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Pathogenic infections cause thymic atrophy, perturb thymic T-cell development, and alter immunological response. Previous studies reported dysregulated T-cell function and lymphopenia in coronavirus disease-19 (COVID-19). However, immunopathological changes in the thymus associated with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection have not been elucidated. Here, we report that SARS-CoV-2 infects thymocytes, and induces CD4 + CD8 + (double positive; DP) T-cell apoptosis leading to thymic atrophy and loss of peripheral TCR repertoire in K18-hACE2 transgenic mice. Infected thymus led to increased CD44 + CD25 - T-cells, indicating an early arrest in the T-cell maturation pathway. Thymic atrophy was notably higher in male hACE2-Tg mice than in females and involved an upregulated de-novo synthesis pathway of thymic glucocorticoid. Further, IFN-γ was crucial for thymic atrophy, as anti-IFN-γ -antibody neutralization blunted thymic involution. Therapeutic use of Remdesivir also rescued thymic atrophy. While the Omicron variant and its sub-lineage BA.5 variant caused marginal thymic atrophy, the delta variant of SARS-CoV-2 exhibited severe thymic atrophy characterized by severely depleted DP T-cells. Recently characterized broadly SARS-CoV-2 neutralizing monoclonal antibody P4A2 was able to rescue thymic atrophy and restore the thymic maturation pathway of T-cells. Together, we report SARS-CoV-2-associated thymic atrophy resulting from impaired T-cell maturation pathway which may contribute to dyregulated T cell response during COVID-19., (© 2024 Wiley‐VCH GmbH.)

Confirmed SARS-coronavirus-2 infection with gastrointestinal symptoms and changes in microbiota associated with coronavirus disease 2019 (COVID-19) severity have been previously reported, but the disease impact on the architecture and cellularity of ileal Peyer's patches (PP) remains unknown. Here we analysed post-mortem tissues from throughout the gastrointestinal (GI) tract of patients who died with COVID-19. When virus was detected by PCR in the GI tract, immunohistochemistry identified virus in epithelium and lamina propria macrophages, but not in lymphoid tissues. Immunohistochemistry and imaging mass cytometry (IMC) analysis of ileal PP revealed depletion of germinal centres (GC), disruption of B cell/T cell zonation and decreased potential B and T cell interaction and lower nuclear density in COVID-19 patients. This occurred independent of the local viral levels. The changes in PP demonstrate that the ability to mount an intestinal immune response is compromised in severe COVID-19, which could contribute to observed dysbiosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Trevelin, Pickering, Todd, Bishop, Pitcher, Garrido Mesa, Montorsi, Spada, Petrov, Green, Shankar-Hari, Neil and Spencer.)

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.)

Given the current lack of understanding of brain volume changes caused by HIV infection, this study aimed to longitudinally assess the changes in regional brain tissue volume following HIV infection and to explore its relationship with peripheral blood absolute CD4+ lymphocyte count (CD4+), the percentage of monocytes in plasma(MON%) and cerebrospinal fluid viral load (CFVL).Four adult male rhesus monkeys were examined in healthy status and following infection with simian immunodeficiency virus using high-resolution 3D T1-weighted sagittal whole brain magnetic resonance imaging. DPABI and SPM were used to process and record changes in brain tissue volume. Correlation analyses were then used to explore the above relationships. Compared with brain tissue volume during the healthy stage, there was no change at 12 and 24 weeks postinoculation (12 wpi, 24 wpi). At 36 wpi, 48 wpi, and 60 wpi, basal ganglia, left inferior temporal gyrus, left occipital gyrus, and left superior frontal gyrus exhibited varying degrees of atrophy. There was no association found between CD4+, MON%, CFVL, and brain volume loss in any brain region. Our research demonstrated that in the early stage of HIV infection, local brain tissue atrophy can be demonstrated by MRI technique; furthermore, MRI can identify the earliest site of atrophy as well as the most severely affected site. Although there was no significant correlation between brain tissue volume loss and CD4+, MON%, and CFVL, our findings provided some evidence in the application of volumetric MR imaging in the early diagnosis and treatment follow-up of patients with HIV infection.

