immunoglobulin class switching

Summary

Summary: Gene rearrangement of the B-lymphocyte which results in a substitution in the type of heavy-chain constant region that is expressed. This allows the effector response to change while the antigen binding specificity (variable region) remains the same. The majority of class switching occurs by a DNA recombination event but it also can take place at the level of RNA processing.

Top Publications

  1. Swanson C, Wilson T, Strauch P, Colonna M, Pelanda R, Torres R. Type I IFN enhances follicular B cell contribution to the T cell-independent antibody response. J Exp Med. 2010;207:1485-500 pubmed publisher
    ..Thus, innate signals have the capacity to enhance TI-2 antibody responses by promoting participation of FO B cells, which then elaborate effective IgG anti-pathogen antibodies. ..
  2. Dinkelmann M, Spehalski E, Stoneham T, Buis J, Wu Y, Sekiguchi J, et al. Multiple functions of MRN in end-joining pathways during isotype class switching. Nat Struct Mol Biol. 2009;16:808-13 pubmed publisher
    ..We propose a model in which MRN stabilizes distant breaks and processes DNA termini to facilitate repair by both the classical and alternative NHEJ pathways...
  3. Sernández I, de Yebenes V, Dorsett Y, Ramiro A. Haploinsufficiency of activation-induced deaminase for antibody diversification and chromosome translocations both in vitro and in vivo. PLoS ONE. 2008;3:e3927 pubmed publisher
    ..These findings suggest that limiting the physiologic levels of AID expression can be a regulatory mechanism that ensures an optimal balance between immune proficiency and genome integrity. ..
  4. Chen K, Xu W, Wilson M, He B, Miller N, Bengten E, et al. Immunoglobulin D enhances immune surveillance by activating antimicrobial, proinflammatory and B cell-stimulating programs in basophils. Nat Immunol. 2009;10:889-98 pubmed publisher
  5. Kracker S, Gardes P, Mazerolles F, Durandy A. Immunoglobulin class switch recombination deficiencies. Clin Immunol. 2010;135:193-203 pubmed publisher
  6. Basu U, Meng F, Keim C, Grinstein V, Pefanis E, Eccleston J, et al. The RNA exosome targets the AID cytidine deaminase to both strands of transcribed duplex DNA substrates. Cell. 2011;144:353-63 pubmed publisher
    ..Our findings reveal a role for noncoding RNA surveillance machinery in generating antibody diversity. ..
  7. Cheng H, Vuong B, Basu U, Franklin A, Schwer B, Astarita J, et al. Integrity of the AID serine-38 phosphorylation site is critical for class switch recombination and somatic hypermutation in mice. Proc Natl Acad Sci U S A. 2009;106:2717-22 pubmed publisher
  8. Pape K, Taylor J, Maul R, Gearhart P, Jenkins M. Different B cell populations mediate early and late memory during an endogenous immune response. Science. 2011;331:1203-7 pubmed publisher
    ..Thus, we propose that memory relies on swIg(+) cells until they disappear and serum immunoglobulin falls to a low level, in which case memory resides with durable IgM(+) reserves. ..
  9. Kobayashi M, Aida M, Nagaoka H, Begum N, Kitawaki Y, Nakata M, et al. AID-induced decrease in topoisomerase 1 induces DNA structural alteration and DNA cleavage for class switch recombination. Proc Natl Acad Sci U S A. 2009;106:22375-80 pubmed publisher
    ..Taken together, AID-induced Top1 reduction alters S region DNA structure probably to non-B form, on which Top1 can introduce nicks but cannot religate, resulting in S region cleavage. ..

More Information

Publications62

  1. Pavri R, Nussenzweig M. AID targeting in antibody diversity. Adv Immunol. 2011;110:1-26 pubmed publisher
    ..We propose a model for AID recruitment based on transcriptional stalling, which reconciles several of the key features of SHM, CSR, and lymphoma-associated translocation. ..
