During the Somatic Hypermutation Process Trends in Antibody Sequence Changes

Total Page:16

File Type:pdf, Size:1020Kb

During the Somatic Hypermutation Process Trends in Antibody Sequence Changes Trends in Antibody Sequence Changes during the Somatic Hypermutation Process Louis A. Clark, Skanth Ganesan, Sarah Papp and Herman W. T. van Vlijmen This information is current as of September 27, 2021. J Immunol 2006; 177:333-340; ; doi: 10.4049/jimmunol.177.1.333 http://www.jimmunol.org/content/177/1/333 Downloaded from References This article cites 32 articles, 9 of which you can access for free at: http://www.jimmunol.org/content/177/1/333.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 27, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Trends in Antibody Sequence Changes during the Somatic Hypermutation Process Louis A. Clark,1 Skanth Ganesan, Sarah Papp, and Herman W. T. van Vlijmen1 Probable germline gene sequences from thousands of aligned mature Ab sequences are inferred using simple computational matching to known V(D)J genes. Comparison of the germline to mature sequences in a structural region-dependent fashion allows insights into the methods that nature uses to mature Abs during the somatic hypermutation process. Four factors determine the residue type mutation patterns: biases in the germline, accessibility from single base permutations, location of mutation hotspots, and functional pressures during selection. Germline repertoires at positions that commonly contact the Ag are biased with tyrosine, serine, and tryptophan. These residue types have a high tendency to be present in mutation hotspot motifs, and their abundance is decreased during maturation by a net conversion to other types. The heavy use of tyrosines on mature Ab interfaces is thus a reflection of the germline composition rather than being due to selection during maturation. Potentially stabilizing Downloaded from changes such as increased proline usage and a small number of double cysteine mutations capable of forming disulfide bonds are ascribed to somatic hypermutation. Histidine is the only residue type for which usage increases in each of the interface, core, and surface regions. The net overall effect is a conversion from residue types that could provide nonspecific initial binding into a diversity of types that improve affinity and stability. Average mutation probabilities are ϳ4% for core residues, ϳ5% for surface residues, and ϳ12% for residues in common Ag-contacting positions, excepting the those coded by the D gene. The Journal of Immunology, 2006, 177: 333–340. http://www.jimmunol.org/ he versatility of the mammalian adaptive immune system single-base transitions over transversions at an ϳ3:1 ratio (7). In- rests on its ability to generate high-affinity Abs to foreign sertions and deletions also occur but are considerably less common T Ags. The set of naive B cells expresses a repertoire of (8, 9). Certain four-base DNA sequence motifs, called hotspots, surface-bound Ab precursors called B cell receptors or BCRs, a are correlated with the mutation locations. The two most com- subset of which can bind most new Ags with low affinity. To make monly cited four-base motifs are RGYW (10) and its inverse re- this possible, the V(D)J recombination process has evolved to mix peat, WRCY (11), where R denotes a purine base, Y a pyrimidine V, D, and J genes during cell development to provide a large base, and W an A or a T base. sequence diversity in the germline L and H chains. Considering It is not always clear how the mutations selected during the by guest on September 27, 2021 only the number of human V, D, and J genes and neglecting a gain affinity maturation process contribute to improving binding affinity in diversity from the joining mechanisms, one gets an estimate of or other properties such as selectivity or stability. Only a few stud- 320 L chain variable domain and 11,000 H chain variants. The ies exist that look at the effect of single somatic hypermutations assumption that any H chain can pair with any L chain yields 3.5 ϫ 6 (12). One expects the residues in contact with the Ag to be the 10 theoretical specificities (1). Additional adaptability comes most critical, but often large affinity improvement come from non- from the somatic hypermutation process, where the recombined surface mutations. Daugherty et al. (13) used phage display on Ab genes undergo error-prone replication during an in vivo selec- Escherichia coli to improve the affinity of a single-chain Fv mol- tion process. Those B cells that produce Abs with higher affinities ecule to cardiac glycoside