| 1. |
- Wilhelmson, Anna S K, et al.
(författare)
-
Androgens regulate bone marrow B lymphopoiesis in male mice by targeting osteoblast-lineage cells.
- 2015
-
Ingår i: Endocrinology. - : The Endocrine Society. - 1945-7170 .- 0013-7227. ; 156:4, s. 1228-36
-
Tidskriftsartikel (refereegranskat)abstract
- Testosterone has profound immune-modulatory actions, which may be important for the sexual dimorphism in immune-related disorders, such as autoimmune diseases. A well-known effect of androgens is inhibition of bone marrow B lymphopoiesis; however, a plausible target cell for this effect has not yet been presented. The aim of this study was to determine the target cell for androgen-mediated regulation of bone marrow B lymphopoiesis in males. We confirm higher number of bone marrow B cells in male mice with global inactivation of the androgen receptor (AR) and these global AR knockout (G-ARKO) mice had increased number of B cell precursors from the pro-B stage. Because osteoblast-lineage cells are known to support B lymphopoiesis at the pro-B stage, we investigated the effect on B lymphopoiesis in osteoblast-lineage cell-specific ARKO (O-ARKO) mice; O-ARKO mice had increased number of B cells in the bone marrow, and the number of B cell precursors was increased from the pro-B stage, demonstrating that O-ARKO mimics the bone marrow B lymphopoiesis pattern of G-ARKO mice. By contrast, O-ARKO mice displayed only minor changes in B cell numbers in the splenic compartment compared with G-ARKO. Further, O-ARKO mice had moderately reduced number of bone trabeculae in the vertebrae, whereas cortical bone was unaffected. In conclusion, androgens exert inhibitory effects on bone marrow B lymphopoiesis in males by targeting the AR in osteoblast-lineage cells. The identification of the likely target cell for androgen-mediated regulation of bone marrow B lymphopoiesis will contribute to elucidation of the mechanisms by which androgens modulate immune-related disorders.
|
|
| 2. |
- Ren, Weicheng, et al.
(författare)
-
Surrogate light chain is required for central and peripheral B-cell tolerance and inhibits anti-DNA antibody production by marginal zone B cells
- 2015
-
Ingår i: European Journal of Immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 45:4, s. 1228-1237
-
Tidskriftsartikel (refereegranskat)abstract
- Selection of the primary antibody repertoire takes place in pro-/pre-B cells, and subsequently in immature and transitional B cells. At the first checkpoint, μ heavy (μH) chains assemble with surrogate light (SL) chain into a precursor B-cell receptor. In mice lacking SL chain, μH chain selection is impaired, and serum autoantibody levels are elevated. However, whether the development of autoantibody-producing cells is due to an inability of the resultant B-cell receptors to induce central and/or peripheral B-cell tolerance or other factors is unknown. Here, we show that receptor editing is defective, and that a higher proportion of BM immature B cells are prone to undergoing apoptosis. Furthermore, transitional B cells are also more prone to undergoing apoptosis, with a stronger selection pressure to enter the follicular B-cell pool. Those that enter the marginal zone (MZ) B-cell pool escape selection and survive, possibly due to the B-lymphopenia and elevated levels of B-cell activating factor. Moreover, the MZ B cells are responsible for the elevated IgM anti-dsDNA antibody levels detected in these mice. Thus, the SL chain is required for central and peripheral B-cell tolerance and inhibits anti-DNA antibody production by MZ B cells.
|
|
| 3. |
|
|
| 4. |
- Stern, Anna, 1980, et al.
(författare)
-
Neonatal Mucosal Immune Stimulation by Microbial Superantigen Improves the Tolerogenic Capacity of CD103(+) Dendritic Cells
- 2013
-
Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 8:9
-
Tidskriftsartikel (refereegranskat)abstract
- Food allergy represents failure to develop tolerance to dietary proteins. Food allergy has increased in prevalence in parallel with decreased exposure to microbes during infancy. In mice, neonatal peroral exposure to the strongly T cell stimulating superantigen staphylococcal enterotoxin A (SEA), enhances the capacity to develop oral tolerance to a novel antigen encountered in adult life. A population of antigen-presenting cells in the gut, the CD103(+) dendritic cells (DCs), is thought to be involved in oral tolerance development, as they convert naive T cells into FoxP3(+) regulatory T cells (Treg). This function depends on their capacity to convert vitamin A to retinoic acid, carried out by the retinal aldehyde dehydrogenase (RALDH) enzyme. Here, newborn mice were treated with superantigen and DC function and tolerogenic capacity was examined at six weeks of age. We observed that, in mice fed superantigen neonatally, the CD11c(+) DCs had increased expression of RALDH and in vitro more efficiently induced expression Foxp3 expression to stimulated T cells. Further, these mice showed an accumulation of FoxP3(+) T cells in the small intestinal lamina propria and had a more Ag-specific FoxP3(+) T cells after oral tolerance induction in vivo. Moreover, the improved oral tolerance, as shown by increased protection from food allergy, was eradicated if the Vitamin A metabolism was inhibited. These observations contribute to the understanding of how a strong immune stimulation during the neonatal period influences the maturation of the immune system and suggests that such stimulation may reduce the risk of later allergy development.
