Unraveling the Immunogenetics of STAT Proteins:Clinical Perspectives on Gain-of-Function and Loss-of-Function Variants

Signal Transducer and Activator of Transcription (STAT) proteins play pivotal roles in immune regulation. The dysregulation of these proteins, attributed to both gain-of-function (GOF) and loss-of-function (LOF) variants, has emerged as a substantial and intricate area of research. This comprehensive review delves into the intricate details of the diverse clinical spectrum associated with STAT variants and the immunological findings linked to these genetic alterations. Although this review does not encompass the treatment of each individual disease, we discuss investigative approaches ranging from immunophenotyping assessment to evaluation of STAT protein activity. These investigations play a crucial role in identifying affected patients and understanding the complexities of STAT.</p

Long-term treatment with selective PI3Kδ inhibitor leniolisib in adults with activated PI3Kδ syndrome

Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) is an inborn error of immunity that manifests as immune deficiency and dysregulation; symptoms include frequent infections and lymphoproliferation. In our dose-finding and phase 3 placebo-controlled trials, treatment with the selective PI3Kδ inhibitor leniolisib reduced lymphoproliferation and normalized lymphocyte subsets. Here, we present 6 years of follow-up from the 6 adult patients in the original dose-finding trial receiving leniolisib. We used data from the ongoing open-label extension study, which was supplemented at later time points by investigators, including health-related quality of life (HRQoL) assessed through a clinician-reported questionnaire. We observed improvements in HRQoL: 5 of 6 patients experienced an increase in physical capabilities and socialization, and a decrease in prescribed medications. Immune subsets improved in all patients: mean transitional B-cell levels decreased from 38.17% to 2.47% and the CD4:CD8 T-cell ratio normalized to 1.11. Manifestations seen before and within the first year of leniolisib exposure, such as infections and gastrointestinal conditions, attenuated after year 2, with few new conditions emerging out to year 6. Thrombocytopenia or lymphopenia remained present in half of patients at year 6. Of 83 adverse events through year 5, 90.36% were grade 1; none were grade 4/5 nor deemed leniolisib related. Collectively, we saw an enhancement in HRQoL as well as durable changes in lymphocyte subsets and clinical manifestations, further supporting the use of leniolisib as a long-term therapeutic option for the treatment of APDS. This trial was registered at www.ClinicalTrials.gov as #NCT02859727.</p

Uveitis causes according to immune status of patients

Purpose: The advances in medicine have led to an increased number of people living with some form of immunodeficiency. Most ocular infections in immunocompromised patients may lead to irreversible blindness. We identify the causes of uveitis in immunocompetent and immunocompromised patients. Methods: A retrospective cohort study of 1354 consecutive patients. All patients underwent a standard work-up for uveitis. Results: An immunocompromised state was identified in 171/1354 patients (13%), of whom 40 had Human immunodeficiency virus (HIV) infection, 52 received immunosuppressive medications, 28 had concurrent malignant disorder and 20 had other causes for their immunosuppression. In addition, 93/1354 patients (7%) had diabetes mellitus (DM). The prevalence of intraocular infections was much higher in immunocompromised patients than in immunocompetent patients and DM (p < 0.001). Causes of uveitis differed between the diverse immunocompromised groups. The non-HIV immunocompromised patients showed primarily intraocular herpes simplex and varicella zoster virus infections, whilst HIV-positive patients exhibited frequently cytomegalovirus (CMV) retinitis and syphilis. Patients with generalized malignancies were characterized by a lower prevalence of infections and higher prevalence of sarcoidosis. Patients with DM typically showed sarcoidosis and bacterial intraocular infections. The percentage of undetermined uveitis diagnoses was markedly lower in immunosuppressed patients (p < 0.001). Conclusion: In immunocompromised patients with uveitis, infections were diagnosed in 46% of cases in contrast to 12% in the immunocompetent patients. The causes of uveitis differed among the various types of immunosuppression. Immunocompromised patients with uveitis require a rapid assessment for the

A Transcriptomic Severity Classifier IMX-SEV-3b to Predict Mortality in Intensive Care Unit Patients with COVID-19:A Prospective Observational Pilot Study