digoxigenin and found that all of the for their Ags selectively proliferate, leading to a further enormous affinity enhancements occurred at non-Ag-contacting residues. increase in diversity and a fine tuning of the affinity. Similarly, Zahnd et al. (14) used a ribosome display to improve Much of somatic hypermutation research to date has focused on single-chain Fv binding to a peptide Ag and found that the most defining the molecular mechanism. This aspect has been reviewed recently (2–5) and, although much remains to be learned, certain effective mutation was not at the interface with the Ag. From our sequence-related aspects are clear. The enzyme AID (activation- own work redesigning Ab-Ag interfaces (34), we find that even induced cytidine deaminase) deamidates cytidine residues, con- Ag-contacting mutation effects are not always rationalizable or verting them to uracil and initiating the somatic hypermutation predictable from three-dimensional structure-based energetic cal- process (6). Further processing of the local DNA may involve culations. Thus, there is great potential to learn from the natural excision of the uracil base and repair by certain error-prone poly- affinity maturation process. merases (see reviews in Refs. 3–5). The overall process favors The work presented here seeks to better define the results of the somatic hypermutation process and to investigate sequence-related aspects of protein-protein recognition. Given a mature sequence, a Biogen Idec Inc., Cambridge, MA 02142 probable germline sequence resulting from the recombination of Received for publication November 4, 2005. Accepted for publication April 19, 2006. species-specific V, D, and J genes (15, 16) can be derived using The costs of publication of this article were defrayed in part by the payment of page sequence matching and consideration of the known mechanistic charges. This article must therefore be hereby marked advertisement in accordance rules of V(D)J recombination (see Materials and Methods). Once with 18 U.S.C. Section 1734 solely to indicate this fact. the germline chain sequence is known, simple comparison with the 1 Address correspondence and reprint requests to Dr. Louis A. Clark and Dr. Herman W. T. van Vlijmen, Biogen Idec Inc., 14 Cambridge Center, Cambridge, MA 02142. aligned mature sequence yields the position and type of mutation E-mail addresses: [email protected] and [email protected] that occurred during the affinity maturation process. Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$02.00 334 TRENDS IN SOMATIC HYPERMUTATIONS Tomlinson et al. (17) have previously used a similar type of the best gene are always assumed to be identical with those in the mature analysis to analyze the diversity of amino acids at specific posi- sequence, and no mutations are recorded. tions in the germline and mature Ab sequences. They found that Algorithm testing was performed in cases where the V(D)J fitting pro- cedure was performed manually. Additionally, D gene fitting was tested on the frequency of somatic hypermutation and the diversity of the cases where the DNA sequence was known. In the small number of cases germline sequences is highest in the CDRs. Rather than focus on examined, translating from the protein sequence to the most probable DNA the mutation frequencies, we examine the type of mutation and its sequence was sufficient to distinguish between available D gene sequences. functional implications deduced from the location in the structure. Typically, one or two related D genes had match scores clearly separated from all other lower-scoring D gene matches The results indicate that residue type changes during the somatic In some cases the algorithm clearly returns nonsensical matches, as hypermutation process are significant and have underlying func- indicated by long stretches of poor base matches. The failures can be traced tional rationales. back to humanized Abs, to Abs from species outside the human and mouse libraries used, or to insertions/deletions. Germline sequence determinations requiring Ͼ20-amino acid mutations relative to the mature sequence are Materials and Methods discarded on the assumption that the problem is inappropriate to the se- Germline V(D)J fitting procedure quence or that the algorithm has failed. Sequences with more than five consecutive mutated residues are discarded for similar reasons. Some se- The V(D)J germline fitting algorithm is intended to provide reasonable quences have so little information in the D and J gene regions that fitting solutions for the germline Ab sequence based on the mature protein se- is impractical.
