ABSTRACT
BACKGROUND: Immunoglobulin (Ig) glycosylation modulates the immune response and plays a critical role in ageing and diseases. Studies have mainly focused on IgG glycosylation, and little is known about the genetics and epidemiology of IgA glycosylation. METHODS: We generated, using a novel liquid chromatography-mass spectrometry method, the first large-scale IgA glycomics dataset in serum from 2423 twins, encompassing 71 N- and O-glycan species. RESULTS: We showed that, despite the lack of a direct genetic template, glycosylation is highly heritable, and that glycopeptide structures are sex-specific, and undergo substantial changes with ageing. We observe extensive correlations between the IgA and IgG glycomes, and, exploiting the twin design, show that they are predominantly influenced by shared genetic factors. A genome-wide association study identified eight loci associated with both the IgA and IgG glycomes (ST6GAL1, ELL2, B4GALT1, ABCF2, TMEM121, SLC38A10, SMARCB1, and MGAT3) and two novel loci specifically modulating IgA O-glycosylation (C1GALT1 and ST3GAL1). Validation of our findings in an independent cohort of 320 individuals from Qatar showed that the underlying genetic architecture is conserved across ancestries. CONCLUSIONS: Our study delineates the genetic landscape of IgA glycosylation and provides novel potential functional links with the aetiology of complex immune diseases, including genetic factors involved in IgA nephropathy risk.
Subject(s)
Genome-Wide Association Study , Glycomics , Immunoglobulin A , Humans , Immunoglobulin A/blood , Immunoglobulin A/genetics , Glycosylation , Female , Male , Polysaccharides/metabolism , Adult , Immunoglobulin G/blood , Middle Aged , AgedABSTRACT
The upper respiratory tract is the initial site of SARS-CoV-2 infection. Nasal spike-specific secretory immunoglobulin A (sIgA) correlates with protection against Omicron breakthrough infection. We report that intranasal vaccination using human adenovirus serotype 5 (Ad5) vectored Omicron spike in people who previously vaccinated with ancestral vaccine could induce robust neutralizing sIgA in the nasal passage. Nasal sIgA was predominantly present in dimeric and multimeric forms and accounted for nearly 40% of total proteins in nasal mucosal lining fluids (NMLFs). A low-level IgG could also be detected in NMLFs but not IgM, IgD, and IgE. After a complete nasal wash, sIgA in the nasal passage could be replenished rapidly within a few hours. A comparison of purified paired serum IgA, serum IgG, and nasal sIgA from the same individuals showed that sIgA was up to 3-logs more potent than serum antibodies in binding to spikes and in neutralizing Omicron subvariants. Serum IgG and IgA failed to neutralize XBB and BA.2.86, while nasal sIgA retained potent neutralization against these newly emerged variants. Further analysis showed that sIgA was more effective than IgG or IgA in blocking spike-mediated cell-to-cell transmission and protecting hACE2 mice from XBB challenge. Using a sIgA monoclonal antibody as a reference, we estimated that the total nasal sIgA contains about 2.6-3.9% spike-specific sIgA in NMLFs collected approximately one month after intranasal vaccination. Our study provided insights for developing intranasal vaccines that can induce sIgA to build an effective and mutation-resistant first-line immune barrier against constantly emerging variants.
