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Hum Immunol. 2023 Jan 3:S0198-8859(22)00251-8. doi: 10.1016/j.humimm.2022.12.003. Online ahead of print.

ABSTRACT

BACKGROUND: Beta-thalassemia major is an autosomal recessive disorder in hemoglobin synthesis. Ineffective erythropoiesis is the main characteristic of the disease, which results in anemia following the extensive destruction of red blood cells. Chronic antigenic stimulation following frequent blood transfusions lead to immune abnormalities, especially regarding T cells, which is one of the reasons for the high susceptibility to infection in beta-thalassemia.

METHODS: Six pediatric patients and six age- and sex-matched healthy children were selected. Immunophenotyping of functional T-cells was performed using flow cytometry with staining for surface and intracellular markers. The proliferative response of T lymphocytes was also investigated after labeling with CFSE and following stimulation with anti-CD3 and anti-CD28.

RESULTS: Examination of T lymphocyte subpopulations showed a significant increase in regulatory T cells (Tregs) in beta-thalassemia patients. Hence, the Treg:Tcons (conventional T cells) and Treg:CD8 ratios were significantly increased. In addition, a significant increase in CD8 T cell proliferation activity was observed. Multivariate analysis showed a significant association of central memory cells with serum ferritin levels and the duration of transfusion. In particular, patients with cytomegalovirus (CMV) infection exhibited a significant increase in CD4 central memory cells.

CONCLUSION: Patients with beta-thalassemia have functionally distinct CD4 and CD8 T cell subsets imbalances, and this may contribute to their high susceptibility to infections and immune dysregulation.

PMID:36604193 | DOI:10.1016/j.humimm.2022.12.003

Eur J Hum Genet. 2023 Jan 4. doi: 10.1038/s41431-022-01278-5. Online ahead of print.

ABSTRACT

Hemolytic-uremic syndrome (HUS), mostly secondary to infectious diseases, is a common cause of acute kidney injury in children. It is characterized by progressive acute kidney failure due to severe thrombotic microangiopathy, associated with nonimmune, Coombs-negative hemolytic anemia and thrombocytopenia. HUS is caused mostly by Shiga toxin-producing E. Coli, and to a lesser extent by Streptococcus pneumonia. In Streptococcus pneumonia HUS (pHUS), bacterial neuraminidase A exposes masked O-glycan sugar residues on erythrocytes, known as the T antigen, triggering a complement cascade causing thrombotic microangiopathy. Atypical HUS (aHUS) is a life-threatening genetic form of the disease, whose molecular mechanism is only partly understood. Through genetic studies, we demonstrate a novel X-linked form of aHUS that is caused by a de-novo missense mutation in C1GALT1C1:c.266 C > T,p.(T89I), encoding a T-synthase chaperone essential for the proper formation and incorporation of the T antigen on erythrocytes. We demonstrate the presence of exposed T antigen on the surface of mutant erythrocytes, causing aHUS in a mechanism similar to that suggested in pHUS. Our findings suggest that both aHUS caused by mutated C1GALT1C1 and pHUS are mediated by the lectin-complement-pathway, not comprehensively studied in aHUS. We thus delineate a shared molecular basis of aHUS and pHUS, highlighting possible therapeutic opportunities.

PMID:36599939 | DOI:10.1038/s41431-022-01278-5

Med Microbiol Immunol. 2023 Jan 3. doi: 10.1007/s00430-022-00759-0. Online ahead of print.

ABSTRACT

Measurement of anti-pneumococcal capsular polysaccharides (anti-PnPs) IgG titers is an important tool in the immunologic assessment of patients with suspected immunodeficiency disorders (ID) to reduce the morbi-mortality and minimize severe infections. Retrospectively, we studied the relationship among anti-PnPs IgG response to 3 doses of Prevenar®13, levels of immune system components, leukocyte populations, and clinical data in children with ID. Serum samples were collected at least 4 weeks post vaccination. Subsequently, multi-serotype enzyme-linked immunosorbent assay (ELISA) was performed. Eighty-seven children (under 12 years) were enrolled. Primary immunodeficiency disorder (PID) was the most common disorder (45) followed by possible immunodeficiency disorder (POID) (19), secondary immunodeficiency disorder (SID) (15), and mixed immunodeficiency disorder (MID) (8). The median age was 3 (1.50-5.33) years, 65% of patients were male. Deficient production of anti-PnPs IgG (titer ≤ 50 mg/L) was detected in 47 patients (54%), especially in the MID group, all of them under immunosuppressive therapy. In PCV13 responders, the mean of leukocyte population levels was higher with statistically significance differences in CD4 + /CD8 + T lymphocytes (p = 0.372, p = 0.014) and CD56 + /CD16 + NK (p = 0.016). Patients with previous bone marrow transplantation were the worst PCV13 responders. Pneumococcal IgG antibody titers (post-vaccination) along with clinical and analytical markers represented.