Recommended publications
  • 1 the Immune System
    1 The immune system The immune response Innate immunity Adaptive immunity The immune system comprises two arms (rapid response) (slow response) functioning cooperatively to provide a Dendritic cell Mast cell comprehensive protective response: the B cell innate and the adaptive immune system. Macrophage γδ T cell T cell The innate immune system is primitive, does not require the presentation of an antigen, Natural and does not lead to immunological memory. killer cell Basophil Its effector cells are neutrophils, Complement protein macrophages, and mast cells, reacting Antibodies Natural Eosinophil killer T cell CD4+ CD8+ within minutes to hours with the help of T cell T cell complement activation and cytokines (CK). Granulocytes Neutrophil B-lymphocytes B-cell receptor The adaptive immune response is provided by the lymphocytes, which precisely recognise unique antigens (Ag) through cell-surface receptors. epitope Receptors are obtained in billions of variations through antigen cut and splicing of genes and subsequent negative T-lymphocytes selection: self-recognising lymphocytes are eradicated. T-cell receptor Immunological memory after an Ag encounter permits a faster and heightened state of response on a subsequent exposure. epitope MHC Lymphocytes develop in primary lymphoid tissue (bone marrow [BM], thymus) and circulate towards secondary Tonsils and adenoids Lymph lymphoid tissue (lymph nodes [LN], spleen, MALT). nodes Lymphatic vessels The Ag reach the LN carried by lymphocytes or by Thymus dendritic cells. Lymphocytes enter the LN from blood Lymph transiting through specialised endothelial cells. nodes The Ag is processed within the LN by lymphocytes, Spleen macrophages, and other immune cells in order to mount a specific immune response.
    [Show full text]
  • Somatic Hypermutation Targeting to Intrinsic Hotspots of Immunoglobulin
    Leukemia (2001) 15, 1772–1778 2001 Nature Publishing Group All rights reserved 0887-6924/01 $15.00 www.nature.com/leu Somatic hypermutation targeting to intrinsic hotspots of immunoglobulin genes in follicular lymphoma and multiple myeloma C Belessi1, K Stamatopoulos2, N Stavroyianni2, K Zoi2, T Papadaki3 and C Kosmas4 1Hematology Laboratory, General Hospital of Nikea, Piraeus; 2First Department of Medicine, Athens University School of Medicine, Laikon General Hospital, Athens; 3Hemopathology Unit, Evangelismos Hospital, Athens; and 4Department of Medicine, Helena Venizelou Hospital, Athens, Greece In this study, we analyzed the targeting of the somatic hyper- of the secondary lymphoid organs where contact with and mutation (SHM) mechanism at specific hotspot sequence 3 ␬ selection by antigen takes place. The molecular hallmark of motifs in the VH and V genes of 10 follicular lymphoma (FL) cases and the V␬ and V␭ genes of 11 ␬- and six ␭-light chain this phase is the introduction of mutations within rearranged expressing multiple myeloma (MM) cases. These sequences IgV genes, at a rate much higher than usual, a phenomenon were analyzed for targeting of specific motifs, ie certain highly described as somatic hypermutation.4 mutable trinucleotides (3-NTPs), the tetranucleotide (4-NTP) Antigen selection in B cell ontogeny is evidenced by non- RGYW and its complementary, WRCY (where R = purine, random distribution of somatic mutations in lg HC and LC V = = Y pyrimidine and W A or T). Comparisons were carried out genes, a feature providing useful information concerning the between mutation frequencies in RGYW vs WRCY and the inci- 5 dence of mutations in complementarity determining region ontogenetic assignment of B cell neoplastic disorders.
    [Show full text]
  • Somatic Hypermutation of T Cell Receptor a Chain Contributes To
    RESEARCH ARTICLE Somatic hypermutation of T cell receptor a chain contributes to selection in nurse shark thymus Jeannine A Ott1, Caitlin D Castro2, Thaddeus C Deiss1, Yuko Ohta2, Martin F Flajnik2, Michael F Criscitiello1,3* 1Comparative Immunogenetics Laboratory, Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, Texas, United States; 2Department of Microbiology and Immunology, University of Maryland at Baltimore, Baltimore, United States; 3Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M Health Science Center, Texas A&M University, Texas, United States Abstract Since the discovery of the T cell receptor (TcR), immunologists have assigned somatic hypermutation (SHM) as a mechanism employed solely by B cells to diversify their antigen receptors. Remarkably, we found SHM acting in the thymus on a chain locus of shark TcR. SHM in developing shark T cells likely is catalyzed by activation-induced cytidine deaminase (AID) and results in both point and tandem mutations that accumulate non-conservative amino acid replacements within complementarity-determining regions (CDRs). Mutation frequency at TcRa was as high as that seen at B cell receptor loci (BcR) in sharks and mammals, and the mechanism of SHM shares unique characteristics first detected at shark BcR loci. Additionally, fluorescence in situ hybridization showed the strongest AID expression in thymic corticomedullary junction and medulla. We suggest that TcRa utilizes SHM to broaden diversification of the primary ab T cell repertoire in sharks, the first reported use in vertebrates. DOI: https://doi.org/10.7554/eLife.28477.001 *For correspondence: [email protected] Competing interests: The Introduction authors declare that no competing interests exist.