Subject(s)
Administration, Intranasal , Antibodies, Neutralizing , Antibodies, Viral , COVID-19 Vaccines , COVID-19 , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Humans , SARS-CoV-2/immunology , SARS-CoV-2/genetics , COVID-19/prevention & control , COVID-19/immunology , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/blood , Animals , Mice , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/genetics , Antibodies, Viral/immunology , Antibodies, Viral/blood , COVID-19 Vaccines/immunology , COVID-19 Vaccines/genetics , COVID-19 Vaccines/administration & dosage , Immunoglobulin A/immunology , Immunoglobulin A/blood , Immunoglobulin A/genetics , Nasal Mucosa/immunology , Nasal Mucosa/virology , Female , Genetic Vectors/immunology , Genetic Vectors/genetics , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/immunology , Immunoglobulin A, Secretory/immunology , Adenoviridae/genetics , Adenoviridae/immunology , Immunoglobulin G/immunology , Immunoglobulin G/blood , MaleABSTRACT
Helicobacter pylori (H. pylori) is associated with gastric inflammation and mucosal antibodies against its cytotoxin-associated gene A (CagA) are protective. Vaccine-elicited immunity against H. pylori requires MHC class II expression, indicating that CD4+ T cells are protective. We hypothesized that the HLA-DR genotypes in human populations include protective alleles that more effectively bind immunogenic CagA peptide fragments and susceptible alleles with an impaired capacity to present CagA peptides. We recruited patients (n = 170) admitted for gastroendoscopy procedures and performed high-resolution HLA-DRB1 typing. Serum anti-CagA IgA levels were analyzed by ELISA (23.2% positive) and H. pylori classified as positive or negative in gastric mucosal tissue slides (72.9% positive). Pearson Chi-square analysis revealed that H. pylori infection was significantly increased in DRB1*11:04-positive individuals (p = 0.027). Anti-CagA IgA was significantly decreased in DRB1*11:04 positive individuals (p = 0.041). In contrast, anti-CagA IgA was significantly increased in DRB1*03:01 positive individuals (p = 0.030). For these HLA-DRB1 alleles of interest, we utilized two in silico prediction methods to compare their capacity to present CagA peptides. Both methods predicted increased numbers of peptides for DRB1*03:01 than DRB1*11:04. In addition, both alleles preferred distinctively different CagA 15mer peptide sequences for high affinity binding. These observations suggest that DRB1*11:04 is a susceptible genotype with impaired CagA immunity, whereas DRB1*03:01 is a protective genotype that promotes enhanced CagA immunity.
Subject(s)
Gastritis , Helicobacter pylori , Humans , Helicobacter pylori/genetics , Antigens, Bacterial/genetics , Bacterial Proteins/genetics , HLA-DRB1 Chains/genetics , Cytotoxins , Gastritis/genetics , Genotype , Peptides/genetics , Immunoglobulin A/geneticsABSTRACT
B cells and their secreted antibodies are fundamental for host-defense against pathogens. The generation of high-affinity class switched antibodies results from both somatic hypermutation (SHM) of the immunoglobulin (Ig) variable region genes of the B-cell receptor and class switch recombination (CSR) which alters the Ig heavy chain constant region. Both of these processes are initiated by the enzyme activation-induced cytidine deaminase (AID), encoded by AICDA. Deleterious variants in AICDA are causal of hyper-IgM syndrome type 2 (HIGM2), a B-cell intrinsic primary immunodeficiency characterised by recurrent infections and low serum IgG and IgA levels. Biallelic variants affecting exons 2, 3 or 4 of AICDA have been identified that impair both CSR and SHM in patients with autosomal recessive HIGM2. Interestingly, B cells from patients with autosomal dominant HIGM2, caused by heterozygous variants (V186X, R190X) located in AICDA exon 5 encoding the nuclear export signal (NES) domain, show abolished CSR but variable SHM. We herein report the immunological and functional phenotype of two related patients presenting with common variable immunodeficiency who were found to have a novel heterozygous variant in AICDA (L189X). This variant led to a truncated AID protein lacking the last 10 amino acids of the NES at the C-terminal domain. Interestingly, patients' B cells carrying the L189X variant exhibited not only greatly impaired CSR but also SHM in vivo, as well as CSR and production of IgG and IgA in vitro. Our findings demonstrate that the NES domain of AID can be essential for SHM, as well as for CSR, thereby refining the correlation between AICDA genotype and SHM phenotype as well as broadening our understanding of the pathophysiology of HIGM disorders.
