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(1) 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 neutralising antibody responses against highly diverse epitopes within the "head" of the viral hemagglutinin (HA) protein. There is increasing interest on redirecting immunity towards the more conserved HA-stem or stalk as a means to broaden 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 immunisation 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 responses. Similarly, we found HA-stem immunogens were poorly immunogenic compared to the full-length HA with abolished sialic acid binding activity, with limiting Tfh 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 pre-existing 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,

(2) 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,

(3) 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,

(4) 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,

(5) Therapeutic effect of human amniotic epithelial cells in murine models of Hashimoto's thyroiditis and Systemic lupus erythematosus.[TOP]

Pubmed ID :30174233
Publication Date : //
The chronic inflammation of autoimmune diseases develops repetitive localized destruction or systemic disorders, represented by Hashimoto's thyroiditis (HT) and Systemic lupus erythematosus (SLE) respectively. Currently, there are no efficient ways to treat these autoimmune diseases. Therefore, it is critically important to explore new therapeutic strategies. The aim of this study was to investigate the therapeutic efficacy of human amniotic epithelial cells (hAECs) in murine models of HT and SLE.

Authors : Tan Bing, Yuan Weixin, Li Jinying, Yang Pengjie, Ge Zhen, Liu Jia, Qiu Chen, Zhu Xiaolong, Qiu Cong, Lai Dongmei, Guo Lihe, Wang Liang, Yu Luyang,

(6) Hyperactivated PI3Kδ promotes self and commensal reactivity at the expense of optimal humoral immunity.[TOP]

Pubmed ID :30127432
Publication Date : //
Gain-of-function mutations in the gene encoding the phosphatidylinositol-3-OH kinase catalytic subunit p110δ (PI3Kδ) result in a human primary immunodeficiency characterized by lymphoproliferation, respiratory infections and inefficient responses to vaccines. However, what promotes these immunological disturbances at the cellular and molecular level remains unknown. We generated a mouse model that recapitulated major features of this disease and used this model and patient samples to probe how hyperactive PI3Kδ fosters aberrant humoral immunity. We found that mutant PI3Kδ led to co-stimulatory receptor ICOS-independent increases in the abundance of follicular helper T cells (T cells) and germinal-center (GC) B cells, disorganized GCs and poor class-switched antigen-specific responses to immunization, associated with altered regulation of the transcription factor FOXO1 and pro-apoptotic and anti-apoptotic members of the BCL-2 family. Notably, aberrant responses were accompanied by increased reactivity to gut bacteria and a broad increase in autoantibodies that were dependent on stimulation by commensal microbes. Our findings suggest that proper regulation of PI3Kδ is critical for ensuring optimal host-protective humoral immunity despite tonic stimulation from the commensal microbiome.

Authors : Preite Silvia, Cannons Jennifer L, Radtke Andrea J, Vujkovic-Cvijin Ivan, Gomez-Rodriguez Julio, Volpi Stefano, Huang Bonnie, Cheng Jun, Collins Nicholas, Reilley Julie, Handon Robin, Dobbs Kerry, Huq Lutfi, Raman Indu, Zhu Chengsong, Li Quan-Zhen, Li Ming O, Pittaluga Stefania, Uzel Gulbu, Notarangelo Luigi D, Belkaid Yasmine, Germain Ronald N, Schwartzberg Pamela L,

(7) Follicular Helper T Cells in Systemic Lupus Erythematosus.[TOP]

Pubmed ID :30123218
Publication Date : //
CD4 follicular helper T (Tfh) cells constitute a subset of effector T cells that participate in the generation of high-affinity humoral responses. They express the chemokine receptor CXCR5 and produce the cytokine IL-21, both of which are required for their contribution to germinal center formation. Uncontrolled expansion of Tfh cells is observed in various mouse models of systemic autoimmune diseases and in patients with these diseases. In particular, the frequency of circulating Tfh is correlated with disease activity and anti-DNA antibody titer in patients with systemic lupus erythematosus. Recent studies reveal functional diversity within the Tfh population in both humans and mice. We will summarize here the molecular mechanisms for Tfh cell generation, survival and function in both humans and mice, and the relationship between Tfh cells and autoimmune disease in animal models and in patients.

