Altered Immune Status Research Articles

Evolving Concepts in Endothelial Pathobiology of Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a deadly disease, characterized by increased vascular resistance, pulmonary arteriolar loss, and occlusive arterial remodeling, leading to eventual right heart failure. Evidence increasingly points to the pulmonary endothelium as a central actor in PAH. Endothelial cell apoptosis can result directly in distal lung arteriolar pruning and indirectly in the formation of complex and occlusive arterial lesions, reflecting an imbalance between endothelial injury and repair in the development and progression of PAH. Many of the mutations implicated in PAH are in genes, which are predominantly, or solely, expressed in endothelial cells, and the endothelium is a major target for therapeutic interventions to restore BMP signaling. We explore how arterial pruning can promote the emergence of occlusive arterial remodeling mediated by ongoing endothelial injury secondary to hemodynamic perturbation and pathological increases in luminal shear stress. The emerging role of endothelial cell senescence is discussed in the transition from reversible to irreversible arterial remodeling in advanced PAH, and we review the sometimes conflicting evidence that female sex hormones can both protect or promote vascular changes in disease. Finally, we explore the contribution of the endothelium to metabolic changes and the altered inflammatory and immune state in the PAH lung, focusing on the role of excessive TGFβ signaling. Given the complexity of the endothelial pathobiology of PAH, we anticipate that emerging technologies that allow the study of molecular events at a single cell level will provide answers to many of the questions raised in this review.

GSK3β and mTORC1 Represent 2 Distinct Signaling Markers in Peripheral Blood Mononuclear Cells of Drug-Naive, First Episode of Psychosis Patients.

Schizophrenia is characterized by a complex interplay between genetic and environmental risk factors converging on prominent signaling pathways that orchestrate brain development. The Akt/GSK3β/mTORC1 pathway has long been recognized as a point of convergence and etiological mechanism, but despite evidence suggesting its hypofunction, it is still not clear if this is already established during the first episode of psychosis (FEP). Here, we performed a systematic phosphorylation analysis of Akt, GSK3β, and S6, a mTORC1 downstream target, in fresh peripheral blood mononuclear cells from drug-naive FEP patients and control subjects. Our results suggest 2 distinct signaling endophenotypes in FEP patients. GSK3β hypofunction exhibits a promiscuous association with psychopathology, and it is normalized after treatment, whereas mTORC1 hypofunction represents a stable state. Our study provides novel insight on the peripheral hypofunction of the Akt/GSK3β/mTORC1 pathway and highlights mTORC1 activity as a prominent integrator of altered peripheral immune and metabolic states in FEP patients.

Facial Demodicidosis Revealing HIV

Demodecidosis is an opportunistic cutaneous ectoparasitosis, common to humans and many mammals, caused by the proliferation of Demodex in the pilosebaceous apparatus. This obligate saprophyte of the skin, ostia-pilosebaceous of seborrheic areas, can become pathogenic in case of cosmetic abuse and debilitated terrain or altered immune status [1] . We report a case of facial demodecia revealing an infection by the human immunodeficiency virus.

Peripheral blood mononuclear cell gene expression and cytokine profiling in patients with intermittent claudication who exhibit exercise induced acute renal injury.

BackgroundIntermittent claudication (IC) is a common manifestation of peripheral arterial disease. Some patients with IC experience a rise in Urinary N-acetyl-β-D-Glucosaminidase (NAG)/ Creatinine (Cr) ratio, a marker of renal injury, following exercise. In this study, we aim to investigate whether peripheral blood mononuclear cells (PBMC) from patients with IC who exhibit a rise in urinary NAG/ Cr ratio following exercise exhibit differential IL-10/ IL-12 ratio and gene expression compared to those who do not have a rise in NAG/ Cr ratio.MethodsWe conducted a single center observational cohort study of patients diagnosed with IC. Blood and urine samples were collected at rest and following a standardised treadmill exercise protocol. For comparative analysis patients were separated into those with any rise in NAG/Cr ratio (Group 1) and those with no rise in NAG/Cr ratio (Group 2) post exercise. Isolated PBMC from pre- and post-exercise blood samples were analysed using flow cytometry. PBMC were also cultured for 20 hours to perform further analysis of IL-10 and IL-12 cytokine levels. RNA-sequencing analysis was performed to identify differentially expressed genes between the groups.Results20 patients were recruited (Group 1, n = 8; Group 2, n = 12). We observed a significantly higher IL-10/IL-12 ratio in cell supernatant from participants in Group 1, as compared to Group 2, on exercise at 20 hours incubation; 47.24 (IQR 9.70–65.83) vs 6.13 (4.88–12.24), p = 0.04. 328 genes were significantly differentially expressed between Group 1 and 2. The modulated genes had signatures encompassing hypoxia, metabolic adaptation to starvation, inflammatory activation, renal protection, and oxidative stress.DiscussionOur results suggest that some patients with IC have an altered immune status making them ‘vulnerable’ to systemic inflammation and renal injury following exercise. We have identified a panel of genes which are differentially expressed in this group of patients.

