Yaa Opokua Antwi-Yeboah
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PROVIDER: S-EPMC527715 | biostudies-literature | 2004 Nov
REPOSITORIES: biostudies-literature
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Project description:There is a general consensus that collagen stability is largely maintained by Pro and its major hydroxylated form, 4-hydroxyproline (4Hyp). However, positional difference in their stabilizing effect at the Xaa or Yaa position of collagenous Gly-Xaa-Yaa sequences has remained inconclusive. Here, we position-specifically evaluated the correlation of imino acid contents to denaturation temperature (Td) of collagen among various vertebrate and invertebrate species, using a recently developed LC-MS methodology. 4Hyp at the Yaa position showed the highest positive correlation with Td, followed by Pro at the Xaa position, which was even further increased by excluding invertebrates. We confirmed that Gly-Pro-4Hyp liberated after bacterial collagenase digestion was highly positively correlated with Td. Furthermore, other tripeptides with Yaa position 4Hyp also had comparable positive correlation, excepting negative correlation of Gly-Gly-4Hyp, while tripeptides with Xaa position Pro did not. These data provide evidence that 4Hyp dominantly contributes to thermal stability of collagen depending on its sequence position, especially in vertebrates.
| S-EPMC8233474 | biostudies-literature
Project description:The Y-linked autoimmune accelerating (Yaa) locus drives the transition to fatal lupus nephritis when combined with B6.Sle1 in our C57BL/6J (B6)-congenic model of systemic autoimmunity. We and others recently demonstrated that the translocation of a cluster of X-linked genes onto the Y chromosome is the genetic lesion underlying Yaa (Subramanian, S. et al., Proc. Natl. Acad. Sci. USA 2006. 103: 9970-9975; Pisitkun, P. et al., Science 2006. 312: 1669-1672). In male mice carrying Yaa, the transcription of several genes within the translocated segment is increased roughly twofold. Although the translocated X chromosome segment in Yaa may contain as many as 16 genes, the major candidate gene for causation of the Yaa-associated autoimmune phenotypes has been TLR7. To confirm the role of TLR7 in Yaa-mediated autoimmune phenotypes, we introgressed a targeted disruption of TLR7 (TLR7(-)) onto B6.Sle1Yaa to produce B6.Sle1YaaTLR7(-) and examined evidence of disease at 6 and 9 months of age. Our results demonstrate that the up-regulation of TLR7 in the B6.Sle1Yaa strain is responsible for splenomegaly, glomerular nephritis and the majority of the cellular abnormalities of B, T and myeloid cells. The up-regulation of TLR7 was also responsible for driving the infiltration and activation of leukocytes in the kidney, in which activated T cells were a primary component. However, the resolution of TLR7 up-regulation did not eliminate the enhanced humoral autoimmunity observed in B6.SleYaa, suggesting that additional elements in the translocation may contribute to the disease phenotype.
| S-EPMC2993003 | biostudies-literature
Project description:Analysis of glomeruli isolated from kidneys of 4 month male BXSB/MpJ-Yaa. The BXSB/MpJ-Yaa mouse strain is a lupus-prone model. Results provide insight into the pathogenic mechanisms linked to glomerulonephritis in BXSB/MpJ-Yaa mice.
2014-01-01 | GSE51230 | GEO
Project description:Analysis of glomeruli isolated from kidneys of 4 month male BXSB/MpJ-Yaa. The BXSB/MpJ-Yaa mouse strain is a lupus-prone model. Results provide insight into the pathogenic mechanisms linked to glomerulonephritis in BXSB/MpJ-Yaa mice. The glomeruli were isolated from 6 BXSB/MpJ-Yaa (glomerulonephritis model) and BXSB/MpJ-Yaa+ (control). 6 glomerular populations of each strain were devided into 3 groups (1 group / 2 populations). 3 glomerulonephritis models versus 3 controls analysis was performed. BXSB/MpJ-Yaa is a recombinant inbred strain developed originally from a C57BL/6 female mouse and a SB/Le male mouse. Yaa (Y-linked autoimmune accelerator locus) localizing on the Y chromosome of BXSB/MpJ-Yaa male mice is the result of a duplication of an about 4 Mbp telomeric segment near the pseudoautosomal region of the X chromosome onto the Y chromosome. BXSB/MpJ-Yaa+ (control) male mice carry the wild-type Y chromosome in place of the mutant Yaa-containing Y chromosome of BXSB/MpJ-Yaa male mice.
