DOCSLIB.ORG

Individuals with Iga Deficiency and Common Variable Immunodeficiency Share Polymorphisms of Major Histocompatibility Complex

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Individuals with Iga Deficiency and Common Variable Immunodeficiency Share Polymorphisms of Major Histocompatibility Complex Proc. Nati. Acad. Sci. USA Vol. 86, pp. 8015-8019, October 1989 Immunology Individuals with IgA deficiency and common variable immunodeficiency share polymorphisms of major histocompatibility complex class III genes (B-cell differentiation/complement component C2/complement component C4/steroid 21-hydroxylase/HLA) F. M. SCHAFFER*, J. PALERMOSt, Z. B. ZHUt, B. 0. BARGER*, M. D. COOPER*§, AND J. E. VOLANAKISt¶ *Division of Developmental and Clinical Immunology, Departments of Pediatrics, Medicine, Microbiology, and Pathology, and The Comprehensive Cancer Center, tDivision of Clinical Immunology and Rheumatology, Department of Medicine, *Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294; and the §Howard Hughes Medical Institute, Birmingham, AL 35294 Contributed by M. D. Cooper, July 11, 1989 ABSTRACT IgA deficiency and common variable immu- to B-cell stage in the X chromosome-linked form of congen- nodeficiency are heritable disorders that can occur within the ital agammaglobulinemia (3, 6). same family. Both immunodeficiencies are characterized by The cause ofthe variable B-cell arrests in CVID and IgA-D arrests in B-cell differentiation that vary in the extent of the is unknown. B cells from individuals with CVID are capable immunoglobulin isotypes involved. A high frequency of major of plasma-cell differentiation, as can be demonstrated after histocompatibility complex supratypes associated with a null their infection with Epstein-Barr virus (7). Because T cells allele of the gene encoding the C4A isotype of complement are needed to help B cells respond with antibody production component C4 has been observed in IgA-deficient individuals. to most antigens, a defect of the T cells has long been In search of a genetic linkage between the two immunodefi- suspected in CVID and IgA-D (8-10). Although T cells are ciencies, we examined the major histocompatibility complex usually present in normal numbers, analysis of affected (MHC) class HI genes encoding complement components C2, individuals sometimes suggests either a deficit in helper C4A, and C4B and steroid 21-hydroxylase in addition to the T-cell function or excessive suppressor activity (8-10). Other HLA serotypes in individuals with either common variable studies suggest that T cells from most of these patients are immunodeficiency or IgA deficiency. Twelve of 19 patients with capable of providing all the necessary elements for B-cell common variable immunodeficiency (63%, P < 0.001) and 9 of growth and differentiation (11, 12). 16 patients with IgA deficiency (56%, P < 0.01) had rare C2 While CVID and IgA-D may represent multifactorial dis- alleles and/or C4A and 21-hydroxylase A deletions, whereas eases, susceptibility appears to be heritable, with family these gene features were seen in only 5 of34 healthy individuals studies suggesting an autosomal recessive mode of inheri- (15%) in the control group. Nine of 11 patients with C4A tance (13, 14). CVID and IgA-D have also been observed in deletion had an HLA haplotype consistent with the MHC immediate relatives (13), suggesting a common gene defect. supratype HLA-Al, Cw7, B8, C4AQO, C4B1, BfS, DR3 pre- In search of a shared genetic basis for CVID and IgA-D, we viously found to be associated with IgA deficiency. The data have turned our attention to the major histocompatibility support the hypothesis that common variable immunodefi- complex (MHC) of genes for two main reasons. First, this ciency and IgA deficiency are related disorders, susceptibility region of chromosome 6 encodes a variety of molecules to which is determined by a gene(s) within or near the MHC involved in antigen presentation and T-cell/B-cell interac- class III gene region on chromosome 6. tions (15). Second, studies of individuals with IgA-D have revealed a relatively high incidence of certain HLA haplo- Common variable immunodeficiency (CVID) and selective types (16, 17) and MHC supratypes, the most consistent IgA deficiency (IgA-D) are diagnostic classifications applied feature of which is the presence of null alleles of the gene to groups of immunodeficient individuals exhibiting de- encoding the A isotype of complement component C4 (C4A) creased levels either ofmultiple immunoglobulin classes or of (14). Our present studies reveal that individuals with CVID IgA alone (1). These are not homogeneous entities, but rather and IgA-D have in common a very high incidence of partic- represent opposite ends of a spectrum of immunoglobulin ular restriction fragment length polymorphisms (RFLPs) or deficiencies. Individuals diagnosed as having CVID are fre- deletions of MHC class III genes. quently panhypogammaglobulinemic but may produce sub- stantial levels of IgM. Conversely, individuals with IgA-D may also be deficient in one or more IgG subclasses (2). MATERIALS AND METHODS