PMID:36595027 | DOI:10.1007/s00430-022-00759-0

Front Oncol. 2022 Dec 14;12:1037535. doi: 10.3389/fonc.2022.1037535. eCollection 2022.

ABSTRACT

INTRODUCTION: Prostate adenocarcinoma (PRAD) is a highly aggressive malignancy with high mortality and poor prognosis, and its potential mechanism remains unclear. Our study aimed to identify novel markers for the prognosis of PRAD using bioinformatics technology.

METHODS: The GSE32571 dataset was downloaded from the GEO database, and analyzed via the limma R package to identify differentially expressed genes (DEGs) and differentially expressed immune score-related genes (DEISRGs). The immune-related genes (IRGs) were further obtained by overlapping DEISRGs and DEGs, and the core gene was identified via survival analysis. Furthermore, the expression level, prognostic value, and potential functions of the core gene were evaluated via multiple bioinformatics databases.

RESULTS: A total of 301 IRGs were identified from the GSE32571 dataset, and IFITM1 was a down-regulated gene in several types of cancer, including PRAD. Besides, low expression of IFITM1 was associated with a poor prognosis in PRAD. GSEA indicated that the vital pathways of IFITM1-associated genes were mainly enriched in primary immunodeficiency, Th17 cell differentiation, Th1, and Th2 cell differentiation, natural killer cell-mediated cytotoxicity, myeloid dendritic cell activation, regulation of leukocyte activation, etc. Furthermore, IFITM1 was closely correlated with 22 types of tumor-infiltrating immune cells.

DISCUSSION: IFITM1 was a prognostic biomarker for PRAD patients, and it can be acted as a potential immune therapy target in PRAD.

PMID:36591519 | PMC:PMC9795034 | DOI:10.3389/fonc.2022.1037535

Front Immunol. 2022 Dec 14;13:984110. doi: 10.3389/fimmu.2022.984110. eCollection 2022.

ABSTRACT

BACKGROUND: Adult antibody deficiency remains under-recognised and under-studied – especially among Asian populations. Patterns of immunoglobulin use and the feasibility of subcutaneous immunoglobulin (SCIg) replacement among Chinese patients remains unclear.

OBJECTIVE: To investigate the trends of immunoglobulin use, burden of adult antibody deficiency and the outcomes of patients on SCIg compared to intravenous immunoglobulin (IVIg) replacement in Hong Kong through a retrospective observational study.

METHODS: Population-wide data of immunoglobulin recipients in Hong Kong between 2012 and 2021, and longitudinal clinical data of adult immunodeficiency patients at Queen Mary Hospital were collected and analysed.

RESULTS: Total immunoglobulin consumption and recurrent immunoglobulin recipients increased continuously from 175,512g to 298,514g (ρ=0.99, p<0.001) and 886 to 1,508 (ρ=0.89, p=0.001) between 2012-21 in Hong Kong. Among 469 immunoglobulin recipients at Queen Mary Hospital in 2021, 344 (73.3%) were indicated for replacement. Compared to those on IVIg (n=14), patients on SCIg replacement (n=8) had fewer immunodeficiency-related hospitalisations (IRR=0.11) and shorter duration of hospitalisation stay (IRR=0.10) per year, as well as better quality of life (SF-36v2 Health Survey and Life Quality Index). Estimated annual healthcare cost of SCIg replacement per patient was lower than that of IVIg (HKD196,850 [USD25,096] vs HKD222,136 [USD28,319]).

CONCLUSION: There was a significantly increasing burden of adult antibody deficiency and immunoglobulin consumption in Hong Kong. SCIg was feasible and more cost-effective when compared to IVIg, with SCIg patients experiencing better clinical outcomes and quality of life. Future prospective studies to confirm the long-term efficacy and superiority of SCIg are required.

PMID:36591300 | PMC:PMC9795180 | DOI:10.3389/fimmu.2022.984110

Cureus. 2022 Nov 28;14(11):e31976. doi: 10.7759/cureus.31976. eCollection 2022 Nov.

ABSTRACT

Common variable immunodeficiency (CVID) is a disease characterized by severe antibody deficiency due to impaired B cell differentiation. It represents the most common form of primary immunodeficiency in children and adults, and its clinical manifestations include recurrent infections and chronic lung disease, gastrointestinal infections, and autoimmunity. Here, we present the case of a 47-year-old female patient with a history of CVID and recurrent Campylobacter jejuni bacteremia. She was undergoing biweekly administration of intravenous immunoglobulin for over 15 years. During hospitalization rapidly progressive oliguric renal failure was observed in association with anasarca and nephrotic syndrome. Bilateral nephromegaly was noted on an abdominal pelvic computed tomography scan. Renal biopsy was consistent with amyloidosis, and serum amyloid A protein was elevated. The diagnosis of AA amyloidosis secondary to CVID was made. The patient was started on hemodialysis and weekly intravenous immunoglobulin administration with favorable clinical outcomes.

