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Summary: The in‐depth understanding of skin resident memory CD8+ T lymphocytes (TRM) may help to uncover strategies for their manipulation during disease. We investigated isolated TRM from healthy human skin, which expressed the residence marker CD69, and compared them to circulating CD8+ T cell populations from the same donors. There were significantly increased proportions of CD8+CD45RA–CD27– T cells in the skin that expressed low levels of killer cell lectin‐like receptor G1 (KLRG1), CD57, perforin and granzyme B. The CD8+ TRM in skin were therefore phenotypically distinct from circulating CD8+CD45RA–CD27– T cells that expressed high levels of all these molecules. Nevertheless, the activation of CD8+ TRM with T cell receptor (TCR)/CD28 or interleukin (IL)‐2 or IL‐15 in vitro induced the expression of granzyme B. Blocking signalling through the inhibitory receptor programmed cell death 1 (PD)‐1 further boosted granzyme B expression. A unique feature of some CD8+ TRM cells was their ability to secrete high levels of tumour necrosis factor (TNF)‐α and IL‐2, a cytokine combination that was not seen frequently in circulating CD8+ T cells. The cutaneous CD8+ TRM are therefore diverse, and appear to be phenotypically and functionally distinct from circulating cells. Indeed, the surface receptors used to distinguish differentiation stages of blood T cells cannot be applied to T cells in the skin. Furthermore, the function of cutaneous TRM appears to be stringently controlled by environmental signals in situ. [ABSTRACT FROM AUTHOR]

Two studies with the same goal, but different instruments, investigated the correlation between basic personality traits and electrodermal reactivity to aversive visual stimuli. Study 1 focused on the Five Factor Model traits, while in Study 2, we investigated the HEXACO model, and an additional trait, Disintegration. In Study 1, emotional reactivity was expressed using Polyscore, a composite polygraph measure in which electrodermal response (EDR) had the largest weight, and it was measured with respect to stimuli with positive, neutral, and negative valences. In Study 2, we employed several measures of EDR to stimuli with negative valence. In both experiments, Conscientiousness correlated positively with EDR to aversive stimuli. Additionally, in Study 2, there was a negative correlation between Disintegration and EDR to aversive stimuli. Other traits were not related to EDR to aversive stimuli, and, in Study 1, we found no relationship between personality traits and reactivity to stimuli with positive or neutral valence.

Background/Aim. Systemic sclerosis (SSc) is a chronic systemic disease of the connective tissue. It is characterized by diffuse microangiopathy, increased activity and creating deposits of collagen in the skin and internal organs. Involvement of the lung function disturbances in SSc is a bad prognostic sign. The aim of our study was to investigate the association between smoking habits and lung function disorder in the SSc patients. Methods. The testing was conducted at the Clinic for Rheumatology and Immunology of the Military Medical Academy in 2016. In this study, we included 42 patients with the newly diagnosed SSc and the patients whose disease had been diagnosed earlier. Results. The patients were classified according to the smoking habits, 14 (33.3%) patients were nonsmokers, while 28 (66.7%) patients were current (23 patients) or ex-smokers (5 patients). We found no significant differences in examined parameters among smokers and nonsmokers. In addition, distribution of the patients with the obstructive pulmonary pattern revealed by spirometry was uniform between smokers and nonsmokers. The concentrations of C reactive protein (CRP) were significantly higher in the SSc patients with the obstructive pulmonary pattern. The patients with the obstructive pattern on spirometry had significantly lower values of forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), FEV1/FVC ratio, diffusing lung capacity for carbon monoxide (DLCO) and FVC/DLCO ratio. Conclusion. In our study, we concluded that in the SSc patients with the obstructive pulmonary pattern revealed by spirometry, there were no significant differences between smokers and nonsmokers. CRP is a significant predictor of the lung involvement existence in the SSc patients.