CVID, typically manifested by recurrent bacterial infections, Participants. All individuals in the is usually recognized in adolescents or young adults and thus Study participating is sometimes called the late-onset form of hypogammaglob- study were Caucasian. Thirty-four healthy individuals (17 ulinemia. In most individuals with CVID, B cells are pro- male and 17 female) randomly selected for study had normal duced in normal numbers but they fail to undergo differen- serum immunoglobulin levels. The 19 CVID patients (12 tiation into antibody-secreting plasma cells (3, 4). Similarly, female and 7 male) and 16 patients with selective IgA-D (6 individuals with IgA-D have normal numbers of IgA-bearing female and 10 male) were selected from a group of immuno- B cells, but these are relatively immature and fail to undergo deficient patients followed in our immunology clinic. In- terminal differentiation into IgA-secreting plasma cells (5). formed consent was obtained from all participants. The arrests in B-cell differentiation seen in CVID and IgA-D are thus similar and contrast with the arrest seen at the pre-B- Abbreviations: MHC, major histocompatibility complex; C2, second component of complement; C4, fourth component of complement; 21-OHase, steroid 21-hydroxylase; IgA-D, IgA deficiency; CVID, The publication costs of this article were defrayed in part by page charge common variable immunodeficiency; RFLP, restriction fragment payment. This article must therefore be hereby marked "advertisement" length polymorphism. in accordance with 18 U.S.C. §1734 solely to indicate this fact. $To whom reprint requests should be addressed. 8015 Downloaded by guest on September 30, 2021 8016 Immunology: Schaffer et al. Proc. Natl. Acad. Sci. USA 86 (1989) 0 5 10 15 20 kb 5' 3'5' C2 }-EU A 6.6* Bam Hi 3.45-32* I 4.4 2.2 1 Sst I 1 2.75-2.5*1 C H 6.6 *----H B 1 2.1 1 4.5 J Taq I FIG. 1. Schematic representation ofthe C2 gene RFLPs. kb, Kilobases. A partial restriction map ofthe C2 gene (23) is shown with the relative positions and sizes ofpolymorphic fragments indicated by asterisks. Probes A and C are the 5' 2-kbp and 3' 1-kbp EcoRI fragments, respectively, of a full-length cDNA for C2 (22). Probe B is a 300-bp DNA fragment derived from the 5' region of a C2 genomic clone (23). Probe A detects two polymorphisms: (i) A BamHI multiallelic polymorphism with five classes of size variants exhibiting fragments of 3.45, 3.40, 3.35, 3.30, and 3.20 kbp. This polymorphism is also detected by using Sst I-digested DNA and probe B. The Sst I polymorphic fragments have corresponding lengths of 2.75, 2.70, 2.65, 2.60, and 2.50 kbp. (ii) A second BamHI polymorphism characterized by the loss of a 4.4-kbp fragment and the appearance of a 6.6-kbp fragment. Probe C detects a Taq I polymorphism mapping to the 3' end of the C2 gene and characterized by the loss of a 4.5-kbp fragment and the appearance of a 6.6-kbp fragment. Immunofluorescence Studies. Mononuclear cells were iso- B gene (24). Both were gifts from David Chaplin (Washington lated from heparinized blood samples by centrifugation over University, Saint Louis). The purified DNA probes were Ficoll/Hypaque density gradients. B and T lymphocytes radiolabeled with [32P]dCTP (Amersham) by the random were enumerated by indirect immunofluorescence using primer method (25). monoclonal antibodies and a FACS Scan II flow cytometry HLA Typing. Typing antisera obtained from the National unit (Beckton Dickinson). The anti-B-cell monoclonal anti- Institutes ofHealth, local screening, and commercial sources bodies were specific for cell surface IgM, IgD, IgA, HLA- were utilized for HLA-A, B, DQ, and DR typing by the DR, HLA-DQ, and the HB-2 antigen (18). The T-cell mono- microdroplet lymphocytotoxicity test (26). clonal antibodies were against the CD3, CD4, and CD8 Statistical Analysis. Differences in the frequency of study antigens. Serum immunoglobulin concentrations were deter- parameters between the control and patient populations were mined by rate nephelometry. assessed by the x2 test with correction for continuity, and Southern Blot Analysis. Genomic DNA was extracted from differences between mean values were assessed by the non- the buffy coat fraction of blood samples collected in EDTA paired Student t test. (19). Ten micrograms of genomic DNA was digested with restriction endonucleases (Taq I, BamHI, HindIII, or Sst I) under conditions suggested by the suppliers. DNA restriction RESULTS fragments were separated by electrophoresis through 0.8% Study Population. Immunological parameters of the 19 agarose gels. Phage A DNA digested with HindIII or EcoRI individuals with CVID and 16 individuals with IgA-D are plus HindIII was used as molecular size markers. After summarized in Table 1. None of the patients was lym- electrophoresis, DNA fragments were transferred to nitro- phopenic. All had normal percentages of T cells as indicated cellulose membranes by the method of Southern (20). Pre- by values for the CD3+, CD4+, and CD8+ cells, although the hybridization and hybridization of the membranes was car- CD4/CD8 ratio was lower in the CVID group.
