, total cholesterol, haptoglobin, albumin, hemoglobin, and leukocytes were selected from the Apolipoprotein MOrtality RISk (AMORIS) database. 17,937 had measurements of non-high-sensitivity CRP. Multivariate Cox proportional hazard models were used to analyze associations between inflammatory markers and PCa.A total of 49 out of 12,063 men developed PCa in the age 45 group, while 207 out of 9,940, 472 out of 8,266, and 276 out of 3,618 were diagnosed in the age 55, 65, and age 75 groups, respectively. Mean follow-up time was 7.5 years (SD: 3.9). No markers showed an association with PCa risk, nor was there a trend by quartiles or an indication for different PCa risks by strata of hypercholesterolemia, hyperglycemia, and hypertriglyceridemia status.The studied markers were not found to be associated with PCa risk. These null-findings might be due to methodological issues, however it is unlikely that strong and long-lasting associations between inflammation and PCa risk were missed as this was a large database with long follow-up. This indicates need for international consensus on appropriate inflammatory markers in the context of cancer that may be practically applied in large studies.
|
|
