| 1. |
- Andersson, Annica, 1983, et al.
(författare)
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Roles of activating functions 1 and 2 of estrogen receptor α in lymphopoiesis.
- 2018
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Ingår i: The Journal of endocrinology. - 1479-6805. ; 236:2
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Tidskriftsartikel (refereegranskat)abstract
- Apart from the role of sex steroids in reproduction, sex steroids are also important regulators of the immune system. 17β-estradiol (E2) represses T and B cell development, but augments B cell function, possibly explaining the different nature of immune responses in men and women. Both E2 and selective estrogen receptors modulators (SERM) act via estrogen receptors (ER). Activating functions (AF)-1 and 2 of the ER bind to coregulators and thus influence target gene transcription and subsequent cellular response to ER activation. The importance of ERαAF-1 and AF-2 in the immunomodulatory effects of E2/SERM has previously not been reported. Thus, detailed studies of T and B lymphopoiesis were performed in ovariectomized E2-, lasofoxifene- or raloxifene-treated mice lacking either AF-1 or AF-2 domains of ERα, and their wild-type littermate controls. Immune cell phenotypes were analyzed with flow cytometry. All E2 and SERM-mediated inhibitory effects on thymus cellularity and thymic T cell development were clearly dependent on both ERαAFs. Interestingly, divergent roles of ERαAF-1 and ERαAF-2 in E2 and SERM-mediated modulation of bone marrow B lymphopoiesis were found. In contrast to E2, effects of lasofoxifene on early B cells did not require functional ERαAF-2, while ERαAF-1 was indispensable. Raloxifene reduced early B cells partly independent of both ERαAF-1 and ERαAF-2. Results from this study increase the understanding of the impact of ER modulation on the immune system, which can be useful in the clarification of the molecular actions of SERMs and in the development of new SERM.
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| 2. |
- Andersson, Annica, 1983, et al.
(författare)
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Selective oestrogen receptor modulators lasofoxifene and bazedoxifene inhibit joint inflammation and osteoporosis in ovariectomised mice with collagen-induced arthritis.
- 2016
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Ingår i: Rheumatology (Oxford, England). - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 55:3, s. 553-563
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Tidskriftsartikel (refereegranskat)abstract
- RA predominantly affects post-menopausal women and is strongly associated with development of generalised osteoporosis. To find treatments that target both joint manifestations and osteoporosis in RA is desirable. The third generation of selective oestrogen receptor modulators (SERMs) [lasofoxifene (LAS) and bazedoxifene (BZA)] are new treatment options for post-menopausal osteoporosis. The aim of this study was to investigate the effects of LAS and BZA on arthritic disease and inflammation-associated bone loss using CIA in mice.
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| 3. |
- Andersson, Annica, 1983, et al.
(författare)
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Suppression of Experimental Arthritis and Associated Bone Loss by a Tissue-Selective Estrogen Complex.
- 2016
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Ingår i: Endocrinology. - : The Endocrine Society. - 1945-7170 .- 0013-7227. ; 157:3, s. 1013-20
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Tidskriftsartikel (refereegranskat)abstract
- In addition to the systemic inflammation present in rheumatoid arthritis (RA), decreased estradiol levels in postmenopausal RA patients further accelerate bone loss in these patients. The tissue-selective estrogen complex (TSEC), an estrogen combined with a selective estrogen receptor modulator, is a new hormone replacement therapy option. The first approved TSEC, containing conjugated estrogens and bazedoxifene (BZA), reduces menopausal symptoms and prevents osteoporosis with an improved safety profile compared with conventional hormone replacement therapy. Previous studies have shown that estrogens strongly inhibit experimental arthritis whereas BZA is mildly suppressive. In this study the antiarthritic potential of combined BZA and estradiol is explored for the first time. Female ovariectomized DBA/1 mice were subjected to collagen-induced arthritis, an experimental postmenopausal RA model, and treated with BZA, 17β-estradiol (E2), combined BZA and E2 (BZA/E2), or vehicle. BZA/E2 suppressed arthritis severity and frequency, synovitis, and joint destruction, equally efficient as E2 alone. Unwanted estrogenic proliferative effects on the endometrium were blocked by the addition of BZA, determined by collecting uterine weights. Bone mineral density was measured by peripheral quantitative computed tomography, and all treatments protected collagen-induced arthritis mice from both trabecular and cortical bone loss. Moreover, BZA/E2, but not E2 alone, inhibited preosteoclast formation and reduced serum anticollagen type II antibodies. In conclusion, a TSEC, herein combined BZA/E2, suppresses experimental arthritis and prevents associated bone loss as efficiently as E2 alone but with minimal uterine effects, highlighting the need for clinical trials that evaluate the addition of a TSEC to conventional postmenopausal RA treatment.