  2. Zhang Y, Gostissa M, Hildebrand D, Becker M, Boboila C, Chiarle R, et al. The role of mechanistic factors in promoting chromosomal translocations found in lymphoid and other cancers. Adv Immunol. 2010;106:93-133 pubmed publisher
  3. Geisberger R, Rada C, Neuberger M. The stability of AID and its function in class-switching are critically sensitive to the identity of its nuclear-export sequence. Proc Natl Acad Sci U S A. 2009;106:6736-41 pubmed publisher
  4. Xu W, Santini P, Sullivan J, He B, Shan M, Ball S, et al. HIV-1 evades virus-specific IgG2 and IgA responses by targeting systemic and intestinal B cells via long-range intercellular conduits. Nat Immunol. 2009;10:1008-17 pubmed publisher
  5. Wang L, Wuerffel R, Feldman S, Khamlichi A, Kenter A. S region sequence, RNA polymerase II, and histone modifications create chromatin accessibility during class switch recombination. J Exp Med. 2009;206:1817-30 pubmed publisher
    ..Thus, the histone methylation pattern produced by transcription localizes accessible chromatin to S regions, thereby focusing AID attack. ..
  6. Misaghi S, Garris C, Sun Y, Nguyen A, Zhang J, Sebrell A, et al. Increased targeting of donor switch region and IgE in Sgamma1-deficient B cells. J Immunol. 2010;185:166-73 pubmed publisher
    ..Thus, prominently transcribed S regions, such as Sgamma1, might provide a sufficient sink for AID protein to titrate away AID from other accessible sites within or outside the Ig locus. ..
  7. Daniel J, Santos M, Wang Z, Zang C, Schwab K, Jankovic M, et al. PTIP promotes chromatin changes critical for immunoglobulin class switch recombination. Science. 2010;329:917-23 pubmed publisher
    ..of downstream switch regions at the immunoglobulin heavy-chain (Igh) locus, leading to defective immunoglobulin class switching. We also showed that PTIP accumulation at DSBs contributes to class switch recombination (CSR) and ..
  8. Boboila C, Jankovic M, Yan C, Wang J, Wesemann D, Zhang T, et al. Alternative end-joining catalyzes robust IgH locus deletions and translocations in the combined absence of ligase 4 and Ku70. Proc Natl Acad Sci U S A. 2010;107:3034-9 pubmed publisher
    ..IgH chromosomal translocations to the c-myc oncogene also are augmented in the combined absence of Ku70 and ligase 4. We discuss the implications of these findings for A-EJ in normal and abnormal DSB repair. ..
  9. Zhang T, Okkenhaug K, Nashed B, Puri K, Knight Z, Shokat K, et al. Genetic or pharmaceutical blockade of p110delta phosphoinositide 3-kinase enhances IgE production. J Allergy Clin Immunol. 2008;122:811-819.e2 pubmed publisher
    ..Blockade of PI3K signaling leads to markedly enhanced B-cell switch to IgE and increased IgE levels in vivo, despite reduced type 2 cytokine production. ..
  10. Pone E, Zan H, Zhang J, Al Qahtani A, Xu Z, Casali P. Toll-like receptors and B-cell receptors synergize to induce immunoglobulin class-switch DNA recombination: relevance to microbial antibody responses. Crit Rev Immunol. 2010;30:1-29 pubmed
    ..Overall, BCR and TLR stimulation and the integration with signals from the pathogen or immune cells and their products determine the ensuing B-cell antibody response...
  11. Maul R, Saribasak H, Martomo S, McClure R, Yang W, Vaisman A, et al. Uracil residues dependent on the deaminase AID in immunoglobulin gene variable and switch regions. Nat Immunol. 2011;12:70-6 pubmed publisher
    ..Our data provide direct evidence for the model that AID functions by deaminating cytosine residues in DNA. ..
  12. Chaganti S, Heath E, Bergler W, Kuo M, Buettner M, Niedobitek G, et al. Epstein-Barr virus colonization of tonsillar and peripheral blood B-cell subsets in primary infection and persistence. Blood. 2009;113:6372-81 pubmed publisher
    ..These findings, supported by histologic evidence, suggest that EBV infection in IM tonsils involves extrafollicular B cells expressing CD38 as an activation antigen and not as a marker of ectopic GC activity. ..