PMID:36589195 | PMC:PMC9796280 | DOI:10.7759/cureus.31976

J Allergy Clin Immunol. 2022 Dec 29:S0091-6749(22)02580-5. doi: 10.1016/j.jaci.2022.12.813. Online ahead of print.

ABSTRACT

BACKGROUND: Granulomatous and lymphocytic interstitial lung disease (gl-ILD) is a major cause of morbidity and mortality among patients with common variable immunodeficiency. Corticosteroids are recommended as first-line treatment for gl-ILD, but evidence for their efficacy is lacking.

OBJECTIVE: We analyzed the effect of high-dose corticosteroids (≥0.3mg/kg prednisone equivalent) on gl-ILD, measured by high-resolution computed tomography (HRCT) scans, pulmonary function test (PFT) results.

METHODS: Patients who had received high-dose corticosteroids but no other immunosuppressive therapy at the time (n=56) and who underwent repeated HRCT scanning or PFT during the retrospective and/or prospective phase of the STILPAD study (n=39) were included in the analysis. Patients without any immunosuppressive treatment were selected as controls (n=23). HRCT scans were blinded, randomized and scored using the Hartman score. Differences between the baseline and follow up HRCT scans and PFT were analyzed.

RESULTS: Treatment with high-dose corticosteroids significantly improved HRCT scores and forced vital capacity. Carbon monoxide diffusion capacity significantly improved in both groups. 13/18 patients, for whom extended follow-up data was available, achieved a long-term, maintenance therapy independent remission. All patients with relapse were re-treated with corticosteroids, but only 1/5 responded. Two opportunistic infections were found in the corticosteroid treatment group, while overall infection rate was similar between cohorts.

CONCLUSION: Induction therapy with high-dose corticosteroids improved HRCT scans and PFT results of patients with gl-ILD and achieved long-term remission in 42% of patients. It was not associated with major side-effects. Low dose maintenance therapy provided no benefit and efficacy was poor in relapsing disease.

PMID:36587851 | DOI:10.1016/j.jaci.2022.12.813

J Allergy Clin Immunol. 2022 Dec 28:S0091-6749(22)02558-1. doi: 10.1016/j.jaci.2022.12.807. Online ahead of print.

ABSTRACT

BACKGROUND: A dysregulated immune response is a hallmark of autoimmune disorders. Evidence suggests that systemic autoimmune diseases and primary immunodeficiency disorders (PID) may be similar diseases with different clinical phenotypes.

OBJECTIVE: This study aimed to investigate the burden of PID-associated genetic variants in patients with childhood-onset systemic lupus erythematosus (cSLE).

METHODS: We enrolled 118 cSLE patients regularly followed at Chang Gung Memorial Hospital. Targeted next-generation sequencing identified PID genetic variants in patients versus 1,475 unrelated healthy individuals that were further filtered by allelic frequency and various functional scores. Customized immune assays tested the functions of the identified variants.

RESULTS: Upon filtration, 36 (30.5%) patients harbored rare variants in PID-associated genes predicted to be damaging. One homozygous TREX1 (c.294dupA) mutation and four heterozygous variants with possible dominant PID traits, including BCL11B (c.G1040T), NFKB1 (c.T695G), and NFKB2 (c.G1210A, c.G1651A), were discovered. With recessive traits, variants were found across all PID types; one-fifth involved phagocyte number or function defects. Predicted pathogenic PID variants were more predominant in those with a family history of lupus regardless of infection susceptibility. Moreover, mutational loads were greater among cSLE patients than controls despite sex or age at disease onset. While greater mutational loads were observed among cSLE patients with peri-pubertal disease onset, no significant difference in sex or phenotype were noted among cSLE patients.

CONCLUSION: Our findings suggest that cSLE is mostly not monogenic. Gene-specific analysis and mutational load investigations suggested that rare and predicted damaging variants in PID-related genes potentially contribute to cSLE susceptibility.

PMID:36586539 | DOI:10.1016/j.jaci.2022.12.807

RMD Open. 2022 Dec;8(2):e002664. doi: 10.1136/rmdopen-2022-002664.

ABSTRACT

OBJECTIVE: The clinical spectrum of primary antibody deficiencies (PADs) and especially common variable immunodeficiency (CVID) includes various autoimmune disorders. We studied the prevalence and the features of articular rheumatic disease in a cohort of patient with PADs.

