ABSTRACT
Intestinal mucus forms the first line of defense against bacterial invasion while providing nutrition to support microbial symbiosis. How the host controls mucus barrier integrity and commensalism is unclear. We show that terminal sialylation of glycans on intestinal mucus by ST6GALNAC1 (ST6), the dominant sialyltransferase specifically expressed in goblet cells and induced by microbial pathogen-associated molecular patterns, is essential for mucus integrity and protecting against excessive bacterial proteolytic degradation. Glycoproteomic profiling and biochemical analysis of ST6 mutations identified in patients show that decreased sialylation causes defective mucus proteins and congenital inflammatory bowel disease (IBD). Mice harboring a patient ST6 mutation have compromised mucus barriers, dysbiosis, and susceptibility to intestinal inflammation. Based on our understanding of the ST6 regulatory network, we show that treatment with sialylated mucin or a Foxo3 inhibitor can ameliorate IBD.
Subject(s)
Gastrointestinal Microbiome , Inflammatory Bowel Diseases , Sialyltransferases/genetics , Animals , Homeostasis , Humans , Inflammatory Bowel Diseases/genetics , Inflammatory Bowel Diseases/metabolism , Intestinal Mucosa/metabolism , Intestinal Mucosa/microbiology , Mice , Mucus/metabolism , Sialyltransferases/metabolism , SymbiosisABSTRACT
Deficiency of the CD40L, expressed on the surface of T lymphocytes, is caused by mutations in the glycoprotein CD40L (CD154) gene. Resulting defective humoral and cellular responses cause a clinical presentation that includes recurrent sinopulmonary bacterial infections, opportunistic infections, sclerosing cholangitis, neutropenia, and autoimmune manifestations. HSCT represents the only curative treatment modality. However, the therapeutic decision to use HSCT proves challenging in many cases, mainly due to the lack of a phenotype-genotype correlation. We retrospectively reviewed patients with CD40L deficiency who were transplanted in Antalya and Göztepe MedicalPark Pediatric HSCT units from 2014 to 2019 and followed by Akdeniz University School of Medicine Department of Pediatric Immunology. The records of eight male cases, including one set of twins, were evaluated retrospectively. As two transplants each were performed on the twins, a total of ten transplants were evaluated. Conditioning regimens were predominantly based on myeloablative protocols, except for the twins, who received a non-myeloablative regimen for their first transplantation. Median neutrophil and platelet engraftment days were 13 (range 10-19) and 14 (range 10-42) days, respectively. In seven of ten transplants, a CMV reactivation was developed without morbidity. None of the patients developed GVHD, except for one mild case of acute GVHD. All patients survived, and the median follow-up was 852 days. Our data show that HSCT for patients with CD40 ligand deficiency is a potentially effective treatment for long-term disease control.
Subject(s)
CD40 Ligand/deficiency , CD40 Ligand/metabolism , Hematopoietic Stem Cell Transplantation/methods , Immunologic Deficiency Syndromes/therapy , Blood Platelets/metabolism , CD4-Positive T-Lymphocytes/cytology , Cell Separation , Child , Child, Preschool , Diseases in Twins , Flow Cytometry , Follow-Up Studies , Genetic Association Studies , Graft vs Host Disease/etiology , Humans , Immunologic Deficiency Syndromes/complications , Infant , Infant, Newborn , Male , Mutation , Neutrophils/metabolism , Quality of Life , Retrospective Studies , T-Lymphocytes/immunology , Transplantation Conditioning/methods , Treatment Outcome , TurkeySubject(s)
BCG Vaccine , Interferon-gamma , BCG Vaccine/adverse effects , Child, Preschool , Humans , Infant , Interleukin-12ABSTRACT
BACKGROUND: Major Histocompatibility Complex Class II (MHC-II) deficiency, a combined immunodeficiency, results from loss of Human Leukocyte Antigen class II expression on antigen-presenting cells. Currently, hematopoietic stem cell transplantation (HSCT) stands as the sole curative approach, though factors influencing patient outcomes remain insufficiently explored. OBJECTIVE: Our aim was to elucidate the clinical, immunological, and genetic profiles associated with MHC-II deficiency and identify prognostic indicators that affect survival rates. METHODS: In this multicenter retrospective analysis, we gathered data from 35 patients diagnosed with MHC-II deficiency across 12 centers in Turkey. We recorded infection