  13. Jabara H, Weng Y, Sannikova T, Geha R. TRAF2 and TRAF3 independently mediate Ig class switching driven by CD40. Int Immunol. 2009;21:477-88 pubmed publisher
    ..These results suggest that TRAF2 and TRAF3 can each independently mediate class switch recombination (CSR) driven by CD40, but both are required for optimal CD40-driven isotype switching. ..
  14. Iwajomo O, Finn A, Moons P, Nkhata R, Sepako E, Ogunniyi A, et al. Deteriorating pneumococcal-specific B-cell memory in minimally symptomatic African children with HIV infection. J Infect Dis. 2011;204:534-43 pubmed publisher
  15. Tsukamoto Y, Nagai Y, Kariyone A, Shibata T, Kaisho T, Akira S, et al. Toll-like receptor 7 cooperates with IL-4 in activated B cells through antigen receptor or CD38 and induces class switch recombination and IgG1 production. Mol Immunol. 2009;46:1278-88 pubmed publisher
    ..IL-4 may be required for the induction of DNA repair system together with AID for the completion of CSR. ..
  16. Eckl Dorna J, Batista F. BCR-mediated uptake of antigen linked to TLR9 ligand stimulates B-cell proliferation and antigen-specific plasma cell formation. Blood. 2009;113:3969-77 pubmed publisher
    ..Thus, the direct conjugation of antigen and CpG reveals a mechanism that may operate during the initiation of primary immune responses, and may prove useful as a strategy for the design of adjuvants suitable for vaccinations. ..
  17. Hu Y, Ericsson I, Torseth K, Methot S, Sundheim O, Liabakk N, et al. A combined nuclear and nucleolar localization motif in activation-induced cytidine deaminase (AID) controls immunoglobulin class switching. J Mol Biol. 2013;425:424-43 pubmed publisher
    ..In addition, our results resolve the problem related to dissociation of deamination activity and CSR activity of AID mutants. ..
  18. Giltiay N, Chappell C, Clark E. B-cell selection and the development of autoantibodies. Arthritis Res Ther. 2012;14 Suppl 4:S1 pubmed publisher
  19. Eccleston J, Yan C, Yuan K, Alt F, Selsing E. Mismatch repair proteins MSH2, MLH1, and EXO1 are important for class-switch recombination events occurring in B cells that lack nonhomologous end joining. J Immunol. 2011;186:2336-43 pubmed publisher
    ..We also find Mlh1-XRCC4(-) B cells have an increased frequency of direct S junctions, suggesting that MLH1 proteins may have additional functions that influence A-EJ-mediated CSR. ..
  20. Haddad D, Oruc Z, Puget N, Laviolette Malirat N, Philippe M, Carrion C, et al. Sense transcription through the S region is essential for immunoglobulin class switch recombination. EMBO J. 2011;30:1608-20 pubmed publisher
  21. Stavnezer J, Björkman A, Du L, Cagigi A, Pan Hammarstrom Q. Mapping of switch recombination junctions, a tool for studying DNA repair pathways during immunoglobulin class switching. Adv Immunol. 2010;108:45-109 pubmed publisher
    ..Herein we review the results of analyses of S-S junctions, suggest minimal information required for these analyses, and attempt to integrate these results in order to increase our understanding of the complex process of CSR. ..
  22. Mohr E, Cunningham A, Toellner K, Bobat S, Coughlan R, Bird R, et al. IFN-{gamma} produced by CD8 T cells induces T-bet-dependent and -independent class switching in B cells in responses to alum-precipitated protein vaccine. Proc Natl Acad Sci U S A. 2010;107:17292-7 pubmed publisher
    ..Thus, T-bet dependence identifies distinct transcriptional pathways in B cells that regulate IFN-?-induced switching to different IgG isotypes...