    [Show full text]
  • Allergic Rhinitis Patients of Switch Recombination in the Nasal Mucosa Local Somatic Hypermutation and Class
    Local Somatic Hypermutation and Class Switch Recombination in the Nasal Mucosa of Allergic Rhinitis Patients This information is current as Heather A. Coker, Stephen R. Durham and Hannah J. Gould of September 23, 2021. J Immunol 2003; 171:5602-5610; ; doi: 10.4049/jimmunol.171.10.5602 http://www.jimmunol.org/content/171/10/5602 Downloaded from References This article cites 33 articles, 7 of which you can access for free at: http://www.jimmunol.org/content/171/10/5602.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 23, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2003 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Local Somatic Hypermutation and Class Switch Recombination in the Nasal Mucosa of Allergic Rhinitis Patients Heather A. Coker,1* Stephen R. Durham,† and Hannah J. Gould2* Immunoglobulin E is produced by nasal B cells in response to allergen.
    [Show full text]
  • B-Helper Neutrophils in Regional Lymph Nodes Correlate with Improved Prognosis in Patients with Head and Neck Cancer
    cancers Article B-Helper Neutrophils in Regional Lymph Nodes Correlate with Improved Prognosis in Patients with Head and Neck Cancer Ekaterina Pylaeva 1,† , Irem Ozel 1,† , Anthony Squire 2, Ilona Spyra 1, Charlotte Wallner 1, Magdalena Korek 1, Georg Korschunow 1, Maksim Domnich 1 , Elena Siakaeva 1, Moritz Goetz 3, Agnes Bankfalvi 3, Stephan Lang 1,4, Benjamin Kansy 1,4,*,‡ and Jadwiga Jablonska 1,4,*,‡ 1 Department of Otorhinolaryngology, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany; [email protected] (E.P.); [email protected] (I.O.); [email protected] (I.S.); [email protected] (C.W.); [email protected] (M.K.); [email protected] (G.K.); [email protected] (M.D.); [email protected] (E.S.); [email protected] (S.L.) 2 Institute of Experimental Immunology and Imaging, University Hospital Essen, University Duisburg-Essen, 45141 Essen, Germany; [email protected] 3 Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; [email protected] (M.G.); [email protected] (A.B.) 4 German Cancer Consortium (DKTK) Partner Site Düsseldorf/Essen, 45147 Essen, Germany * Correspondence: [email protected] (B.K.); [email protected] (J.J.) † These authors contributed equally. ‡ These authors contributed equally. Simple Summary: Neutrophils exhibit multiple functions during cancer progression and are believed Citation: Pylaeva, E.; Ozel, I.; Squire, to regulate adaptive immune responses to cancer. In addition to their interactions with T cells in A.; Spyra, I.; Wallner, C.; Korek, M.; this context, these cells are also believed to interact with B cells.