The prediction of disease outcomes in COVID-19 patients in the ICU is of critical importance, and the examination of host gene expressions is a promising tool. The 29-host mRNA Inflam-matix-Severity-3b (IMX-SEV-3b) classifier has been reported to predict mortality in emergency department COVID-19 patients and surgical ICU patients. The accuracy of the IMX-SEV-3b in predicting mortality in COVID-19 patients admitted to the ICU is yet unknown. Our aim was to investigate the accuracy of the IMX-SEV-3b in predicting the ICU mortality of COVID-19 patients. In addition, we assessed the predictive performance of routinely measured biomarkers and the Sequential Organ Failure Assessment (SOFA) score as well. This was a prospective observational study enrolling COVID-19 patients who received mechanical ventilation on the ICU of the Erasmus MC, the Netherlands. The IMX-SEV-3b scores were generated by amplifying 29 host response genes from blood collected in PAXgene® Blood RNA tubes. A severity score was provided, ranging from 0 to 1 for increasing disease severity. The primary outcome was the accuracy of the IMX-SEV-3b in predicting ICU mortality, and we calculated the AUROC of the IMX-SEV-3b score, the biomarkers C-reactive protein (CRP), D-dimer, ferritin, leukocyte count, interleukin-6 (IL-6), lactate dehydrogenase (LDH), neutrophil-to-lymphocyte ratio (NLR), procalcitonin (PCT) and the SOFA score. A total of 53 patients were included between 1 March and 30 April 2020, with 47 of them being included within 72 h of their admission to the ICU. Of these, 18 (34%) patients died during their ICU stay, and the IMX-SEV-3b scores were significantly higher in non-survivors compared to survivors (0.65 versus 0.57, p = 0.05). The Area Under the Receiver Operating Characteristic Curve (AUROC) for prediction of ICU mortality by the IMX-SEV-3b was 0.65 (0.48–0.82). The AUROCs of the biomarkers ranged from 0.52 to 0.66, and the SOFA score had an AUROC of 0.81 (0.69–0.93). The AUROC of the pooled biomarkers CRP, D-dimer, ferritin, leukocyte count, IL-6, LDH, NLR and PCT for prediction of ICU mortality was 0.81 (IQR 0.69–0.93). Further validation in a larger interventional trial of a point-of-care version of the IMX-SEV-3b classifier is warranted to determine its value for patient management.</p

Cortistatin rather than somatostatin as a potential endogenous ligand for somatostatin receptors in the human immune system

Cells of the human immune system have been shown to express somatostatin receptors (sst). The expression of sst suggests a functional role of the peptide somatostatin (SS). However, SS expression has not been demonstrated yet in different human immune tissues. Therefore, we investigated by RT-PCR the expression of both SS and cortistatin (CST), a SS-like peptide, in various human lymphoid tissues and immune cells. We detected SS mRNA expression in the human thymus only, while not in thymocytes. CST mRNA was clearly expressed in the immune cells, lymphoid tissues, and bone marrow. Using quantitative RT-PCR, significant differences in expression levels between tissues were demonstrated. Expression of CST mRNA was up-regulated during differentiation of monocytes into macrophages and dendritic cells and could be up-regulated by lipopolysaccharide stimulation. Two differently sized cDNA fragments of CST were detected in the majority of cells and tissues. However, although both fragments were detected in nearly all T-cell lines (7 of 8), most of the B-cell lines expressed the short fragment only (8 of 10). Usin

Bioinformatic meta-analysis reveals novel differentially expressed genes and pathways in sarcoidosis

IntroductionSarcoidosis is a multi-system inflammatory disease of unknown origin with heterogeneous clinical manifestations varying from a single organ non-caseating granuloma site to chronic systemic inflammation and fibrosis. Gene expression studies have suggested several genes and pathways implicated in the pathogenesis of sarcoidosis, however, due to differences in study design and variable statistical approaches, results were frequently not reproducible or concordant. Therefore, meta-analysis of sarcoidosis gene-expression datasets is of great importance to robustly establish differentially expressed genes and signalling pathways.MethodsWe performed meta-analysis on 22 published gene-expression studies on sarcoidosis. Datasets were analysed systematically using same statistical cut-offs. Differentially expressed genes were identified by pooling of p-values using Edgington’s method and analysed for pathways using Ingenuity Pathway Analysis software.ResultsA consistent and significant signature of novel and well-known genes was identified, those collectively implicated both type I and type II interferon mediated signalling pathways in sarcoidosis. In silico functional analysis showed consistent downregulation of eukaryotic initiation factor 2 signalling, whereas cytokines like interferons and transcription factor STAT1 were upregulated. Furthermore, we analysed affected tissues to detect differentially expressed genes likely to be involved in granuloma biology. This revealed that matrix metallopeptidase 12 was exclusively upregulated in affected tissues, suggesting a crucial role in disease pathogenesis.DiscussionOur analysis provides a concise gene signature in sarcoidosis and expands our knowledge about the pathogenesis. Our results are of importance to improve current diagnostic approaches and monitoring strategies as well as in the development of targeted therapeutics

