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Clinical Immunology (Orlando, Fla.) Aug 2023X-Linked Hyper-IgM Syndrome is caused by pathogenic variants in CD40LG. Three patients with atypical clinical and immunological features were identified with variants in...
X-Linked Hyper-IgM Syndrome is caused by pathogenic variants in CD40LG. Three patients with atypical clinical and immunological features were identified with variants in CD40LG requiring further characterization. Flow cytometry was used to evaluate CD40L protein expression and binding capacity to a surrogate receptor, CD40-muIg. Though functional anomalies were observed, there was still a lack of clarity regarding the underlying mechanism. We developed structural models for wild-type and the three variants of CD40L protein observed in these patients (p. Lys143Asn, Leu225Ser and Met36Arg) to evaluate structural alterations by molecular mechanic calculations, and assess protein movement by molecular dynamic simulations. These studies demonstrate that functional analysis of variants of unknown significance in CD40LG can be supplemented by advanced computational analysis in atypical clinical contexts. These studies in combination identify the deleterious effects of these variants and potential mechanisms for protein dysfunction.
Topics: Humans; CD40 Antigens; CD40 Ligand; Hyper-IgM Immunodeficiency Syndrome; Hyper-IgM Immunodeficiency Syndrome, Type 1; Immunoglobulin M; Mutation
PubMed: 37433422
DOI: 10.1016/j.clim.2023.109692 -
Journal of Clinical Immunology Oct 2023
Topics: Humans; Hyper-IgM Immunodeficiency Syndrome; Hyper-IgM Immunodeficiency Syndrome, Type 1; Homozygote; Lymphopenia; Cytidine Deaminase; Immunoglobulin M
PubMed: 37402930
DOI: 10.1007/s10875-023-01546-z -
The Journal of Allergy and Clinical... Sep 2023Secretory IgA interacts with commensal bacteria, but its impact on human mycobiota ecology has not been widely explored. In particular, whether human IgA-deficiency is...
BACKGROUND
Secretory IgA interacts with commensal bacteria, but its impact on human mycobiota ecology has not been widely explored. In particular, whether human IgA-deficiency is associated with gut fungal dysbiosis remains unknown.
OBJECTIVES
Our goal was to study the impact of IgA on gut mycobiota ecology.
METHODS
The Fungi-Flow method was used to characterize fecal, systemic, and maternal IgA, IgM, and IgG responses against 14 representative fungal strains (yeast/spores or hyphae forms) in healthy donors (HDs) (n = 34, 31, and 20, respectively) and to also compare gut mycobiota opsonization by secretory antibodies in HDs (n = 28) and patients with selective IgA deficiency (SIgAd) (n = 12). Stool mycobiota composition was determined by internal transcribed spacer gene sequencing in HDs (n = 23) and patients with SIgAd (n = 17). Circulating CD4 T-cell cytokine secretion profiles were determined by intracellular staining. The impact of secretory IgA, purified from breast milk (n = 9), on Candidaalbicans growth and intestinal Caco-2 cell invasion was tested in vitro.
RESULTS
Homeostatic IgA binds commensal fungi with a body fluid-selective pattern of recognition. In patients with SIgAd, fungal gut ecology is preserved by compensatory IgM binding to commensal fungi. Gut Calbicans overgrowth nevertheless occurs in this condition but only in clinically symptomatic patients with decreased T17/T22 T-cell responses. Indeed, secretory IgA can reduce in vitro budding and invasion of intestinal cells by Calbicans and therefore exert control on this pathobiont.
CONCLUSION
IgA has a selective impact on Calbicans ecology to preserve fungal-host mutualism.
Topics: Female; Humans; Candida albicans; Caco-2 Cells; IgA Deficiency; Immunoglobulin A; Immunoglobulin A, Secretory; Immunoglobulin M
PubMed: 37169153
DOI: 10.1016/j.jaci.2023.03.033 -
Clinical and Experimental Medicine Oct 2023Studies are scarce regarding IgG anti-tissue transglutaminase 2 (tTG) normalization in selective IgA deficient (SIgAD) celiac disease (CD) patients after beginning a...
Studies are scarce regarding IgG anti-tissue transglutaminase 2 (tTG) normalization in selective IgA deficient (SIgAD) celiac disease (CD) patients after beginning a gluten free diet (GFD). The aim of this study is to analyse the decreasing dynamics of IgG anti-tTG in patients diagnosed with CD who start a GFD. To achieve this objective, IgG and IgA anti-tTG levels at diagnosis and during follow-up in 11 SIgAD CD patients and in 20 IgA competent CD patients were retrospectively evaluated. At diagnosis, statistical differences were not found when comparing IgA anti-tTG levels of IgA competent subjects with IgG anti-tTG levels of SIgAD subjects. Regarding the decreasing dynamics, even though no statistical differences were found (p = 0.06), normalization rates were slower for SIgAD CD patients. After 1 and 2 years on GFD, respectively, only 18.2% and 36.3% of the SIgAD CD patients normalized IgG anti-tTG levels; otherwise, IgA anti-tTG reached values under the reference values in 30% and 80% of the IgA competent patients in the same time-points. Although IgG anti-tTG has demonstrated a high diagnostic efficiency in SIgAD CD pediatric patients, this test does not appear to be as precise for long-term GFD response monitoring as IgA anti-tTG levels in IgA sufficient patients.
Topics: Humans; Autoantibodies; Celiac Disease; Diet, Gluten-Free; IgA Deficiency; Immunity; Immunoglobulin A; Immunoglobulin G; Retrospective Studies; Transglutaminases
PubMed: 36913036
DOI: 10.1007/s10238-023-01040-1