histories, gene mutations, immune cell subsets, and surface MHC-II expression on blood cells. We conducted survival analyses to evaluate the impact of various factors on patient outcomes. RESULTS: Predominant symptoms observed were pneumonia (n=29, 82.9%), persistent diarrhea (n=26, 74.3%), and severe infections (n=26, 74.3%). The RFXANK gene mutation (n=9) was the most frequent, followed by mutations in RFX5 (n=8), CIITA (n=4), and RFXAP (n=2) genes. Patients with RFXANK mutations presented with later onset and diagnosis compared to those with RFX5 mutations (p=0.0008 and p=0.0006, respectively), alongside a more significant diagnostic delay (p=0.020). A notable founder effect was observed in 5 patients with a specific RFX5 mutation (c.616G>C). The overall survival rate for patients was 28.6% (n=10), showing a significantly higher proportion in individuals with HSCT (n=8, 80%). Early demise (p=0.006) and higher CD8+ T-cell counts were observed in patients with the RFX5 mutations compared to RFXANK-mutant patients (p=0.006 and p=0.009, respectively). CONCLUSION: The study delineates the genetic and clinical panorama of MHC-II deficiency, emphasizing the prevalence of specific gene mutations such as RFXANK and RFX5. These insights facilitate early diagnosis and prognosis refinement, significantly contributing to the management of MHC-II deficiency.
ABSTRACT
AIM: In the presence of food allergies, especially egg allergies, primary physicians in Turkey avoid vaccine administration and refer children to a hospital setting. We aimed to evaluate children who had allergies or suspected allergies and were referred to our Well Child Clinic in a university hospital for vaccination. MATERIAL AND METHODS: Charts of all children referred to our clinic due to concerns for allergies in the last two years, were reviewed. Demographic data, laboratory evaluation and reactions after immunization were recorded. RESULTS: A total of 122 children with or without a confirmed diagnosis of allergies were referred by primary physicians. In the history, 50 children (43.5%) had reactions with egg, 42 (36.5%) had reactions with multiple foods, nine (7.8%) had reactions with milk and seven (6.1%) had reactions with a previous vaccination. The most common reaction was rash (n=89, 86.4%). Nine children reported anaphylaxis. Skin testing or serum allergen specific IgE measurement revealed that 66 (54.1%) children had sensitization to egg white and 25 (20.5%) had sensitization to egg yolk. Most children (n=87, 71.9%) were referred for all the 12th-month vaccines, and 21 children were referred only for the measles-mumps-rubella vaccine (n=21, 17.4%). The median delay time in the administration of the measles-mumps-rubella vaccine was 20.0 (interquartile range: 8.7-41.2) days. No reaction was observed except for one child reporting a slight rash several hours after vaccination. CONCLUSION: Egg allergy was the most common barrier of vaccine administration in children referred from family physicians. Given the absence of any reactions, we support the administration of the measles-mumps-rubella vaccine in primary care settings to prevent delays in national vaccine schedule.
ABSTRACT
BACKGROUND AND OBJECTIVE: Adverse reactions related to intravenous immunoglobulin (IVIG) infusions vary from 1 to 81%, with an average of 20%. They may be classified as immediate; occurring during the infusion itself or delayed; occurring after the infusion has been ceased. In the present study, we aimed to evaluate the frequency of immediate adverse reactions due to IVIG infusions in primary immune deficiency (PID) patients. METHODS: The study population was composed of 109 patients. A total of 763 infusions were recorded for demographic data and adverse reactions. RESULTS: The participants included 32 girls (29%) and 77 boys (71%). The mean age was 11.8 ± 5.7 years (0.6- 33.5 years). Early adverse events (AE) were recorded in 34 (4.5%) among 763 IVIG infusions including 30 mild (88.2%), 3 moderate (8.8%) and 1 severe (2.9%). The most common immediate adverse reactions were fever (29.4%) and headache (29.4%). The risk of AE was higher among primary antibody deficiency (PAD), compared to combined immunodeficiency (OR 2.61, 95%CI 1.061-6.475; p = 0.037). CONCLUSIONS: Use of various intravenous immunoglobulin treatments should be considered with regard to side effect profiles observed. In our cohort, PID patient experienced mostly mild AE; PAD was associated with an increased risk of AE.