METHODS: In this retrospective cohort study, complete clinical data of 268 patients with PADs, mainly consisting of patients with CVID, visiting the immunology outpatient clinic of a German tertiary hospital between 2018 and 2021 were collected. Those included case history, physical examination, laboratory as well as radiological findings.

RESULTS: Inflammatory arthritis was diagnosed in 16.4% of studied patients and was significantly more common among patients with PAD-associated enteropathy (OR 13.39, p=0.0001), splenomegaly (OR 6.09, p=0.0001) or atopic diseases (OR 3.31, p=0.021). Given HLA-B27 status, the involvement of the axial skeleton and the presence of features, such as anterior uveitis, inflammatory bowel disease, psoriasis and/or dactylitis, 75% of studied patients fulfilled the Assessment of Spondyloarthritis International Society classification criteria.

CONCLUSION: PAD-associated arthritis frequently shares features with spondyloarthritis (SpA) and enteropathic arthritis. The latter may suggest the interconnected pathomechanisms of inflammatory arthritis in SpA and PADs.

PMID:36583733 | DOI:10.1136/rmdopen-2022-002664

Khirurgiia (Mosk). 2022;(1):13-22. doi: 10.17116/hirurgia202301113.

ABSTRACT

OBJECTIVE: To describe treatment of cicatricial tracheal stenosis and tracheoesophageal fistula in patients with COVID-19 pneumonia.

MATERIAL AND METHODS: There were 91 patients with cicatricial tracheal stenosis for the period from August 2020 to April 2022 (21 months). Of these, 32 (35.2%) patients had cicatricial tracheal stenosis, tracheoesophageal fistula and previous coronavirus infection with severe acute respiratory syndrome. Incidence of iatrogenic tracheal injury following ventilation for viral pneumonia in the pandemic increased by 5 times compared to pneumonia of other genesis. Majority of patients had pneumonia CT grade 4 (12 patients) and grade 3 (8 patients). Other ones had pulmonary parenchyma lesion grade 2-3 or mixed viral-bacterial pneumonia. Isolated tracheoesophageal fistula without severe cicatricial stenosis of trachea or esophagus was diagnosed in 4 patients. In other 2 patients, tracheal stenosis was combined with tracheoesophageal fistula. Eight (25%) patients had tracheostomy at the first admission. This rate was almost half that of patients treated for cicatricial tracheal stenosis in pre-pandemic period.

RESULTS: Respiratory distress syndrome occurred in 1-7 months after discharge from COVID hospital. All patients underwent surgery. In 7 patients, we preferred palliative treatment with dilation and stenting until complete rehabilitation. In 5 patients, stent was removed after 6-9 months and these ones underwent surgery. There were 3 tracheal resections with anastomosis, and 2 patients underwent tracheoplasty. Resection was performed in 3 patients due to impossible stenting. Postoperative course in these patients was standard and did not differ from that in patients without viral pneumonia. In case of tracheoesophageal fistula, palliative interventions rarely allowed isolation of trachea. Four patients underwent surgery through cervical approach. There were difficult surgeries in 2 patients with tracheoesophageal fistula and cicatricial tracheal stenosis. One of them underwent separation of fistula and tracheal resection via cervical approach at primary admission. In another patient with thoracic fistula, we initially attempted to insert occluder. However, open surgery was required later due to dislocation of device.

CONCLUSION: Absolute number of patients with tracheal stenosis, tracheoesophageal fistula and previous COVID-19 has increased by several times compared to pre-pandemic period. This is due to greater number of patients requiring ventilation with risk of tracheal injury, non-compliance with preventive protocol for tracheal injury including anti-ischemic measures during mechanical ventilation. The last fact was exacerbated by involvement of allied physicians with insufficient experience of safe ventilation in the «red zone», immunodeficiency in these patients aggravating purulent-inflammatory process in tracheal wall. The number of patients with tracheostomy was 2 times less that was associated with peculiarity of mechanical ventilation in SARS-CoV-2. Indeed, tracheostomy was a poor prognostic sign and physicians tried to avoid this procedure. Incidence of tracheoesophageal fistula in these patients increased by 2 times compared to pre-pandemic period. In subacute period of COVID-associated pneumonia, palliative measures for cicatricial tracheal stenosis and tracheoesophageal fistula should be preferred. Radical treatment should be performed after 3-6 months. Absolute indication for circular tracheal resection with anastomosis is impossible tracheal stenting and ensuring safe breathing by endoscopic methods, as well as combination of cicatricial tracheal stenosis with tracheoesophageal fistula and resistant aspiration syndrome. Incidence of postoperative complications in patients with cicatricial tracheal stenosis and previous mechanical ventilation for COVID-19 pneumonia and patients in pre-pandemic period is similar.

PMID:36583489 | DOI:10.17116/hirurgia202301113