Background: Systemic sclerosis (SSc) is an autoimmune connective tissue disease which affects various tissues and organs, including skin, lungs, kidneys, gastrointestinal tract and cardiovascular system. Cardiac involvement is the most commonly recognized problem and a significant cause of morbidity. The brain natriuretic peptide (BNP) is a previously known marker of elevated cardiovascular risk in SSc, but the levels of BNP in various forms of SSc have not been investigated so far. Aim: The aim of our study was to evaluate the influence of SSc on the function of the right ventricle and the right atrium using the echocardiographic parameters. Moreover, we examined the levels of BNP in different forms of SSc as well as the association of disease severity with the plasma concentrations of BNP Methods: We included 42 patients with newly diagnosed SSc and patients whose disease had been diagnosed earlier. SSc patients and non-SSc control patients were examined by using echocardiography and the concentrations of BNP were determined. Results: We analyzed differences in the parameters of right ventricle (RV) function and right atrium (RA) function between SSc patients and healthy controls. The two groups had similar distribution of gender, but SSc patients were significantly older than controls. RV wall thickness was increased in SSc patients (p< 0.001), while right ventricular end-systolic area (RVesa; p= 0.408) and right ventricular end-diastolic area (RVEDa; p= 0.368) did not differ among the examines. In contrast, RA minor-axis dimension (p=0.001) and the tricuspid annular plane systolic excursion (TAPSE) (p= 0.001) were significantly higher in SSc patients. Also, we analyzed differences in brain natriuretic peptide (BNP) concentrations between diffuse cutaneous systemic sclerosis (DSSc) and limited cutaneous systemic sclerosis (LSSc) patients. DSSc patients had significantly higher concentrations of BNP. We found that levels of BNP were in significant positive correlations with age (p= 0.007), disease duration (p= 0.023), C reactive protein (CRP) (p= 0.032), right ventricle fractional area change (FAC) (p= 0.022), pulmonary vascular resistance (PVR) and Rodnan score (p= 0.019). Conclusions: Given the obtained results, the laboratory determination of BNP could be useful in differentiating different forms of systemic sclerosis as well as in predicting the severity of the disease and future cardiovascular complications.

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Introduction/Objective. Increasing incidence of spinal cord injuries presents a very important issue. These patients are usually very young, treatment is very tough, long, expensive and, in general, of little success rate. The aim of this study was to evaluate the angiogenic potential of the omental graft in spinal cord revascularization after the injury. Methods. The study included 19 patients, who underwent recurrent surgical procedure for pain syndrome or surgical complication, and one patient in whom angiography revealed no flow in distal part of omental graft. Results. Our study confirmed angiogenic capabilities of omental graft placed in the course of omentomyelopexy for the injured spinal cord revascularization, macroscopically and histopathologically. Study results are limited due to inclusion of patients, only when the postoperative period was complicated. Conclusion. Our study provides some insight into the angiogenic capabilities. Although, further (likely less invasive) studies are needed to provide more insight into omental angiogenesis and to include patients in whom the procedure went well.

Background/Aim. Sarcoidosis is a multisystem infmammatory disease of unknown etiology, with the lungs and intrathoracic lymph nodes the most commonly involved. The aim of this study was to assess the contribution of conventional transbronchial needle aspiration (TBNA) cytology in the diagnosis of sarcoidosis presenting as mediastinal/hilar lymphadenopathy. Methods. In this retrospective study, 58 patients with suspicion of stage I and II sarcoidosis underwent first flexibile, and then, a rigid bronhoscopy, during which TBNA of mediastinal or hilar lumph node with a 19 gauge (G) needle was done. Material from the needle was put on glass slide and prepared for the cytological and histopathological examination. Results. Out of 58 patients submitted to TBNA of mediastinal or hilar lymph nodes, adequate material for cytological diagnostics was obtained in 53 (91.37%). Out of 53 adequate cytological samples, in 38 (71.69%) noncaseous granulomatous inflammation (NGI) was found, while in corresponding histopathological samples, NGI was found in 48 (90.56%), which was significantly higher (p < 0.05). Of cytological smears, out of the cell types typical for granulomatous inflammation, in 26 (63.15%) patients the clusters of the epitheloid cells were found, in 8 (21.05%) there were both, clusters of epitheloid cells and giant multinuclear hystiocytes, and in 6 (15.76%) only single scattered epitheloid cells or small clusters of several epitheloid cells were found. The sensitivity of TBNA cytology in our group of patients with sarcoidosis was 76%, specificity 100% and accuracy 77.34%. Conclusion. TBNA is an efficient and safe procedure in the diagnosis of sarcoidosis, minimally invasive and with a little risk of complications. Using 19 G needle enables obtaining material for histological and cytological analyses, as well which contribute to the sensitivity of diagnosting sarcoidosis. The value of this type of diagnostics depends on qualification and experience both of bronchoscopist and cytologist/pathologist, as well, of the interpreter of such a material.