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| 4. |
- Barman, Malin, 1983, et al.
(författare)
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Nutritional impact on Immunological maturation during Childhood in relation to the Environment (NICE): a prospective birth cohort in northern Sweden
- 2018
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Ingår i: BMJ Open. - : BMJ. - 2044-6055 .- 2044-6055. ; 8:10
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Tidskriftsartikel (refereegranskat)abstract
- © Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. INTRODUCTION: Prenatal and neonatal environmental factors, such as nutrition, microbes and toxicants, may affect health throughout life. Many diseases, such as allergy and impaired child development, may be programmed already in utero or during early infancy. Birth cohorts are important tools to study associations between early life exposure and disease risk. Here, we describe the study protocol of the prospective birth cohort, 'Nutritional impact on Immunological maturation during Childhood in relation to the Environment' (NICE). The primary aim of the NICE cohort is to clarify the effect of key environmental exposures-diet, microbes and environmental toxicants-during pregnancy and early childhood, on the maturation of the infant's immune system, including initiation of sensitisation and allergy as well as some secondary outcomes: infant growth, obesity, neurological development and oral health.METHODS AND ANALYSIS: The NICE cohort will recruit about 650 families during mid-pregnancy. The principal inclusion criterion will be planned birth at the Sunderby Hospital in the north of Sweden, during 2015-2018. Questionnaires data and biological samples will be collected at 10 time-points, from pregnancy until the children reach 4 years of age. Samples will be collected primarily from mothers and children, and from fathers. Biological samples include blood, urine, placenta, breast milk, meconium, faeces, saliva and hair. Information regarding allergic heredity, diet, socioeconomic status, lifestyle including smoking, siblings, pet ownership, etc will be collected using questionnaires. Sensitisation to common allergens will be assessed by skin prick testing and allergic disease will be diagnosed by a paediatrician at 1 and 4 years of age. At 4 years of age, the children will also be examined regarding growth, neurobehavioural and neurophysiological status and oral health.ETHICS AND DISSEMINATION: The NICE cohort has been approved by the Regional Ethical Review Board in Umeå, Sweden (2013/18-31M). Results will be disseminated through peer-reviewed journals and communicated on scientific conferences.
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| 5. |
- Bernardi, Angelina I, et al.
(författare)
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Effects of lasofoxifene and bazedoxifene on B cell development and function.
- 2014
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Ingår i: Immunity, inflammation and disease. - : Wiley. - 2050-4527. ; 2:4, s. 214-25
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Tidskriftsartikel (refereegranskat)abstract
- The third generation selective estrogen receptor modulators lasofoxifene (las) and bazedoxifene (bza) are indicated for treatment of postmenopausal osteoporosis. 17β-Estradiol (E2) and the second generation SERM raloxifene (ral) have major effects on the immune system, particularly on B cells. Treatment with E2 or ral inhibits B lymphopoiesis and treatment with E2, but not ral, stimulates antibody production. The effects of las and bza on the immune system have not been studied. Therefore, the aim of this study was to investigate their role in B cell development, maturation, and function. C57BL/6 mice were sham-operated or ovariectomized (ovx) and treated with vehicle, E2, ral, las, or bza. All substances increased total bone mineral density in ovx mice, as measured by peripheral quantitative computed tomography. In uterus, bza alone lacked agonistic effect in ovx mice and even acted as an antagonist in sham mice. As expected, E2 decreased B cell numbers at all developmental stages from pre-BI cells (in bone marrow) to transitional 1 (T1) B cells (in spleen) and increased marginal zone (MZ) B cells as determined by flow cytometry. However, treatment with las or bza only decreased the last stages of bone marrow B cell development and splenic T1 B cells, but had no effect MZ B cells. E2 increased antibody-producing cells quantified by ELISPOT, but las or bza did not. In conclusion, las and bza differ from E2 by retaining normal number of cells at most B cell stages during B lymphopoiesis and maturation and by not increasing antibody-producing cells.
