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Infection and Immunity Jan 1991The gene for protein D, a membrane-associated protein with specific affinity for human immunoglobulin D, was cloned from a nontypeable strain of Haemophilus influenzae....
The gene for protein D, a membrane-associated protein with specific affinity for human immunoglobulin D, was cloned from a nontypeable strain of Haemophilus influenzae. The gene was expressed in Escherichia coli from an endogenous promoter, and the gene product has an apparent molecular weight equal to that of H. influenzae protein D (42,000). The complete nucleotide sequence of the gene for protein D was determined, and the deduced amino acid sequence of 364 residues includes a putative signal sequence of 18 amino acids containing a consensus sequence, Leu-Ala-Gly-Cys, for bacterial lipoproteins. The sequence of protein D shows no similarity to those of other immunoglobulin-binding proteins. Protein D is the first example of immunoglobulin receptors from gram-negative bacteria that has been cloned and sequenced.
Topics: Amino Acid Sequence; Bacterial Proteins; Base Sequence; Carrier Proteins; Cloning, Molecular; DNA, Bacterial; Escherichia coli; Haemophilus influenzae; Immunoglobulin D; Lipoproteins; Molecular Sequence Data; Molecular Weight
PubMed: 1987023
DOI: 10.1128/iai.59.1.119-125.1991 -
Immunology May 2006Antibodies are adaptor molecules that neutralize pathogens and link humoral and cellular defence mechanisms. Immunoglobulin D (IgD), one of the five antibody classes...
Antibodies are adaptor molecules that neutralize pathogens and link humoral and cellular defence mechanisms. Immunoglobulin D (IgD), one of the five antibody classes present in mammals, is expressed as an antigen receptor on naïve B cells. The functional role that IgD plays in the immune response is still poorly understood, but the recent characterization of immunoglobulin heavy constant delta genes (IGHD) in a variety of species challenges the view that IgD is of minor importance and is not present in many animals. On the basis of serological studies, IgD appears to be expressed in the majority of mammalian species examined. To confirm, at the molecular level, that IgD is present in different species, we cloned and sequenced IGHD cDNA from dogs and five non-human primate species (chimpanzee, rhesus macaque, cynomolgus macaque, baboon and sooty mangabey). Our results show that in all six species, IgD heavy chains possess three immunoglobulin domains and a long hinge region encoded by two exons. Only the hinge region of non-human primates is similar to the human hinge region, with conservation of O-glycosylation sites and multiple charged residues at opposing ends. The preservation of IgD in primates, dogs and previously characterized species suggests an important functional role for IgD, possibly involving binding to a receptor. The high degree of similarity existing between the structural features of human and non-human primate IgD suggests that non-human primates are suitable for in vivo studies designed to define the role that IgD plays in the immune response.
Topics: Amino Acid Sequence; Animals; Cercopithecidae; DNA, Complementary; Dogs; Genes, Immunoglobulin; Humans; Immunoglobulin Constant Regions; Immunoglobulin D; Immunoglobulin delta-Chains; Mammals; Molecular Sequence Data; Pan troglodytes; Phylogeny; RNA, Messenger; Sequence Alignment; Sequence Analysis, DNA; Species Specificity
PubMed: 16630026
DOI: 10.1111/j.1365-2567.2006.02345.x -
Orphanet Journal of Rare Diseases Apr 2006Mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (HIDS) represent the two ends of a clinical spectrum of disease caused by deficiency of mevalonate kinase... (Review)
Review
Mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (HIDS) represent the two ends of a clinical spectrum of disease caused by deficiency of mevalonate kinase (MVK), the first committed enzyme of cholesterol biosynthesis. At least 30 patients with MVA and 180 patients with HIDS have been reported worldwide. MVA is characterized by psychomotor retardation, failure to thrive, progressive cerebellar ataxia, dysmorphic features, progressive visual impairment and recurrent febrile crises. The febrile episodes are commonly accompanied by hepatosplenomegaly, lymphadenopathy, abdominal symptoms, arthralgia and skin rashes. Life expectancy is often compromised. In HIDS, only febrile attacks are present, but a subgroup of patients may also develop neurological abnormalities of varying degree such as mental retardation, ataxia, ocular symptoms and epilepsy. A reduced activity of MVK and pathogenic mutations in the MVK gene have been demonstrated as the common genetic basis in both disorders. In MVA, the diagnosis is established by detection of highly elevated levels of mevalonic acid excreted in urine. Increased levels of immunoglobulin D (IgD) and, in most patients of immunoglobulin A (IgA), in combination with enhanced excretion of mevalonic acid provide strong evidence for HIDS. The diagnosis is confirmed by low activity of mevalonate kinase or by demonstration of disease-causing mutations. Genetic counseling should be offered to families at risk. There is no established successful treatment for MVA. Simvastatin, an inhibitor of HMG-CoA reductase, and anakinra have been shown to have beneficial effect in HIDS.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypergammaglobulinemia; Immunoglobulin D; Mevalonic Acid; Phosphotransferases (Alcohol Group Acceptor); Simvastatin; Syndrome
PubMed: 16722536
DOI: 10.1186/1750-1172-1-13 -
Acta Pharmacologica Sinica Feb 2022Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by synovitis and the destruction of small joints. Emerging evidence shows that...