Subject(s)
Cytidine Deaminase , Hyper-IgM Immunodeficiency Syndrome , Immunoglobulin Class Switching , Humans , Cytidine Deaminase/genetics , Cytidine Deaminase/metabolism , Hyper-IgM Immunodeficiency Syndrome/genetics , Immunoglobulin A/genetics , Immunoglobulin Class Switching/genetics , Immunoglobulin G/genetics , Phenotype , Somatic Hypermutation, ImmunoglobulinABSTRACT
Immunoglobulin A (IgA) plays a crucial role in the human immune system, particularly in mucosal immunity. IgA antibodies that target the mucosal surface are made up of two to five IgA monomers linked together by the joining chain, forming polymeric molecules. These IgA polymers are transported across mucosal epithelial cells by the polymeric immunoglobulin receptor pIgR, resulting in the formation of secretory IgA (SIgA). This review aims to explore recent advancements in our molecular understanding of IgA, with a specific focus on SIgA, and the interaction between IgA and pathogen molecules.
Subject(s)
Immunoglobulin A, Secretory , Immunoglobulin A , Humans , Immunoglobulin A, Secretory/immunology , Immunoglobulin A, Secretory/metabolism , Immunoglobulin A/immunology , Immunoglobulin A/chemistry , Immunoglobulin A/metabolism , Immunoglobulin A/genetics , Animals , Receptors, Polymeric Immunoglobulin/genetics , Receptors, Polymeric Immunoglobulin/immunology , Receptors, Polymeric Immunoglobulin/metabolism , Receptors, Polymeric Immunoglobulin/chemistry , Immunity, MucosalABSTRACT
The joining (J) chain regulates polymerization of multimeric Immunoglobulin(Ig)M and IgA, forming a disulfide bond to the C termini of their Ig heavy chains, and it controls IgM/IgA transport across mucosal epithelia. Like Ig itself and human-like adaptive immunity, J chain emerged in jawed vertebrates (gnathostomes), but its origin has remained mysterious since its discovery over 50 y ago. Here, we show unexpectedly that J chain is a member of the CXCL chemokine family. The J chain gene (JCHAIN) is linked to clustered CXCL chemokine loci in all gnathostomes except actinopterygians that lost JCHAIN. JCHAIN and most CXCL genes have four exons with the same intron phases, including the same cleavage site for the signal peptide/mature protein. The second exon of both genes encodes a CXC motif at the same position, and the lengths of exons 1 to 3 are similar. No other gene in the human secretome shares all of these characteristics. In contrast, intrachain disulfide bonds of the two proteins are completely different, likely due to modifications in J chain to direct Ig polymerization and mucosal transport. Crystal structures of CXCL8 and J chain share a conserved beta-strand core but diverge otherwise due to different intrachain disulfide bonds and extension of the J chain C terminus. Identification of this ancestral affiliation between J chain and CXCL chemokines addresses an age-old problem in immunology.
Subject(s)
Immunoglobulin A , Immunoglobulin J-Chains , Animals , Humans , Immunoglobulin J-Chains/metabolism , Exons , Immunoglobulin A/genetics , Disulfides , Chemokines/genetics , Immunoglobulin MABSTRACT
Dimeric IgA (dIgA) engineered to target mutated cytoplasmic oncodrivers abrogates tumor growth.