Targeted Proteomics Reveals Inflammatory Pathways that Classify Immune Dysregulation in Common Variable Immunodeficiency

Patients with common variable immunodeficiency (CVID) can develop immune dysregulation complications such as autoimmunity, lymphoproliferation, enteritis, and malignancy, which cause significant morbidity and mortality. We aimed to (i) assess the potential of serum proteomics in stratifying patients with immune dysregulation using two independent cohorts and (ii) identify cytokine and chemokine signaling pathways that underlie immune dysregulation in CVID. A panel of 180 markers was measured in two multicenter CVID cohorts using Olink Protein Extension Assay technology. A classification algorithm was trained to distinguish CVID with immune dysregulation (CVIDid, n = 14) from CVID with infections only (CVIDio, n = 16) in the training cohort, and validated on a second testing cohort (CVIDid n = 23, CVIDio n = 24). Differential expression in both cohorts was used to determine relevant signaling pathways. An elastic net classifier using MILR1, LILRB4, IL10, IL12RB1, and CD83 could discriminate between CVIDid and CVIDio patients with a sensitivity of 0.83, specificity of 0.75, and area under the curve of 0.73 in an independent testing cohort. Activated pathways (fold change > 1.5, FDR-adjusted p < 0.05) in CVIDid included Th1 and Th17-associated signaling, as well as IL10 and other immune regulatory markers (LAG3, TNFRSF9, CD83). Targeted serum proteomics provided an accurate and reproducible tool to discriminate between patients with CVIDid and CVIDio. Cytokine profiles provided insight into activation of Th1 and Th17 pathways and indicate a possible role for chronic inflammation and exhaustion in immune dysregulation. These findings serve as a first step towards the development of biomarkers for immune dysregulation in CVID

Immune Responses 6 Months After mRNA-1273 COVID-19 Vaccination and the Effect of a Third Vaccination in Patients with Inborn Errors of Immunity

Purpose: Patients with inborn errors of immunity (IEI) are at increased risk of severe coronavirus disease-2019 (COVID-19). Effective long-term protection against COVID-19 is therefore of great importance in these patients, but little is known about the decay of the immune response after primary vaccination. We studied the immune responses 6 months after two mRNA-1273 COVID-19 vaccines in 473 IEI patients and subsequently the response to a third mRNA COVID-19 vaccine in 50 patients with common variable immunodeficiency (CVID).Methods: In a prospective multicenter study, 473 IEI patients (including X-linked agammaglobulinemia (XLA) (N = 18), combined immunodeficiency (CID) (N = 22), CVID (N = 203), isolated or undefined antibody deficiencies (N = 204), and phagocyte defects (N = 16)), and 179 controls were included and followed up to 6 months after two doses of the mRNA-1273 COVID-19 vaccine. Additionally, samples were collected from 50 CVID patients who received a third vaccine 6 months after primary vaccination through the national vaccination program. SARS-CoV-2-specific IgG titers, neutralizing antibodies, and T cell responses were assessed.Results: At 6 months after vaccination, the geometric mean antibody titers (GMT) declined in both IEI patients and healthy controls, when compared to GMT 28 days after vaccination. The trajectory of this decline did not differ between controls and most IEI cohorts; however, antibody titers in CID, CVID, and isolated antibody deficiency patients more often dropped to below the responder cut-off compared to controls. Specific T cell responses were still detectable in 77% of controls and 68% of IEI patients at 6 months post vaccination. A third mRNA vaccine resulted in an antibody response in only two out of 30 CVID patients that did not seroconvert after two mRNA vaccines.Conclusion: A similar decline in IgG titers and T cell responses was observed in patients with IEI when compared to healthy controls 6 months after mRNA-1273 COVID-19 vaccination. The limited beneficial benefit of a third mRNA COVID-19 vaccine in previous non-responder CVID patients implicates that other protective strategies are needed for these vulnerable patients.</p