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Targeting Anti-Insulin B Cell Receptors Improves Receptor Editing in Type 1 Diabetes-Prone Mice.
Bonami RH, Thomas JW
(2015) J Immunol 195: 4730-41
MeSH Terms: Animals, Antibodies, Monoclonal, Autoantigens, Autoimmunity, B-Lymphocytes, DNA-Binding Proteins, Diabetes Mellitus, Type 1, Immune Tolerance, Immunoglobulin M, Immunoglobulin kappa-Chains, Immunomodulation, Insulin, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Molecular Sequence Data, Receptors, Antigen, B-Cell
Show Abstract · Added April 1, 2016
Autoreactive B lymphocytes that commonly arise in the developing repertoire can be salvaged by receptor editing, a central tolerance mechanism that alters BCR specificity through continued L chain rearrangement. It is unknown whether autoantigens with weak cross-linking potential, such as insulin, elicit receptor editing, or whether this process is dysregulated in related autoimmunity. To resolve these issues, we developed an editing-competent model in which anti-insulin Vκ125 was targeted to the Igκ locus and paired with anti-insulin VH125Tg. Physiologic, circulating insulin increased RAG-2 expression and was associated with BCR replacement that eliminated autoantigen recognition in a proportion of developing anti-insulin B lymphocytes. The proportion of anti-insulin B cells that underwent receptor editing was reduced in the type 1 diabetes-prone NOD strain relative to a nonautoimmune strain. Resistance to editing was associated with increased surface IgM expression on immature (but not transitional or mature) anti-insulin B cells in the NOD strain. The actions of mAb123 on central tolerance were also investigated, because selective targeting of insulin-occupied BCR by mAb123 eliminates anti-insulin B lymphocytes and prevents type 1 diabetes. Autoantigen targeting by mAb123 increased RAG-2 expression and dramatically enhanced BCR replacement in newly developed B lymphocytes. Administering F(ab')2123 induced IgM downregulation and reduced the frequency of anti-insulin B lymphocytes within the polyclonal repertoire of VH125Tg/NOD mice, suggesting enhanced central tolerance by direct BCR interaction. These findings indicate that weak or faulty checkpoints for central tolerance can be overcome by autoantigen-specific immunomodulatory therapy.
Copyright © 2015 by The American Association of Immunologists, Inc.
2 Communities
1 Members
0 Resources
17 MeSH Terms
Genetic interactions between hepatocyte nuclear factor-6 and Notch signaling regulate mouse intrahepatic bile duct development in vivo.
Vanderpool C, Sparks EE, Huppert KA, Gannon M, Means AL, Huppert SS
(2012) Hepatology 55: 233-43
MeSH Terms: Animals, Bile Ducts, Intrahepatic, Cell Lineage, Cholestasis, Gene Expression Regulation, Developmental, Hepatocyte Nuclear Factor 1-beta, Hepatocyte Nuclear Factor 6, Hepatocytes, Immunoglobulin J Recombination Signal Sequence-Binding Protein, Immunoglobulin kappa-Chains, Integrases, Mice, Mice, Inbred Strains, Mice, Knockout, Receptors, Notch, SOX9 Transcription Factor, Signal Transduction
Show Abstract · Added December 5, 2013
UNLABELLED - Notch signaling and hepatocyte nuclear factor-6 (HNF-6) are two genetic factors known to affect lineage commitment in the bipotential hepatoblast progenitor cell (BHPC) population. A genetic interaction involving Notch signaling and HNF-6 in mice has been inferred through separate experiments showing that both affect BHPC specification and bile duct morphogenesis. To define the genetic interaction between HNF-6 and Notch signaling in an in vivo mouse model, we examined the effects of BHPC-specific loss of HNF-6 alone and within the background of BHPC-specific loss of recombination signal binding protein immunoglobulin kappa J (RBP-J), the common DNA-binding partner of all Notch receptors. Isolated loss of HNF-6 in this mouse model fails to demonstrate a phenotypic variance in bile duct development compared to control. However, when HNF-6 loss is combined with RBP-J loss, a phenotype consisting of cholestasis, hepatic necrosis, and fibrosis is observed that is more severe than the phenotype seen with Notch signaling loss alone. This phenotype is associated with significant intrahepatic biliary system abnormalities, including an early decrease in biliary epithelial cells, evolving to ductular proliferation and a decrease in the density of communicating peripheral bile duct branches. In this in vivo model, simultaneous loss of both HNF-6 and RBP-J results in down-regulation of both HNF-1β and Sox9 (sex determining region Y-related HMG box transcription factor 9).
CONCLUSION - HNF-6 and Notch signaling interact in vivo to control expression of downstream mediators essential to the normal development of the intrahepatic biliary system. This study provides a model to investigate genetic interactions of factors important to intrahepatic bile duct development and their effect on cholestatic liver disease phenotypes.