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When B cells engage in an immune response, metabolic reprogramming is key to meeting cellular energetic and biosynthetic demands. Epstein-Barr virus (EBV) is a highly prevalent gamma-herpesvirus, latently infecting B cells for the human host's lifetime. By hijacking signaling pathways of T cell-dependent humoral immunity, EBV activates B cells in a T cell-independent manner, forcing lymphoblastoid transformation. Interlinked with this coercion of signaling pathways, EBV has also evolved strategies to manipulate B cell metabolism. In this opinion article we integrate recent findings from studies of B cell metabolic reprogramming after EBV infection and during antigen-specific activation, respectively. We hypothesize that defining EBV host-cell metabolic vulnerabilities that differ from pathways required for B cell immunity might uncover novel therapeutic targets against EBV-related diseases., Competing Interests: Declaration of interests C.H., B.M-D., and G.R.B. are inventors on a patent relating to a study referenced in this manuscript filed by the University of Basel (EP 21161105.8) which is being developed in a start-up company (Hornet Therapeutics Ltd; Scientific Founder: C.H.). C.H. is a board member of Hornet Therapeutics. The authors declare that they have no other competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

After infection of B cells, Epstein-Barr virus (EBV) engages host pathways that mediate cell proliferation and transformation, contributing to the propensity of the virus to drive immune dysregulation and lymphomagenesis. We found that the EBV protein EBNA2 initiates nicotinamide adenine dinucleotide (NAD) de novo biosynthesis by driving expression of the metabolic enzyme indoleamine 2,3-dioxygenase 1 (IDO1) in infected B cells. Virus-enforced NAD production sustained mitochondrial complex I activity, to match adenosine triphosphate (ATP) production with bioenergetic requirements of proliferation and transformation. In transplant patients, IDO1 expression in EBV-infected B cells, and a serum signature of increased IDO1 activity, preceded development of lymphoma. In humanized mice infected with EBV, IDO1 inhibition reduced both viremia and lymphomagenesis. Virus-orchestrated NAD biosynthesis is therefore a druggable metabolic vulnerability of EBV-driven B cell transformation, opening therapeutic possibilities for EBV-related diseases.

Whether screening the metabolic activity of immune cells facilitates discovery of molecular pathology remains unknown. Here we prospectively screened the extracellular acidification rate as a measure of glycolysis and the oxygen consumption rate as a measure of mitochondrial respiration in B cells from patients with primary antibody deficiency. The highest oxygen consumption rate values were detected in three study participants with persistent polyclonal B cell lymphocytosis (PPBL). Exome sequencing identified germline mutations in SDHA, which encodes succinate dehydrogenase subunit A, in all three patients with PPBL. SDHA gain-of-function led to an accumulation of fumarate in PPBL B cells, which engaged the KEAP1-Nrf2 system to drive the transcription of genes encoding inflammatory cytokines. In a single patient trial, blocking the activity of the cytokine interleukin-6 in vivo prevented systemic inflammation and ameliorated clinical disease. Overall, our study has identified pathological mitochondrial retrograde signaling as a disease modifier in primary antibody deficiency.

