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(1) Understanding Resistance vs. Susceptibility in Visceral Leishmaniasis Using Mouse Models of Infection.[TOP]

Pubmed ID :30881923
Publication Date : //
Every year, up to 90,000 new cases of Visceral Leishmaniasis and 30,000 resultant deaths are estimated to occur worldwide. Such numbers give relevance to the continuous study of this complex form of the disease: a zoonosis and an anthroponosis; two known etiological agents ( and , respectively); with an estimated average ratio of 1 symptomatic per 10 asymptomatic individuals; and sometimes associated with atypical clinical presentations. This complexity, which results from a long co-evolutionary process involving vector-host, host-pathogen, and pathogen-vector interactions, is still not completely understood. The determinants of visceralization are not fully defined and the dichotomy resistance vs. susceptibility remains unsolved, translating into obstacles that delay the progress of global disease control. Inbred mouse models, with different susceptibility patterns to infection, have been very useful in exploring this dichotomy. BALB/c and C57BL/6 mice were described as susceptible strains to visceral infection, while SV/129 was considered resistant. Here, we used these three mouse models, but in the context of infection, the other species that cause visceral disease in humans, and dynamically compared their local and systemic infection-induced immune responses in order to establish a parallel and to ultimately better understand susceptibility vs. resistance in visceral leishmaniasis. Overall, our results suggest that C57BL/6 mice develop an intermediate "infection-phenotype" in comparison to BALB/c and SV/129 mouse strains, considering both the splenic parasite burden and the determined target organs weights. However, the immune mechanisms associated with the control of infection seem to be different in each mouse strain. We observed that both BALB/c and SV/129, but not C57BL/6 mice, show an infection-induced increase of splenic T follicular helper cells. On the other hand, differences detected in terms of CD21 expression by B cells early after infection, together with the quantified anti- specific antibodies, suggest that SV/129 are faster than BALB/c and C57BL/6 mice in the assembly of an efficient B-cell response. Additionally, we observed an infection-induced increase in polyfunctional CD4+ T cells in the resistant SV/129 model, opposing an infection-induced increase in CD4+IL-10+ cells in susceptible BALB/c mice. Our data aligns with the observations reported for infection and suggest that not only a single mechanism, but an interaction of several could be necessary for the control of this parasitic disease.

Authors : Pérez-Cabezas Begoña, Cecílio Pedro, Gaspar Tiago Bordeira, Gärtner Fátima, Vasconcellos Rita, Cordeiro-da-Silva Anabela,

(2) Transplantation of umbilical cord-derived mesenchymal stem cells on a collagen scaffold improves ovarian function in a premature ovarian failure model of mice.[TOP]

Pubmed ID :30820812
Publication Date : //
Premature ovarian failure (POF) is a refractory disease; one of the most important goals of treatment is to improve fertility. In the study, collagen scaffold loaded with human umbilical cord-derived mesenchymal stem cells (collagen/UC-MSCs) transplantation in POF mice preserved ovarian function, as supported by increased estrogen (E) and anti-Mullerian hormone (AMH) levels, increased ovarian volume, and an increased number of antral follicles. Immunohistochemistry results of Ki67 indicated transplantation of collagen/UC-MSCs promoted granulosa cell proliferation, which is crucial to oocyte maturation and follicular development. Additionally, transplantation of collagen/UC-MSCs significantly promoted ovarian angiogenesis with the increased expression of CD31. In general, collagen/UC-MSCs transplantation probably is an effective therapeutic strategy of POF.

Authors : Yang Yanjun, Lei Lei, Wang Shanshan, Sheng Xiaoqiang, Yan Guijun, Xu Lu, Liu Jingyu, Liu Mengyuan, Zhen Xin, Ding Lijun, Sun Haixiang,

(3) Toll-Like Receptor Signaling Drives Btk-Mediated Autoimmune Disease.[TOP]