Subject(s)
Immunoglobulin A , Humans , Immunoglobulin A/genetics , MutationABSTRACT
Helicobacter pylori was reported as an important cause of gastritis, and gastric ulcers and CagA oncoprotein-producing H. pylori subgroups were blamed to increase the severity of gastritis. Disparities were reported in that the presence of serum anti-CagA IgA was not parallel with CagA-positive H. pylori cohabitation. We hypothesized that the HLA-DQA1 ~ DQB1 haplotypes in human populations include protective haplotypes that more effectively present immunogenic CagA peptides and susceptible haplotypes with an impaired capacity to present CagA peptides. We recruited patients (n = 201) admitted for gastroendoscopy procedures and performed high-resolution HLA-DQA1 and DQB1 typing. Serum anti-CagA IgA levels were analyzed by ELISA (23.0% positive), and H. pylori was classified as positive or negative in gastric mucosal tissue slides (72.6% positive). The HLA DQA1*05:05 allele (29.1%) and HLA DQB1*03:01 allele (32.8%) were found at the highest frequency among gastritis patients of Turkish descent. In HLA DQA1*05:05 ~ DQB1*03:01 double homozygous (7.3%) and heterozygous (40.7%) haplotype carriers, the presence of anti-CagA IgA decreased dramatically, the presence of H. pylori increased, and the presence of metaplasia followed a decreasing trend. The DQ protein encoded by HLA DQA1*05:05-DQ*03:01 showed a low binding affinity to the CagA peptide when binding capacity was analyzed by the NetMHCIIPan 4.0 prediction method. In conclusion, HLA DQA1 ~ DQB1 polymorphisms are crucial as host defense mechanisms against CagA H. pylori since antigen binding capacity plays a crucial role in anti-CagA IgA production.
Subject(s)
Gastritis , Helicobacter Infections , Helicobacter pylori , Humans , Haplotypes , HLA-DQ Antigens/genetics , HLA-DQ alpha-Chains/genetics , HLA-DQ beta-Chains/genetics , Gastritis/genetics , Helicobacter Infections/complications , Helicobacter Infections/genetics , Alleles , Peptides , Metaplasia , Immunoglobulin A/genetics , Gene Frequency , HLA-DRB1 ChainsABSTRACT
Introduction: Hypermutated high-affinity immunoglobulin A (IgA), neutralizes toxins and drives the diversification of bacteria communities to maintain intestinal homeostasis although the mechanism underlies the impact of moderate aerobic exercise (MAE) on the IgA-generation via T-dependent (TD) is not fully know. Therefore, the aim of this study was to determine the effect of long-time MAE on the production of IgA through the TD pathway in Peyer´s patches of the small intestine from aged mice. Methods: MAE protocol consisted of twenty 3-month-old (young) BALB/c mice running in an endless band at 0° inclination and a speed of 10 m/h for 5 days a week and resting 2 days on the weekend until reaching 6-month-old (adulthood, n=10) or 24-month-old (aging, n=10). Groups of young, adult, or elderly mice were included as sedentary controls (n=10/per group). At 6 or 24 months old, all were sacrificed, and small intestine samples were dissected to prepare intestinal lavages for IgA quantitation by ELISA and to obtain suspensions from Peyer´s patches (PP) and lamina propria (LP) cells for analysis of T, B, and plasma cell subpopulations by flow cytometry and mRNA analysis expression by RT-qPCR of molecular factors related to differentiation of B cells to IgA+ plasma cells, class switch recombination, and IgA-synthesis. Statistical analysis was computed with two-way ANOVA (factor A=age, factor B=group) and p<0.05 was considered for statistically significant differences. Results: Compared to age-matched sedentary control, in exercised elderly mice, parameters were either increased (IgA concentration, IL-21, IL-10 and RDH mRNA expression), decreased (α-chain mRNA, B cells, mIgA+ B cells, mIgM+ B cells and IL-4 mRNA) or unchanged (PP mIgA+ plasmablasts and LP cyt-IgA+ plasma cells). Regarding the exercised adult mice, they showed an up-modulation of IgA-concentration, mRNA expression IL-21, IL-10, and RDH and cells (PP B and T cells, mIgM+ plasmablasts and LP cyt-IgA+plasma cells). Conclusion: Our findings suggest that MAE restored the IgA production in adult mice via the TD cell pathway but does not in aged mice. Other studies are necessary to know in more detail the impact of long-time MAE on the TD pathway to produce IgA in aging.