Background: Spinal cord (SC) affection is a hallmark symptom of neuromyelitis optica spectrum disorders (NMOSD). Patients with aquaporin-4 (AQP4-IgG+) or myelin oligodendrocyte glycoprotein (MOG-IgG+) antibody seropositivity show this overlapping clinical phenotype., Objective: Quantitative comparison of SC lesions and atrophy in AQP4-IgG+ and MOG-IgG+ NMOSD., Methods: AQP4-IgG+ ( n  = 38), MOG-IgG+ ( n  = 15) NMOSD patients and healthy controls (HC, n  = 24) were analysed for SC lesion (prevalence, length, location), atrophy as mean upper cervical cord area (MUCCA), Expanded Disability Status Scale (EDSS), timed 25-foot walk speed (T25FWS) and 9-hole peg test (9HPT) measures., Results: In total, 92% (35/38) of AQP4-IgG+ and 53% (8/15) of MOG-IgG+ patients had myelitis attacks (χ 2  = 6.47, p  = 0.011). 65.8%/26.7% of AQP4-/MOG-IgG+ patients had chronic SC lesions (χ 2  = 5.16, p  = 0.023), with similar proportions in cervical, upper thoracic and lower thoracic cord, and no length differences. MUCCA was decreased in AQP4-IgG+ ( t  = -2.27, p  = 0.028), but not MOG-IgG+ patients ( t  = 0.58, p  = 0.57) compared to HC. MUCCA associated with myelitis attacks (rho = -0.33, p  = 0.016), EDSS (rho = -0.31, p  = 0.030), pyramidal functional score (rho = -0.42, p  = 0.003), T25FWS ( r  = 0.43, p  = 0.010) and 9HPT Z-score ( r  = 0.32, p  = 0.037), regardless of antibody status., Conclusion: AQP4-IgG+ patients had more myelitis attacks, SC lesions and SC atrophy was more pronounced than in MOG-IgG+ patients. MUCCA is associated with clinical myelitis attacks and disability in all NMOSD patients.

Background & Aims: Potential celiac disease is characterized by positive results from serologic tests for tissue transglutaminase antibodies (anti-TG2) but normal duodenal architecture (Marsh stages 0-1). There is controversy over the best way to manage these patients. We investigated risk factors associated with the development of villous atrophy in children with potential celiac disease., Methods: We performed a prospective study of 280 children (ages 2-18 years) in Italy with suspected celiac disease, followed for up to 12 years (range, 18-150 months; median 60 months). The subjects had 2 consecutive positive results from tests for anti-TG2, tested positive for the endomysial antibody (anti-EMA), had total serum levels of immunoglobulin A in the normal range, normal duodenal architecture (Marsh stages 0-1) in 5 biopsies, and HLA DQ2- or DQ8-positive haplotypes. The children underwent serologic tests and clinical analyses every 6 months and a small bowel biopsy was taken every 2 years. A total of 210 patients of the original cohort were assessed at the 9-year follow-up evaluation. We performed multivariate analyses of clinical, genetic, and histologic data to identify factors associated with progression to villous atrophy., Results: During the follow-up period, 42 (15%) of 280 children developed villous atrophy, whereas 89 (32%) children no longer tested positive for anti-TG2 or anti-EMA. The cumulative incidence of progression to villous atrophy was 43% at 12 years. In multivariate analysis, the baseline factors most strongly associated with development of villous atrophy were numbers of γδ intraepithelial lymphocyte cells followed by age and homozygosity for the HLA DQB1*02. In discriminant analysis, these baseline factors identified 80% of the children who developed baseline atrophy., Conclusions: In a long-term study of 280 children with suspected celiac disease (based on anti-TG2 and anti-EMA) on gluten-containing diets, the cumulative incidence of progression to villous atrophy was 43% over a 12-year period. We identified factors that can be used to identify children at highest risk for villous atrophy. This approach might be used to determine whether children with suspected celiac disease should immediately start a gluten-free diet or be monitored on their regular diet., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Elevated expression of the proinflammatory cytokine interleukin 1β (IL-1β) has been observed in expressed prostatic secretions of patients with chronic prostatitis/chronic pelvic pain syndrome, and genetic polymorphisms associated with the IL1B gene are linked to increased risk for aggressive prostate cancer., Methods: To study the role of IL-1β expression in prostate inflammation, we examined IL1B expression in human prostatic proliferative inflammatory atrophy (PIA) lesions and developed a tetracycline-regulated human IL1B transgene in the mouse prostate., Results: Here, we demonstrate that IL1B expression is a common finding in human PIA lesions, which harbored focal IL1B expression in epithelial and stromal compartments. Human IL1B expression in the mouse prostate elicited acute and chronic inflammation. Penetrance and expressivity were variable and tunable by altering transgene dosage and the presence of an exogenous inducible marker antigen (green fluorescent protein). Inflammation was characterized by infiltration of CD4 + T cells, demonstrating an adaptive immune response. Chronic inflammation persisted after doxycycline (Dox) withdrawal. Reactive epithelia increased expression of downstream cytokines, and altered glandular architecture was observed upon sustained induction of IL1B. Immunohistochemical analyses revealed a higher proliferative index and decreased Nkx3.1 expression in inflamed mouse prostates., Conclusions: These data implicate IL-1β in human prostate pathology and this model provides a versatile platform to interrogate molecular mechanisms of inflammation-associated prostate pathologies associated with episodic or sustained IL-1β expression., (© 2019 Wiley Periodicals, Inc.)