Latent Epstein-Barr virus (EBV) infection can clinically reactivate in immunosuppressed individuals causing lymphoproliferative disease and rarely hepatitis. In this study, we provide in vivo and in vitro evidence that Treponema pallidum infection can cause EBV reactivation with hepatitis in an immunocompetent patient. We report the diagnostic challenges and immunological findings of coinciding syphilis and EBV-associated hepatitis. Using an in vitro EBV-reactivation assay, we demonstrate that T pallidum reactivates latent EBV in a Toll-like receptor (TLR)2/B-cell receptor signaling-dependent manner. Epstein-Barr virus-associated reactivation or lymphoproliferation should be considered in infections with pathogens that activate TLR2., (© The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Natural killer cells lacking expression of CD56 (CD56 neg NK cells) have been described in chronic HIV and hepatitis C virus infection. Features and functions of CD56 neg NK cells in the context of latent infection with CMV and / or EBV with age are not known. In a cohort of healthy donors >60 years of age, we found that co-infection with CMV and EBV drives expansion of CD56 neg NK cells. Functionally, CD56 neg NK cells displayed reduced cytotoxic capacity and IFN-γ production, a feature that was enhanced with CMV / EBV co-infection. Further, the frequency of CD56 neg NK cells correlated with accumulation of end-stage-differentiated T cells and a reduced CD4 / CD8 T cell ratio, reflecting an immune risk profile. CD56 neg NK cells had a mature phenotype characterized by low CD57 and KIR expression and lacked characteristics of cell senescence. No changes in their activating NK cell receptor expression, and no upregulation of the negative co-stimulation receptors PD-1 or TIM-3 were observed. In all, our data identify expansion of dysfunctional CD56 neg NK cells in CMV + EBV + elderly individuals suggesting that these cells may function as shape-shifters of cellular immunity and argue for a previously unrecognized role of EBV in mediating immune risk in the elderly.

Mitogen-activated protein kinases (MAPKs) including Erk, Jnk and p38 regulate diverse cellular functions and are thought to be controlled by independent upstream activation cascades. Here we show that the sestrins bind to and coordinate simultaneous Erk, Jnk and p38 MAPK activation in T lymphocytes within a new immune-inhibitory complex (sestrin-MAPK activation complex (sMAC)). Whereas sestrin ablation resulted in broad reconstitution of immune function in stressed T cells, inhibition of individual MAPKs allowed only partial functional recovery. T cells from old humans (>65 years old) or mice (16-20 months old) were more likely to form the sMAC, and disruption of this complex restored antigen-specific functional responses in these cells. Correspondingly, sestrin deficiency or simultaneous inhibition of all three MAPKs enhanced vaccine responsiveness in old mice. Thus, disruption of sMAC provides a foundation for rejuvenating immunity during aging.

NK cells are the first line of defense against infected and transformed cells. Defective NK cell activity was shown to increase susceptibility for viral infections and reduce tumor immune-surveillance. With age, the incidence of infectious diseases and malignancy rises dramatically, suggesting that impaired NK cell function might contribute to disease in these individuals. We found an increased frequency of NK cells with high expression of the inhibitory killer cell lectin-like receptor G1 (KLRG1) in individuals >70 y. The role of KLRG1 in ageing is not known, and the mechanism of KLRG1-induced inhibition of NK cell function is not fully understood. We report that NK cells with high KLRG1 expression spontaneously activate the metabolic sensor AMP-activated protein kinase (AMPK) and that activation of AMPK negatively regulates NK cell function. Pre-existing AMPK activity is further amplified by ligation of KLRG1 in these cells, which leads to internalization of the receptor and allows interaction with AMPK. We show that KLRG1 activates AMPK by preventing its inhibitory dephosphorylation by protein phosphatase-2C rather than inducing de novo kinase activation. Finally, inhibition of KLRG1 or AMPK prevented KLRG1-induced activation of AMPK and reductions in NK cell cytotoxicity, cytokine secretion, proliferation, and telomerase expression. This novel signaling pathway links metabolic sensing, effector function, and cell differentiation with inhibitory receptor signaling that may be exploited to enhance NK cell activity during ageing., (Copyright © 2016 by The American Association of Immunologists, Inc.)