Comparative antitoxic potency of honey and natamycin-supplemented diets against aflatoxicosis and their influences on growth, serum biochemistry, immunohistochemistry, and residual deposition in Nile tilapia (Oreochromis niloticus)

Dietary aflatoxins are a major risk to the health of aquaculture species and their animal and human consumers. This study reports a first comparative antitoxic and antifungal activity of natural probiotic (honey) and antifungal drug (natamycin)-supplemented diets to alleviate the toxicity induced by the fungus (A. flavus) or it's producing aflatoxins. A set of experiments were primarily conducted in vitro including determining the minimum inhibitory concentration (MIC) of A. flavus for natamycin and honey and the antifungal activity of the honey, besides contaminating a fish diet with toxigenic strain A. flavus then detecting the dietary presence of aflatoxins, using TLC, before and after cultivating the fungus. We further investigated the influence of honey and natamycin on growth; biochemical parameters; histology and immunohistochemistry; and liver residual deposition (using HPLC to identify the aflatoxin type and amount). One hundred and eighty Nile tilapia (Oreochromis niloticus) (25.99 ± 3.31 g) were allocated into six groups in triplicates (10 fish/replicate). A control group (G1) and five other groups, G2, G3, G4, G5, and G6, were fed daily a basal diet and basal diets enriched with honey (70% concentration, 200 ml kgL−1 diet)) (H), natamycin (2.5 g kgL−1) (N), aflatoxins, and combined aflatoxins groups (aflatoxins+H and aflatoxins+N) respectively for 45 days. Fish received aflatoxins-contaminated diet (G4) showed low growth, and alterations in immune status, hepatic antioxidant, and hepato-renal biomarkers. Additionally, it revealed histological changes in liver and kidneys tissues, besides a strong caspase-3 and weak BCL-2 immunohistoreactivity compared to combined groups (G5, G6), and higher tissues bioaccumulation. The dietary additive of honey (G2) significantly (P < 0.05) elevated growth parameters; serum immunological biomarkers including lysozyme, nitric oxide (NO), and Myeloperoxidase (MPO); tissue antioxidant indicators including superoxide dismutase (SOD) and reduced glutathione (GSH) implying oxidative protection; and retrieved the malondialdehyde (MDA), antistress indicator (cortisol), hepato-renal parameters including ALP, AST, ALT, urea, creatinine. At the tissue and cellular level, honey sustained the histological architecture, modulated the immunohistochemical parameters, and efficiently mitigated the aflatoxins residual deposition in hepatic tissues compared to natamycin (G3) and control (G1). Comparing the antitoxic efficiency of honey and natamycin for the supplemented groups with aflatoxins (G5 and G6), natamycin was more effective in ameliorating the toxicity with aflatoxins reflected in modulating all measured parameters and low mortalities compared to honey. The dietary additive of natamycin had the ability to eliminate aflatoxin B1 and reduced the amount of aflatoxin G1, while honey eliminated aflatoxin G1 and decreased the aflatoxin B1 level. From the study outcomes, and to overcome the usage of antifungal drugs, the dietary additive of honey is a research hotspot both for the beneficial impacts including growth promoter, immune stimulator, hepatic antioxidant protection, tissue architecture maintaining, and aflatoxins detoxification in O. niloticus, and as a safe alternative to the antifungal drug.

Exposure to ultraviolet radiation during pregnancy influences offspring immune and inflammatory responses in Wistar-strain rats.