Recent studies showed that B cells play a major role in the pathogenesis of neurodegeneration in multiple sclerosis (MS). In this study, we aimed to determine the possible link between immunoglobulin free light chains (FLC) and brain atrophy in patients with MS. Ninety-two patients (32 males and 60 females) with MS were included. Kappa and lambda FLC concentrations in serum and cerebrospinal fluid (CSF) samples of MS patients were measured using ELISA assay. FLC quotients (Q-k and Q-λ, respectively) were calculated. In a cross-sectional group (n = 92), the MRI data were acquired within 6 months from the date of the lumbar puncture. Twenty patients from this cohort performed a follow-up MRI after 1 year of observation. Brain volumes were calculated with SIENAX and the brain atrophy (percentage brain volume change (PBVC)) was assessed with SIENA. Spearman's test was performed to assess correlations. We have shown statistically significant correlation of Expanded Disability Status Scale (EDSS) level with normalized brain volume (NBV, r = - 0.2721, p = 0.0062), white matter volume (WMV, r = - 0.2425, p = 0.015), and gray matter volume (GMV, r = - 0.216, p = 0.0309). Multiple Sclerosis Severity Score (MSSS) score correlated with NBV (r = - 0.2521, p = 0.0352) and WMV (r = - 0.315, p = 0.0079). Neither EDSS, nor MSSS scores correlated with the age of patients and relapse rate during the first year and 5 years. In our study, we found statistically significant correlations of k-FLC in the CSF with NBV (r = - 0.311, p = 0.003) and with GMV (r = - 0.213, p = 0.0423). Q-k correlated only with NBV (r = - 0.340, p = 0.006) and Q-λ were negatively correlated with WMV (r = - 0.366, p = 0.003). We did not find correlations of k-FLC in CSF, λ-FLC in CSF, Q-k, and Q-λ with duration of MS course, EDSS, MSSS, number of relapses during the first year, and during the first 5 years of disease. Additionally, we subdivided the study population in accordance with level of k-FLC CSF, Q-k, and Q-λ on the 25th and 75th percentile subgroups (25-k-FLC CSF /75-k-FLC CSF ; 25-λ-FLC CSF /75-λ-FLC CSF ; 25-Q-k/75-Q-k; 25-Q-λ/75-Q-λ). We found statistically significant difference of NBV and GMV between 25-k-FLC CSF and 75-k-FLC CSF subgroups (p = 0.0047, p = 0.0297 respectively), NBV between 25-Q-k and 75-Q-k subgroups (p = 0.038), and NBV and WMV between 25-Q-λ and 75-Q-λ subgroups (p = 0.0446, p = 0.0026 respectively). PBVC in the prospective group showed negative correlation with kappa FLC in the CSF (r = - 0.4853, p = 0.0301) and Q-k (r = - 0.6132, p = 0.0224), but not with other clinical, epidemiological data. In this study, we showed a strong negative correlation of k-FLC, Q-k, and Q-λ with brain atrophy in MS patients. Additionally, patients with high concentration of FLC had lower brain volumes. We did not find correlations of FLC with the relapse rate, age of patients, and MS time course. In the prospective group, the rate of atrophy was correlated with k-FLC and Q-k. We suggest that level of intrathecal production of FLC can be a good prognostic biomarker for MS.