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by synovitis and the destruction of small joints. Emerging evidence shows that immunoglobulin D (IgD) stimulation induces T-cell activation, which may contribute to diseases pathogenesis in RA. In this study, we investigated the downstream signaling pathways by which IgD activated T cells as well as the possible role of IgD in the T-B interaction. Peripheral blood mononuclear cells were isolated from peripheral blood of healthy controls and RA patients. We demonstrated that IgD activated T cells through IgD receptor (IgDR)-lymphocyte-specific protein tyrosine kinase (Lck)-zeta-associated protein 70 (ZAP70)/phosphatidylinositol 3-kinase (PI3K)/nuclear factor kappa-B (NF-κB) signaling pathways; IgD-induced CD4 T cells promoted the proliferation of CD19 B cells in RA patients. A novel fusion protein IgD-Fc-Ig (composed of human IgD-Fc domain and IgG Fc domain, which specifically blocked the IgD-IgDR binding) inhibited the coexpression of IgDR and phosphorylated Lck (p-Lck) and the expression levels of p-Lck, p-ZAP70, p-PI3K on CD4 T cells, and decreased NF-κB nuclear translocation in Jurkat cells. Meanwhile, IgD-Fc-Ig downregulated the expression levels of CD40L on CD4 T cells as well as CD40, CD86 on CD19 B cells in RA patients and healthy controls. It also decreased the expression levels of CD40L on CD4 T cells and CD40 on CD19 B cells from spleens of collagen-induced arthritis (CIA) mice and reduced IL-17A level in mouse serum. Moreover, administration of IgD-Fc-Ig (1.625-13 mg/kg, iv, twice a week for 4 weeks) in CIA mice dose-dependently decreased the protein expression levels of CD40, CD40L, and IgD in spleens. IgD-Fc-Ig restrains T-cell activation through inhibiting IgD-IgDR-Lck-ZAP70-PI3K-NF-κB signaling, thus inhibiting B-cell activation. Our data provide experimental evidences for application of IgD-Fc-Ig as a highly selective T cell-targeting treatment for RA.
Topics: Animals; Arthritis, Rheumatoid; B-Lymphocytes; Coculture Techniques; Flow Cytometry; Humans; Immunoglobulin D; Lymphocyte Activation; Lymphocyte Specific Protein Tyrosine Kinase p56(lck); Male; Mice; Mice, Inbred DBA; Microscopy, Confocal; Receptors, Fc; Recombinant Proteins; Signal Transduction; T-Lymphocytes
PubMed: 33864023
DOI: 10.1038/s41401-021-00665-w -
Scientific Reports Oct 2022Graves' disease (GD) is an organ-specific autoimmune disease, but there are a few studies that have evaluated how immunophenotypes are related to clinical symptoms and...
Graves' disease (GD) is an organ-specific autoimmune disease, but there are a few studies that have evaluated how immunophenotypes are related to clinical symptoms and intractable pathology, or the effects of treatment on immunophenotypes. We performed peripheral blood immunophenotyping in GD. We assessed the proportion of functional subsets of T helper cells (such as Th1, Th17, Treg and Tfh cells), B cells (Naïve, IgM memory, Class-switched, IgDCD27 double negative and Plasmablasts cells), Monocytes, Dendritic cells and NK cells, and evaluated the relationship of immunophenotypes with clinical indices, disease activity, risk of relapse, and changes in immunophenotypes after treatment with antithyroid drugs. The activated Th17 cells, activated T follicular helper (Tfh) cells, and IgDCD27 double-negative B cells were higher in newly onset GD compared with healthy participants. Th17 cells were associated with thyroid autoantibodies, thyroid function, thyroid enlargement, and Graves' Recurrent Events After Therapy (GREAT) score; while double-negative B cells were associated with thyroid autoantibodies. Treatment with antithyroid drugs decreased the activated Tfh cells in parallel with the improvement in thyroid function. However, activated Th17 cells were not associated with clinical improvement and remained unchanged. Peripheral blood immunophenotyping identified the differential involvement of T and B cell subsets in the pathogenesis of GD. Abnormalities in the differentiation of Th17, Tfh, and double-negative B cells reflected the clinical pathology associated with autoantibody production and excess thyroid hormones. And Th17 cells are significantly associated with the marker for resistance to treatment. These results suggest the involvement of Th17 cell activation in the intractable pathology associated with potential immune abnormalities in GD. Clinical trial registration: #UMIN000017726 (Date: June 1st, 2015).