During pregnancy, maternal exposure to ultraviolet radiation (UVR) has been linked to altered offspring immune and health status. This study was therefore designed to investigate some markers of immune response in the offspring of pregnant Wistar rats exposed to UVR at various points of gestation. Thirty pregnant rats were divided into 6 groups (n=5) as follows; group I, control, consisting of pregnant rats unexposed to UVR. Animals in groups II, III, IV, V and VI were exposed to UVR for one hour daily, on gestational days 1-7,8-14,15-21,1-14 and 1-21, respectively. Animals were allowed to come to term and offspring birth weight was taken. On postnatal Day 10, weight of each offspring was taken again. Thereafter, blood samples were collected from each offspring per group and evaluated for total protein, albumin, globulin, C-reactive protein, interleukin-1β, and complement component protein-3 (C3). Offspring hepatic samples were evaluated using standard histological techniques. Offspring birthweight increased (p<0.05), while weight gain on postnatal day 10 reduced in all experimental groups compared to controls. No significant differences were observed for offspring total protein, albumin, and C3 levels across all groups. Globulin increased (p<0.05) only in group VI, while C-reactive protein increased (p<0.05) in all experimental groups, except group III, compared to controls. Interleukin-1β in groups II, III, V and VI increased significantly compared to controls. Offspring hepatic samples exhibited hepatocellular degeneration and necrosis that was independent of gestational stage of maternal exposure to UVR. Maternal exposure to ultraviolet radiation during gestation in Wistar rats activates offspring immune and inflammatory responses.

Identifying Unique Inflammatory Cytokine Profiles in Maternal-Fetal Dyads with COVID-19

Dysregulated immunity plays a critical role in determining COVID-19 disease severity. Pregnancy increases the risk for severe morbidity, yet little is known about how this altered immune state influences maternal-fetal immunity. We investigated cytokine responses to SARS-CoV-2 in maternal-fetal dyad pairs.

The risk factors potentially influencing risk of serious illness/death in people with diabetes, following SARS-CoV-2 infection: What needs to be done from here

Since early 2020 the whole world has been challenged by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus coronavirus disease 2019 (COVID-19) and the associated global pandemic [1]. People with diabetes are particularly at high risk of becoming seriously unwell after contracting this virus [2,3]. As yet we do not fully understand the underlying factors which contribute to such risk and their respective contributions to outcomes. In this regard, Barron et al. [4] reported an odds ratio (OR) for in-hospital COVID-19-related death of 2.03 (1.97–2.09) in people with type 2 diabetes mellitus (T2DM). A body of work is emerging in relation to the reasons why people with diabetes are more likely to become seriously unwell and in some cases die following a COVID-19 infection. Two recent landmark articles [5,6] have brought into sharp focus the factors that mediate increased risk of serious consequences of a COVID-19 infection in relation to hospital admission and mortality for vaccinated individuals and for nonvaccinated individuals in England. For the postvaccination study [6] the risk algorithm explained 74.1% of the variation in time to COVID-19 related death. An early COVID-19 pandemic study from Mexico [7] concluded that early-onset T2DM conferred an increased risk of hospitalization and obesity conferred an increased risk for ICU admission and intubation. The predictive score for COVID-19 lethality included age ≥65 years, diabetes, early-onset diabetes, obesity, age <40 years, chronic kidney disease, hypertension, immunosuppression and significantly discriminated lethal from nonlethal COVID-19 cases. We previously showed that in one area of the UK, the month-by-month mortality rate for people with T2DM was up to 2.2 times higher than that in the same month averaged over the previous 5 years in the early stages of the COVID-19 pandemic, with age the strongest independent predictor of death [8]. Work is continuing to understand how much a previous diagnosis of diabetes type 1 diabetes mellitus (T1DM) or T2DM increases the risk of becoming seriously unwell following a COVID-19 infection vs. absence of diabetes as a diagnosis. Since these early studies, the advent of treatment of hospitalized patients with Dexamethasone has significantly reduced mortality rates across the world. In patients hospitalized with COVID-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization [9]. Potential pathogenetic links between the SARS-CoV-2 virus and diabetes include the influence of glucose homeostasis and potentially altered immune status on the progression of the viral infection once established [10]. COVID-19 infection aggravates inflammation and alters immune system responses, leading to difficulties in blood glucose control. COVID-19 infection also increases the risk of thromboembolism and is more likely to induce cardiopulmonary failure in patients with diabetes than in patients without diabetes [11]. All of these mechanisms are now believed to contribute to the poor prognosis of some patients with preexisting diabetes and a COVID-19 infection. In conclusion, as the COVID-19 pandemic moves into a new phase in Europe and some other parts of the world, much remains to be determined about why having diabetes increases the risk of serious consequences of a COVID-19 infection. The COVID-19 global pandemic poses considerable health hazards, for patients with diabetes. The estimation of risk will require the combination of population based studies using primary and secondary care data and studies that evaluate the immunologic, metabolic and haematologic response following a COVID-19 infection at both a specific tissue and a whole body level, while keeping in mind that basic strategies such as optimizing pharmacologic management for patients at elevated cardiometabolic risk, with targeted choice of glucose lowering, antihypertensive and lipid lowering medications are as relevant to current and future research as to everyday clinical practice. Acknowledgements There was no external funding for this study. The data that support the findings of this study are available from the corresponding author upon reasonable request. Conflicts of interest There are no conflicts of interest.