Background: Gulf War Illness (GWI) is a multisystem disorder that has affected a substantial number of veterans who served in the 1990-91 Gulf War. The brain is prominently affected, as manifested by the presence of neurological, cognitive and mood symptoms. We reported previously on the protective role of six Human Leukocyte Antigen (HLA) alleles in GWI (Georgopoulos et al., 2016) and their association with regional brain function (James et al., 2016). More recently, we reported on the presence of subcortical brain atrophy in GWI (Christova et al., 2017) and discussed its possible relation to immune mechanisms. Here we focused on one of the six HLA GWI-protective HLA alleles, DRB1*13:02, which has been found to have a protective role in a broad range of autoimmune diseases (Furukawa et al., 2017), and tested its effects on brain volumes., Methods: Seventy-six Gulf War veterans (55 with GWI and 21 healthy controls) underwent a structural Magnetic Resonance Imaging (sMRI) scan to measure the volumes of 9 subcortical brain regions to assess differences between participants with (N=11) and without (N=65) HLA class II allele DRB1*13:02., Findings: We found that DRB1*13:02 spared subcortical brain atrophy in Gulf War veterans; overall subcortical volume was 6.6% higher in carriers of DRB1*13:02 (P=0.007). The strongest effect was observed in the volume of cerebellar gray matter which was 9.6% higher (P=0.007) in carriers of DRB1*13:02 than in non-carriers. By contrast, DRB1*13:01 had no effect., Interpretation: These findings document the protective effect of DRB1*13:02 on brain atrophy in Gulf War veterans and are in keeping with recent results documenting sharing of brain mechanisms between GWI and other immune-related diseases (Georgopoulos et al., 2017). We hypothesize that the protective role of DRB1*13:02 is due to its successful elimination of external antigens to which Gulf War veterans were exposed, antigens that otherwise would persist causing low-grade inflammation and possibly leading to autoimmunity., Funding Source: U.S. Department of Defense (W81XWH-15-1-0520), Department of Veterans Affairs, American Legion Brain Sciences Chair, and University of Minnesota., (Published by Elsevier B.V.)

Postnatal thymic epithelial cell (TEC) homeostatic defect- or natural aging-induced thymic atrophy results in a decline in central T-cell tolerance establishment, which is constituted by thymocyte negative selection and cluster of differentiation (CD) 4+ thymic regulatory T (tTreg) cell generation. Emerging evidence shows this decline mainly results from defects in negative selection, but there is insufficient evidence regarding whether tTreg cell generation is also impaired. We mechanistically studied tTreg cell generation in the atrophied thymus by utilizing both postnatal TEC-defective (resulting from FoxN1-floxed conditional knockout [cKO]) and naturally aged mouse models. We found that the capacity of tTreg cell generation was not impaired compared to CD4+ thymic conventional T cells, suggesting thymic atrophy positively influences tTreg cell generation. This is potentially attributed to decreased T cell receptor (TCR) signaling strength due to inefficiency in promiscuous expression of self-antigens or presenting a neo-self-antigen by medullary TECs, displaying decreased negative selection-related marker genes (Nur77 and CD5high) in CD4 single positive (SP) thymocytes. Our results provide evidence that the atrophied thymus attempts to balance the defective negative selection by enhancing tTreg cell generation to maintain central T-cell tolerance in the elderly. Once the balance is broken, age-related diseases could take place.

