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Germinal centre hypoxia and regulation of antibody qualities by a hypoxia response system.
Cho SH, Raybuck AL, Stengel K, Wei M, Beck TC, Volanakis E, Thomas JW, Hiebert S, Haase VH, Boothby MR
(2016) Nature 537: 234-238
MeSH Terms: Animals, Antibodies, B-Lymphocytes, Cell Hypoxia, Cell Proliferation, Cell Survival, Cytosine Deaminase, Germinal Center, Hypoxia, Immunoglobulin Class Switching, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Inbred C57BL, Multiprotein Complexes, TOR Serine-Threonine Kinases
Show Abstract · Added August 9, 2016
Germinal centres (GCs) promote humoral immunity and vaccine efficacy. In GCs, antigen-activated B cells proliferate, express high-affinity antibodies, promote antibody class switching, and yield B cell memory. Whereas the cytokine milieu has long been known to regulate effector functions that include the choice of immunoglobulin class, both cell-autonomous and extrinsic metabolic programming have emerged as modulators of T-cell-mediated immunity. Here we show in mice that GC light zones are hypoxic, and that low oxygen tension () alters B cell physiology and function. In addition to reduced proliferation and increased B cell death, low impairs antibody class switching to the pro-inflammatory IgG2c antibody isotype by limiting the expression of activation-induced cytosine deaminase (AID). Hypoxia induces HIF transcription factors by restricting the activity of prolyl hydroxyl dioxygenase enzymes, which hydroxylate HIF-1α and HIF-2α to destabilize HIF by binding the von Hippel-Landau tumour suppressor protein (pVHL). B-cell-specific depletion of pVHL leads to constitutive HIF stabilization, decreases antigen-specific GC B cells and undermines the generation of high-affinity IgG, switching to IgG2c, early memory B cells, and recall antibody responses. HIF induction can reprogram metabolic and growth factor gene expression. Sustained hypoxia or HIF induction by pVHL deficiency inhibits mTOR complex 1 (mTORC1) activity in B lymphoblasts, and mTORC1-haploinsufficient B cells have reduced clonal expansion, AID expression, and capacities to yield IgG2c and high-affinity antibodies. Thus, the normal physiology of GCs involves regional variegation of hypoxia, and HIF-dependent oxygen sensing regulates vital functions of B cells. We propose that the restriction of oxygen in lymphoid organs, which can be altered in pathophysiological states, modulates humoral immunity.
1 Communities
3 Members
0 Resources
15 MeSH Terms
Class-switched anti-insulin antibodies originate from unconventional antigen presentation in multiple lymphoid sites.
Wan X, Thomas JW, Unanue ER
(2016) J Exp Med 213: 967-78
MeSH Terms: Animals, Antigen Presentation, B-Lymphocytes, CD40 Antigens, Diabetes Mellitus, Type 1, Germinal Center, Immunoglobulin Class Switching, Insulin, Interleukin-4, Islets of Langerhans, Mice, Mice, Knockout, T-Lymphocytes
Show Abstract · Added November 23, 2016
Autoantibodies to insulin are a harbinger of autoimmunity in type 1 diabetes in humans and in non-obese diabetic mice. To understand the genesis of these autoantibodies, we investigated the interactions of insulin-specific T and B lymphocytes using T cell and B cell receptor transgenic mice. We found spontaneous anti-insulin germinal center (GC) formation throughout lymphoid tissues with GC B cells binding insulin. Moreover, because of the nature of the insulin epitope recognized by the T cells, it was evident that GC B cells presented a broader repertoire of insulin epitopes. Such broader recognition was reproduced by activating naive B cells ex vivo with a combination of CD40 ligand and interleukin 4. Thus, insulin immunoreactivity extends beyond the pancreatic lymph node-islets of Langerhans axis and indicates that circulating insulin, despite its very low levels, can have an influence on diabetogenesis.
© 2016 Wan et al.
2 Communities
0 Members
0 Resources
13 MeSH Terms
Immunodominance of the VH1-46 antibody gene segment in the primary repertoire of human rotavirus-specific B cells is reduced in the memory compartment through somatic mutation of nondominant clones.