  23. Doseth B, Visnes T, Wallenius A, Ericsson I, Sarno A, Pettersen H, et al. Uracil-DNA glycosylase in base excision repair and adaptive immunity: species differences between man and mouse. J Biol Chem. 2011;286:16669-80 pubmed publisher
    ..Our results reveal significant species differences in genomic uracil processing. These findings should be taken into account when mouse models are used in studies of uracil DNA repair and adaptive immunity. ..
  24. Saribasak H, Maul R, Cao Z, McClure R, Yang W, McNeill D, et al. XRCC1 suppresses somatic hypermutation and promotes alternative nonhomologous end joining in Igh genes. J Exp Med. 2011;208:2209-16 pubmed publisher
    ..Our results imply that AID-induced single-strand breaks in Igh variable and switch regions become substrates simultaneously for BER and mutagenesis pathways. ..
  25. Palacios F, Moreno P, Morande P, Abreu C, Correa A, Porro V, et al. High expression of AID and active class switch recombination might account for a more aggressive disease in unmutated CLL patients: link with an activated microenvironment in CLL disease. Blood. 2010;115:4488-96 pubmed publisher
    ..Overall, this work outlines the importance of a cellular subset in PB of UM CLL patients with a poor clinical outcome, high AID levels, and ongoing CSR, whose presence might be a hallmark of a recent contact with the microenvironment. ..
  26. Bergqvist P, Stensson A, Lycke N, Bemark M. T cell-independent IgA class switch recombination is restricted to the GALT and occurs prior to manifest germinal center formation. J Immunol. 2010;184:3545-53 pubmed publisher
    ..These findings reconcile that IgA CSR can occur in PP in the absence of GC with the fact that CD40(-/-) mice host near normal levels of IgA plasma cells in the LP. ..
  27. Barone F, Patel P, Sanderson J, Spencer J. Gut-associated lymphoid tissue contains the molecular machinery to support T-cell-dependent and T-cell-independent class switch recombination. Mucosal Immunol. 2009;2:495-503 pubmed publisher
    ..APRIL and its receptors were only observed alongside AID in GALT, showing that GALT contains the apparatus to support both T-independent and T-dependent routes to IgA CSR. ..
  28. Masuda K, Ouchida R, Li Y, Gao X, Mori H, Wang J. A critical role for REV1 in regulating the induction of C:G transitions and A:T mutations during Ig gene hypermutation. J Immunol. 2009;183:1846-50 pubmed publisher
  29. Callén E, Jankovic M, Wong N, Zha S, Chen H, Difilippantonio S, et al. Essential role for DNA-PKcs in DNA double-strand break repair and apoptosis in ATM-deficient lymphocytes. Mol Cell. 2009;34:285-97 pubmed publisher
    ..Our experiments reveal a DNA-PKcs-dependent pathway that regulates DNA repair and activation of p53 in the absence of ATM. ..
  30. Sellars M, Reina San Martin B, Kastner P, Chan S. Ikaros controls isotype selection during immunoglobulin class switch recombination. J Exp Med. 2009;206:1073-87 pubmed publisher
    ..We show that Ikaros is a master regulator of this competition. ..
  31. Dil N, Marshall A. Role of phosphoinositide 3-kinase p110 delta in TLR4- and TLR9-mediated B cell cytokine production and differentiation. Mol Immunol. 2009;46:1970-8 pubmed publisher
    ..Together, these results indicate that PI3K delta functions in influencing the type of B cell cytokine production and differentiation response induced by TLR-ligands. ..
  32. Perlot T, Alt F. Cis-regulatory elements and epigenetic changes control genomic rearrangements of the IgH locus. Adv Immunol. 2008;99:1-32 pubmed publisher
    ..Furthermore, we review the functions of well-described and potential new cis-regulatory elements with regard to processes such as V(D)J recombination, allelic exclusion, and IgH class switch recombination. ..