    [Show full text]
  • A Natural Killer Cell-Centric Approach Toward New Therapeutics For
    A natural killer cell-centric approach toward new therapeutics for autoimmune disease A dissertation submitted to the Graduate School of the University of Cincinnati in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Ph.D.) in the Immunology Graduate Training Program of the College of Medicine 2019 By Seth D. Reighard B.S., University of Pittsburgh, 2010 Thesis Advisor: Stephen N. Waggoner, Ph.D. Dissertation Committee Chair: William M. Ridgway, M.D. 1 Abstract The debilitating autoimmune disease systemic lupus erythematosus (SLE) is the 5th leading cause of death for African American and Hispanic women between 15 and 24 years of age. Current therapeutics for SLE are blunt weapons that broadly suppress a patient’s immune system, and only one new treatment option has been approved in over 50 years. Standard treatments for SLE potentially lack efficacy because they do not specifically target the immune dysfunction underlying disease. SLE is characterized by the abnormal production of self-targeting autoantibodies that cause widespread organ damage. SLE autoantibodies are generated by rampant germinal center (GC) reactions: immune processes wherein memory B cells and antibody secreting cells (ASC) arise from naïve B lymphocytes following clonal expansion, somatic hypermutation, affinity maturation, and antibody class switching while receiving critical help from follicular helper T (TFH) cells. We hypothesize that inhibition of TFH and GC responses in SLE may be accomplished by harnessing the therapeutic potential of the natural killer (NK) cell. Though classically implicated in anti-tumor and antiviral immunity, NK cells also suppress activated TFH, resulting in reduced GC reactions and decreased antibodies.
    [Show full text]
  • Of B Cells in Vitro Signals That Initiate Somatic Hypermutation
    Signals That Initiate Somatic Hypermutation of B Cells In Vitro1 Sigridur Bergthorsdottir,* Aoife Gallagher,2* Sandra Jainandunsing,* Debra Cockayne,† James Sutton,* Tomas Leanderson,‡ and David Gray2,3* Somatic hypermutation is initiated as B lymphocytes proliferate in germinal centers. The signals that switch on the mutation process are unknown. We have derived an in vitro system to define signals that will initiate mutation in normal, naive splenic B cells. We find that three signals are required to allow detection of somatic mutation in vitro; these are anti-Ig, anti-CD40, and anti-CD38. If any one of these is omitted, mutation remains off. We show that CD40 is obligatory in vivo, as CD40 knockout mice exhibit no Ag-driven mutation. In contrast, CD38 is not, as CD38 knockout mice mutate normally. We believe that, in vitro, CD38, in combination with other stimuli, drives extensive cell division, allowing the detection of mutated sequences. However, in germinal centers in vivo, proliferative activity is instigated by a different molecule. This is the first demonstration of the initiation of hypermutation in vitro with normal splenic B cells using defined stimuli. The Journal of Immunology, 2001, 166: 2228–2234. ffinity maturation of the Ab response occurs largely as a liferation, or what causes differentiation within the GC (e.g., the result of selection of the Ig V gene products that have transition of centroblast to centrocyte). CD40 is implicated in the A undergone a process of somatic hypermutation. The vast first two functions as CD40 knockout mice develop no GC (8, 9); majority of late primary and secondary response Abs exhibit however, its role in GC induction may be an indirect one as rudi- changes from the germline V sequence (1, 2), and most memory B mentary GC can be regenerated in these mice simply by injection 4 cells carry somatically mutated B cell receptors (BCR) (3).
    [Show full text]
  • Regulation of AID, the B-Cell Genome Mutator
    Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Regulation of AID, the B-cell genome mutator Celia Keim, David Kazadi, Gerson Rothschild, and Uttiya Basu1 Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA The mechanisms by which B cells somatically engineer (Huang et al. 2005), and macrophages (Koppel et al. 2005), their genomes to generate the vast diversity of antibodies the latter two of which derive from CMP cells and are required to challenge the nearly infinite number of produced during the sentinel innate immune response. antigens that immune systems encounter are of tremen- Dendritic cells and macrophages travel to the site of an dous clinical and academic interest. The DNA cytidine infection and function as phagocytic cells (macrophages) deaminase activation-induced deaminase (AID) catalyzes or as cells specialized in taking up antigens and present- two of these mechanisms: class switch recombination ing peptide fragments to lymphocytes for recognition (CSR) and somatic hypermutation (SHM). Recent discov- (dendritic cells). Briefly, then, the HSC-derived myeloid eries indicate a significant promiscuous targeting of this progenitor macrophages and dendritic cells present anti- B-cell mutator enzyme genome-wide. Here we discuss gens to the HSC-derived lymphoid progenitor B and T the various regulatory elements that control AID activ- cells, allowing the immune response to proceed. CMP ity and prevent AID from inducing genomic instability cells are not restricted to just phagocytic or antigen and thereby initiating oncogenesis. presentation roles, however, as they also encompass members of the granulocyte and mast cell lineages.