Pubmed ID :30761150
Publication Date : //
Bruton's tyrosine kinase (Btk) is a signaling molecule involved in development and activation of B cells through B-cell receptor (BCR) and Toll-like receptor (TLR) signaling. We have previously shown that transgenic mice that overexpress human Btk under the control of the CD19 promoter (CD19-hBtk) display spontaneous germinal center formation, increased cytokine production, anti-nuclear autoantibodies (ANAs), and systemic autoimsmune disease upon aging. As TLR and BCR signaling are both implicated in autoimmunity, we studied their impact on splenic B cells. Using phosphoflow cytometry, we observed that phosphorylation of ribosomal protein S6, a downstream Akt target, was increased in CD19-hBtk B cells following BCR stimulation or combined BCR/TLR stimulation, when compared with wild-type (WT) B cells. The CD19-hBtk transgene enhanced BCR-induced B cell survival and proliferation, but had an opposite effect following TLR9 or combined BCR/TLR9 stimulation. Although the expression of TLR9 was reduced in CD19-hBtk B cells compared to WT B cells, a synergistic effect of TLR9 and BCR stimulation on the induction of CD25 and CD80 was observed in CD19-hBtk B cells. In splenic follicular (Fol) and marginal zone (MZ) B cells from aging CD19-hBtk mice BCR signaling stimulated IL-10 production in synergy with TLR4 and particularly TLR9 stimulation, but not with TLR3 and TLR7. The enhanced capacity of CD19-hBtk Fol B cells to produce the pro-inflammatory cytokines IFNγ and IL-6 compared with WT B cells was however not further increased following BCR or TLR9 stimulation. Finally, we used crosses with mice deficient for the TLR-associated molecule myeloid differentiation primary response 88 (MyD88) to show that TLR signaling was crucial for spontaneous formation of germinal centers, increased IFNγ, and IL-6 production by B cells and anti-nuclear autoantibody induction in CD19-hBtk mice. Taken together, we conclude that high Btk expression does not only increase B cell survival following BCR stimulation, but also renders B cells more sensitive to TLR stimulation, resulting in increased expression of CD80, and IL-10 in activated B cells. Although BCR-TLR interplay is complex, our findings show that both signaling pathways are crucial for the development of pathology in a Btk-dependent model for systemic autoimmune disease.

Authors : Rip Jasper, de Bruijn Marjolein J W, Appelman Marjolein K, Pal Singh Simar, Hendriks Rudi W, Corneth Odilia B J,

(4) Evidence that growth hormone can improve mitochondrial function in oocytes from aged mice.[TOP]

Pubmed ID :30668522
Publication Date : //
Decline in successful conception decreases more rapidly after 38 years of age owing to follicular depletion and decreased oocyte quality. However, limited information is available regarding the underlying mechanism and the useful treatment. This study aimed to evaluate the effects of growth hormone supplementation on oocyte maturation in vivo in aged and young mice and to determine its effect on mitochondrial function. The influence of three different doses of recombinant human growth hormone (rhGH) (0.4 mg/kg/d, 0.8 mg/kg/d, and 1.6 mg/kg/d) for 8 weeks before ovarian stimulation was analyzed. Superovulated oocytes were released from the oviduct of Twelve-week-old (12W) and fourty-week-old (40W) female C57BL/6J mice 14-16 h after administration of human chorionic gonadotropin. Ovarian follicle and morphological analysis and oocyte maturation parameters were then evaluated. This study is the first, to our knowledge, to report that medium- and high-dose rhGH significantly increases antral follicles in aged mice but anti-Müllerian hormone (AMH) levels. Furthermore, derived oocytes, MII stage oocyte rate, adenosine triphosphate (ATP) levels, mitochondrial membrane potential and frequencies of homogeneous mitochondrial distribution increased. In contrast, in both aged and young mice, the mitochondrial DNA (mtDNA) copy numbers per oocyte were similar before rhGH administration, and upon saline administration, they did not differ significantly. We conclude that medium-dose rhGH supplementation before standard ovarian stimulation regimens improves oocyte quality in aged mice, probably by enhancing mitochondrial functionality.

Authors : Hou Haiyan, Wang Xi, Yu Qi, Li Hong-Yi, Li Shao-Jie, Tang Rui-Yi, Guo Zai-Xin, Chen Ya-Qiong, Hu Chun-Xiu, Yang Zhi-Juan, Zhang Wen-Ke, Qin Yan,

(5) Mature IgD B cells maintain tolerance by promoting regulatory T cell homeostasis.[TOP]

Pubmed ID :30643147
Publication Date : //
A number of different B cell subsets have been shown to exhibit regulatory activity using a variety of mechanisms to attenuate inflammatory diseases. Here we show, using anti-CD20-mediated partial B cell depletion in mice, that a population of mature B cells distinguishable by IgD expression maintains tolerance by, at least in part, promoting CD4Foxp3 regulatory T cell homeostatic expansion via glucocorticoid-induced tumor necrosis factor receptor ligand, or GITRL. Cell surface phenotyping, transcriptome analysis and developmental study data show that B cells expressing IgD at a low level (BD) are a novel population of mature B cells that emerge in the spleen from the transitional-2 stage paralleling the differentiation of follicular B cells. The cell surface phenotype and regulatory function of BD are highly suggestive that they are a new B cell subset. Human splenic and peripheral blood IgD B cells also exhibit BD regulatory activity, rendering them of therapeutic interest.