Copyright © 2011 American Association for the Study of Liver Diseases.
3 Communities
2 Members
1 Resources
17 MeSH Terms
Vkappa polymorphisms in NOD mice are spread throughout the entire immunoglobulin kappa locus and are shared by other autoimmune strains.
Henry RA, Kendall PL, Woodward EJ, Hulbert C, Thomas JW
(2010) Immunogenetics 62: 507-20
MeSH Terms: Amino Acid Substitution, Animals, Autoimmunity, B-Lymphocytes, Base Sequence, DNA Primers, Diabetes Mellitus, Type 1, Genes, Immunoglobulin Heavy Chain, Genes, Immunoglobulin Light Chain, Immunoglobulin Variable Region, Immunoglobulin kappa-Chains, Insulin, Mice, Mice, Inbred NOD, Mice, Transgenic, Molecular Sequence Data, Polymorphism, Genetic, Sequence Homology, Nucleic Acid, Species Specificity, T-Lymphocytes
Show Abstract · Added December 10, 2013
The diversity of immunoglobulin (Ig) and T cell receptor (TCR) genes available to form the lymphocyte repertoire has the capacity to produce a broad array of both protective and harmful specificities. In type 1 diabetes (T1D), the presence of antibodies to insulin and other islet antigens predicts disease development in both mice and humans, and demonstrate that immune tolerance is lost early in the disease process. Anti-insulin T cells isolated from T1D-prone non-obese diabetic (NOD) mice use polymorphic TCRalpha chains, suggesting that the available T cell repertoire is altered in these autoimmune mice. To probe whether insulin-binding B cells also possess polymorphic V genes, Ig light chains were isolated and sequenced from NOD mice that harbor an Ig heavy chain transgene. Three insulin-binding Vkappa genes were identified, all of which were polymorphic to the closest germline sequence matches present in the GenBank database. Additional analysis of over 300 light chain sequences from multiple sources, including germline DNA, shows that polymorphisms are spread throughout the entire NOD Igkappa locus, as these polymorphic sequences represent 43 distinct Vkappa genes which belong to 14 Vkappa families. Database searches reveal that a majority of polymorphic Vkappa genes identified in NOD are identical to Vkappa genes isolated from SLE-prone NZBxNZW F1 or MRL strains of mice, suggesting that a shared Igkappa haplotype may be present. Predicted amino acid changes preferentially occur in CDR, and thus could alter antigen recognition by the germline B cell repertoire of autoimmune versus non-autoimmune mouse strains.
2 Communities
2 Members
0 Resources
20 MeSH Terms
Multiple germline kappa light chains generate anti-insulin B cells in nonobese diabetic mice.
Woodward EJ, Thomas JW
(2005) J Immunol 175: 1073-9
MeSH Terms: Animals, Antibody Diversity, Autoantibodies, B-Lymphocyte Subsets, Base Sequence, Bone Marrow Cells, Gene Rearrangement, B-Lymphocyte, Light Chain, Genetic Predisposition to Disease, Immunoglobulin Variable Region, Immunoglobulin kappa-Chains, Insulin, Insulin Antibodies, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, Transgenic, Molecular Sequence Data, Multigene Family, Polymorphism, Genetic, Protein Binding, Receptors, Antigen, B-Cell
Show Abstract · Added November 6, 2013
The highly selective nature of organ-specific autoimmune disease is consistent with a critical role for adaptive immune responses against specific autoantigens. In type 1 diabetes mellitus, autoantibodies to insulin are important markers of the disease process in humans and nonobese diabetic (NOD) mice; however, the Ag-specific receptors responsible for these autoantibodies are obscured by the polyclonal repertoire. NOD mice that harbor an anti-insulin transgene (Tg) (V(H)125Tg/NOD) circumvent this problem by generating a tractable population of insulin-binding B cells. The nucleotide structure and genetic origin of the endogenous kappa L chain (Vkappa or IgL) repertoire that pairs with the V(H)125Tg were analyzed. In contrast to oligoclonal expansion observed in systemic autoimmune disease models, insulin-binding B cells from V(H)125Tg/NOD mice use specific Vkappa genes that are clonally independent and germline encoded. When compared with homologous IgL genes from nonautoimmune strains, Vkappa genes from NOD mice are polymorphic. Analysis of the most frequently expressed Vkappa1 and Vkappa9 genes indicates these are shared with lupus-prone New Zealand Black/BINJ mice (e.g., Vkappa1-110*02 and 9-124) and suggests that NOD mice use the infrequent b haplotype. These findings show that a diverse repertoire of anti-insulin B cells is part of the autoimmune process in NOD mice and structural or regulatory elements within the kappa locus may be shared with a systemic autoimmune disease.
