Immunoglobulin D Deficiency Publications (227)
Immunoglobulin D Deficiency Publications
pneumoniae to leverage a ChoP-remodeling enzyme (Pce) to remove PAF from the airway. S. pneumoniae-mediated PAF deprivation impaired viability, activation, and bactericidal capacity among responding neutrophils. In the absence of Pce, neutrophils rapidly cleared S. pneumoniae from the airway and impeded invasive disease and transmission between mice. Abrogation of PAF signaling rendered Pce dispensable for S. pneumoniae persistence, reinforcing that this enzyme deprives neutrophils of essential PAF-mediated stimulation. Accordingly, exogenous activation of neutrophils overwhelmed Pce-mediated phagocyte disruption. Haemophilus influenzae also uses an enzyme, GlpQ, to hydrolyze ChoP and subvert PAF function, suggesting that mimicry-driven immune evasion is a common paradigm among respiratory pathogens. These results identify a mechanism by which shared molecular structures enable microbial enzymes to subvert host lipid signaling, suppress inflammation, and ensure bacterial persistence at the mucosa.
A further 20 variants, which are present in human genome databases, were also analysed. Variants associated with MA are clustered into a "hotspot" consisting of residues 8-35 and 234-338 and tended to result in a prediction of severely reduced protein stability. Four of the uncharacterised variants, p.H24P, p.G198R, p. R253W, and p.G335S, were likely to be associated with MA. This method could be used as the basis for initial predictions of severity when new MVK variants are discovered.
A questionnaire was sent to French paediatric and adult rheumatologists to retrospectively collect information from genetically confirmed patients with MKD regarding the first symptoms of the disease, the different diagnoses made previously, the treatments received, and the disease burden evaluated mainly by the number of hospitalizations.
Thirteen patients were analyzed. The mean age at onset was 9.5months (birth to 36months). The average diagnosis delay was 7.1years. Eleven of them were hospitalized at least 5 times before the establishment of the diagnosis. A wide variety of diseases had been suspected: systemic juvenile idiopathic arthritis, periodic fever aphtous stomatitis pharyngitis adenitis syndrome, other hereditary recurrent fever, vasculitis, connective tissue disease, inflammatory bowel disease, gastritis, infections and immunodeficiency. Before the right diagnosis, 9 patients received corticosteroids and 6 patients received non-steroidal-anti-inflammatory drugs. Half patients had received repeated antibiotics, one third had received intravenous immunoglobulin, and the others were treated with immunosuppressive drugs or hydroxychloroquine.
MKD is a serious disease still difficult to treat, however earlier accurate medical referral and care, by increasing physicians' awareness, is critical to improve both the disease course and quality of life.
R277G, in our analysis, lowers the binding affinity for some enzyme's substrates. Interestingly, we found that p.R277G mutation inhibits binding of Isopentenyl Pyrophosphate (IPP) (binding free energy=0 kcal/mol), one of isoprenoids responsible for feedback-inhibition of MVK. IPP is known to be an activator of a specific class of T-cells and we can hypothesize that increased levels of this metabolite generate an aberrant immune system response. Indeed other experiments are needed to verify this hypothesis; however, this work demonstrates usefulness of molecular modeling in generating novel pathogenic hypothesis.
In a subset of patients, MKD is also associated with elevated serum immunoglobulin D (IgD) levels (hyperimmunoglobulinemia D syndrome, HIDS). The clinical phenotype of MKD varies widely and depends on the severity of the impaired mevalonate kinase activity. Complete impairment results in the severe metabolic disease, mevalonic aciduria, while a partial deficiency results in a broad spectrum of clinical presentation, including HIDS. The precise molecular mechanisms behind the elevated serum IgD levels and inflammation that occurs in MKD remain unknown. Children who exhibit symptoms of MKD should be tested for mutations in the MKD gene. However, the complexity of MKD often results in delays in its definitive diagnosis and the outcome in adult age is not completely known. Therapeutic options for MKD are based on limited data and include non-steroidal anti-inflammatory drugs, corticosteroids, and biological agents that target specific cytokine pathways. In recent years, some studies have reported promising results for new biological drugs; however, these cases have failed to achieve satisfactory remission. Therefore, further studies are needed to understand the pathogenesis of MKD and identify innovative therapeutic tools for its management.
The aim of this study was to determine if receipt of a conjugate vaccine containing protein D from H. influenzae is associated with improvement in NTHi-specific cytokine responses in children with chronic suppurative lung disease.
Blood mononuclear cells from 107 young children with chronic suppurative lung disease and 32 healthy control children were stimulated in vitro with NTHi. We compared the cytokine production of stimulated mononuclear cells from children who had received the pneumococcal H. influenzae protein D conjugate vaccine with cells from children who received pneumococcal vaccines without protein D. Protein D-specific IgG1 was quantified in plasma.