Authors : Ray Avijit, Khalil Mohamed I, Pulakanti Kirthi L, Burns Robert T, Gurski Cody J, Basu Sreemanti, Wang Demin, Rao Sridhar, Dittel Bonnie N,

(6) C5aR1 regulates T follicular helper differentiation and chronic graft-versus-host disease bronchiolitis obliterans.[TOP]

Pubmed ID :30568034
Publication Date : //
CD4+ follicular helper T (Tfh) cells are specialized providers of T cell help to B cells and can function as pathogenic mediators of murine antibody-dependent chronic graft-versus-host disease (GvHD). Using a parent→F1 model of lupus-like chronic GvHD, in which Tfh cell and germinal center (GC) B cell differentiation occurs over 14 days, we demonstrate that absence of CD4+ T cell-expressed C5a receptor 1 (C5ar1) or pharmacological C5aR1 blockade abrogated generation/expansion of Tfh cells, GC B cells, and autoantibodies. In a Tfh cell-dependent model of chronic GvHD manifested by bronchiolitis obliterans syndrome (BOS), C5aR1 antagonism initiated in mice with established disease ameliorated BOS and abolished the associated differentiation of Tfh and GC B cells. Guided by RNA-sequencing data, mechanistic studies performed using murine and human T cells showed that C5aR1 signaling amplifies IL-6-dependent expression of the transcription factor c-MAF and the cytokine IL-21 via phosphorylating phosphokinase B (AKT) and activating the mammalian target of rapamycin (mTOR). In addition to linking C5aR1-initiated signaling to Tfh cell differentiation, our findings suggest that C5aR1 may be a useful therapeutic target for prevention and/or treatment of individuals with Tfh cell-dependent diseases, including those chronic GvHD patients who have anti-host reactive antibodies.

Authors : Verghese Divya A, Chun Nicholas, Paz Katelyn, Fribourg Miguel, Woodruff Trent M, Flynn Ryan, Hu Yuan, Xiong Huabao, Zhang Weijia, Yi Zhengzi, Du Jing, Blazar Bruce R, Heeger Peter S,

(7) Subdominance and poor intrinsic immunogenicity limit humoral immunity targeting influenza HA stem.[TOP]

Pubmed ID :30521496
Publication Date : //
Both natural influenza infection and current seasonal influenza vaccines primarily induce neutralizing antibody responses against highly diverse epitopes within the "head" of the viral hemagglutinin (HA) protein. There is increasing interest in redirecting immunity toward the more conserved HA stem or stalk as a means of broadening protective antibody responses. Here we examined HA stem-specific B cell and T follicular helper (Tfh) cell responses in the context of influenza infection and immunization in mouse and monkey models. We found that during infection, the stem domain was immunologically subdominant to the head in terms of serum antibody production and antigen-specific B and Tfh cell responses. Similarly, we found that HA stem immunogens were poorly immunogenic compared with the full-length HA with abolished sialic acid binding activity, with limiting Tfh cell elicitation a potential constraint to the induction or boosting of anti-stem immunity by vaccination. Finally, we confirm that currently licensed seasonal influenza vaccines can boost preexisting memory responses against the HA stem in humans. An increased understanding of the immune dynamics surrounding the HA stem is essential to inform the design of next-generation influenza vaccines for broad and durable protection.

Authors : Tan Hyon-Xhi, Jegaskanda Sinthujan, Juno Jennifer A, Esterbauer Robyn, Wong Julius, Kelly Hannah G, Liu Yi, Tilmanis Danielle, Hurt Aeron C, Yewdell Jonathan W, Kent Stephen J, Wheatley Adam K,

(8) Evaluation of Z-VAD-FMK as an anti-apoptotic drug to prevent granulosa cell apoptosis and follicular death after human ovarian tissue transplantation.[TOP]

Pubmed ID :30390176
Publication Date : //
To evaluate the efficiency of ovarian tissue treatment with Z-VAD-FMK, a broad-spectrum caspase inhibitor, to prevent follicle loss induced by ischemia/reperfusion injury after transplantation.