2 Communities
1 Members
0 Resources
22 MeSH Terms
A 66-year-old woman with progressive renal insufficiency, nephrotic syndrome, and monoclonal protein.
Chang IJ, Cheunsuchon B, Miller FJ, Fogo AB
(2003) Am J Kidney Dis 41: 508-17
MeSH Terms: Aged, Antibodies, Monoclonal, Female, Humans, Immunoglobulin Light Chains, Immunoglobulin kappa-Chains, Nephrotic Syndrome, Paraproteinemias, Referral and Consultation, Renal Insufficiency
Added January 20, 2012
1 Communities
1 Members
0 Resources
10 MeSH Terms
Quiz page. Light chain cast nephropathy with light chain deposition disease.
Fogo AB
(2002) Am J Kidney Dis 39: xlii
MeSH Terms: Biopsy, Fluorescent Antibody Technique, Humans, Immunoglobulin kappa-Chains, Kidney Diseases, Male, Microscopy, Electron, Middle Aged
Added January 20, 2012
1 Communities
1 Members
0 Resources
8 MeSH Terms
Lack of expression of surface immunoglobulin light chains in B-cell non-Hodgkin lymphomas.
Kaleem Z, Zehnbauer BA, White G, Zutter MM
(2000) Am J Clin Pathol 113: 399-405
MeSH Terms: Adult, Aged, Aged, 80 and over, Biomarkers, Tumor, Bone Marrow, Clone Cells, DNA, Neoplasm, Female, Flow Cytometry, Gene Rearrangement, B-Lymphocyte, Light Chain, Humans, Immunoglobulin kappa-Chains, Immunoglobulin lambda-Chains, Immunophenotyping, Lymph Nodes, Lymphoma, B-Cell, Male, Middle Aged, Receptors, Antigen, B-Cell
Show Abstract · Added February 16, 2014
We describe 10 cases of B-cell non-Hodgkin lymphoma (NHL) that did not express immunoglobulin kappa or lambda light chains by dual-color flow cytometry. Cases were identified from 298 consecutive cases of B-cell NHL and included follicular center cell lymphoma, diffuse large B-cell lymphoma, small noncleaved cell lymphoma, and small lymphocytic lymphoma. One case did not express any immunoglobulin heavy chain (IgH) as well; however, isolated expression of IgG heavy chain was seen in another case. Immunoglobulin heavy chains were not part of the lymphoma panel in other cases. All 3 cases in which gene rearrangement studies were performed showed rearrangement of IgH genes, including the case that did not express surface IgH chains. Immunoglobulin kappa light chain genes were rearranged in 2 of 3 cases and were in germline configuration in the third. All 147 cases of benign lymph nodes analyzed by flow cytometry showed polyclonal expression of immunoglobulin kappa and lambda light chains. Because of the absence of surface immunoglobulin light chains, these tumors must be distinguished from precursor B-cell acute lymphoblastic leukemia, plasma cell tumors, and rare cases of florid follicular hyperplasia that do not express surface immunoglobulins. The absence of immunoglobulin expression on malignant B cells can result from defects at any level from gene transcription to translocation of fully assembled proteins to the cell surface.
1 Communities
1 Members
0 Resources
19 MeSH Terms
Recurrent Goodpasture's disease due to a monoclonal IgA-kappa circulating antibody.
Fervenza FC, Terreros D, Boutaud A, Hudson BG, Williams RA, Donadio JV, Schwab TR
(1999) Am J Kidney Dis 34: 549-55
MeSH Terms: Anti-Glomerular Basement Membrane Disease, Basement Membrane, Glomerulonephritis, IGA, Humans, Immunoglobulin A, Immunoglobulin kappa-Chains, Kidney Function Tests, Kidney Glomerulus, Kidney Tubules, Male, Middle Aged, Monoclonal Gammopathy of Undetermined Significance, Recurrence
Show Abstract · Added December 10, 2013
We describe the case of a 54-year-old man who first presented with a clinical syndrome manifested by recurrent pulmonary hemorrhage, hematuria, and mild renal insufficiency. Direct immunofluorescence of renal biopsy sections showed linear deposition of IgA-kappa in the glomerular (GBM) and tubular basement membranes. Serum protein immunoelectrophoresis was positive for a monoclonal immunoglobulin A (IgA)-kappa protein. Serum analysis showed circulating IgA anti-GBM antibodies. Treatment with high-dose steroids, cyclophosphamide, and plasma exchange resulted in resolution of the clinical picture. To the best of our knowledge, this is the first report of Goodpasture's disease associated with the presence of a circulating monoclonal IgA-kappa antibody.