  33. Xiong H, Curotto de Lafaille M, Lafaille J. What is unique about the IgE response?. Adv Immunol. 2012;116:113-41 pubmed publisher
  34. Wesemann D, Portuguese A, Magee J, Gallagher M, Zhou X, Panchakshari R, et al. Reprogramming IgH isotype-switched B cells to functional-grade induced pluripotent stem cells. Proc Natl Acad Sci U S A. 2012;109:13745-50 pubmed publisher
    ..We conclude that culture conditions of activated B cells before and at early stages of reprogramming influence the developmental potency of resultant iPSCs...
  35. Wang J, Gostissa M, Yan C, Goff P, Hickernell T, Hansen E, et al. Mechanisms promoting translocations in editing and switching peripheral B cells. Nature. 2009;460:231-6 pubmed publisher
    ..Our studies show peripheral B cells that attempt secondary V(D)J recombination, and determine a role for mechanistic factors in promoting recurrent translocations in tumours...
  36. Frasca D, Romero M, Diaz A, Alter Wolf S, Ratliff M, Landin A, et al. A molecular mechanism for TNF-?-mediated downregulation of B cell responses. J Immunol. 2012;188:279-86 pubmed publisher
    ..Finally, anti-TNF-? given in vivo increased B cell function in old, but not in young, follicular B cells. These results suggest new molecular mechanisms that contribute to reduced Ab responses in aging. ..
  37. Nowak U, Matthews A, Zheng S, Chaudhuri J. The splicing regulator PTBP2 interacts with the cytidine deaminase AID and promotes binding of AID to switch-region DNA. Nat Immunol. 2011;12:160-6 pubmed publisher
    ..PTBP2 is thus an effector of CSR that promotes the binding of AID to switch-region DNA. ..
  38. Frasca D, Blomberg B. Aging affects human B cell responses. J Clin Immunol. 2011;31:430-5 pubmed publisher
    ..We here provide an overview of age-related changes in B cell markers and functions. Our studies have shown that intrinsic changes in B cells with age contribute to reduced antibody responses such as those to the influenza vaccine. ..
  39. Hackney J, Misaghi S, Senger K, Garris C, Sun Y, Lorenzo M, et al. DNA targets of AID evolutionary link between antibody somatic hypermutation and class switch recombination. Adv Immunol. 2009;101:163-89 pubmed publisher
    ..Common properties of SHM and CSR target sequences suggest that evolution of S regions might involve the duplication and selection of SHM hotspots. ..
  40. Ise W, Kohyama M, Schraml B, Zhang T, Schwer B, Basu U, et al. The transcription factor BATF controls the global regulators of class-switch recombination in both B cells and T cells. Nat Immunol. 2011;12:536-43 pubmed publisher
    ..Thus, BATF functions at multiple hierarchical levels in two cell types to globally regulate switched antibody responses in vivo. ..
  41. Zhang T, Franklin A, Boboila C, McQuay A, Gallagher M, Manis J, et al. Downstream class switching leads to IgE antibody production by B lymphocytes lacking IgM switch regions. Proc Natl Acad Sci U S A. 2010;107:3040-5 pubmed publisher
  42. Okazaki I, Okawa K, Kobayashi M, Yoshikawa K, Kawamoto S, Nagaoka H, et al. Histone chaperone Spt6 is required for class switch recombination but not somatic hypermutation. Proc Natl Acad Sci U S A. 2011;108:7920-5 pubmed publisher
    ..These results suggest that Spt6 is involved in differential regulation of CSR and SHM by AID. ..
  43. Vuong B, Lee M, Kabir S, Irimia C, Macchiarulo S, McKnight G, et al. Specific recruitment of protein kinase A to the immunoglobulin locus regulates class-switch recombination. Nat Immunol. 2009;10:420-6 pubmed publisher
    ..We propose that PKA nucleates the formation of active AID complexes specifically on S regions to generate the high density of DNA lesions required for CSR. ..
  44. Teichmann L, Ols M, Kashgarian M, Reizis B, Kaplan D, Shlomchik M. Dendritic cells in lupus are not required for activation of T and B cells but promote their expansion, resulting in tissue damage. Immunity. 2010;33:967-78 pubmed publisher
    ..These findings reveal that DCs operate in unanticipated ways in murine lupus and validate them as a potential therapeutic target in autoimmunity. ..