Host Response to SARS-CoV2 and Emerging Variants in Pre-Existing Liver and Gastrointestinal Diseases.

BackgroundNovel coronavirus SARS-CoV2 is evolving continuously with emergence of several variants of increasing transmission capabilities and pandemic potential. Generation of variants occurs through accumulation of mutations due to the RNA nature of viral genome, which is further enhanced by variable selection pressures of this ongoing pandemic. COVID-19 presentations of SARS-CoV2 are mainly pulmonary manifestations with or without mild gastrointestinal (GI) and hepatic symptoms. However, the virus has evolved beyond pulmonary manifestations to multisystem disorder due to systemic inflammation and cytokine storm. Definitive cause of acute or late onset of inflammation, infection in various organs, and host response to emerging variants lacks clarity and needs elucidation. Several studies have reported underlying diseases including diabetes, hypertension, obesity, cardio- and cerebrovascular disorders, and immunocompromised conditions as significant risk factors for severe form of COVID-19. Pre-existing liver and GI diseases are also highly predominant in the population, which can alter COVID-19 outcome due to altered immune status and host response. We aim to review the emerging variants of SARS-CoV2 and host response in patients with pre-existing liver and GI diseases.MethodsIn this review, we have elucidated the emergence and characteristic features of new SARS-CoV2 variants, mechanisms of infection and host immune response, GI and hepatic manifestation with radiologic features of COVID-19, and outcomes in pre-existing liver and GI diseases.Key FindingsEmerging variants of concern (VOC) have shown increased transmissibility and virulence with severe COVID-19 presentation and mortality. There is a drastic swift of variants from the first wave to the next wave of infections with predominated major VOC including alpha (B.1.1.7, UK), beta (B.1.351, South Africa), gamma (B.1.1.28.1, Brazil), and delta (B1.1.617, India) variants. The mutations in the spike protein of VOC are implicated for increased receptor binding (N501Y, P681R) and immune escape (L452R, E484K/Q, T478K/R) to host response. Pre-existing liver and GI diseases not only have altered tissue expression and distribution of viral entry ACE2 receptor but also host protease TMPRSS2, which is required for both spike protein binding and cleavage to initiate infection. Altered immune status due to pre-existing conditions results in delayed virus clearance or prolonged viremia. Even though GI and hepatic manifestations of SARS-CoV2 are less severe, the detection of virus in patient’s stool indicates GI tropism, replication, and shedding from the GI tract. COVID-19-induced liver injury, acute hepatic decompensation, and incidences of acute-on-chronic liver failure may change the disease outcomes.ConclusionsThe changes in the spike protein of emerging variants, immunomodulation by viral proteins, and altered expression of host viral entry receptor in pre-existing diseases are the key determinants of host response to SARS-CoV2 and its disease outcome.

T-Cell Homeostatic Imbalance in Placentas From Women With Human Immunodeficiency Virus in the Absence of Vertical Transmission.