Subject(s)
Immunoglobulin A , T-Lymphocytes , Humans , Mice , Animals , Adult , Infant , Immunoglobulin A/genetics , Interleukin-10 , Intestines , RNA, MessengerABSTRACT
Immunoglobulin A vasculitis (IgAV), also known as Henoch-Schönlein purpura, has complex etiology and pathogenesis which have not been fully clarified. The latest research shows that SARS-CoV-2 and related vaccines, human papilloma vaccine, and certain biological agents can also induce IgAV. Most studies believe that the formation of galactose-deficient IgA1 (Gd-IgA1) and Gd-IgA1-containing immune complex plays a crucial role in the pathogenesis of IgAV. It is hypothesized that the pathogenesis of IgAV is associated with the binding of IgA1 to anti-endothelial cell antibodies. In addition, genetics also constitutes a major focus of IgAV research. This article reviews the new advances in the etiology of IgAV and summarizes the role of Gd-IgA1, Gd-IgA1-containing immune complex, anti-endothelial antibody, IgA1 conjugates, T lymphocyte immunity, and genetic factors in the pathogenesis of IgAV.
Subject(s)
IgA Vasculitis , Humans , Antigen-Antibody Complex , Immunoglobulin A/geneticsABSTRACT
BACKGROUND: The polymeric immunoglobulin receptor (pIgR) is a transmembrane transporter of polymeric IgA through the intestinal epithelium. Its overexpression has been reported in several cancers, but its role as a diagnostic and prognostic biomarker of oncogenesis is currently unclear. METHOD: A literature search was conducted to summarize the functions of pIgR, its expression levels, and its clinical implications. RESULTS: pIgR expression has previously been investigated by proteomic analysis, RNA sequencing, and tissue microarray at the level of both RNA and protein in various cancers including pancreatic, esophageal, gastric, lung, and liver. However, studies have reported inconsistent results on how pIgR levels affect clinical outcomes such as survival rate and chemotherapy resistance. Possible explanations include pIgR mRNA levels being minimally correlated with the rate of downstream pIgR protein synthesis, and the diversity of antibodies used in immunohistochemistry studies further magnifying this ambiguity. In ovarian cancer cells, the transcytosis of IgA accompanied a series of transcriptional changes in intracellular inflammatory pathways that inhibit the progression of cancer, including the upregulation of IFN-gamma and downregulation of tumor-promoting ephrins. These findings suggest that both the levels of pIgR and secreted IgA from tumor-infiltrating B cells affect clinical outcomes. CONCLUSION: Overall, no direct correlation was observed between the levels of pIgR inside tumor tissue and the clinical features in cancer patients. Measuring pIgR protein levels with a more specific and possibly chemically defined antibody, along with tumoral IgA, is a potential solution to better understand the pathways and consequences of pIgR overexpression in cancer cells.
Subject(s)
Neoplasms , Receptors, Polymeric Immunoglobulin , Humans , Down-Regulation , Immunoglobulin A/genetics , Immunoglobulin A/metabolism , Neoplasms/genetics , Proteomics , Receptors, Polymeric Immunoglobulin/genetics , Receptors, Polymeric Immunoglobulin/metabolismABSTRACT
Background: Immunoglobulin A (IgA) is the mammalian mucosal antibody, providing an important line of defense against pathogens. With 15 IgA subclasses, the European rabbit has an extremely complex IgA system, strikingly more complex than most other mammals, which have only one IgA or, in the case of hominoids, two IgA subclasses. Similar to the two hominoid primate IGHA genes, the expansion of the rabbit IGHA genes appears to have begun in an ancestral lagomorph since multiple IgA copies were found by Southern blot analysis for the genera Sylvilagus, Lepus, and Ochotona. Results: To gain a better insight into the extraordinary lagomorph IgA evolution, we sequenced, for the first time, expressed IgA genes for two Lepus species, L. europaeus and L. granatensis. These were aligned with the 15 rabbit IgA isotypes, and evolutionary analyses were conducted. The obtained phylogenetic tree shows that the Lepus IgA sequences cluster with and among the rabbit IgA isotypes, and the interspecies and intraspecies nucleotide genetic distances are similar. A comparison of the amino acid sequences of the Lepus and rabbit IgA confirms that there are two trans-species polymorphisms and that the rabbit and Lepus sequences share a common genetic pool. In fact, the main differences between the studied leporids IgAs reside in the characteristics of the hinge region. Conclusion: The Lepus IgA sequences we have obtained strongly suggest that the great expansion of the leporid IGHA genes occurred in a common ancestral species and was then maintained in the descendants. A strong selective pressure caused the extraordinary expansion of the IGHA genes but then subsided, leading to the maintenance of the acquired polymorphisms in the descendants, with little subsequent divergence. This is a unique evolutionary pattern in which an ancient gene expansion has been maintained for approximately 18 million years.