Tian C, Luskin GK, Dischert KM, Higginbotham JN, Shepherd BE, Crowe JE
(2008) J Immunol 180: 3279-88
MeSH Terms: Adult, Antibodies, Viral, Antigens, Viral, B-Lymphocyte Subsets, Capsid Proteins, Clone Cells, Epitopes, B-Lymphocyte, Humans, Immunodominant Epitopes, Immunoglobulin Class Switching, Immunoglobulin Heavy Chains, Immunoglobulin Variable Region, Immunologic Memory, Middle Aged, Resting Phase, Cell Cycle, Rotavirus, Somatic Hypermutation, Immunoglobulin
Show Abstract · Added August 6, 2012
Detailed characterization of Ag-specific naive and memory B cell Ab repertoires elucidates the molecular basis for the generation of Ab diversity and the optimization of Ab structures that bind microbial Ags. In this study, we analyzed the immunophenotype and VH gene repertoire of rotavirus (RV) VP6-specific B cells in three circulating naive or memory B cell subsets (CD19+IgD+CD27-, CD19+IgD+CD27+, or CD19+IgD-CD27+) at the single-cell level. We aimed to investigate the influence of antigenic exposure on the molecular features of the two RV-specific memory B cell subsets. We found an increased frequency of CD19+IgD+CD27+ unclass-switched memory B cells and a low frequency of somatic mutations in CD19+IgD-CD27+ class-switched memory B cells in RV-specific memory B cells, suggesting a reduced frequency of isotype switching and somatic mutation in RV VP6-specific memory B cells compared with other memory B cells. Furthermore, we found that dominance of the VH1-46 gene segment was a prominent feature in the VH gene repertoire of RV VP6-specific naive B cells, but this dominance was reduced in memory B cells. Increased diversity in the VH gene repertoire of the two memory B cell groups derived from broader usage of VH gene segments, increased junctional diversity that was introduced by differential TdT activities, and somatic hypermutation.
0 Communities
1 Members
0 Resources
17 MeSH Terms
Hyperacute rejection by anti-Gal IgG1, IgG2a, and IgG2b is dependent on complement and Fc-gamma receptors.
Ding JW, Zhou T, Zeng H, Ma L, Verbeek JS, Yin D, Shen J, Chong AS
(2008) J Immunol 180: 261-8
MeSH Terms: Animals, Antibodies, Monoclonal, Complement Activation, Complement System Proteins, Disaccharides, Graft Rejection, Heart Transplantation, Hybridomas, Immunoglobulin Class Switching, Immunoglobulin G, Killer Cells, Natural, Mice, Mice, Knockout, Rats, Rats, Inbred Lew, Receptors, IgG
Show Abstract · Added December 10, 2013
We have previously reported that anti-Gal-alpha1,3Gal (Gal) IgG3 mAbs mediate a classical complement-dependent hyperacute rejection (HAR), while anti-Gal IgG1 mAbs mediate HAR that is dependent on complement, the Fc-gamma receptors FcgammaRII/III (CD32/CD16), and NK cells. IgG2a and IgG2b subclasses can activate complement and have FcgammaR binding properties in vitro. Whether these IgG subclasses can mediate HAR in vivo and the mechanisms by which they would do so are not known. In this study, we isolated spontaneous IgG switch mutants from an anti-Gal IgG1 hybridoma. In vitro complement-mediated hemolytic assays with mouse complement indicate that both anti-Gal IgG2a and IgG2b mAbs were more potent compared with the parent anti-Gal IgG1. In vivo administration of anti-Gal IgG2a and IgG2b mAbs into Gal-/- mice induced HAR of rat cardiac xenografts. HAR induced by anti-Gal IgG2a and IgG2b was dependent on complement activation and the presence of NK cells. Using FcgammaRIII-deficient (Gal-/-CD16-/-) recipients, we observed that HAR mediated by different anti-Gal IgG subclasses was variably dependent on FcgammaRIII, with IgG1>IgG2b>IgG2a=IgG3. Using FcgammaRI-deficient (Gal-/-CD64-/-) recipients, we observed that HAR mediated by anti-Gal IgG1, IgG2a, and IgG2b, but not by anti-Gal IgG3, was dependent on FcgammaRI. Collectively, these studies demonstrate the necessity and sufficiency of complement in IgG3-mediated HAR and the necessity of both complement and FcgammaR, especially FcgammaRI, in IgG1-, IgG2a-, and IgG2b-mediated HAR.
0 Communities
1 Members
0 Resources
16 MeSH Terms
Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program.
Shaffer AL, Lin KI, Kuo TC, Yu X, Hurt EM, Rosenwald A, Giltnane JM, Yang L, Zhao H, Calame K, Staudt LM
(2002) Immunity 17: 51-62
MeSH Terms: Animals, Base Sequence, Binding Sites, Cell Differentiation, Cell Line, DNA-Binding Proteins, Gene Expression Profiling, Gene Expression Regulation, Humans, Immunoglobulin Class Switching, Mice, Models, Immunological, Oligonucleotide Array Sequence Analysis, Plasma Cells, Positive Regulatory Domain I-Binding Factor 1, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-6, RNA, Messenger, Receptors, Antigen, B-Cell, Repressor Proteins, Signal Transduction, Spleen, Transcription Factors, Tumor Cells, Cultured
Show Abstract · Added March 5, 2014
Blimp-1, a transcriptional repressor, drives the terminal differentiation of B cells to plasma cells. Using DNA microarrays, we found that introduction of Blimp-1 into B cells blocked expression of a remarkably large set of genes, while a much smaller number was induced. Blimp-1 initiated this cascade of gene expression changes by directly repressing genes encoding several transcription factors, including Spi-B and Id3, that regulate signaling by the B cell receptor. Blimp-1 also inhibited immunoglobulin class switching by blocking expression of AID, Ku70, Ku86, DNA-PKcs, and STAT6. These findings suggest that Blimp-1 promotes plasmacytic differentiation by extinguishing gene expression important for B cell receptor signaling, germinal center B cell function, and proliferation while allowing expression of important plasma cell genes such as XBP-1.