Implementation of universal antiretroviral therapy (ART) has significantly lowered vertical transmission rates but has also increased numbers of human immunodeficiency virus (HIV)-exposed uninfected children, who remain vulnerable to morbid effects. In the current study, we investigated whether T-cell alterations in the placenta contribute to altered immune status in HIV-exposed uninfected. We analyzed T cells from term placenta decidua and villous tissue and paired cord blood from pregnant women living with HIV (PWH) who initiated ART late in pregnancy (n = 21) with pregnant women not living with HIV (PWNH) (n = 9). Placentas from PWH showed inverted CD4/CD8 ratios and higher proportions of tissue resident CD8+ T cells in villous tissue relative to control placentas. CD8+ T cells in the fetal capillaries, which were of fetal origin, were positively correlated with maternal plasma viremia before ART initiation, implying that imbalanced T cells persisted throughout pregnancy. In addition, the expanded memory differentiation of CD8+ T cells was confined to the fetal placental compartment and cord blood but was not observed in the maternal decidua. T-cell homeostatic imbalance in the blood circulation of PWH is reflected in the placenta. The placenta may be a causal link between HIV-induced maternal immune changes during gestation and altered immunity in newborn infants in the absence of vertical transmission.

Implications of Inflammatory States on Dysfunctional Immune Responses in Aging and Obesity.

Aging and obesity are two conditions characterized by chronic, low-grade inflammation. While both conditions are also associated with dysfunctional immune responses, the shared and distinct underlying mechanisms are just starting to be uncovered. In fact, recent findings have suggested that the effects of obesity on the immune system can be thought of as a state of accelerated aging. Here we propose that chronic, low-grade inflammation seen in obesity and aging is complex, affects multiple cell types, and results in an altered basal immune state. In aging, part of this altered state is the emergence of regulatory immune populations that lead to further immune dysfunction in an attempt to reduce chronic inflammation. While in obesity, part of the altered state is the effect of expanding adipose tissue on immune cell function. Thus, in this review, we compare, and contrast altered immune states in aging and obesity and discuss their potential contribution to a shared clinical problem- decreased vaccine responsiveness.

Does diabetes mellitus mitigate the gender gap in COVID-19 mortality?

In this SARS-COV2-pandemic, diabetes mellitus (DM) soon emerged as one of the most prominent risk factors for a severe course of corona virus disease-2019 (COVID-19) and increased mortality due to hyperglycemia/insulin resistance, obesity, inflammation, altered immune status, and cardiovascular complications. In general, men are at a higher risk of severe or fatal COVID-19 disease irrespective of age, region and despite comparable infection rates in both sexes. In COVID-19, there is also a male predominance among hospitalized patients with diabetes, however, overall, data among patients with diabetes are ambiguous so far. Of note, similar to cardiovascular complications, women with type 2 diabetes (DM2) appear to lose their biological female advantage resulting in comparable death rates to those of men. The complex interplay of biological and behavioral factors, which may put men at greater risk of a severe or fatal course of COVID-19, and gender-related psychosocial factors, which may cause disadvantage to women concerning the infection rates, might explain why sex-disaggregated data among infected patients with diabetes are conflicting. Better knowledge on biological factors leading to functionally different immune responses and of gender-sensitive sociocultural determinants of COVID-19 infection rates may help to optimize prevention and management in the high-risk groups of men and women with diabetes.

Therapy of Type 2 Diabetes in Patients with SARS-CoV-2 Infection.

COVID-19 infection poses an important clinical therapeutic problem, especially in patients with coexistent diseases such as type 2 diabetes. Potential pathogenetic links between COVID-19 and diabetes include inflammation, effects on glucose homeostasis, haemoglobin deoxygenation, altered immune status and activation of the renin-angiotensin-aldosterone system (RAAS). Moreover, drugs often used in the clinical care of diabetes (dipeptidyl peptidase 4 inhibitors, glucagon-like peptide 1 receptor agonists, sodium-glucose cotransporter 2 inhibitors, metformin and insulin) may influence the course of SARS-CoV-2 infection, so it is very important to verify their effectiveness and safety. This review summarises the new advances in diabetes therapy and COVID-19 and provides clinical recommendations that are essential for medical doctors and for patients suffering from type 2 diabetes.

