Cytomegalovirus Cell-Mediated Immunity: Ready for Routine Use?

Antiviral prophylaxis; Cytomegalovirus management; Innate immunityProfilaxis antiviral; Gestión de citomegalovirus; Inmunidad innataProfilaxi antiviral; Gestió del citomegalovirus; Immunitat innataUtilizing assays that assess specific T-cell-mediated immunity against cytomegalovirus (CMV) holds the potential to enhance personalized strategies aimed at preventing and treating CMV in organ transplantation. This includes improved risk stratification during transplantation compared to relying solely on CMV serostatus, as well as determining the optimal duration of antiviral prophylaxis, deciding on antiviral therapy when asymptomatic replication occurs, and estimating the risk of recurrence. In this review, we initially provide an overlook of the current concepts into the immune control of CMV after transplantation. We then summarize the existent literature on the clinical experience of the use of immune monitoring in organ transplantation, with a particular interest on the outcomes of interventional trials. Current evidence indicates that cell-mediated immune assays are helpful in identifying patients at low risk for replication for whom preventive measures against CMV can be safely withheld. As more data accumulates from these and other clinical scenarios, it is foreseeable that these assays will likely become part of the routine clinical practice in organ transplantation.OB’s research is supported by a research grant network from the RICORS (Redes de Investigación Cooperativa Orientadas a Resultados en Salud) consortia by the Instituto de Salud Carlos III and co-funded by European Union (ERDF/ESF)- A way to build Europe. MF-R holds a research contract “Miguel Servet” (CP18/00073) from the Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation, also co-funded by the European Union. OB, HK, LC, and OM participate in the HORUS project, which has received funding from HORIZON Europe under the grant agreement No.101057651

Immunological exhaustion: How to make a disparate concept operational?

In this essay, we show that 3 distinct approaches to immunological exhaustion coexist and that they only partially overlap, generating potential misunderstandings. Exploring cases ranging from viral infections to cancer, we propose that it is crucial, for experimental and therapeutic purposes, to clarify these approaches and their interconnections so as to make the concept of exhaustion genuinely operational.Immunity, DEvelopment and Microbiota: Understanding the Continuous Construction of Biological Identit

Unconventional T cells and kidney disease

Unconventional T cells are a diverse and underappreciated group of relatively rare lymphocytes that are distinct from conventional CD4+ and CD8+ T cells, and that mainly recognize antigens in the absence of classical restriction through the major histocompatibility complex (MHC). These non-MHC-restricted T cells include mucosal-associated invariant T (MAIT) cells, natural killer T (NKT) cells, γδ T cells and other, often poorly defined, subsets. Depending on the physiological context, unconventional T cells may assume either protective or pathogenic roles in a range of inflammatory and autoimmune responses in the kidney. Accordingly, experimental models and clinical studies have revealed that certain unconventional T cells are potential therapeutic targets, as well as prognostic and diagnostic biomarkers. The responsiveness of human Vγ9Vδ2 T cells and MAIT cells to many microbial pathogens, for example, has implications for early diagnosis, risk stratification and targeted treatment of peritoneal dialysis-related peritonitis. The expansion of non-Vγ9Vδ2 γδ T cells during cytomegalovirus infection and their contribution to viral clearance suggest that these cells can be harnessed for immune monitoring and adoptive immunotherapy in kidney transplant recipients. In addition, populations of NKT, MAIT or γδ T cells are involved in the immunopathology of IgA nephropathy and in models of glomerulonephritis, ischaemia–reperfusion injury and kidney transplantation

The Inverse Amplitude Method in ππ\pi\pi Scattering in Chiral Perturbation Theory to Two Loops

The inverse amplitude method is used to unitarize the two loop $\pi\pi$ scattering amplitudes of SU(2) Chiral Perturbation Theory in the $I=0,J=0$, $I=1,J=1$ and $I=2,J=0$ channels. An error analysis in terms of the low energy one-loop parameters $\bar l_{1,2,3,4,}$ and existing experimental data is undertaken. A comparison to standard resonance saturation values for the two loop coefficients $\bar b_{1,2,3,4,5,6}$ is also carried out. Crossing violations are quantified and the convergence of the expansion is discussed.Comment: (Latex, epsfig) 30 pages, 13 figures, 8 table