    [Show full text]
  • Somatic Hypermutation of the New Antigen Receptor Gene (NAR)
    Proc. Natl. Acad. Sci. USA Vol. 95, pp. 14343–14348, November 1998 Immunology, Evolution Somatic hypermutation of the new antigen receptor gene (NAR) in the nurse shark does not generate the repertoire: Possible role in antigen-driven reactions in the absence of germinal centers MARILYN DIAZ,ANDREW S. GREENBERG, AND MARTIN F. FLAJNIK* University of Miami School of Medicine, Department of Microbiology and Immunology, Miami, FL 33136 Communicated by Masatoshi Nei, Pennsylvania State University, University Park, PA, October 2, 1998 (received for review July 7, 1998) ABSTRACT The new antigen receptor (NAR) gene in the to generate the repertoire in some species; studies of somatic nurse shark diversifies extensively by somatic hypermutation. It hypermutation in the cartilaginous fish address this issue. is not known, however, whether NAR somatic hypermutation In the nurse shark, Ginglymostoma cirratum, a new class of generates the primary repertoire (like in the sheep) or rather is antigen receptor gene (NAR) was discovered in our laboratory. used in antigen-driven immune responses. To address this issue, NAR is a covalently linked dimer, each monomer consisting of the sequences of NAR transmembrane (Tm) and secretory (Sec) one V domain and five constant (C) domains. NAR is found in forms, presumed to represent the primary and secondary rep- both transmembrane (Tm) and secretory (Sec) forms, but it ertoires, respectively, were examined from the peripheral blood differs from bona fide Ig in that it does not associate with Ig light lymphocytes of three adult nurse sharks. More than 40% of the chains (2, 12). Further, the NAR V region is more similar to Ig y Sec clones but fewer than 11% of Tm clones contained five light chain T-cell receptor V than to Ig heavy chain V (2).
    [Show full text]
  • Activation-Induced Cytidine Deaminase (AID) Linking Immunity, Chronic Inflammation, and Cancer
    Cancer Immunol Immunother (2012) 61:1591–1598 DOI 10.1007/s00262-012-1255-z SYMPOSIUM-IN-WRITING PAPER Activation-induced cytidine deaminase (AID) linking immunity, chronic inflammation, and cancer Diana Mechtcheriakova • Martin Svoboda • Anastasia Meshcheryakova • Erika Jensen-Jarolim Received: 12 January 2012 / Accepted: 27 March 2012 / Published online: 19 April 2012 Ó The Author(s) 2012. This article is published with open access at Springerlink.com Abstract Activation-induced cytidine deaminase (AID) of fundamental aspects is still lacking as (1) what are the is critically involved in class switch recombination and crucial factors triggering an aberrant AID expression/ somatic hypermutation of Ig loci resulting in diversification activity including the impact of Th2-driven inflammation of antibodies repertoire and production of high-affinity and (2) to what extent may aberrant AID in human non-B antibodies and as such represents a physiological tool to cells lead to abnormal cell state associated with an introduce DNA alterations. These processes take place increased rate of genomic alterations as point mutations, within germinal centers of secondary lymphoid organs. small insertions or deletions, and/or recurrent chromosomal Under physiological conditions, AID is expressed pre- translocations during solid tumor development and dominantly in activated B lymphocytes. Because of the progression. mutagenic and recombinogenic potential of AID, its expression and activity is tightly regulated on different Keywords Activation-induced cytidine deaminase Á levels to minimize the risk of unwanted DNA damage. Gene network Á Inflammation Á Cancer Á Multigene However, chronic inflammation and, probably, combina- signature approach Á AllergoOncology tion of other not-yet-identified factors are able to create a symposium-in-writing microenvironment sufficient for triggering an aberrant AID expression in B cells and, importantly, in non-B-cell background.