The effects of l-arginine (Arg) supplementation on intestinal mucosal immune barrier function in weaned pigs after Escherichia coli LPS challenge were evaluated. Twenty-four weaned pigs were allotted to four treatments including: (i) non-challenged control; (ii) LPS-challenged control; (iii) LPS + 0.5% Arg; and (iv) LPS + 1.0% Arg. On d 16, pigs in the LPS, LPS + 0.5% Arg and LPS + 1.0% Arg groups were challenged by injection with 100 µg/kg of body mass LPS, whereas the control group were given sterile saline. At 48 h post-challenge, all pigs were sacrificed for evaluation of small intestinal morphology and mucosal immune barrier function. In the jejunum and ileum, LPS caused villous atrophy and intestinal morphology disruption, whereas 0.5% or 1.0% Arg supplementation mitigated villus atrophy and intestinal morphology impairment caused by LPS challenge. Arg (0.5%) supplementation increased the numbers of IgA-secreting cells, CD8(+) and CD4(+) T cells in the ileum (P < 0.05). Arg supplementation prevented the elevation of mast cell numbers induced by LPS challenge (P < 0.05). Dietary supplementation of Arg caused a decreased lymphocyte apoptosis of Peyer's patches in pigs challenged by LPS (P < 0.05). These results indicated that Arg supplementation protects and enhances intestinal mucosal immune barrier function and maintains intestinal integrity in weaned pigs after E. coli LPS challenge.

Hypergastrinemia in INS-GAS mice leads to accelerated carcinogenesis of the stomach, but the mechanisms have not been well defined. We investigated the possible role of gastrin-induced gastric cell apoptosis in the development of gastric cancer. We examined apoptosis and the expression of Bcl-2 family proteins in INS-GAS mice of different ages, as well as in gastrin-deficient (GAS-KO) mice after gastrin-17 (G-17) infusion. In addition, we studied the effects of the gastrin/cholecystokinin-2 (CCK-2) receptor antagonist YF476 and/or histamine H2 (H-2) receptor antagonist loxtidine on apoptosis and atrophy in INS-GAS mice with or without Helicobacter felis (H. felis) infection. INS-GAS mice had age-associated increases in Bax protein expression and decreases in Bcl-2 protein expression, along with increased glandular and epithelial cell apoptosis. At 8-week gastrin infusions in GAS-KO mice resulted in a similar pattern of altered Bax and Bcl-2 expression, followed by gastric cell apoptosis. H. felis infection of INS-GAS mice led to increased apoptosis and the development of atrophy, whereas treatment with either YF476 and/or loxtidine strongly inhibited both apoptosis and atrophy. In vitro studies with Fas-expressing RGM1 cells showed that gastrin stimulation alone directly induced apoptosis via gastrin/CCK-2 receptor and synergized with FasL stimulation. These results indicate that gastrin can induce apoptosis in gastric epithelial cells and contribute to the development of gastric carcinogenesis.

Thymic pathology occurs in 80-90% of myasthenia gravis patients. Significant associations between different thymic alterations and clinical findings are discussed. To highlight peculiarities in thymoma-associated myasthenia gravis, we briefly review myasthenia gravis associated with thymic lymphofollicular hyperplasia (TFH) and thymic atrophy.

After ingestion of food, immune complexes containing food proteins as antigens were demonstrated in the serum of normal and atopic subjects. In the atopic patients challenged with the food to which they were sensitive, abnormal levels were detected. The same atopic patients pretreated with oral sodium cromoglycate had less antigen entry, diminished immune-complex formation, and no atopic symptoms. Tests for antigen entry and immune-complex formation after oral challenge may permit objective assessment of food allergy and may show whether drugs such as oral sodium cromoglycate are likely to benefit individual patients.