American Association of Immunologists

Background: Immunization information systems (IISs) in the United States forecast vaccine due dates, which can inform when providers recommend vaccines to patients. IIS forecasting for HPV vaccination at 9 years, the minimum age of licensure, and when vaccination is likely most effective is not documented or well-understood. Methods: We documented characteristics of HPV vaccination forecasts in jurisdictional IISs through Internet searches and requests to immunization program managers. Next, we conducted focus groups with stakeholders from seven jurisdictions to elucidate their processes for determining and implementing HPV vaccination forecasts. Results: Forecast data were available from 49 out of 64 CDC-funded jurisdictions, of which 14 (29%) recommended HPV vaccination at age 9 and 35 (71%) recommended HPV vaccination starting at ages 11 through to 15. Jurisdictions that recommended HPV vaccination at age 9 cited the positions of the American Cancer Society and American Academy of Pediatrics and reported little or no provider opposition to this recommendation. Jurisdictions reported variable flexibility in programming their forecasts. Those that changed their HPV vaccination forecast from 11 to 9 years did so easily while some experienced limitations. Other jurisdictions adhered strictly to the CDC’s routine recommendation at age 11–12 years and would only update the forecast in tandem with updated CDC guidance. The impact of IISs and electronic health record interoperability on how providers view and utilize IIS forecasting is unclear. Conclusions: Jurisdictions can share best practices for forecasting at 9 and future studies can evaluate the effects of forecasting age on the vaccination rates, providing evidence for nationwide vaccination recommendations.

Human type 2 cytotoxic T (Tc2) cells are enriched in severe eosinophilic asthma and can contribute to airway eosinophilia. Prostaglandin D2 (PGD2) and its receptor prostaglandin D2 receptor 2 (DP2) play important roles in Tc2 cell activation including migration, cytokine production and survival. In this study, we revealed novel functions of the PGD2/DP2 axis in Tc2 cells to induce tissue remodelling effects and immunoglobulin E (IgE)-independent PGD2 autocrine production. PGD2 upregulated the expression of tissue remodelling genes in Tc2 cells, which enhanced fibroblast proliferation and protein production required for tissue repair and myofibroblast differentiation. PGD2 stimulated Tc2 cells to produce PGD2 using the routine PGD2 synthesis pathway, which also contributed to T cell receptor-dependent PGD2 production in Tc2 cells. Using fevipiprant, a specific DP2 antagonist, we demonstrated that competitive inhibition of DP2 not only completely blocked the cell migration, adhesion, proinflammatory cytokine production and survival of Tc2 cells triggered by PGD2, but also attenuated the tissue remodelling effects and autocrine/paracrine PGD2 production in Tc2 induced by PGD2 and other stimulators. These findings further confirmed the anti-inflammatory effect of fevipiprant and provided a better understanding of the role of Tc2 cells in the pathogenesis of asthma.

Thiagarajan, D., S. L. Lundström, G. Pershagen, C. Almqvist Malmros, E. Andolf, A. Hedman, O. Berg, N. Oparina, and J. Frostegård. 2020. Antibodies against phosphorylcholine and malondialdehyde during the first two years of life. J. Immunol. 205: [2109–2116][1]. The fourth author’s surname

Pandey, J. P., J. Olsson, B. Weidung, R. T. Kothera, A. Johansson, S. Eriksson, G. Hallmans, F. Elgh, and H. Lövheim. 2020. An Ig γ marker genotype is a strong risk factor for Alzheimer disease, independent of apolipoprotein E ε4 genotype. J. Immunol. 205: [1318–1322][1]. The footnotes for [

Transcriptional programs regulated by the NF-κB family are essential for the inflammatory response as well as for innate and adaptive immunity. NF-κB activation occurs via two major signaling pathways: the canonical and the noncanonical. The canonical NF-κB pathway responds to diverse immune stimulations and leads to rapid but transient activation. As a member of the canonical NF-κB family, p65 is thought to be a key regulator of viral infection. Because of the embryonic lethality of p65-null mice, the physiological role of p65 in the antiviral immune response is still unclear. In this study, we generated p65-null zebrafish, which were viable and indistinguishable from their wildtype (WT) siblings under normal conditions. However, p65-null zebrafish were more sensitive to spring viremia of carp virus infection than their WT siblings. Further assays indicated that proinflammatory and antiviral genes, including IFN, were downregulated in p65-null zebrafish after spring viremia of carp virus infection compared with their WT siblings. Our results thus suggested that p65 is required for the antiviral response, activating not only proinflammatory genes but also antiviral genes (including IFN).