Bethe-Salpeter Approach for Unitarized Chiral Perturbation Theory

The Bethe-Salpeter equation restores exact elastic unitarity in the $s-$ channel by summing up an infinite set of chiral loops. We use this equation to show how a chiral expansion can be undertaken in the two particle irreducible amplitude and the propagators accomplishing exact elastic unitarity at any step. Renormalizability of the amplitudes can be achieved by allowing for an infinite set of counter-terms as it is the case in ordinary Chiral Perturbation Theory. Crossing constraints can be imposed on the parameters to a given order. Within this framework, we calculate the leading and next-to-leading contributions to the elastic $\pi \pi$ scattering amplitudes, for all isospin channels, and to the vector and scalar pion form factors in several renormalization schemes. A satisfactory description of amplitudes and form factors is obtained. In this latter case, Watson's theorem is automatically satisfied. From such studies we obtain a quite accurate determination of some of the ChPT $SU(2)-$low energy parameters ({\bar l}_1 - {\bar l}_2 = -6.1\er{0.1}{0.3} and ${\bar l}_6= 19.14 \pm 0.19$). We also compare the two loop piece of our amplitudes to recent two--loop calculations.Comment: 63 pages, 9 figures. Some discussions on off-shell ambiguities and convergence of the expansion adde

KK bar scattering amplitude to one loop in chiral perturbation theory, its unitarization and pion form factors

We have calculated the KK bar --> KK bar scattering amplitude to next to leading order in Chiral Perturbation Theory. Then, making use of a unitarization procedure with one or several coupled channels (\pi\pi, KK bar in our case) we have calculated the \pi\pi --> \pi\pi, \pi\pi --> KK bar and KK bar --> KK bar S and P waves in good agreement with the experiment up to \sqrt{s}= 1.2 GeV. The \pi\pi scattering lengths with isospin and spin (I,J) equal to (0,0), (1,1) and (2,0) are also calculated in agreement with experiment and former Chiral Perturbation Theory calculations. Finally we have employed these amplitudes, making use of an Omnes representation, to calculate the scalar and the vector pion form factors, obtaining a good agreement with the available experimental data.Comment: 22 pages, 10 figures, LaTeX. Submitted to Nucl. Phys.

Left Hand Singularities, Hadron Form Factors and the Properties of the Sigma Meson

By applying analyticity and single channel unitarity we derive a new formula which is useful to analyze the role of the left-hand singularities in hadron form factors and in the determination of the resonance parameters. Chiral perturbation theory is used to estimate the left-hand cut effects in $\pi\pi$ scattering processes. We find that in the IJ=11 channel the left-hand cut effect is negligible and in the IJ=20 channel the phase shift is dominated by the left-hand cut effect. In the IJ=00 channel the left-hand cut contribution to the phase shift has the wrong sign comparing with the experimental data and therefore it necessitates the $\sigma$ resonance. The new experimental results from the E865 collaboration is crucial in reducing the uncertainty in the determination of the mass and width of the $\sigma$ resonance within our scheme.Comment: 24 pages, 1 tex file + 7 eps figures; The new experimental result from the E865 Collaboration is incorporate

Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.Fibrotic idiopathic interstitial pneumonias (fIIP) are a group of fatal lung diseases with largely unknown etiology and without definitive treatment other than lung transplant to prolong life. There is strong evidence for the importance of both rare and common genetic risk alleles in familial and sporadic disease. We have previously used genome-wide single nucleotide polymorphism data to identify 10 risk loci for fIIP. Here we extend that work to imputed genome-wide genotypes and conduct new RNA sequencing studies of lung tissue to identify and characterize new fIIP risk loci.We performed genome-wide genotype imputation association analyses in 1616 non-Hispanic white (NHW) cases and 4683 NHW controls followed by validation and replication (878 cases, 2017 controls) genotyping and targeted gene expression in lung tissue. Following meta-analysis of the discovery and replication populations, we identified a novel fIIP locus in the HLA region of chromosome 6 (rs7887 P meta  = 3.7 × 10(-09)). Imputation of classic HLA alleles identified two in high linkage disequilibrium that are associated with fIIP (DRB1*15:01 P = 1.3 × 10(-7) and DQB1*06:02 P = 6.1 × 10(-8)). Targeted RNA-sequencing of the HLA locus identified 21 genes differentially expressed between fibrotic and control lung tissue (Q < 0.001), many of which are involved in immune and inflammatory response regulation. In addition, the putative risk alleles, DRB1*15:01 and DQB1*06:02, are associated with expression of the DQB1 gene among fIIP cases (Q < 1 × 10(-16)).We have identified a genome-wide significant association between the HLA region and fIIP. Two HLA alleles are associated with fIIP and affect expression of HLA genes in lung tissue, indicating that the potential genetic risk due to HLA alleles may involve gene regulation in addition to altered protein structure. These studies reveal the importance of the HLA region for risk of fIIP and a basis for the potential etiologic role of auto-immunity in fIIP.National Heart, Lung and Blood Institute R01-HL095393 R01-HL097163 P01-HL092870 RC2-HL101715 U01-HL089897 U01-HL089856 U01-HL108642 P50-HL089493

