Immunoglobulin D Deficiency Publications (227)

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Immunoglobulin D Deficiency Publications

Regulation of neutrophil activity is critical for immune evasion among extracellular pathogens, yet the mechanisms by which many bacteria disrupt phagocyte function remain unclear. Here, we have shown that the respiratory pathogen Streptococcus pneumoniae disables neutrophils by exploiting molecular mimicry to degrade platelet-activating factor (PAF), a host-derived inflammatory phospholipid. Using mass spectrometry and murine upper airway infection models, we demonstrated that phosphorylcholine (ChoP) moieties that are shared by PAF and the bacterial cell wall allow S. Read More

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.

2015Nov
Ann. Hum. Genet.
Ann Hum Genet 2015 Nov 29;79(6):451-9. Epub 2015 Sep 29.
School of Biological Sciences, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL, UK.
2015Jul
Joint Bone Spine
Joint Bone Spine 2015 Jul 9;82(4):240-4. Epub 2015 Feb 9.
Department of Pediatric Rheumatology, National referral centre for auto-inflammatory diseases (CEREMAI), CHU de Bicêtre, AP-HP, Le Kremlin-Bicêtre, France; University of Paris Sud, Le Kremlin-Bicêtre, France; Inserm U1018 CESP, Le Kremlin-Bicêtre, France.

Mevalonate kinase deficiency (MKD) is an autosomic recessive auto-inflammatory disease caused by mutations of the MVK gene. MKD being a very rare disease, numerous misdiagnoses and medical referrals may precede the right diagnosis, amplifying the burden of the disease.
To evaluate the patient's medical referrals between the first symptom and the diagnosis of MKD and the diagnosis delay. Read More


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.

2015Jan
Int J Immunopathol Pharmacol
Int J Immunopathol Pharmacol 2014 Oct-Dec;27(4):491-8
Institute of Pediatrics, Universita’ Cattolica Sacro Cuore, Rome, Italy.

Mevalonate kinase deficiency (MKD) is a rare autosomal recessive autoinflammatory metabolic disease that is caused by mutations in the MVK gene. Patients with MKD typically have an early onset in infancy. MKD is characterized by recurrent episodes of high fever, abdominal distress, diffuse joint pain, and skin rashes. Read More

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.

2015Jan
Vaccine
Vaccine 2015 Jan 22;33(2):321-6. Epub 2014 Nov 22.
Division of Child Health, Menzies School of Health Research, Charles Darwin University, NT, Australia; Department of Respiratory Medicine, Queensland Children's Medical Research Institute, Royal Children's Hospital, QLD, Australia.

Endobronchial infections related to non-typeable Haemophilus influenzae (NTHi) are common in children and adults with suppurative airway disease such as bronchiectasis and COPD. Impaired cell mediated immune responses to NTHi have been described in these patients. Currently there are no interventions known to correct the deficiency in cell mediated immune responses to NTHi. Read More

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.

2014Nov
J. Clin. Immunol.
J Clin Immunol 2014 Nov 23;34(8):971-8. Epub 2014 Sep 23.
Department of Pathology and Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA.

Common variable immunodeficiency (CVID) is the most frequent form of primary symptomatic hypogammaglobulinemia. CVID patients display a number of abnormalities in lymphocyte subpopulations including chronic T-cell activation and decreased numbers of circulating CD4(+) T cells and NK cells. We and others have recently shown that CVID is associated with increased concentration of soluble CD14 (sCD14) and other factors indicating limited microbial translocation. Read More


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.

2014Sep
J. Immunol.
J Immunol 2014 Sep 15;193(6):2881-90. Epub 2014 Aug 15.
Division of Cancer Pathobiology, Department of Pathology and Laboratory Medicine, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104; Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; and Immunology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104

Coordination of V rearrangements between loci on homologous chromosomes is critical for Ig and TCR allelic exclusion. The Ataxia Telangietasia mutated (ATM) protein kinase promotes DNA repair and activates checkpoints to suppress aberrant Ig and TCR rearrangements. In response to RAG cleavage of Igκ loci, ATM inhibits RAG expression and suppresses further Vκ-to-Jκ rearrangements to enforce Igκ allelic exclusion. Read More

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.

2014Sep
J. Immunol.
J Immunol 2014 Sep 23;193(5):2546-53. Epub 2014 Jul 23.
Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112
2014Aug
J. Immunol.
J Immunol 2014 Aug 25;193(3):1071-9. Epub 2014 Jun 25.
Department of Experimental Immunohematology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, 1066 CX Amsterdam, the Netherlands; and

B cell memory to T cell-dependent (TD) Ags are considered to largely reside in class-switched CD27(+) cells. However, we previously observed that anti-RhD (D) Igs cloned from two donors, hyperimmunized with D(+) erythrocytes, were predominantly of the IgM isotype. We therefore analyzed in this study the phenotype and frequency of D- and tetanus toxoid-specific B cells by culturing B cells in limiting dilution upon irradiated CD40L-expressing EL4. Read More

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.