Wang, B., Q. Zhou, Y. Bi, W. Zhou, Q. Zeng, Z. Liu, X. Liu, and Z. Zhan. 2019. Phosphatase PPM1L prevents excessive inflammatory responses and cardiac dysfunction after myocardial infarction by inhibiting IKKβ activation. J. Immunol . 203: [1338–1347][1]. In the published version of [Fig. 1F][2

Altered intestinal epithelial integrity is an important susceptibility trait in inflammatory bowel disease (IBD), and early life stressors are reported to contribute to this disease susceptibility in adulthood. To identify disease mechanisms associated with early-life trauma that exacerbate IBD in adulthood, we used a "double-hit" neonatal inflammation (NI) and adult inflammation (AI) model that exhibits more severe mucosal injury in the colon later in life. In this study, we explore the underlying mechanisms of this aggravated injury. In rats exposed to both NI and AI, we found sustained increases in colonic permeability accompanied by significantly attenuated expression of the epithelial junction protein E-cadherin. Quantitative RT-PCR revealed a decreased Cdh1 (gene of E-cadherin) mRNA expression in NI + AI rats compared with NI or AI rats. Next, we performed microRNA microarrays to identify potential regulators of E-cadherin in NI + AI rats. We confirmed the overexpression of miR-155, a predicted regulator of E-cadherin, and selected it for further analysis based on reported significance in human IBD. Using ingenuity pathway analysis software, the targets and related canonical pathway of miR-155 were analyzed. Mechanistic studies identified histone hyperacetylation at the Mir155 promoter in NI + AI rats, concomitant with elevated RNA polymerase II binding. In vitro, E-cadherin knockdown markedly increased epithelial cell permeability, as did overexpression of miR-155 mimics, which significantly suppressed E-cadherin protein. In vivo, NI + AI colonic permeability was significantly reversed with administration of miR-155 inhibitor rectally. Our collective findings indicate that early-life inflammatory stressors trigger a significant and sustained epithelial injury by suppressing E-cadherin through epigenetic mechanisms.

Yan, S., H. Shen, Q. Lian, W. Jin, R. Zhang, X. Lin, W. Gu, X. Sun, G. Meng, Z. Tian, Z. W. Chen, and B. Sun. 2018. Deficiency of the AIM2–ASC signal uncovers the STING-driven overreactive response of type I IFN and reciprocal depression of protective IFN-γ immunity in mycobacterial infection. J

Folliculin interacting protein 1 (Fnip1) is a cytoplasmic protein originally discovered through its interaction with the master metabolic sensor 5' AMP-activated protein kinase (AMPK) and Folliculin, a protein mutated in individuals with Birt-Hogg-Dubé Syndrome. In response to low energy, AMPK stimulates catabolic pathways such as autophagy to enhance energy production while inhibiting anabolic pathways regulated by the mechanistic target of rapamycin complex 1 (mTORC1). We previously found that constitutive disruption of Fnip1 in mice resulted in a lack of peripheral B cells because of a block in B cell development at the pre-B cell stage. Both AMPK and mTORC1 were activated in Fnip1-deficient B cell progenitors. In this study, we found inappropriate mTOR localization at the lysosome under nutrient-depleted conditions. Ex vivo lysine or arginine depletion resulted in increased apoptosis. Genetic inhibition of AMPK, inhibition of mTORC1, or restoration of cell viability with a Bcl-xL transgene failed to rescue B cell development in Fnip1-deficient mice. Fnip1-deficient B cell progenitors exhibited increased nuclear localization of transcription factor binding to IgHM enhancer 3 (TFE3) in developing B cells, which correlated with an increased expression of TFE3-target genes, increased lysosome numbers and function, and increased autophagic flux. These results indicate that Fnip1 modulates autophagy and energy response pathways in part through the regulation of AMPK, mTORC1, and TFE3 in B cell progenitors.

Mucosal-associated invariant T (MAIT) cells play a key role in local and systemic immune responses. Studies suggest that type 2 diabetes (T2D) is associated with alterations in the human MAIT cell response. However, the mechanisms that regulate the survival and homeostasis of human MAIT cells are poorly defined. In this study, we demonstrate that the costimulatory TNF superfamily receptor OX40 was highly expressed in MAIT cells of patients with T2D. Compared with OX40-negative MAIT cells, OX40-positive MAIT cells showed a high activation and a memory phenotype. Surprisingly, OX40 expression was negatively correlated with the frequency of MAIT cells in the peripheral blood of T2D patients. Increased cleaved caspase-3 levels were observed in OX40+-expressing MAIT cells in T2D patients. In vitro, activated OX40 signaling by recombinant OX40L protein promoted caspase-3 activation and apoptosis of MAIT cells. Inhibition of caspase-3 restored apoptosis of MAIT cells induced by OX40 signaling. These results identify OX40 as an amplifier of activation-induced cell death of human blood MAIT cells and shed new light on the regulation of MAIT cells in the phase of immune responses in T2D.