The role of resveratrol on skeletal muscle cell differentiation and myotube hypertrophy during glucose restriction

Glucose restriction (GR) impairs muscle cell differentiation and evokes myotube atrophy. Resveratrol treatment in skeletal muscle cells improves inflammatory-induced reductions in skeletal muscle cell differentiation. We therefore hypothesised that resveratrol treatment would improve muscle cell differentiation and myotube hypertrophy in differentiating C2C12 myoblasts and mature myotubes during GR. Glucose restriction at 0.6 g/L (3.3 mM) blocked differentiation and myotube hypertrophy versus high-glucose (4.5 g/L or 25 mM) differentiation media (DM) conditions universally used for myoblast culture. Resveratrol (10 μM) treatment increased SIRT1 phosphorylation in DM conditions, yet did not improve differentiation when administered to differentiating myoblasts in GR conditions. Resveratrol did evoke increases in hypertrophy of mature myotubes under DM conditions with corresponding elevated Igf-I and Myhc7 gene expression, coding for the ‘slow’ type I MYHC protein isoform. Inhibition of SIRT1 via EX-527 administration (100 nM) also reduced myotube diameter and area in DM conditions and resulted in lower gene expression of Myhc 1, 2 and 4 coding for ‘intermediate’ and ‘faster’ IIx, IIa and IIb protein isoforms, respectively. Resveratrol treatment did not appear to modulate phosphorylation of energy-sensing protein AMPK or protein translation initiator P70S6K. Importantly, in mature myotubes, resveratrol treatment was able to ameliorate reduced myotube growth in GR conditions over an acute 24-h period, but not over 48–72 h. Overall, resveratrol evoked myotube hypertrophy in DM conditions while favouring ‘slower’ Myhc gene expression and acutely ameliorated impaired myotube growth observed during glucose restriction

A genome-wide association study of myasthenia gravis

IMPORTANCE: Myasthenia gravis is a chronic, autoimmune, neuromuscular disease characterized by fluctuating weakness of voluntary muscle groups. Although genetic factors are known to play a role in this neuroimmunological condition, the genetic etiology underlying myasthenia gravis is not well understood. OBJECTIVE: To identify genetic variants that alter susceptibility to myasthenia gravis, we performed a genome-wide association study. DESIGN, SETTING, AND PARTICIPANTS: DNA was obtained from 1032 white individuals from North America diagnosed as having acetylcholine receptor antibody–positive myasthenia gravis and 1998 race/ethnicity-matched control individuals from January 2010 to January 2011. These samples were genotyped on Illumina OmniExpress single-nucleotide polymorphism arrays. An independent cohort of 423 Italian cases and 467 Italian control individuals were used for replication. MAIN OUTCOMES AND MEASURES: We calculated P values for association between 8114394 genotyped and imputed variants across the genome and risk for developing myasthenia gravis using logistic regression modeling. A threshold P value of 5.0 × 10(−8) was set for genome-wide significance after Bonferroni correction for multiple testing. RESULTS: In the over all case-control cohort, we identified association signals at CTLA4 (rs231770; P = 3.98 × 10(−8); odds ratio, 1.37; 95% CI, 1.25–1.49), HLA-DQA1 (rs9271871; P = 1.08 × 10(−8); odds ratio, 2.31; 95% CI, 2.02 – 2.60), and TNFRSF11A (rs4263037; P = 1.60 × 10(−9); odds ratio, 1.41; 95% CI, 1.29–1.53). These findings replicated for CTLA4 and HLA-DQA1 in an independent cohort of Italian cases and control individuals. Further analysis revealed distinct, but overlapping, disease-associated loci for early- and late-onset forms of myasthenia gravis. In the late-onset cases, we identified 2 association peaks: one was located in TNFRSF11A (rs4263037; P = 1.32 × 10(−12); odds ratio, 1.56; 95% CI, 1.44–1.68) and the other was detected in the major histocompatibility complex on chromosome 6p21 (HLA-DQA1; rs9271871; P = 7.02 × 10(−18); odds ratio, 4.27; 95% CI, 3.92–4.62). Association within the major histocompatibility complex region was also observed in early-onset cases (HLA-DQA1; rs601006; P = 2.52 × 10(−11); odds ratio, 4.0; 95% CI, 3.57–4.43), although the set of single-nucleotide polymorphisms was different from that implicated among late-onset cases. CONCLUSIONS AND RELEVANCE: Our genetic data provide insights into aberrant cellular mechanisms responsible for this prototypical autoimmune disorder. They also suggest that clinical trials of immunomodulatory drugs related to CTLA4 and that are already Food and Drug Administration approved as therapies for other autoimmune diseases could be considered for patients with refractory disease