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| 6. |
- Bernardi, Angelina I
(författare)
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Immune regulation by selective estrogen receptor modulators
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- At menopause, the levels of estrogen decline, leading to loss of estrogen-mediated protective effects on bone and an increased risk of osteoporosis. Hormone replacement therapy, containing estrogen, has been used for many years to prevent and treat osteoporosis in postmenopausal women. However, the estrogen receptor agonistic effects on the reproductive organs increases the risk of developing cancer. Therefore, selective estrogen receptor modulators (SERMs) have been developed, that can act as tissue-specific estrogen receptor agonists or antagonists. This enables SERMs to mediate the positive effects of estrogen on bone metabolism while avoiding side effects on the reproductive organs. Estrogen has a number of effects on the immune system; it decreases B- and T lymphopoiesis and increases antibody production. In addition, estrogen potently inhibits T-cell dependent inflammation and suppresses synovitis and inflammation-mediated bone loss in arthritis. Similarly to estrogen, the second-generation SERM raloxifene suppresses B-cell development and ameliorates arthritis. However, raloxifene lacks effects on antibody production and T-cell dependent inflammation. Lasofoxifene and bazedoxifene are third-generation SERMs, approved for treatment of postmenopausal osteoporosis. The bone-protective properties of these compounds are well documented; however the effects of lasofoxifene and bazedoxifene on the immune system have not earlier been assessed. Therefore, the aim of the studies included in this thesis was to investigate the immune-regulating effects of these third-generation SERMs. We found that lasofoxifene and bazedoxifene suppressed B-cell development in ovariectomized (ovx) mice, but lacked effects on antibody production and on T-cell development. Furthermore, lasofoxifene and bazedoxifene did not suppress T-cell dependent inflammation, but potently inhibited synovitis and bone loss in mice subjected to experimental postmenopausal arthritis. Phenotypic analysis of lymph nodes in arthritic mice showed that while estrogen increased a subpopulation of dendritic cells (DCs), as well as T helper 17 (Th17) cells, B cells and surface markers connected to antigen-presentation on B cells, the SERMs lacked these effects. In conclusion, the third-generation SERMs lasofoxifene and bazedoxifene suppressed experimental arthritis and inhibited B-cell development in ovx mice, but lacked effects on T-cell development and T-cell dependent inflammation. SERMs also lacked effects on lymph node DCs, B cells and T cells in arthritic mice. Therefore, further investigation is needed to find the target for the suppressive effects of SERMs on arthritis. Nonetheless, the anti-arthritic effects of the third-generation SERMs suggest possibility for an extension of the clinical indications of these drugs to include also postmenopausal RA.
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| 7. |
- Bernardi, Angelina I, et al.
(författare)
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Selective estrogen receptor modulators in T cell development and T cell dependent inflammation
- 2015
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Ingår i: Immunobiology. - : Elsevier BV. - 0171-2985. ; 220:10, s. 1122-1128
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Tidskriftsartikel (refereegranskat)abstract
- Lasofoxifene (las) and bazedoxifene (bza) are third generation selective estrogen receptor modulators (SERMs) with minimal estrogenic side effects, approved for treatment of postmenopausal osteoporosis. T cells are involved in the pathology of postmenopausal osteoporosis and previous studies have established an important role for 17 beta-estradiol (E2) in T cell development and function. E2 causes a drastic thymic atrophy, alters the composition of thymic T cell populations, and inhibits T cell dependent inflammation. In contrast, the second generation SERM raloxifene (ral) lacks these properties. Although las and bza are drugs approved for treatment of postmenopausal bone loss, it is of importance to study their effects on other biological aspects in order to extend the potential use of these compounds. Therefore, the aim of this study was to investigate if treatment with las and bza affects T lymphopoiesis and T cell dependent inflammation. C57BI6 mice were ovariectomized (ovx) and treated with vehicle, E2, ral, las or bza. As expected, E2 reduced both thymus weight and decreased the proportion of early T cell progenitors while increasing more mature T cell populations in the thymus. E2 also suppressed the T cell dependent delayed-type hypersensitivity (DTH) reaction to oxazolone (OXA). Ral and las, but not bza, decreased thymus weight, while none of the SERMs had any effects on T cell populations in the thymus or on inflammation in DTH. In conclusion, this study shows that treatment with las or bza does not affect T lymphopoiesis or T cell dependent inflammation. (C) 2015 The Authors. Published by Elsevier GmbH.