A radiomic signature model to predict the chemoradiation-induced alteration in tumor-infiltrating CD8+ cells in locally advanced rectal cancer

Background and purposeRegarding the altered tumor immune status following cytotoxic treatment, this study aims to develop a radiomic signature to predict CD8+ tumor-infiltrating lymphocyte (TIL) density changes in chemoradiotherapy (CRT) of rectal cancer. Materials and methodsWe used the magnetic resonance imaging (MRI) and immunohistochemistry data before and after neoadjuvant CRT. The discovery datasets consisted of pre-CRT dataset A1 (n = 113), post-CRT datasets A2 (n = 32; predominance of tumor) and A3 (n = 20; pure fibrosis). The developed model was validated in dataset B (n = 28). Thirty-eight radiomic features from T2-weighted MRI scans were incorporated into the least absolute shrinkage and selection operator method. ResultsIn pre-CRT dataset A1, the area under the receiver operating characteristic curve (AUC) values of radiomic score for predicting CD8+ TILs were 0.760 and 0.729 for training and validation subsets, respectively. A significant correlation was observed between the signature and CD8+ TIL density in the post-CRT dataset A2 (Pearson’s R = −0.372, P = 0.036), whereas no association was found in dataset A3 (Pearson’s R = −0.069, P = 0.77). The association was also observed in the validation dataset B (Pearson’s R = −0.374, P = 0.049). In dataset A2, the radiomic score difference predicted changes in CD8+ TIL density (AUC = 0.824). ConclusionWe established the MRI-derived radiomic signature for predicting CRT-induced alterations in CD8+ TILs. This study suggests the clinical utility of radiomics-immunophenotype modeling to evaluate tumor immune status following neoadjuvant chemoradiation in rectal cancer.

Serum Immunoglobulin Subclass Levels in Non-Hodgkin's Lymphoma in Ibadan, South Western Nigeria

BACKGROUND: Change in immunoglobulin (Ig) subclass levels, a manifestation of altered immune status, is thought to contribute to pathogenesis of non-Hodgkin's lymphoma (NHL). Furthermore, pretreatment Ig level in NHL patients scheduled to receive immunotherapy has prognostic significance. AIMS AND OBJECTIVES: This study was carried out to provide information on the levels of Ig subclass in patients with NHL in our center. METHODS: A descriptive cross-sectional study of patients diagnosed with NHL over an 8-month period was conducted. Controls were apparently healthy voluntary blood donors. Clinical information and results of hematology and clinical biochemistry investigations were retrieved from patients' case notes. The working formulation classification was used to subtype the NHL. Serum IgG, IgA, IgM, and IgE concentrations were assayed for for the levels in patients and controls. RESULTS: A total of 68 participants (cases n = 35, controls – 33) were included in this study. The mean age of the patients was 48.67 ± 17.3 years (range: 18–85). The hematological and clinical biochemistry results were within reference values for the population except hematocrit (Hct) which was low (28% ± 7%) and high erythrocyte sedimentation rate of 72 mm/h (interquartile range [IQR] – 52.0–100.0). IgD levels were significantly lower in the cases than the controls (P = 0.029) with a Cohen's medium effect size. There was a significant drop in IgE from Stage I to III of the disease (χ2(3) = 7.93, P = 0.047). Furthermore, there were significant positive correlations between IgD, IgA, IgM, and Hct and platelets. CONCLUSION: Immune paresis is associated with progressive disease or late clinical presentation, and this should be taken into consideration when managing these patients.

P-79: COVID-19 Presentation in Pediatric Patients with Visceral Transplantation

Introduction: Coronavirus disease 2019 (COVID-19) pandemic has become one of the most challenging episodes in the history of modern public health, with particular emphasis in high risk population. However, the evidence regarding their response to the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov-2), the agent responsible for COVID-19 is scant. Herein we present the clinical course of the SARS-CoV-2 infection in four pediatric patients that had underwent visceral transplantation. Methods: pediatric patients (3 with mulvisceral transplant and 1 hepatointestinal transplant; median age: 13,75 years, range: 12-17 years) were diagnosed with SARS-CoV-2 infection by nucleic acid amplification test, antigen test or serologic anti-SARS-CoV-2 IgM detection. Lymphocytes count, clinical signs and seroconversion were assessed. Results:3/4 consulted for symptoms compatible with COVID-19 and had a mild clinical presentation. Patient I: headache and muscle pain, Patient II: Anosmia and agusia, cough and rhinorrhea, Patient III: sore throat, cough and rhinorrhea. Patient IV was asymptomatic and consult for epidemiological environment. Lymphocytes count at the time of diagnosis was between normal range (media: 3600 cells/ul of blood, range 2600-4600 cells/ul of blood) and, interestingly, no gastrointestinal symptoms were reported. Of note, immunosuppression was not suspended nor diminished during the episode. 4/4 were receiving Tacrolimus (blood levels: median 7.7ng/ml, range: 6.7-8.4 ng/ml) and 3/4 also corticoids (median 5 mg/day, range 2-10 mg/day). Finally, until today we could detect specific IgG antibodies against SARS-CoV-2 in serum after recovery in 3 of the patients (one is still pending). Conclusion: The results presented here suggest that SARS-CoV-2 infection in pediatric patients with visceral transplantation is asymptomatic/mild. Interestingly, despite their graft altered immune status, no gastrointestinal symptoms were observed. Additionally, despite the high immunosuppression levels used, seroconversion was achieved in all patients so far. All together, these results suggest that collaboration between B and T cells was not affected by the pharmacological treatment and that pediatric patients would not constitute a risk group.