Subject(s)
Hares , Lagomorpha , Animals , Rabbits , Explosions , Immunoglobulin A/genetics , Immunoglobulin Isotypes , PhylogenyABSTRACT
PHRF1 is an E3 ligase that promotes TGF-ß signaling by ubiquitinating a homeodomain repressor TG-interacting factor (TGIF). The suppression of PHRF1 activity by PML-RARα facilitates the progression of acute promyelocytic leukemia (APL). PHRF1 also contributes to non-homologous end-joining in response to DNA damage by linking H3K36me3 and NBS1 with DNA repair machinery. However, its role in class switch recombination (CSR) is not well understood. In this study, we report the importance of PHRF1 in IgA switching in CH12F3-2A cells and CD19-Cre mice. Our studies revealed that Crispr-Cas9 mediated PHRF1 knockout and shRNA-silenced CH12F3-2A cells reduced IgA production, as well as decreased the amounts of PARP1, NELF-A, and NELF-D. The introduction of PARP1 could partially restore IgA production in PHRF1 knockout cells. Intriguingly, IgA, as well as IgG1, IgG2a, and IgG3, switchings were not significantly decreased in PHRF1 deficient splenic B lymphocytes isolated from CD19-Cre mice. The levels of PARP1 and NELF-D were not decreased in PHRF1-depleted primary splenic B cells. Overall, our findings suggest that PHRF1 may modulate IgA switching in CH12F3-2A cells.
Subject(s)
DNA-Binding Proteins , Immunoglobulin Class Switching , Mice , Animals , DNA-Binding Proteins/genetics , Immunoglobulin Class Switching/genetics , DNA Repair , DNA End-Joining Repair , Immunoglobulin A/geneticsABSTRACT
IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. Here we performed a genome-wide association study of 10,146 kidney-biopsy-diagnosed IgAN cases and 28,751 controls across 17 international cohorts. We defined 30 genome-wide significant risk loci explaining 11% of disease risk. A total of 16 loci were new, including TNFSF4/TNFSF18, REL, CD28, PF4V1, LY86, LYN, ANXA3, TNFSF8/TNFSF15, REEP3, ZMIZ1, OVOL1/RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The risk loci were enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. We also observed a positive genetic correlation between IgAN and serum IgA levels. High polygenic score for IgAN was associated with earlier onset of kidney failure. In a comprehensive functional annotation analysis of candidate causal genes, we observed convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand-receptor pairs, prioritizing potential new drug targets.