Load more

Recommended publications
  • Fine-Tuned Characterization of RCCX Copy Number Variants and Their Relationship with Extended MHC Haplotypes
    Genes and Immunity (2012) 13, 530–535 & 2012 Macmillan Publishers Limited All rights reserved 1466-4879/12 www.nature.com/gene ORIGINAL ARTICLE Fine-tuned characterization of RCCX copy number variants and their relationship with extended MHC haplotypes ZBa´nlaki1, M Doleschall1, K Rajczy2, G Fust1 and A´ Szila´gyi1 The human RCCX is a common multiallelic copy number variation locus whose number of segments varies between one and four in a chromosome. The monomodular form normally comprises four functional genes, but in duplicated RCCX segments generally only the gene-encoding complement component C4 produces a protein. C4 genes can code either for a C4A or a C4B isotype protein and exhibit dichotomous size variation. Distinct RCCX variants show association with numerous diseases; however, identification of the basis of these associations is often challenging, not least because the RCCX is localized in the major histocompatibility complex (MHC) region, a genomic area characterized by exceedingly long-range linkage disequilibrium. Here we present a detailed analysis on RCCX variants and their relationship with so-called ‘ancestral’ or ‘conserved extended’ MHC haplotypes in healthy Caucasians. In addition to former investigations, precise order and size of all C4A and C4B genes were determined even in trimodular RCCX structures. Considering C4 copy numbers, length, isotype specificity and CYP21A2 copy numbers, we have identified 15 distinct RCCX variants and described the RCCX structures involved in 29 repeatedly occurring MHC haplotypes. The
    [Show full text]
  • Major Histocompatibility Complex Class III Genes and Susceptibility to Immunoglobulin a Deficiency and Common Variable Immunodeficiency
    Major histocompatibility complex class III genes and susceptibility to immunoglobulin A deficiency and common variable immunodeficiency. J E Volanakis, … , H W Schroeder Jr, M D Cooper J Clin Invest. 1992;89(6):1914-1922. https://doi.org/10.1172/JCI115797. Research Article We have proposed that significant subsets of individuals with IgA deficiency (IgA-D) and common variable immunodeficiency (CVID) may represent polar ends of a clinical spectrum reflecting a single underlying genetic defect. This proposal was supported by our finding that individuals with these immunodeficiencies have in common a high incidence of C4A gene deletions and C2 rare gene alleles. Here we present our analysis of the MHC haplotypes of 12 IgA-D and 19 CVID individuals from 21 families and of 79 of their immediate relatives. MHC haplotypes were defined by analyzing polymorphic markers for 11 genes or their products between the HLA-DQB1 and the HLA-A genes. Five of the families investigated contained more than one immunodeficient individual and all of these included both IgA-D and CVID members. Analysis of the data indicated that a small number of MHC haplotypes were shared by the majority of immunodeficient individuals. At least one of two of these haplotypes was present in 24 of the 31 (77%) immunodeficient individuals. No differences in the distribution of these haplotypes were observed between IgA-D and CVID individuals. Detailed analysis of these haplotypes suggests that a susceptibility gene or genes for both immunodeficiencies are located within the class III region of the MHC, possibly between the C4B and C2 genes. Find the latest version: https://jci.me/115797/pdf Major Histocompatibility Complex Class Ill Genes and Susceptibility to Immunoglobulin A Deficiency and Common Variable Immunodeficiency John E.