  45. Fulcher D, Avery D, Fewings N, Berglund L, Wong S, Riminton D, et al. Invariant natural killer (iNK) T cell deficiency in patients with common variable immunodeficiency. Clin Exp Immunol. 2009;157:365-9 pubmed publisher
    ..We propose that the decreased proportion of iNK T cells in CVID might be linked to the failure of memory B cell generation, which may contribute to reduced antibody production in these patients...
  46. Spolski R, Leonard W. IL-21 and T follicular helper cells. Int Immunol. 2010;22:7-12 pubmed publisher
    ..Here, we review the role of IL-21 in the regulation of normal T(FH) development and function as well as in progression of autoimmune responses. ..
  47. Doi T, Kato L, Ito S, Shinkura R, Wei M, Nagaoka H, et al. The C-terminal region of activation-induced cytidine deaminase is responsible for a recombination function other than DNA cleavage in class switch recombination. Proc Natl Acad Sci U S A. 2009;106:2758-63 pubmed publisher
    ..Therefore, AID does not distinguish between the V and S regions for cleavage, but carries another function specific to CSR. ..
  48. Humby F, Bombardieri M, Manzo A, Kelly S, Blades M, Kirkham B, et al. Ectopic lymphoid structures support ongoing production of class-switched autoantibodies in rheumatoid synovium. PLoS Med. 2009;6:e1 pubmed publisher
    ..These data identify AID as a potential therapeutic target in RA and suggest that survival of functional synovial B cell niches may profoundly influence chronic inflammation, autoimmunity, and response to B cell-depleting therapies. ..
  49. Xiong H, Dolpady J, Wabl M, Curotto de Lafaille M, Lafaille J. Sequential class switching is required for the generation of high affinity IgE antibodies. J Exp Med. 2012;209:353-64 pubmed publisher
    ..We demonstrate that a small amount of high affinity IgE can cause anaphylaxis and is pathogenic. Low affinity IgE competes with high affinity IgE for binding to Fc? receptors and prevents anaphylaxis and is thus beneficial. ..
  50. Pone E, Zhang J, Mai T, White C, Li G, Sakakura J, et al. BCR-signalling synergizes with TLR-signalling for induction of AID and immunoglobulin class-switching through the non-canonical NF-?B pathway. Nat Commun. 2012;3:767 pubmed publisher
    ..Thus, by integrating signals of the non-canonical and canonical NF-?B pathways, BCR and TLRs synergize to induce AID and T-cell-independent class switch DNA recombination. ..
  51. Mai T, Zan H, Zhang J, Hawkins J, Xu Z, Casali P. Estrogen receptors bind to and activate the HOXC4/HoxC4 promoter to potentiate HoxC4-mediated activation-induced cytosine deaminase induction, immunoglobulin class switch DNA recombination, and somatic hypermutation. J Biol Chem. 2010;285:37797-810 pubmed publisher
    ..Thus, estrogen enhances AID expression by activating the HOXC4/HoxC4 promoter and inducing the critical AID gene activator, HoxC4. ..
  52. Wang J, Alt F, Gostissa M, Datta A, Murphy M, Alimzhanov M, et al. Oncogenic transformation in the absence of Xrcc4 targets peripheral B cells that have undergone editing and switching. J Exp Med. 2008;205:3079-90 pubmed publisher
    ..Thus, Xrcc4/p53-deficient pro-B lymphomas routinely activate c-myc by gene amplification, whereas Xrcc4/p53-deficient peripheral B cell lymphomas routinely ectopically activate a single c-myc copy...
  53. Puga I, Cols M, Barra C, He B, Cassis L, Gentile M, et al. B cell-helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen. Nat Immunol. 2011;13:170-80 pubmed publisher
    ..Splenic neutrophils induced immunoglobulin class switching, somatic hypermutation and antibody production by activating MZ B cells through a mechanism that ..