Topics: Antithyroid Agents; Autoantibodies; Graves Disease; Humans; Immunoglobulin D; Immunoglobulin M; Immunophenotyping; Th17 Cells; Thyroid Hormones
PubMed: 36207336
DOI: 10.1038/s41598-022-19556-z -
PLoS Neglected Tropical Diseases Feb 2022The laborious microscopic agglutination test (MAT) is the gold standard serologic test for laboratory diagnosis of leptospirosis. We developed EIA based serologic assays...
The laborious microscopic agglutination test (MAT) is the gold standard serologic test for laboratory diagnosis of leptospirosis. We developed EIA based serologic assays using recombinant proteins (rLigA, rLigB, rLipL32) and whole-cell extracts from eight Leptospira serovars as antigen and assessed the diagnostic performance of the new assay within each class, against MAT positive (MAT+) human sera panels from Portugal/PT (n = 143) and Angola/AO (n = 100). We found that a combination of recombinant proteins rLigA, rLigB and rLipL32 correctly identified antigen-specific IgG from patients with clinical and laboratory confirmed leptospirosis (MAT+) with 92% sensitivity and ~ 97% specificity (AUC 0.974) in serum from the provinces of Luanda (LDA) and Huambo (HBO) in Angola. A combination of whole cell extracts of L. interrogans sv Copenhageni (LiC), L. kirschneri Mozdok (LkM), L. borgpetersenii Arborea (LbA) and L. biflexa Patoc (LbP) accurately identified patients with clinical and laboratory confirmed leptospirosis (MAT+) with 100% sensitivity and ~ 98% specificity for all provinces of Angola and Portugal (AUC: 0.997 for AO/LDA/HBO, 1.000 for AO/HLA, 0.999 for PT/AZ and 1.000 for PT/LIS). Interestingly, we found that MAT+ IgG+ serum from Angola had a significantly higher presence of IgD and that IgG3/IgG1 isotypes were significantly increased in the MAT+ IgG+ serum from Portugal. Given that IgM/IgD class and IgG3/IgG1 specific isotypes are produced in the earliest course of infection, immunoglobulin G isotyping may be used to inform diagnosis of acute leptospirosis. The speed, ease of use and accuracy of EIA tests make them excellent alternatives to the laborious and expensive MAT for screening acute infection in areas where circulating serovars of pathogenic Leptospira are well defined.
Topics: Acute Disease; Agglutination Tests; Antibodies, Bacterial; Antigens, Bacterial; Cell Extracts; Enzyme-Linked Immunosorbent Assay; Humans; Immunoenzyme Techniques; Immunoglobulin D; Immunoglobulin G; Leptospira; Leptospirosis; Recombinant Proteins; Serologic Tests
PubMed: 35196321
DOI: 10.1371/journal.pntd.0010241 -
Immunology Aug 2006Signalling through the B cell antigen receptor (BCR) is required for peripheral B lymphocyte maturation, maintenance, activation and silencing. In mature B cells, the... (Review)
Review
Signalling through the B cell antigen receptor (BCR) is required for peripheral B lymphocyte maturation, maintenance, activation and silencing. In mature B cells, the antigen receptor normally consists of two isotypes, membrane IgM and IgD (mIgM, mIgD). Although the signals initiated from both isotypes differ in kinetics and intensity, in vivo, the BCR of either isotype seems to be able to compensate for the loss of the other, reflected by the mild phenotypes of mice deficient for mIgM or mIgD. Thus, it is still unclear why mature B cells need expression of mIgD in addition to mIgM. In the current review we suggest that the view that IgD has a simply definable function centred around the basic signalling function should be replaced by the assumption that IgD fine tunes humoral responses, modulates B cell selection and homeostasis and thus shapes the B cell repertoire, defining IgD to be a key modulator of the humoral immune response.
Topics: Animals; Antibody Formation; Antibody Specificity; B-Lymphocytes; Immunoglobulin D; Immunoglobulin M; Lymphocyte Activation; Mammals; Receptors, Antigen, B-Cell; Signal Transduction
PubMed: 16895553
DOI: 10.1111/j.1365-2567.2006.02386.x -
Annals of Oncology : Official Journal... Feb 2011To analyze the clinical features, outcomes including efficacy of treatment, and prognostic factors of patients with immunoglobulin D multiple myeloma (IgD MM).
BACKGROUND
To analyze the clinical features, outcomes including efficacy of treatment, and prognostic factors of patients with immunoglobulin D multiple myeloma (IgD MM).
DESIGN AND METHODS
Seventy-five patients diagnosed with IgD MM were selected from the Korean Myeloma Registry database (www.myeloma.or.kr).