Subject(s)
Glomerulonephritis, IGA , Animals , Mice , Glomerulonephritis, IGA/drug therapy , Glomerulonephritis, IGA/genetics , Glomerulonephritis, IGA/diagnosis , Genome-Wide Association Study , Immunoglobulin A/geneticsABSTRACT
In this study, recombinant Fc-fused Prostate acid phosphatase (PAP) proteins were produced in transgenic plants. PAP was fused to immunoglobulin (Ig) A and M Fc domain (PAP-IgA Fc and PAP-IgM Fc), which were tagged to the ER retention sequence KDEL to generate PAP-IgA FcK and PAP-IgM FcK. Agrobacteriummediated transformation was performed to produce transgenic tobacco plants expressing four recombinant proteins. Genomic PCR and RT-PCR analyses confirmed the transgene insertion and mRNA transcription of PAP-IgA Fc, PAP-IgM Fc, PAP-IgA FcK, and PAP-IgM FcK in tobacco plant leaves. Western blot confirmed the expression of PAP-IgA Fc, PAP-IgM Fc, PAP-IgA FcK, and PAP-IgM FcK proteins. SEC-HPLC and Bio-TEM analyses were performed to confirm the size and shape of the plant-derived recombinant PAP-Fc fusion proteins. In mice experiments, the plant-derived IgA and IgM Fc fused proteins induced production of total IgGs including IgG1 against PAP. This result suggests that IgA and IgM Fc fusion can be applied to produce recombinant PAP proteins as a prostate cancer vaccine in plant expression system. [BMB Reports 2023; 56(7): 392-397].
Subject(s)
Immunoglobulin A , Prostatic Neoplasms , Humans , Male , Animals , Mice , Immunoglobulin A/genetics , Immunoglobulin A/metabolism , Plant Proteins/genetics , Recombinant Proteins , Recombinant Fusion Proteins/genetics , Plants, Genetically Modified/genetics , Plants, Genetically Modified/metabolism , Immunity , Immunoglobulin M/geneticsABSTRACT
The X-linked hyper-IgM syndrome (X-HIGM1) is a rare primary immunodeficiency disorder (PID) caused by mutations in the gene encoding the CD154 protein, also known as CD40 ligand (CD40LG). X-HIGM1 is characterized by normal or elevated serum levels of IgM in association with decreased levels of IgG, IgA, and IgE. The CD40LG protein expressed on activated T cells interacts with its receptor protein, CD40, on B lymphocytes and dendritic cells. Mutations in the CD40LG gene lead to the production of an abnormal CD40L protein that fails to attach to its receptor, CD40 on B cells resulting in failure to produce IgG, IgA, and IgE antibodies. In the present study, we investigated the molecular defects underlying such a PID in a patient presenting with clinical history of pneumonia and acute respiratory distress syndrome (ARDS) at 7 months of age and diagnosed as transient hypogammaglobulinemia with decreased levels of IgG and increased levels of IgM. We have identified a novel and yet to be reported frame shift deletion of a single base pair (c.229delA) in exon 2 (p.Arg77AspfsTer6) of the CD40L gene ensuing the premature truncation of the protein by 6 amino acids by targeted gene sequencing. This frame shift mutation identified as a CD40L variant was found to be pathogenic which was also validated by Sanger sequencing. The in-silico analysis of c.229 del A mutation also predicted the change to be pathological affecting the structure and function of the CD40L (CD40L, CD154) protein and its protein-protein interaction properties.