1 Communities
1 Members
0 Resources
13 MeSH Terms
T cell-independent response to Brucella-insulin identifies a preimmune repertoire for insulin.
Thomas JW, Kralick PM, Ewulonu UK
(1997) J Immunol 159: 2334-41
MeSH Terms: Amino Acid Sequence, Animals, Antibodies, Bacterial, Antibodies, Monoclonal, Antibody Affinity, Antibody Specificity, Antigens, T-Independent, B-Lymphocyte Subsets, Base Sequence, Brucella abortus, Gene Rearrangement, B-Lymphocyte, Genes, Immunoglobulin, Immunity, Innate, Immunoglobulin Heavy Chains, Immunoglobulin Variable Region, Immunoglobulin kappa-Chains, Immunologic Memory, Insulin, Insulinoma, Mice, Mice, Inbred BALB C, Molecular Sequence Data, Pancreatic Neoplasms, Rats, Sequence Alignment, Sequence Homology, Specific Pathogen-Free Organisms
Show Abstract · Added November 6, 2013
An early or preimmune repertoire for anti-insulin B cells was examined using the T cell-independent (TI) response to insulin conjugated to Brucella abortus (BA-ins). mAbs from the BA-ins response reflect a repertoire present 7 to 10 days before the first Ab-forming cells (AFC) are detected in primary T cell-dependent (TD) responses to insulin. Although 4 of 6 BA-ins mAb express IgG2 isotype, evidence for somatic mutation is limited. A total of 9 of 12 V regions are identical with known V(H) or Vkappa genes, and consensus sequences suggest two other V genes may be in germ-line configuration. The relative avidities (50% inhibition of binding) of TI anti-insulins cover a broad range and are consistent with a germ-line anti-insulin repertoire that is functionally diverse. The V(H)s of 5 mAb are from two subsets of J558 genes (205.1 and 186.3) that dominate the B cell pool of adult mice and are different from the V(H)s used by anti-insulin mAb in primary TD responses. One IgM anti-insulin (mAb 301) uses V(H)-J606 and Vkappa1, and this mAb binds beta cells. Other TI mAb use either Vkappa5 or Vkappa19.3 genes and are similar to Vkappa genes used by anti-insulin mAb from TD responses. The data show that mutations in germ-line genes are not required for measurable insulin binding by monospecific mAb from adult mice. The recurrent use of Vkappa genes in both early (TI response) and late (TD responses) suggest that these structures are important in insulin binding.
1 Communities
0 Members
0 Resources
27 MeSH Terms
Restricted V gene repertoire in the secondary response to insulin in young BALB/c mice.
Tikhomirov OYu , Thomas JW
(1997) J Immunol 158: 4292-300
MeSH Terms: Age Factors, Amino Acid Sequence, Animals, Antibodies, Monoclonal, Antibody Affinity, Base Sequence, Genes, Immunoglobulin, Immunoglobulin kappa-Chains, Immunologic Memory, Insulin, Mice, Mice, Inbred BALB C, Molecular Sequence Data, Mutation, Sequence Alignment, Sequence Homology, Amino Acid, Sequence Homology, Nucleic Acid
Show Abstract · Added November 6, 2013
Previous data on the genetic origin of insulin Abs in BALB/c mice are derived from immune responses following a single or primary immunization. This primary response, however, may not represent the repertoire established by chronic insulin administration, which is used in the treatment of diabetes mellitus and in protocols to alter beta cell destruction in pre-insulin-dependent (type 1) diabetes mellitus. In this study, the genetic composition and structure of 16 anti-insulin mAbs from the secondary response of a single BALB/c mouse were determined. In contrast to studies on other protein Ags, the V genes in the secondary response to insulin show only a low level of somatic mutation and the majority of the response is represented by restricted sets of V(H) and Vkappa genes. The restriction of V genes is not chiefly due to oligoclonal expansion but reflects recurrent usage of structurally similar V regions of independent origin. Secondary anti-insulin V(H) genes in 12 of 16 mAbs are derived from related J558 subsets, and 8 of 16 mAbs used the Vkappa19.34 gene without mutations in CDRLs. The CDHR3s of half of the mAbs are generated from an uncommon second reading frame of DSP2, suggesting that the amino acid motif STMIT may contact insulin and contribute to selection of these B cells. A total of 14 of 15 mAbs bind autologous rodent insulin with 40 to 100% of the activity on human insulin, and all mAbs bind proinsulin. These data show that a preferred set of V(H), D, and Vkappa gene segments dominate secondary responses to insulin and suggest that specific structural interactions with epitopes that are shared with autologous insulin shape this secondary response.
1 Communities
0 Members
0 Resources
17 MeSH Terms