    [Show full text]
  • 19 and Prophylactive Measures to Contain Spread of the Disease
    Journal of Biology, Agriculture and Healthcare www.iiste.org ISSN 2224-3208 (Paper) ISSN 2225-093X (Online) Vol.11, No.4, 2021 Investigating Covid- 19 and Prophylactive Measures to Contain Spread of the Disease B.M Mustapha R.Z Usman College of Agriculture and Animal Science ,Division of Agricultural College.Ahmadu Bello University Zaria.Nigeria Abstract Covid-19 disease is a highly infectious and contagious disease and the outbreak has caused high mortality and morbidity with rates of about 5% and 0.9% it is a global pandemic requiring immediate attention,some of the symptoms include Anemia ,dehydration,Emaciation,weakness ,pneumonitis and Death. The etiology is covid-19 ,the problem at the moment is the lack of cure for the disease.In this study five continents where of interest and they include North and South America,Europe,Africa and Asia.Data was obtained from the internet from worldometer.info/coronavirus/country and cases from February to 15 december 2020 were considered and analysed statistically using analysis of variants to determine monthly incidence and prevalence,case fatality,morbidity ,mortality and population at risk.The reason for this survey is to establish ways to decrease the high morbidity and mortality rates , reduce the devastating economic impact of this disease and increase daily socialization among Humans and curb hunger and boredom that covid-19 has caused.More so the it is a global pandemic needing urgent attention.In conclusion the morbidity and mortality where highest in the months of July and October and the population at risk are 95%-98%.Prophylactic measure to help alleviate the incidence of this disease include daily administration of blood tonic and ascorbic acid in their daily recommended dosages pre- infection to enhance growth of tissues and cellular epithelization and boost energy generation and build .
    [Show full text]
  • Xenopus in the Amphibian Ancestral Organization of the MHC Revealed
    Ancestral Organization of the MHC Revealed in the Amphibian Xenopus Yuko Ohta, Wilfried Goetz, M. Zulfiquer Hossain, Masaru Nonaka and Martin F. Flajnik This information is current as of September 26, 2021. J Immunol 2006; 176:3674-3685; ; doi: 10.4049/jimmunol.176.6.3674 http://www.jimmunol.org/content/176/6/3674 Downloaded from References This article cites 70 articles, 21 of which you can access for free at: http://www.jimmunol.org/content/176/6/3674.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 26, 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 Ancestral Organization of the MHC Revealed in the Amphibian Xenopus1 Yuko Ohta,2* Wilfried Goetz,* M. Zulfiquer Hossain,* Masaru Nonaka,† and Martin F. Flajnik* With the advent of the Xenopus tropicalis genome project, we analyzed scaffolds containing MHC genes. On eight scaffolds encompassing 3.65 Mbp, 122 MHC genes were found of which 110 genes were annotated.
    [Show full text]
  • Major Histocompatibility Complex Gene Mapping in the Amphibian Xenopus Implies a Primordial Organization (Evolution͞linkage Groups͞antigen Presentation)
    Proc. Natl. Acad. Sci. USA Vol. 94, pp. 5789–5791, May 1997 Immunology Major histocompatibility complex gene mapping in the amphibian Xenopus implies a primordial organization (evolutionylinkage groupsyantigen presentation) MASARU NONAKA*, CHISATO NAMIKAWA*, YOICHI KATO*, MAKOTO SASAKI*, LUISA SALTER-CID*, AND MARTIN F. FLAJNIK† *Department of Biochemistry, Nagoya City University Medical School, Mizuho-Ku, Nagoya 467, Japan; and †Department of Microbiology and Immunology, University of Miami School of Medicine, P.O. Box 016960, R-138, Miami, FL 33101 Communicated by Irving L. Weissman, Stanford University School of Medicine, Stanford, CA, March 25, 1997 (received for review November 13, 1996) ABSTRACT One of the most provocative recent discov- it is difficult or impossible to identify functional orthologous eries in immunology was the description of a genetic linkage class I genes even among certain primate groups (1, 5–7). Thus, in the major histocompatibility complex (MHC) between two major questions have arisen: (i) why are class I antigen structurally unrelated genes whose products are involved in processing genes in the class II region? and (ii) why is the class processing and presentation of antigens for recognition by T I region unstable relative to classes II and III? lymphocytes. Genes encoding MHC class I molecules, which The Xenopus MHC is remarkably similar to its mouse and bind and present at the cell surface proteolytic fragments of human counterparts (8). Classes Ia (9), IIb (10), and class IIa cytosolic proteins, are linked to nonhomologous genes whose (ref. 11; Lin, Y., and M.F.F., unpublished work), the comple- products are involved in the production and subsequent ment components factor B (Bf; ref.