Subject(s)
Hyper-IgM Immunodeficiency Syndrome, Type 1 , Humans , Hyper-IgM Immunodeficiency Syndrome, Type 1/genetics , Hyper-IgM Immunodeficiency Syndrome, Type 1/diagnosis , CD40 Ligand/genetics , CD40 Ligand/chemistry , Ligands , Mutation , Immunoglobulin M/genetics , Immunoglobulin A/genetics , Immunoglobulin E , Immunoglobulin G/geneticsABSTRACT
Garole sheep exhibits within-breed difference in resistance to natural gastrointestinal nematode infection predominated by Haemonchus contortus. In the present study, interferon gamma gene (IFN-γ) was characterized in relation to parasitological, haematological, and immune response against H. contortus in resistant and susceptible Garole sheep. Resistant and susceptible Garole sheep were selected from the field based on consistent low faecal egg counts (FEC) for one year and single nucleotide polymorphisms (SNPs) in the IFN-γ gene. The partial amplification of IFN-γ gene (1282 bp) revealed 4 SNPs exclusively in resistant sheep and 3 SNPs were shared between resistant and susceptible Garole sheep. The selected resistant and susceptible Garole sheep were challenged with H. contortus infection. The parasitological, haematological, immunological responses, and expression of IFN-γ gene were compared between the resistant and susceptible Garole sheep. The FEC of resistant sheep was significantly (P < 0.05) lower than the susceptible sheep infected with H. contortus. There was spontaneous elimination of H. contortus from 28 to 33 days post infection (DPI) in resistant sheep. Haemoglobin and packed cell volume were significantly (P < 0.05) higher in resistant sheep than the susceptible sheep. The serum concentration of immunoglobulin (Ig)G1 and IgA and cytokine IFN-γ activity and also the expression of IFN-γ gene were significantly (P < 0.05) higher in the infected resistant sheep from 14 to 28 DPI compared to the susceptible sheep. In resistant sheep, IgA and IgG1 and cytokine IFN-γ positively correlated with expression of IFN-γ gene, and the SNPs recorded in the resistant sheep only might play an important role in conferring resistance against H. contortus. Further studies are required to elucidate the role of IFN-γ gene in H. contortus resistance in Garole sheep.
Subject(s)
Haemonchiasis , Haemonchus , Sheep Diseases , Sheep , Animals , Haemonchus/genetics , Interferon-gamma/genetics , Feces , Polymorphism, Single Nucleotide , Immunoglobulin A/genetics , Sheep Diseases/genetics , Haemonchiasis/genetics , Haemonchiasis/veterinary , Parasite Egg Count/veterinaryABSTRACT
Immunoglobulin A vasculitis (IgAV) or Henoch-Schönlein purpura is the most prevalent systemic small vessel vasculitis in childhood. High mobility group box 1 protein (HMBG1) is a pleiotropic cytokine that functions as a pro-inflammatory signal, important for the activation of antigen-presenting cells and propagation of inflammation. HMGB1 is implicated in the pathophysiology of a variety of inflammatory diseases. The aim of this study was to investigate the role of single nucleotide polymorphism rs41369348 for HMGB1 gene in the susceptibility and clinical features of patients meeting the classification criteria for IgAV. DNA was extracted from blood cells of 76 children with IgAV and 150 age-matched healthy controls. Clinical data and laboratory parameters were collected for all IgAV patients. Although there was a higher frequency of heterozygous A/delA genotype of this gene polymorphism in IgAV group as compared with control group, no genotype difference was observed between these two groups. No statistically significant genotype differences were disclosed when patients with different IgAV clinical features were compared. In conclusion, in this study, polymorphism rs41369348 for HMGB1 was not associated with increased susceptibility to childhood IgAV, its severity or different clinical manifestations.
Subject(s)
HMGB1 Protein , IgA Vasculitis , Vasculitis , Child , Humans , IgA Vasculitis/genetics , IgA Vasculitis/complications , HMGB1 Protein/genetics , Vasculitis/complications , Immunoglobulin A/genetics , Polymorphism, Single NucleotideABSTRACT
Immunoglobulin A vasculitis (IgAV), also known as Henoch-Schönlein purpura, has complex etiology and pathogenesis which have not been fully clarified. The latest research shows that SARS-CoV-2 and related vaccines, human papilloma vaccine, and certain biological agents can also induce IgAV. Most studies believe that the formation of galactose-deficient IgA1 (Gd-IgA1) and Gd-IgA1-containing immune complex plays a crucial role in the pathogenesis of IgAV. It is hypothesized that the pathogenesis of IgAV is associated with the binding of IgA1 to anti-endothelial cell antibodies. In addition, genetics also constitutes a major focus of IgAV research. This article reviews the new advances in the etiology of IgAV and summarizes the role of Gd-IgA1, Gd-IgA1-containing immune complex, anti-endothelial antibody, IgA1 conjugates, T lymphocyte immunity, and genetic factors in the pathogenesis of IgAV.