Authors : Fransolet Maïté, Noël Laure, Henry Laurie, Labied Soraya, Blacher Silvia, Nisolle Michelle, Munaut Carine,

(9) Dietary Docosahexaenoic Acid Prevents Silica-Induced Development of Pulmonary Ectopic Germinal Centers and Glomerulonephritis in the Lupus-Prone NZBWF1 Mouse.[TOP]

Pubmed ID :30258439
Publication Date : //
Ectopic lymphoid structures (ELS) consist of B-cell and T-cell aggregates that are initiated in inflamed tissues outside of secondary lymphoid organs. When organized within follicular dendritic cell (FDC) networks, ELS contain functional germinal centers that can yield autoantibody-secreting plasma cells and promote autoimmune disease. Intranasal instillation of lupus-prone mice with crystalline silica (cSiO), a respirable particle linked to human lupus, triggers ELS formation in the lung, systemic autoantibodies, and early onset of glomerulonephritis. Here we tested the hypothesis that consumption of docosahexaenoic acid (DHA), an ω-3 polyunsaturated fatty acid with anti-inflammatory properties, influences the temporal profile of cSiO-induced pulmonary ectopic germinal center formation and development of glomerulonephritis. Female NZBWF1 mice (6-wk old) were fed purified isocaloric diets supplemented with 0, 4, or 10 g/kg DHA - calorically equivalent to 0, 2, or 5 g DHA per day consumption by humans, respectively. Beginning at age 8 wk, mice were intranasally instilled with 1 mg cSiO, or saline vehicle alone, once per wk, for 4 wk. Cohorts were sacrificed 1, 5, 9, or 13 wk post-instillation (PI) of the last cSiO dose, and lung and kidney lesions were investigated by histopathology. Tissue fatty acid analyses confirmed uniform dose-dependent DHA incorporation across all cohorts. As early as 1 wk PI, inflammation comprising of B (CD45R) and T (CD3) cell accumulation was observed in lungs of cSiO-treated mice compared to vehicle controls; these responses intensified over time. Marked follicular dendritic cell (FDC; CD21/CD35) networking appeared at 9 and 13 wk PI. IgG plasma cells suggestive of mature germinal centers were evident at 13 wk. DHA supplementation dramatically suppressed cSiO-triggered B-cell, T-cell, FDC, and IgG plasma cell appearance in the lungs as well as anti-dsDNA IgG in bronchial lavage fluid and plasma over the course of the experiment. cSiO induced glomerulonephritis with concomitant B-cell accumulation in the renal cortex at 13 wk PI but this response was abrogated by DHA feeding. Taken together, realistic dietary DHA supplementation prevented initiation and/or progression of ectopic lymphoid neogenesis, germinal center development, systemic autoantibody elevation, and resultant glomerulonephritis in this unique preclinical model of environment-triggered lupus.

Authors : Bates Melissa A, Akbari Peyman, Gilley Kristen N, Wagner James G, Li Ning, Kopec Anna K, Wierenga Kathryn A, Jackson-Humbles Daven, Brandenberger Christina, Holian Andrij, Benninghoff Abby D, Harkema Jack R, Pestka James J,

(10) C-Abl is not actıvated in DNA damage-induced and Tap63-mediated oocyte apoptosıs in human ovary.[TOP]

Pubmed ID :30237472
Publication Date : //
There is a controversy in literature as to whether c-Abl is crucial for the induction of TAp63-mediated apoptosis and whether that inhibition of c-Abl with imatinib, which was designed to inhibit the oncogenic kinase BCR-ABL and c-kit, protects oocytes from chemotherapy-induced apoptosis in mice. No human data are available on this issue. We therefore aimed to explore whether genomic damage induced by chemotherapy drug cisplatin activates c-Abl along with TAp63 and the inhibition of c-Abl with imatinib prevents cisplatin-induced oocyte death and follicle loss in human ovary. Exposure to cisplatin induced DNA damage, activated TAp63 and SAPK/JNK pathway, and triggered apoptosis in the oocytes and granulosa cells. However, TAp63 activation after cisplatin was not associated with any increase in the expression of c-Abl. Imatinib did not prevent cisplatin-induced apoptosis of the granulosa cells or oocytes. Moreover, treatment with this drug resulted in the formation of bizarre shaped follicles lacking oocytes and increased follicular atresia by inducing apoptosis of granulosa cells and oocytes. Similar toxic effects were observed when ovarian tissue samples were incubated with a c-kit antagonist drug anti-CD117, but not with another c-Abl tyrosine kinase inhibitor GNF-2, which lacks an inhibitory action on c-kit. Intraperitoneal administration of imatinib to the xenografted animals produced similar histomorphological abnormalities in the follicles in human ovarian grafts and did not prevent cisplatin-induced follicle loss when co-administered with cisplatin. Our findings provide, for the first time, a molecular evidence for ovarian toxicity of this drug in human. Furthermore, this study together with two previous case reports of a severely compromised ovarian response to gonadotropin stimulation and premature ovarian failure in patients, while receiving imatinib, further heighten the concerns about its potential gonadotoxicity on human ovary and urge caution in its use in young female patients.

Authors : Bildik Gamze, Acılan Ceyda, Sahin Gizem Nur, Karahuseyinoglu Sercin, Oktem Ozgur,