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| 8. |
- Grimsholm, Ola, 1979, et al.
(författare)
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Absence of surrogate light chain results in spontaneous autoreactive germinal centres expanding V(H)81X-expressing B cells
- 2015
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Random recombination of antibody heavy- and light-chain genes results in a diverse B-cell receptor (BCR) repertoire including self-reactive BCRs. However, tolerance mechanisms that prevent the development of self-reactive B cells remain incompletely understood. The absence of the surrogate light chain, which assembles with antibody heavy chain forming a pre-BCR, leads to production of antinuclear antibodies (ANAs). Here we show that the naive follicular B-cell pool is enriched for cells expressing prototypic ANA heavy chains in these mice in a non-autoimmune background with a broad antibody repertoire. This results in the spontaneous formation of T-cell-dependent germinal centres that are enriched with B cells expressing prototypic ANA heavy chains. However, peripheral tolerance appears maintained by selection thresholds on cells entering the memory B-cell and plasma cell pools, as exemplified by the exclusion of cells expressing the intrinsically self-reactive V(H)81X from both pools.
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| 9. |
- Johansson, Maria E, 1977, et al.
(författare)
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alpha 7 Nicotinic Acetylcholine Receptor Is Expressed in Human Atherosclerosis and Inhibits Disease in Mice-Brief Report
- 2014
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Ingår i: Arteriosclerosis Thrombosis and Vascular Biology. - : Ovid Technologies (Wolters Kluwer Health). - 1079-5642 .- 1524-4636. ; 34:12, s. 2632-2636
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Tidskriftsartikel (refereegranskat)abstract
- Objective-Cholinergic pathways of the autonomic nervous system are known to modulate inflammation. Because atherosclerosis is a chronic inflammatory condition, we tested whether cholinergic signaling operates in this disease. We have analyzed the expression of the alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR) in human atherosclerotic plaques and studied its effects on the development of atherosclerosis in the hypercholesterolemic Ldlr(-/-) mouse model. Approach and Results-alpha 7nAChR protein was detected on T cells and macrophages in surgical specimens of human atherosclerotic plaques. To study the role of alpha 7nAChR signaling in atherosclerosis, male Ldlr(-/-) mice were lethally irradiated and reconstituted with bone marrow from wild-type or alpha 7nAChR-deficient animals. Ablation of hematopoietic cell alpha 7nAChR increased aortic atherosclerosis by 72%. This was accompanied by increased aortic interferon-gamma mRNA, implying increased Th1 activity in the absence of a7nAChR signaling. Conclusions-The present study shows that signaling through hematopoietic alpha 7nAChR inhibits atherosclerosis and suggests that it operates by modulating immune inflammation. Given the observation that alpha 7nAChR is expressed by T cells and macrophages in human plaques, our findings support the notion that cholinergic regulation may act to inhibit disease development also in man.
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| 10. |
- Mårtensson, Inga-Lill, 1957, et al.
(författare)
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The pre-B cell receptor checkpoint.
- 2010
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Ingår i: FEBS letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 584:12, s. 2572-9
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Forskningsöversikt (refereegranskat)abstract
- B lymphocytes are essential antibody-producing cells of the immune system. During the development of progenitor B cells to mature B cells that express a membrane-bound antibody, the B cell receptor (BCR), the cells undergo selection at several checkpoints, which ensures that a diverse antibody repertoire is generated and that the BCRs recognise foreign-, but not self-, antigens. In this review, we consider the pre-BCR checkpoint. Mutations or alterations that affect this checkpoint underpin the development of pre-B cell leukemias, primary immunodeficiency, and possibly, systemic autoimmunity.
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