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Abdominal pain, loose stools, weight loss, stunted growth, arthritis, clubbing of the fingers, blurred vision: all of these hallmarks of Crohn disease can leave children feeling burdened and isolated. And though there is no cure, nurses can help children and families to manage it. [ABSTRACT FROM AUTHOR]

Type-I interferon (IFN-I) signals exert a critical role in disease progression during viral infections. However, the immunomodulatory mechanisms by which IFN-I dictates disease outcomes remain to be fully defined. Here we report that IFN-I signals mediate thymic atrophy in viral infections, with more severe and prolonged loss of thymic output and unique kinetics and subtypes of IFN-α/β expression in chronic infection compared to acute infection. Loss of thymic output was linked to inhibition of early stages of thymopoiesis (DN1-DN2 transition, and DN3 proliferation) and pronounced apoptosis during the late DP stage. Notably, infection-associated thymic defects were largely abrogated upon ablation of IFNαβR and partially mitigated in the absence of CD8 T cells, thus implicating direct as well as indirect effects of IFN-I on thymocytes. These findings provide mechanistic underpinnings for immunotherapeutic strategies targeting IFN-1 signals to manipulate disease outcomes during chronic infections and cancers., (Copyright © 2021. Published by Elsevier Inc.)

We evaluated the immunogenicity of a prime/boost vaccine strategy combining 5 lipopeptides (HIV-Lipo-5) and a recombinant modified vaccinia virus Ankara (rMVA-HIV) in cynomolgus macaques. Both of these vaccine components deliver HIV LAI Gag, Pol, and Nef antigens. Systemic and local safety was excellent in all groups. Immunization with HIV-Lipo-5 alone induced significant serum anti-HIV antibody titers which were not modified by rMVA-HIV immunization. However, induction of T-cell responses, as measured by IFNγ and IL-2 producing cells upon short-term stimulation with HIV peptide pools, required combined immunization with rMVA-HIV. Responses were preferentially observed against Gag antigen. Interestingly, HIV-Lipo-5 efficiently primed HIV induced T-cell responses upon the injection of rMVA-HIV, which may help to reduce the required number of vector injections. Our results provide a rationale for the use of a strategy involving HIV-Lipo-5 priming followed by rMVA-HIV booster immunization as a prophylactic or therapeutic vaccine approach against HIV infection and AIDS., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Blastomycosis (Blastomyces dermatitidis) is a fungal disease that is endemic in the southern United States. This case report illustrates the clinical, MRI and histopathologic findings in a dog with invasion of a retrobulbar blastomycotic lesion into the calvarium. A 5-year-old intact female Weimaraner was referred for a 2-month history of change in behavior and recent onset of visual deficits. Magnetic resonance imaging (MRI) examination revealed a large (5.8 × 2.0 × 2.5 cm) mass extending from the left orbit through a circular defect in the left cranioventral aspect of the calvarium caudally to the level of the pituitary fossa and interthalamic adhesion. The mass was heterogeneously iso- to hypointense on T2-W images, slightly hypointense on T1-W images, did not attenuate on fluid attenuated inversion recovery (FLAIR) images, and did not show evidence of susceptibility artifact on T2*-W gradient recalled echo (GRE) images. Vasogenic edema and associated mass effect were noted. The mass showed strong homogeneous contrast enhancement with well-defined margins and had thickening of the adjacent meninges (dural tail sign). Based on MRI findings a malignant neoplastic process was considered most likely and the patient was placed on oral prednisone to decrease peri-tumoral inflammation. The dog initially improved but was euthanized 3 weeks later for worsening clinical signs. Histopathologic assessment of the mass revealed marked pyogranulomatous optic neuritis with intralesional fungal yeasts consistent with blastomycosis (Blastomyces dermatitidis). To our knowledge this is the first report of invasion of a retrobulbar blastomycotic lesion into the calvarium in a dog., (© 2011 American College of Veterinary Ophthalmologists.)

Secretin is a polypeptide hormone that stimulates secretion of bicarbonate from the exocrine pancreas and, in healthy human subjects, causes transient pancreatic duct dilation observable sonographically. In humans with chronic pancreatitis, secretin administration fails to cause pancreatic duct dilation, theoretically due to the restrictive effects of periductal fibrosis. We characterized the effect of exogenous secretin administration on the width of the pancreatic duct in nine healthy domestic cats. Cats were given a commercially available secretin product (ChiRho Stim) while the pancreatic duct was monitored sonographically. Mean pancreatic duct diameter increased from 0.77 +/- 0.33 to 1.42 +/- 0.40 mm after secretin administration (P = 0.0017). The mean percent increase in pancreatic duct diameter over basal diameter for all time points up to 15 min postsecretin administration was 101.9 +/- 58.8%. Applicability of this technique to diagnose chronic pancreatitis in cats will need to be investigated.

An IFN-alpha heteroduplex-tracking assay (IFN-HTA) was developed to quantify the frequency of expression of the 16 genes coding for related interferon-alpha (IFN-alpha) subtypes in mice. In mLN of mice treated with Poly (I:C), we observed the induction of three sequential waves of type I IFN production, instead of two as is commonly described: early IFNs after 1 h (IFN-beta), late IFNs after 3 h (mostly IFN-alpha1, -alpha2, -alpha 4 and -alpha 5) and "secondary late IFNs" after 6 h (IFN-alpha 6T and -alpha 8/6). The late IFN wave was associated with the upregulation of the interferon regulatory factor (IRF)-7 mRNA and proteins, whereas the secondary late IFN wave was associated with a slight upregulation of IRF-8 mRNA. Type I IFNs produced in the thymus were associated with a distinct IRF mRNA expression pattern. This IFN-HTA strategy can serve as a useful tool to qualify and quantify the expression of various IFN-alpha subtypes under distinct immune responses and thus provides a first step in evaluating their function.