Age-dependency of terminal ileum tissue resident memory T cell responsiveness profiles to S. Typhi following oral Ty21a immunization in humans

BackgroundThe impact of aging on the immune system is unequivocal and results in an altered immune status termed immunosenescence. In humans, the mechanisms of immunosenescence have been examined almost exclusively in blood. However, most immune cells are present in tissue compartments and exhibit differential cell (e.g., memory T cells -TM) subset distributions. Thus, it is crucial to understand immunosenescence in tissues, especially those that are exposed to pathogens (e.g., intestine). Using a human model of oral live attenuated typhoid vaccine, Ty21a, we investigated the effect of aging on terminal ileum (TI) tissue resident memory T (TRM) cells. TRM provide immediate adaptive effector immune responsiveness at the infection site. However, it is unknown whether aging impacts TRMS. Typhi-responsive cells at the site of infection (e.g., TI). Here, we determined the effect of aging on the induction of TI S. Typhi-responsive TRM subsets elicited by Ty21a immunization.ResultsWe observed that aging impacts the frequencies of TI-lamina propria mononuclear cells (LPMC) TM and TRM in both Ty21a-vaccinated and control groups. In unvaccinated volunteers, the frequencies of LPMC CD103- CD4+ TRM displayed a positive correlation with age whilst the CD4/CD8 ratio in LPMC displayed a negative correlation with age. We observed that elderly volunteers have weaker S. Typhi-specific mucosal immune responses following Ty21a immunization compared to adults. For example, CD103+ CD4+ TRM showed reduced IL-17A production, while CD103- CD4+ TRM exhibited lower levels of IL-17A and IL-2 in the elderly than in adults following Ty21a immunization. Similar results were observed in LPMC CD8+ TRM and CD103- CD8+ T cell subsets. A comparison of multifunctional (MF) profiles of both CD4+ and CD8+ TRM subsets between elderly and adults also showed significant differences in the quality and quantity of elicited single (S) and MF responses.ConclusionsAging influences tissue resident TMS. Typhi-specific responses in the terminal ileum following oral Ty21a-immunization. This study is the first to provide insights in the generation of local vaccine-specific responses in the elderly population and highlights the importance of evaluating tissue immune responses in the context of infection and aging.Trial registrationThis study was approved by the Institutional Review Board and registered on ClinicalTrials.gov (identifierNCT03970304, Registered 29 May 2019 - Retrospectively registered).

Severe Altered Immune Status After Burn Injury Is Associated With Bacterial Infection and Septic Shock

Introduction: Burn injury is associated with a high risk of death. Whether a pattern of immune and inflammatory responses after burn is associated with outcome is unknown. The aim of this study was to explore the association between systemic immune and inflammatory responses and outcome in severely-ill burn patients.Materials and Methods: Innate immunity, adaptive immunity, activation and stress and inflammation biomarkers were collected at admission and days 2, 7, 14, and 28 in severely-ill adult burn patients. Primary endpoint was mortality at day 90, secondary endpoint was secondary infections. Healthy donors (HD) served as controls. Multiple Factorial Analysis (MFA) was used to identify patterns of immune response.Results: 50 patients were included. Age was 49.2 (44.2–54.2) years, total burn body surface area was 38.0% (32.7–43.3). Burn injury showed an upregulation of adaptive immunity and activation biomarkers and a down regulation of innate immunity and stress/inflammation biomarkers. High interleukin-10 (IL-10) at admission was associated with risk of death. However, no cluster of immune/inflammatory biomarkers at early timepoints was associated with mortality. HLA-DR molecules on monocytes at admission were associated with bacterial infections and septic shock. Later altered immune/inflammatory responses in patients who died may had been driven by the development of septic shock.Conclusion: Burn injury induced an early and profound upregulation of adaptive immunity and activation biomarkers and a down regulation of innate immunity and stress/inflammation biomarkers. Immune and inflammatory responses were associated with bacterial infection and septic shock. Absence of immune recovery patterns was associated with poor prognosis.