    [Show full text]
  • Defect in Igv Gene Somatic Hypermutation in Common Variable Immuno-Deficiency Syndrome
    Proc. Natl. Acad. Sci. USA Vol. 95, pp. 13135–13140, October 1998 Immunology Defect in IgV gene somatic hypermutation in Common Variable Immuno-Deficiency syndrome YVES LEVY*†‡,NEETU GUPTA†,FRANC¸OISE LE DEIST§,CORINNE GARCIA†,ALAIN FISCHER§,JEAN-CLAUDE WEILL†, AND CLAUDE-AGNE`S REYNAUD† *Unite´d’immunologie clinique, Hoˆpital Henri Mondor, 51, avenue du Mare´chalde Lattre de Tassigny, 94010 Cre´teilCedex 10, France; †Institut National de la Sante´et de la Recherche Me´dicaleUnite´373, Faculte´deMe´decine Necker-Enfants Malades, 156, rue de Vaugirard, 75730 Paris Cedex 15, France; and §Institut National de la Sante´et de la Recherche Me´dicaleUnite´429, Hoˆpital Necker-Enfants Malades, 149, rue de Se`vres, 75730 Paris Cedex 15, France Edited by Max D. Cooper, University of Alabama, Birmingham, AL, and approved September 8, 1998 (received for review June 8, 1998) ABSTRACT Common Variable Immuno-Deficiency from eight patients (six CVID and 2 hypogammaglobulinemic (CVID) is the most common symptomatic primary antibody- patients with recurrent infections). In two CVID cases, 40 to 75% deficiency syndrome, but the basic immunologic defects under- of the pool of circulating IgG memory B cells were found totally lying this syndrome are not well defined. We report here that devoid of somatic mutation, suggesting that the process of Ig among eight patients studied (six CVID and two hypogamma- affinity maturation can be severely hampered in some CVID globulinemic patients with recurrent infections), there is in two patients. Finally, functional analysis of the T cell compartment, CVID patients a dramatic reduction in Ig V gene somatic including an in vitro assay of the capacity of peripheral T cells to hypermutation with 40–75% of IgG transcripts totally devoid of induce somatic hypermutation in a human B cell line, argues in mutations in the circulating memory B cell compartment.
    [Show full text]
  • Somatic Hypermutation of the New Antigen Receptor Gene
    Proc. Natl. Acad. Sci. USA Vol. 95, pp. 14343–14348, November 1998 Immunology, Evolution Somatic hypermutation of the new antigen receptor gene (NAR) in the nurse shark does not generate the repertoire: Possible role in antigen-driven reactions in the absence of germinal centers MARILYN DIAZ,ANDREW S. GREENBERG, AND MARTIN F. FLAJNIK* University of Miami School of Medicine, Department of Microbiology and Immunology, Miami, FL 33136 Communicated by Masatoshi Nei, Pennsylvania State University, University Park, PA, October 2, 1998 (received for review July 7, 1998) ABSTRACT The new antigen receptor (NAR) gene in the to generate the repertoire in some species; studies of somatic nurse shark diversifies extensively by somatic hypermutation. It hypermutation in the cartilaginous fish address this issue. is not known, however, whether NAR somatic hypermutation In the nurse shark, Ginglymostoma cirratum, a new class of generates the primary repertoire (like in the sheep) or rather is antigen receptor gene (NAR) was discovered in our laboratory. used in antigen-driven immune responses. To address this issue, NAR is a covalently linked dimer, each monomer consisting of the sequences of NAR transmembrane (Tm) and secretory (Sec) one V domain and five constant (C) domains. NAR is found in forms, presumed to represent the primary and secondary rep- both transmembrane (Tm) and secretory (Sec) forms, but it ertoires, respectively, were examined from the peripheral blood differs from bona fide Ig in that it does not associate with Ig light lymphocytes of three adult nurse sharks. More than 40% of the chains (2, 12). Further, the NAR V region is more similar to Ig y Sec clones but fewer than 11% of Tm clones contained five light chain T-cell receptor V than to Ig heavy chain V (2).
    [Show full text]