Children with chronic suppurative lung disease who received ≥ 3 doses of the protein D conjugate vaccine produced significantly more IFNγ than children who received the alternative vaccines without protein D (median 939 versus 338 pg/ml; p = 0.007). Importantly, the amount of IFNγ produced by those vaccinated with the conjugate vaccine approached the levels observed in cells from healthy children. The conjugate vaccine was also associated with small but significant increases in IL-13 (p < 0.001) and IL-5 (p = 0.007). Protein D-specific IgG1 levels correlated with the number of PHiD-CV doses (p = 0.02).
Vaccination with PHiD-CV is associated with improvements in NTHi-specific cell-mediated and humoral immune responses in children with chronic suppurative lung disease.
To address the mechanisms of chronic immune activation in CVID, we performed a detailed analysis of cytokine serum levels in 36 patients with CVID, 52 patients with selective IgA deficiency (IgAD), and 56 healthy volunteers.
We show that CVID is associated with elevated serum levels of CXCL-10/IP-10, IL-1R antagonist, TNF-α, IL-10, IL-12 (p40), CCL-2/MCP-1, G-CSF, and CCL-11/eotaxin. The detected cytokine signature is consistent with an ongoing activation of cells of myeloid lineage. In contrast, the levels of cytokines typically produced by CD4(+) T helper cells of Th1 (IFN-γ, IL-2), Th2 (IL-9, IL-13), and Th17 (IL-17) subtypes were suppressed in CVID patients compared to healthy donors.
Presented data suggest that the altered cytokine profile observed in patients with CVID may be attributed to the activation of monocyte-macrophage and granulocyte lineages, possibly driven by the translocation of bacterial components across the gastrointestinal or respiratory tracts mucosal barrier.
Because V recombination between alleles is more strictly regulated for TCRβ and IgH loci, we evaluated the ability of ATM to restrict biallelic expression and V-to-DJ recombination of TCRβ and IgH genes. We detected greater frequencies of lymphocytes with biallelic expression or aberrant V-to-DJ rearrangement of TCRβ or IgH loci in mice lacking ATM. A preassembled DJβ complex that decreases the number of TCRβ rearrangements needed for a productive TCRβ gene further increased frequencies of ATM-deficient cells with biallelic TCRβ expression. IgH and TCRβ proteins drive proliferation of prolymphocytes through cyclin D3 (Ccnd3), which also inhibits VH transcription. We show that inactivation of Ccnd3 leads to increased frequencies of lymphocytes with biallelic expression of IgH or TCRβ genes. We also show that Ccnd3 inactivation cooperates with ATM deficiency to increase the frequencies of cells with biallelic TCRβ or IgH expression while decreasing the frequency of ATM-deficient lymphocytes with aberrant V-to-DJ recombination. Our data demonstrate that core components of the DNA damage response and cell cycle machinery cooperate to help enforce IgH and TCRβ allelic exclusion and indicate that control of V-to-DJ rearrangements between alleles is important to maintain genomic stability.
Intriguingly, the analysis of IgM and IgD expression by maturing and mature naive B cells demonstrated an elevated level of IgM gene products and a virtual loss of IgD products. Transcriptome analysis of Zfp318-deficient B cells revealed that only two gene products showed altered expression in the absence of Zfp318 (Ighd and Sva), demonstrating a remarkable specificity of Zfp318 action. In the absence of Zfp318, Ighm/Ighd transcripts, which would normally encode IgM and IgD from heterogeneous nuclear RNA transcripts via alternative splicing, lack intron and exon sequences from the IgD (Ighd)-encoding region. This finding indicates that Zfp318, in a novel manner, functions by repressing recognition of the transcriptional termination site at the 3' end of the terminal IgM-encoding exon, allowing for synthesis of the complete Ighm/Ighd heterogeneous nuclear RNA.
B5 cells and testing the culture supernatant. Most Ag-specific B cells for both TD Ags were found to reside in the IgM-expressing B cells, including CD27(-) B cells, in both hyperimmunized donors and nonhyperimmunized volunteers. Only shortly after immunization a sharp increase in Ag-specific CD27(+)IgG(+) B cells was observed. Next, B cells were enriched with D(+) erythrocyte ghosts and sorted as single cells. Sequencing of IGHV, IGLV, IGKV, and BCL6 genes from these D-specific B cell clones demonstrated that both CD27(-)IgM(+) and CD27(+)IgM(+) B cells harbored somatic mutations, documenting their Ag-selected nature. Furthermore, sequencing revealed a clonal relationship between the CD27(-)IgM(+), CD27(+)IgM(+), and CD27(+)IgG(+) B cell subsets. These data strongly support the recently described multiple layers of memory B cells to TD Ags in mice, where IgM(+) B cells represent a memory reservoir which can re-enter the germinal center and ensure replenishment of class-switched memory CD27(+) B cells from Ag-experienced precursors.