0 Communities
1 Members
0 Resources
24 MeSH Terms
Primary gamma delta cell clones can be defined phenotypically and functionally as Th1/Th2 cells and illustrate the association of CD4 with Th2 differentiation.
Wen L, Barber DF, Pao W, Wong FS, Owen MJ, Hayday A
(1998) J Immunol 160: 1965-74
MeSH Terms: Amino Acid Sequence, Animals, Apoptosis, B-Lymphocytes, CD4 Antigens, Cell Differentiation, Cells, Cultured, Clone Cells, Cytokines, Fas Ligand Protein, Gene Expression, Immunoglobulin Class Switching, Immunoglobulin Isotypes, Immunophenotyping, Membrane Glycoproteins, Mice, Mice, Knockout, Mice, SCID, Molecular Sequence Data, Receptors, Antigen, T-Cell, alpha-beta, Th1 Cells, Th2 Cells, fas Receptor
Show Abstract · Added March 24, 2014
The division of CD4+ alpha beta T cells into Th1 and Th2 subsets has become an established and important paradigm. The respective activities of these subsets appear to have profound effects on the course of infectious and autoimmune diseases. It is believed that specific programs of differentiation induce the commitment of an uncommitted Th0 precursor cell to Th1 or Th2. A component of these programs is hypothesized to be the nature of MHC-peptide antigen presentation to the alpha beta T cell. It has heretofore remained uncertain whether a Th1/Th2 classification likewise defines, at the clonal level, gamma delta T cells. Such cells do not, as a general rule, express either CD4 or CD8 alpha beta, and they do not commonly recognize peptide-MHC. In this report, gamma delta cell clones are described that conform strikingly to the Th1/Th2 classification, both by cytokine expression and by functional activities of the clones in vitro and in vivo. Provocatively, both the gamma delta cell clones and primary gamma delta cells in vivo showed a strong association of the Th2 phenotype with CD4 expression. These results are discussed with regard to the immunoregulatory role that is increasingly emerging for gamma delta cells.
0 Communities
1 Members
0 Resources
23 MeSH Terms
Germinal center formation, immunoglobulin class switching, and autoantibody production driven by "non alpha/beta" T cells.
Wen L, Pao W, Wong FS, Peng Q, Craft J, Zheng B, Kelsoe G, Dianda L, Owen MJ, Hayday AC
(1996) J Exp Med 183: 2271-82
MeSH Terms: Animals, Autoantibodies, Clone Cells, Flow Cytometry, Germinal Center, Humans, Immunoglobulin Class Switching, Immunoglobulin E, Immunoglobulin G, Lupus Erythematosus, Systemic, Lymphocyte Depletion, Mice, Mice, Inbred NOD, Mice, Inbred Strains, Mice, Knockout, Mice, SCID, Receptors, Antigen, T-Cell, alpha-beta, Spleen, T-Lymphocytes
Show Abstract · Added March 24, 2014
The production of class-switched antibodies, particularly immunoglobulin (Ig) G1 and IgE, occurs efficiently in T cell receptor (TCR) alpha-/- mice that are congenitally devoid of alpha/beta T cells. This finding runs counter to a wealth of data indicating that IgG1 and IgE synthesis are largely dependent on the collaboration between B and alpha/beta T cells. Furthermore, many of the antibodies synthesized in TCR alpha-/- mice are reactive to a similar spectrum of self-antigens as that targeted by autoantibodies characterizing human systemic lupus erythematosus (SLE). SLE, too, is most commonly regarded as an alpha/beta T cell-mediated condition. To distinguish whether the development of autoantibodies in TCR alpha-/- mice is due to an intrinsic de-regulation of B cells, or to a heretofore poorly characterized collaboration between B and "non-alpha/beta T" cells, the phenotype has been reconstituted by transfer of various populations of B and non-alpha/beta T cells including cloned gamma/delta T cells derived from TCR alpha-/- mice, to severe combined immunodeficient (SCID) mice. The results establish that the reproducible production of IgG1 (including autoantibodies) is a product of non-alpha/beta T cell help that can be provided by gamma/delta T cells. This type of B-T collaboration sustains the production of germinal centers, lymphoid follicles that ordinarily are anatomical signatures of alpha/beta T-B cell collaboration. Thus, non-alpha/beta T cell help may drive Ig synthesis and autoreactivity under various circumstances, especially in cases of alpha/beta T cell immunodeficiency.
0 Communities
1 Members
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19 MeSH Terms