Vascular Inflammation and Dysfunction in Lupus-Prone Mice-IL-6 as Mediator of Disease Initiation.

Background: Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease and patients are under an increased risk for cardiovascular (CV) events and mortality. The increased CV risk for patients with SLE seems to be caused by a premature and accelerated atherosclerosis, attributable to lupus-specific risk factors (i.e., increased systemic inflammation, altered immune status), apart from traditional CV risk factors. To date, there is no established experimental model to explore the pathogenesis of this increased CV risk in SLE patients. Methods: Here we investigated whether MRL-Faslpr mice, which develop an SLE-like phenotype, may serve as a model to study lupus-mediated vascular disease. Therefore, MRL-Faslpr, MRL-++, and previously generated Il6−/− MRL-Faslpr mice were used to evaluate vascular changes and possible mechanisms of vascular dysfunction and damage. Results: Contrary to MRL-++ control mice, lupus-prone MRL-Faslpr mice exhibited a pronounced vascular and perivascular leukocytic infiltration in various organs; expression of pro-inflammatory cytokines in the aorta and kidney was augmented; and intima-media thickness of the aorta was increased. IL-6 deficiency reversed these changes and restored aortic relaxation. Conclusion: Our findings demonstrate that the MRL-Faslpr mouse model is an excellent tool to investigate vascular damage in SLE mice. Moreover, IL-6 promotes vascular inflammation and damage and could potentially be a therapeutic target for the treatment of accelerated arteriosclerosis in SLE.

Primary Immun Deficiency in Patients with Non-Cystic Fibrosis Bronchiectasis and Its Relationship with Clinical Parameters.

Bronchiectasis is characterized by chronic respiratory infection. The role of immunodeficiency in this disease is poorly studied in relation to clinical indices. The primary aim of this study was to determine the frequency of these neglected altered immune status by evaluating immunoglobulins, lymphocyte subsets, complement levels, and neutrophil function, and to assess its relationship with clinical parameters in adult patients with non-cystic fibrosis bronchiectasis (NCFB). A total of 74 (30 men and 44 women with a mean age of 47±17 years) adult patients with stable NCFB were enrolled in this study. The bronchiectasis severity index (BSI) and FACED (F:FEV1, A: Age, C: Chronic colonization, E: Extension, D: Dyspnea) scores were assessed. Peripheral blood samples were collected for the detection of total IgG, IgA, IgM, IgE, and IgG subclasses and C3 and C4 levels. The counts of CD3, CD4, CD8, CD19, CD16/56 expressing peripheral blood lymphocytes and neutrophil oxidative function were evaluated. In the study population, BSI and FACED severity index scores increased with longer duration of the disease (p=0.01 and p=0.040, respectively). Of the 74 patients, 27 (37%) showed humoral aberrations. The number of male patients were higher in this group (p=0.03). High serum total IgE levels were associated with high scores in BSI (moderate-severe group versus mild group, p=0.030). Patients with bronchiectasis demonstrated lower CD3+ T cell count, lower CD4+ T helper cell percentage, and lower CD4+ T cell count (p=0.031, p=0.030, p=0.029, respectively) than healthy subjects. A significant negative correlation was found between the percentage and count of CD16/56+ natural killer (NK) cells and the number of exacerbations within the past year (r=-0.230, p=0.049 and r=-0.264, p=0.023, respectively). Humoral aberrations in adult patients with NCFB were found to be frequent. IgE levels were related to high scores for disease severity indices. Furthermore, patients with low percentage and counts of NK cells had higher rates of exacerbations. These results emphasize the importance of immune function assessment in adult patients with NCFB.