RESULTS
Median age was 57 years and the main presenting features were bone pain (77%). Renal function impairment and hypercalcemia were present in 40 (53%) and 20 (27%) patients. Sixty-seven patients (89%) had lambda light chains. Forty-eight patients (64%) were of stage III by International Staging System. Twenty-six patients (53%) had chromosomal abnormalities mostly by conventional cytogenetics. Thirty-nine patients (54%) were treated with vincristine, adriamycin, and dexamethasone chemotherapy; the overall response rate (ORR) of 56%. Sixteen patients (22%) received first-line chemotherapy including new drugs (bortezomib or thalidomide), with an ORR of 81%. At a median follow-up time of 28.6 months, median overall survival (OS) was 18.5 months. Age, extramedullary plasmacytoma, del(13) or hypoploidy, serum β(2) microglobulin level, and platelet count were significant prognostic factors for OS.
CONCLUSIONS
IgD MM is an aggressive disease that is usually detected at an advanced stage. Despite a positive initial response, survival after relapse was dismal. Intensive treatment strategies before and following stem cell transplantation may improve outcomes in younger patients.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin D; Male; Middle Aged; Multiple Myeloma; Survival Analysis; Treatment Outcome
PubMed: 20682550
DOI: 10.1093/annonc/mdq393 -
Frontiers in Bioscience (Scholar... Jan 2012A number of microorganisms are capable of binding immunoglobulins (Igs) in a manner, which excludes binding to conventional antigen binding sites. Interaction of such... (Review)
Review
A number of microorganisms are capable of binding immunoglobulins (Igs) in a manner, which excludes binding to conventional antigen binding sites. Interaction of such bacterial proteins with surface immunoglobulins leads to polyclonal activation of B-lymphocytes. A recent example is Moraxella catarrhalis that binds to B lymphocytes in an IgD-dependent manner and induces proliferation and differentiation of B lymphocytes leading to the production of unspecific Igs. The activation is mediated by Moraxella IgD binding protein (MID), which specifically binds to both soluble IgD and the IgD B cell receptor (BCR). Besides cross-linking the BCR, whole Moraxella and outer membrane vesicles (OMVs) engage Toll like receptors (TLRs) to further increase the response. TLR activation leads to initiation of signaling pathways, which evoke a proinflammatory response against the invading microbes. Polyclonal B cell activation has in general been implicated in various phenomenons that are detrimental for the host but beneficial for pathogens, for example, autoimmune manifestations and redirection of the immune system.
Topics: Animals; Antigens, Bacterial; B-Lymphocytes; Humans; Immunoglobulin D; Lymphocyte Activation; Moraxella catarrhalis; Signal Transduction; Superantigens; Toll-Like Receptors; alpha-Macroglobulins
PubMed: 22202107
DOI: 10.2741/s316 -
Frontiers in Immunology 2020We have previously shown that the sequence of the immunoglobulin diversity gene segment (D ) helps dictate the structure and composition of complementarity determining...
We have previously shown that the sequence of the immunoglobulin diversity gene segment (D ) helps dictate the structure and composition of complementarity determining region 3 of the immunoglobulin heavy chain (CDR-H3). In order to test the role of germline D sequence on the diversity of the preimmune TCRβ repertoire of T cells, we generated a mouse with a mutant TCRβ DJC locus wherein the Dβ2-Jβ2 gene segment cluster was deleted and the remaining diversity gene segment, Dβ1 (IMGT:TRDB1), was replaced with DSP2.3 (IMGT:IGHD2-02), a commonly used B cell immunoglobulin D gene segment. Crystallographic studies have shown that the length and thus structure of TCR CDR-B3 places amino acids at the tip of CDR-B3 in a position to directly interact with peptide bound to an MHC molecule. The length distribution of complementarity determining region 3 of the T cell receptor beta chain (CDR-B3) has been proposed to be restricted largely by MHC-specific selection, disfavoring CDR-B3 that are too long or too short. Here we show that the mechanism of control of CDR-B3 length depends on the Dβ sequence, which in turn dictates exonucleolytic nibbling. By contrast, the extent of N addition and the variance of created CDR3 lengths are regulated by the cell of origin, the thymocyte. We found that the sequence of the D and control of N addition collaborate to bias the distribution of CDR-B3 lengths in the pre-immune TCR repertoire and to focus the diversity provided by N addition and the sequence of the D on that portion of CDR-B3 that is most likely to interact with the peptide that is bound to the presenting MHC.
Topics: Animals; Antibody Diversity; B-Lymphocytes; Cells, Cultured; Complementarity Determining Regions; Genetic Engineering; Genetic Variation; Germ Cells; Immunoglobulin D; Immunoglobulin Heavy Chains; Mice; Mice, Inbred C57BL; Receptors, Antigen, T-Cell, alpha-beta
PubMed: 33042119
DOI: 10.3389/fimmu.2020.02079