TLRs constitute a first set of sensors that detect viral nucleic acids including dsRNA which triggers TLR3. We report the early, direct, and detrimental effect of polyinosine-polycytidilic acid treatment on T cell development. Inhibition of thymopoiesis was targeted to several thymocyte subpopulations. First, both a blockade of the double negative (DN)1-DN2 transition and a severe down-regulation of DN3-DN4 thymocyte proliferation were observed. In addition, an important decrease in the absolute numbers of double-positive thymocytes, concomitant with an increase in frequencies of apoptotic cells in this population were shown. This inhibition of thymopoiesis resulted in a reduced thymic output, as evidenced by a drop of the absolute numbers of naive T cells and TCR excision circles levels. The decrease in thymic cellularity and defects in thymic development were severely reduced, but not completely abolished in IFN-alpha/betaR(-/-) mice, showing a direct contribution of type I IFNs, known to be massively up-regulated in viral infections, to the inhibition of T cell development. Strikingly, the TCR repertoire in treated mice was biased toward shorter CDR3 lengths as a result of a decreased expression of TdT and Rag2. However, thymic integrity remained intact since thymopoiesis was restored both quantitatively and qualitatively 14 days after the cessation of polyinosine-polycytidilic acid treatment. These results demonstrate a novel immunomodulatory role for virally encoded TLR ligands and RNA sensors; they further illustrate the diversity of mechanisms that viruses use to interfere with the development of a pathogen-specific immune responses.

The interactions between TLRs and their ligands have profound immune modulation properties. Attention has focused mostly on the impact of TLR ligands on peripheral innate and adaptive immunity during viral infections, whereas little impact of TLR activation has been shown on thymic development. Here we show that treatment of murine fetal thymic organ cultures (FTOCs) with TLR3 or TLR7 ligands induced rapid expression of IFN-alpha and -beta mRNA, hallmarks of acute and chronic viral infections. This resulted in an early developmental blockade, increased frequencies of apoptotic cells, and decreased proliferation of thymocytes, which led to an immediate decrease in cellularity. FTOCs infected with vesicular stomatitis virus, known to act through TLR7, were similarly affected. Down-regulation of IL-7R alpha-chain expression, together with an increased expression of suppressor of cytokine signaling-1 and a concomitant decreased expression of the transcriptional regulator growth factor independence 1 were observed in TLR ligands or IFN-treated FTOCs. This indicates a role for these pathways in the observed changes in thymocyte development. Taken together, our data demonstrate that TLR activation and ensuing type I IFN production exert a deleterious effect on T cell development. Because TLR ligands are widely used as vaccine adjuvants, their immunomodulatory actions mediated mainly by IFN-alpha suggested by our results should be taken in consideration.

New Zeland Black (NZB) mice develop an autoimmune disease involving an abnormal B cell response to peripheral self Ags. This disease is associated with defects in other cell types and thymic stromal organization. We present evidence that NZB cells of various lineages, including thymocytes, fibroblasts, and dendritic precursor cells, show impaired proliferation and enhanced cell death in culture upon stimulation compared with non-autoimmune-prone mice such as C57BL/6. This phenotype explains the reduced efficiency of maturation of bone marrow-derived dendritic cells and the loss of TNF- or IL-1-dependent thymocyte costimulation. Upon TNF-induced activation of NZB thymocytes, nuclear translocation and DNA binding of RelA- and RelB-dependent NF-kappaB heterodimers are significantly reduced. This phenotype has a transcriptional signature, since the NZB, but not the nonobese diabetic, thymic transcriptome shows striking similarities with that of RelB-deficient thymuses. This partial NF-kappaB deficiency detected upon activation by proinflammatory cytokines could explain the disorganization of thymic microenvironments in NZB mice. These combined effects might reduce the efficiency of central tolerance and expose apoptotic debris generated during inflammatory processes to self recognition.

Thymocyte maturation is controlled by successive developmental checkpoints connected to the acquisition of a functional T cell receptor (TCR). During thymocyte selection, engagement of the TCR regulates the fine balance between death and survival signals. At the final stages of single-positive (SP) thymocyte maturation, the coupling of the TCR changes from death- to proliferation-inducing signals, a competence required for optimal effector functions in the periphery. We show here that in RelB mutant thymuses, thymocyte differentiation of CD24(-) SP cells is partially impaired. Competitive bone marrow reconstitution experiments show that this defect is constitutive to the lymphoid compartment. This is accompanied by an increased proportion of apoptotic thymocytes and a drastically reduced proliferation upon activation with anti-CD3 antibody/PMA stimulation. Thus, the RelB protein contributes to the quality of cell signaling in thymocytes by providing anti-apoptotic signals. These results suggest that in addition to its major role on the activation of antigen-presenting cell function, the RelB protein is intrinsically required for terminal thymocyte differentiation and activation.

The authors compared three urea nitrogen methods using six instruments: (1) the diacetyl monoxime method used with a continuous flow analyzer Sequential Multiple Analyzer Model 4 + 2; (2) the diacetyl monoxime method used with an older continuous flow analyzer (Sequential Multiple Analyzer Model 6/60; (3) the diacetyl monoxime method used with a third continuous flow system, AutoAnalyzer Model I; (4) the urease-conductivity method performed on the Beckman System I; (5) the urease-glutamate dehydrogenase method performed on the DuPont Automatic Clinical Analyzer; (6) the urease-glutamate dehydrogenase method done on a centrifugal analyzer, CentrifiChem. We evaluated each method for the following: (1) within-run precision; (2) between-day precision; (3) linearity of the relationship between concentration and instrument output; (4) specificity; (5) carry-over; (6) comparison of urea nitrogen values for samples from patients.