2014-01-01 | E-GEOD-51230 | biostudies-arrayexpress
Project description:Male NZW/BXSB.Yaa (W/B) mice express two copies of TLR7 and develop pathogenic autoantibodies, whereas females with only one copy of TLR7 have attenuated disease. Our goal was to analyze the regulation of the autoantibody response in male and female W/B mice bearing the autoreactive site-directed H chain transgene 3H9. Serum anti-dsDNA Abs appeared in males at 12 wk, and most had high-titer IgG anti-dsDNA and anti-cardiolipin Abs and developed >300 mg/dl proteinuria by 8 mo. Females had only low-titer IgG anti-cardiolipin Abs, and none developed proteinuria by 1 y. Males had a smaller marginal zone than females with a repertoire that was distinct from the follicular repertoire, indicating that the loss of marginal zone B cells was not due to diversion to the follicular compartment. Vk5-43 and Vk5-48, which were rare in the naive repertoire, were markedly overrepresented in the germinal center repertoire of both males and females, but the VJ junctions differed between males and females with higher-affinity autoreactive B cells being selected into the germinal centers of males. Administration of IFN-α to females induced anti-cardiolipin and anti-DNA autoantibodies and proteinuria and was associated with a male pattern of junctional diversity in Vk5-43 and Vk5-48. Our studies are consistent with the hypothesis that presence of the Yaa locus, which includes an extra copy of Tlr7, or administration of exogenous IFN-α relaxes the stringency for selection in the germinal centers resulting in increased autoreactivity of the Ag-driven B cell repertoire.
| S-EPMC3478483 | biostudies-literature
Project description:Interleukin 21 (IL-21) is a pleiotropic cytokine produced by CD4 T cells that affects the differentiation and function of T, B, and NK cells by binding to a receptor consisting of the common cytokine receptor gamma chain and the IL-21 receptor (IL-21R). IL-21, a product associated with IL-17-producing CD4 T cells (T(H)17) and follicular CD4 T helper cells (T(FH)), has been implicated in autoimmune disorders including the severe systemic lupus erythematosus (SLE)-like disease characteristic of BXSB-Yaa mice. To determine whether IL-21 plays a significant role in this disease, we compared IL-21R-deficient and -competent BXSB-Yaa mice for multiple parameters of SLE. The deficient mice showed none of the abnormalities characteristic of SLE in IL-21R-competent Yaa mice, including hypergammaglobulinemia, autoantibody production, reduced frequencies of marginal zone B cells and monocytosis, renal disease, and premature morbidity. IL-21 production associated with this autoimmune disease was not a product of T(H)17 cells and was not limited to conventional CXCR5(+) T(FH) but instead was produced broadly by ICOS(+) CD4(+) splenic T cells. IL-21 arising from an abnormal population of CD4 T cells is thus central to the development of this lethal disease, and, more generally, could play an important role in human SLE and related autoimmune disorders.
| S-EPMC2635818 | biostudies-literature
Project description:T cells from many patients with systemic lupus erythematosus are hypoproliferative in response to TCR ligation. This defect is mediated, at least in part, through down regulation of the TCR zeta chain. Investigation of this phenomenon in lupus-prone mice revealed that the hypoproliferative T cell phenotype apparent in BXSB males is mediated in part by the Yaa locus. The BXSB model of lupus is a recombinant inbred strain that was originally derived from a cross between a male SB/LE mouse and a female C57BL/6 mouse. BXSB is unique among lupus-prone mouse strains, in that males carry an autoimmune accelerating factor on the Y chromosome, termed Yaa, which accelerates disease onset in male BXSB mice so that fatal glomerulonephritis occurs around 6 months of age. It was recently reported that the Yaa locus is a translocation of a short stretch of genes including that encoding Toll-like receptor 7 (Tlr-7) from the X to the Y chromosome, leading to a two-fold over expression of a subset of these genes, including Tlr-7, and hypersensitivity of Yaa+ cells to TLR-7 agonists. To more fully understand the functional significance of the Yaa gene and how it plays a part in the modulation of CD4+ T cell responses, we performed microarray analysis using Affymetrix 430 2.0 arrays on spleens from B6 male B6.Yaa male samples. The analysis revealed an enhanced signature of innate immunity, including increased expression not only of Tlr7 and Tlr8, in line with reports that the Yaa locus leads to a duplication of the murine Tlr7 and Tlr8 genes , but also of Tlr2, Tlr5, Cd14, Lbp, C2, C3 and genes for several heat-shock proteins. T cells from B6.Yaa mice also displayed decreased TCRζ expression. Interestingly, cell surface levels of the inhibitory molecule B7-H1 were increased on B6.Yaa B cells and monocytes/macrophages. In line with increased TLR-7 expression reported in B6.Yaa mice, the TLR-7 agonist imiquimod increased B7-H1 expression on normal B cells. Restoration of proliferation in co-cultures of B6 T cells and B6.Yaa APC with B7-H1 blocking Ab demonstrated a mechanistic contribution of B7-H1 up-regulation to Yaa-mediated APC-dependent T cell hypoproliferation. In addition, T cell hypoproliferation was induced in normal B6 T cells in vitro by the application of imiquimod. However, this defect was not mediated by B7-H1 or secreted factors but was independent of APC and mediated through direct imiquimod stimulation of T cells themselves. We postulate that excessive TLR-7 stimulation in Yaa+ mice mediates T cell hypoproliferation in part through up-regulation of B7-H1 and possibly also through direct T cell-mediated effects. Keywords: differential gene expression, RNA, spleen, C57Bl/6J, B6.SB-Yaa/J, male, wild type, Yaa
2009-12-15 | GSE9287 | GEO
Project description:The immune system includes a subpopulation of CD8(+) T cells equipped to inhibit the expansion of follicular T helper (T(FH)) cells, resulting in suppression of autoantibody production and associated lupus-like disease. These CD8(+) T regulatory (Treg) cells recognize Qa-1/peptide complexes on target T(FH) cells and depend on the IL-15 cytokine for development and function. Here we show that these CD8(+) Treg cells express a triad of surface receptors--CD44, CD122, and the class I MHC receptor Ly49--and account for <5% of CD8(+) T cells. Moreover, the development of systemic lupus erythematosus-like disease in B6-Yaa mutant mice is associated with a pronounced defect in CD8(+) Treg cell activity, suggesting that this regulatory subset may represent an effective therapeutic approach to systemic lupus erythematosus-like autoimmune disease.