Authors : Kim Sun Jung, Lee Kyungwoo, Diamond Betty,

(8) The role of AKT and FOXO3 in preventing ovarian toxicity induced by cyclophosphamide.[TOP]

Pubmed ID :30071053
Publication Date : //
Cyclophosphamide (CTX) has immunosuppressive effects and has been wildly used as one anti-cancer drug in clinical. Significant toxicity has been noticed particularly in the reproductive system. CTX promotes the maturation of ovarian follicles, decreases follicular reserve, and ultimately lead to ovarian failure or even premature ovarian failure (POF). The placental extract (HPE) has been shown to have some beneficial impact on reproductive system; however, little is known regarding to the effect of HPE on protecting CTX-induced ovarian injury and the mechanism involved. Whether human placental extracts (HPE) has a protective effect on CTX-induced toxicity on ovarian was studied by using a CTX-induced ovarian injury animal model. The effects of HEP on histopathology, the number of atretic follicles, the weight of the ovary, serum hormone levels, and apoptosis in granulosa cells were studied in mice with CTX or control vehicle. Our results have demonstrated that HPE inhibited p-Rictor, reduced the expression of Bad, Bax and PPAR, and activated Akt and Foxo3a (increased their phosphorylation). Mice treated with HPE showed higher ovarian weight, lower number of atretic follicles, higher serum levels of the hormones E2 and progesterone, and lower apoptosis and serum levels of LH and FSH in granulosa cells, than that in the control animal group. Our data show that ovarian injury can be attenuated by HPE. HPE likely protects follicular granulosa cells from undergoing significant apoptosis and reduce atresia follicle formation, therefore, alleviates CTX-induced ovarian injury.

Authors : Zhang Bao-Fang, Hu YaXin, Liu Xinyan, Cheng Zhuo, Lei Yu, Liu YongMei, Zhao Xueke, Mu Mao, Yu Lei, Cheng Ming-Liang,

(9) Identification of Human B-1 Helper T Cells With a Th1-Like Memory Phenotype and High Integrin CD49d Expression.[TOP]

Pubmed ID :30061889
Publication Date : //
Human B-1 cells have been proposed to be CD20CD27CD43CD1c B cells found in the umbilical cord and adult peripheral blood, but their regulatory mechanisms have not been well elucidated. Previously, we reported that mouse CD49d CD4 T cells could enhance the secretion of natural antibodies by B-1 cells. In this study, we aimed to investigate the presence and helper functions of the human equivalents of murine CD49d CD4 T cells. Here, we showed that human CD49d CD4 T cells found in the peritoneal cavity (PEC), spleen, and peripheral blood can enhance the production of IgM antibodies by B-1 cells. As revealed in mouse, CD49d CD4 T cells were more abundant in the PEC and showed a higher tendency to form conjugates with B cells than CD49d CD4 T cells. Moreover, CD49d CD4 T cells showed a Th1-like memory phenotype, characterized by high expression of CD44 and CXCR3; low expression of CD62L and CCR7; rapid production of IFN-γ, tumor necrosis factor-α, and IL-2 upon stimulation with phorbol myristate acetate and ionomycin; and rapid proliferation upon stimulation with anti-CD3 and anti-CD28 antibodies. These cells also expressed high levels of PD-1, ICOS, and CD5, suggesting that they are undergoing chronic stimulation. Remarkably, CD49d CD4 T cells specifically helped B-1 cells, but not follicular memory B cells (CD27 CD43CD1c) or marginal zone B cells (CD27CD43CD1c), produce IgM and IgG antibodies. In parallel, the titer of human anti-blood group A IgM was positively correlated with the frequency of CD49d CD4 T cells. In conclusion, we identified human CD49d CD4 T cells with a Th1-like memory phenotype that secrete Th1 proinflammatory cytokines and help B-1 cells secrete antibodies, thereby aiding in primary defense. We suggest that these CD49d CD4 T cells are a unique type of B-cell helper T cells distinct from follicular helper T cells.

Authors : Lee Jae-Ghi, Jang Joon Young, Fang Taishi, Xu Yixuan, Yan Ji-Jing, Ryu Jung-Hwa, Jeon Hee Jung, Koo Tai Yeon, Kim Dong Ki, Oh Kook-Hwan, Kim Tae Jin, Yang Jaeseok,

(10) Xenotransplantation of pre-pubertal ovarian cortex and prevention of follicle depletion with anti-Müllerian hormone (AMH).[TOP]

Pubmed ID :30043336
Publication Date : //
To determine whether recombinant AMH (rAMH) could prevent post-transplant follicular depletion by acting on the stemness markers Oct-4, Sox2, and NANOG.

Authors : Detti Laura, Fletcher Nicole M, Saed Ghassan M, Sweatman Trevor W, Uhlmann Rebecca A, Pappo Alberto, Peregrin-Alvarez Irene,