|
|
| 5. |
- Stern, Anna, 1980
(författare)
-
The immunomodulatory function of staphylococcal superantigen on oral tolerance
- 2010
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Exposure to soluble proteins via the gut gives rise to systemic tolerance, a phenomenon called oral tolerance. Failure of oral tolerance results in allergy, a disease that has increased during the last decades in Western industrialized countries. The cause of this rapid increase is unknown. However, according to the hygiene hypothesis and many epidemiological studies, there is a clear correlation between a hygienic lifestyle and the prevalence of allergy. The hygiene hypothesis is also supported by the results of animal studies. Specifically, germ-free mice have been found to be deficient in the development of oral tolerance and have less functional regulatory T cells. We have observed that Swedish infants have a less diverse gut microbial flora and a slower strain turnover compared to infants in developing countries, suggesting that certain microbes may have particularly strong immunoregulatory potential. Thus, neonatal colonization by Staphylococcus aureus (S. aureus) in the gut protects against food allergy development. Most S. aureus strains can produce one or more toxins with superantigenic function, including staphylococcal enterotoxins (SE) A, B, C, D, and E, as well as toxic shock syndrome toxin-1 (TSST-1). Superantigens are the strongest known T cell stimulants, as they stimulate 5-30% of all T cells in an antigen-independent manner by cross-linking MHC class II molecules on antigen-presenting cells with the Vβ region of the T cell receptor. The purpose of this thesis was to study the immunomodulatory role of staphylococcal superantigen on oral tolerance in animal models of allergy. Newborn pups were exposed to SEA during the first two weeks of life. Oral tolerance was induced at 6 weeks of age by feeding the mice the model antigen ovalbumin (OVA). Oral tolerization was followed by sensitization and challenge according to an airway allergy model or a food allergy model. Neonatal SEA treatment resulted in enhanced development of oral tolerance, as evidenced by decreased sensitization in both allergy models. Further, when colonizing germ-free mice with superantigen-producing S. aureus, improved oral tolerance induction in the food allergy model was observed compared to mice colonized by a non toxin-producing strain. To investigate the long-term effect of SEA on the immune system, immune cells were studied at the time for oral tolerization. We found that mice neonatally treated with SEA had higher proportions of lymphocytes expressing the gut migratory markers chemokine receptor CCR9 and integrin α4β7. This was associated with higher numbers of FoxP3+ regulatory T cells in the small intestinal lamina propria. In addition, neonatal SEA treatment rendered dendritic cells (DCs) more tolerogenic demonstrated by lower expression of co-stimulatory markers, higher expression of MHC class II, and reduced T cell stimulatory properties. A subpopulation of gut DCs expressing CD103 have been suggested to be important for oral tolerance. This DC subset specifically imprints gut migratory potential on stimulated T cells and can convert naïve T cells into regulatory T cells. The unique properties of the CD103+ DCs depend on their expression of retinal dehydrogenases (RALDHs), enzymes that convert vitamin A to retinoic acid (RA). By interfering with the vitamin A metabolism in vivo by giving mice the RALDH inhibitor Citral in their drinking water, the improvement in oral tolerance noted after neonatal SEA treatment was lost. In addition, Citral intake affected gut DCs by lowering the expression of MHC class II, suggesting that high expression of antigens via MHC class II is important for oral tolerance. In conclusion, neonatal exposure to superantigen or colonization of germ-free mice by superantigen-producing S. aureus confers an increased ability for oral tolerance several weeks after treatment. This improvement is likely dependent upon an interaction between gut-residing DCs and gut-migrating lymphocytes, particularly regulatory T cells. SEA treatment affects gut DCs inducing prolonged capacity in this subset to evoke gut-homing potential to T cells. In addition, the improved oral tolerance observed following neonatal SEA treatment might also be dependent on functional vitamin A metabolism.
|
|
| 6. |
- Tengvall, Sara, 1977, et al.
(författare)
-
Gene Therapy Induces Antigen-Specific Tolerance in Experimental Collagen-Induced Arthritis
- 2016
-
Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 11:5
-
Tidskriftsartikel (refereegranskat)abstract
- Here, we investigate induction of immunological tolerance by lentiviral based gene therapy in a mouse model of rheumatoid arthritis, collagen II-induced arthritis (CIA). Targeting the expression of the collagen type II (CII) to antigen presenting cells (APCs) induced antigen-specific tolerance, where only 5% of the mice developed arthritis as compared with 95% of the control mice. In the CII-tolerized mice, the proportion of Tregs as well as mRNA expression of SOCS1 (suppressors of cytokine signaling 1) increased at day 3 after CII immunization. Transfer of B cells or non-B cell APC, as well as T cells, from tolerized to naive mice all mediated a certain degree of tolerance. Thus, sustainable tolerance is established very early during the course of arthritis and is mediated by both B and non-B cells as APCs. This novel approach for inducing tolerance to disease specific antigens can be used for studying tolerance mechanisms, not only in CIA but also in other autoimmune diseases.
|
|