| S-EPMC3033298 | biostudies-literature
Project description:Polymorphisms in the transcription factor IFN regulatory factor 5 (IRF5) are strongly associated in human genetic studies with an increased risk of developing the autoimmune disease systemic lupus erythematosus. However, the biological role of IRF5 in lupus pathogenesis has not previously been tested in an animal model. In this study, we show that IRF5 is absolutely required for disease development in the FcgammaRIIB(-/-)Yaa and FcgammaRIIB(-/-) lupus models. In contrast to IRF5-sufficient FcgammaRIIB(-/-)Yaa mice, IRF5-deficient FcgammaRIIB(-/-)Yaa mice do not develop lupus manifestations and have a phenotype comparable to wild-type mice. Strikingly, full expression of IRF5 is required for the development of autoimmunity, as IRF5 heterozygotes had dramatically reduced disease. One effect of IRF5 is to induce the production of the type I IFN, IFN-alpha, a cytokine implicated in lupus pathogenesis. To address the mechanism by which IRF5 promotes disease, we evaluated FcgammaRIIB(-/-)Yaa mice lacking the type I IFN receptor subunit 1. Unlike the IRF5-deficient and IRF5-heterozygous FcgammaRIIB(-/-)Yaa mice, type I IFN receptor subunit 1-deficient FcgammaRIIB(-/-)Yaa mice maintained a substantial level of residual disease. Furthermore, in FcgammaRIIB(-/-) mice lacking Yaa, IRF5-deficiency also markedly reduced disease manifestations, indicating that the beneficial effects of IRF5 deficiency in FcgammaRIIB(-/-)Yaa mice are not due only to inhibition of the enhanced TLR7 signaling associated with the Yaa mutation. Overall, we demonstrate that IRF5 plays an essential role in lupus pathogenesis in murine models and that this is mediated through pathways beyond that of type I IFN production.
| S-EPMC2858062 | biostudies-literature
Project description:Background'Yaa Chud' is a non-prescribed poly-pharmaceutical pack containing several types of drugs, including antibiotics and steroids, which can be purchased over the counter in Thailand for self-medication. Although it is illegal, it is still available at some community outlets. This study aimed to understand access to and use of Yaa Chud at the community level in order to raise awareness on its usage and to provide policy recommendations to address the problem.MethodsThis study employed qualitative methods, including in-depth interviews with 18 drug suppliers and 16 community members, and six focus group discussions. It included inventories from 17 drug suppliers. Data were collected in selected communities of the Kanchanaburi Demographic Surveillance System, located in the western region of Thailand.Thematic analysis was based upon the Health Services Utilization Model and conducted using the Open Code qualitative software program.ResultsOvercrowding, long waiting times, and a perceived unwelcoming environment at public health-care service outlets were identified as factors that drive people into the private sector, where loose regulation of drug laws facilitates access and use of Yaa Chud. Migrants and older people were most likely to seek and use Yaa Chud, especially for mild illness. Availability, easy access through a user's network, low cost, and perceived effectiveness were identified as factors that enable access and use of Yaa Chud.ConclusionsThough illegal in Thailand, Yaa Chud is likely to remain available for self-medication by community members, due to the persisting demand by the elderly and migrant workers. There is an urgent need to replace these mixed medications with better choices. Safer Yaa Chud may be a preferred, first-line health-care option, which could help reduce congestion in the formal health-care setting. At the same time, enforcement of regulatory compliance needs to be continued in order to stop the supply of unsafe Yaa Chud.
| S-EPMC6647088 | biostudies-literature