    [Show full text]
  • Immunobiology of Allograft Human Leukocyte Antigens in the New Microenvironment Mepur H
    www.symbiosisonline.org Symbiosis www.symbiosisonlinepublishing.com Research Article SOJ Immunology Open Access Immunobiology of Allograft Human Leukocyte Antigens in the New Microenvironment Mepur H. Ravindranath*, Vadim Jucaud, Paul I. Terasaki Terasaki Foundation Laboratory, 11570 W, Olympic Blvd, Los Angeles, CA 90064, California, USA Received: August 19, 2015; Accepted: August 28, 2015; Published: October 21, 2015 *Corresponding author: Mepur H. Ravindranath, Terasaki Foundation Laboratory, 11570 W. Olympic Blvd, Los Angeles, CA 90064, USA, Tel: +310- 479-6101 ext. 103; Fax: +310-445-3381; E-mail: [email protected] Abbreviations Absract The antibodies formed by allograft recipients against β2m: β2-Microglobulin; β2m-free HC: β2m-free Heavy donors’ mismatched allo-human leukocyte antigens (allo-HLA) Chain; CTL: CD8+ Cytotoxic T Lymphocytes; DSA: Donor correlate with graft rejection. This review’s aim is to elucidate the Specific Antibodies; HC: Heavy Chain Polypeptide; HLA: Human immunological events associated with allografts’ mismatched HLA Leukocyte Antigens; HLA-I: Human Leukocyte Antigen Class I; from transplantation to acute/chronic rejection. Such clarification may permit more precisely relevant therapeutic strategies that HLA-II: Human Leukocyte Antigen Class II; IFNγ: Interferon-γ; can facilitate better graft survival. The trigger event in the allograft kDa: kilodalton; MHC: Major Histocompatibility Complex; MMP: microenvironment is an inflammatory response, promoting Matrix Metalloproteinase; rHLA: Recombinant HLA; sHLA: overexpression of allo-HLA as dimers or monomers. Overexpression solubleIntroduction HLA of membrane- bound HLA is accompanied by matrix membrane proteases that dissociate and release monomeric HLA from the cell surface, forming soluble HLA (sHLA), and the recipient’s immune components interacting with both membrane-bound and sHLA.
    [Show full text]
  • MHC-Related Molecules in Human Lung Macrophages Suppress
    Extracellular Vesicles from Pseudomonas aeruginosa Suppress MHC-Related Molecules in Human Lung Macrophages David A. Armstrong, Min Kyung Lee, Haley F. Hazlett, John A. Dessaint, Diane L. Mellinger, Daniel S. Aridgides, Gregory M. Hendricks, Moemen A. K. Abdalla, Brock C. Christensen and Downloaded from Alix Ashare ImmunoHorizons 2020, 4 (8) 508-519 doi: https://doi.org/10.4049/immunohorizons.2000026 http://www.immunohorizons.org/content/4/8/508 http://www.immunohorizons.org/ This information is current as of October 1, 2021. Supplementary http://www.immunohorizons.org/content/suppl/2020/08/20/4.8.508.DCSupp Material lemental References This article cites 56 articles, 11 of which you can access for free at: http://www.immunohorizons.org/content/4/8/508.full#ref-list-1 by guest on October 1, 2021 Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://www.immunohorizons.org/alerts ImmunoHorizons is an open access journal published by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 All rights reserved. ISSN 2573-7732. RESEARCH ARTICLE Innate Immunity Extracellular Vesicles from Pseudomonas aeruginosa Suppress MHC-Related Molecules in Human Lung Macrophages David A. Armstrong,*,1 Min Kyung Lee,†,‡,1 Haley F. Hazlett,§ John A. Dessaint,* Diane L. Mellinger,* Daniel S. Aridgides,* Gregory M. Hendricks,{ Moemen A. K. Abdalla,k Brock C. Christensen,†,‡,# and Alix Ashare*,‡ † *Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756;
    [Show full text]
  • Molecular Genetics of the Swine Major Histocompatibility Complex, the SLA Complex
    Developmental and Comparative Immunology 33 (2009) 362–374 Contents lists available at ScienceDirect Developmental and Comparative Immunology journal homepage: www.elsevier.com/locate/dci Molecular genetics of the swine major histocompatibility complex, the SLA complex Joan K. Lunney a,1,*, Chak-Sum Ho b,1, Michal Wysocki a, Douglas M. Smith b a USDA, ARS, BARC, APDL, Beltsville, MD 20705, USA b Pathology Department, University of Michigan Medical School, Ann Arbor, MI, USA ARTICLE INFO ABSTRACT Article history: The swine major histocompatibility complex (MHC) or swine leukocyte antigen (SLA) complex is one of Available online 27 August 2008 the most gene-dense regions in the swine genome. It consists of three major gene clusters, the SLA class I, class III and class II regions, that span 1.1, 0.7 and 0.5 Mb, respectively, making the swine MHC the Keywords: smallest among mammalian MHC so far examined and the only one known to span the centromere. This Swine leukocyte antigen complex review summarizes recent updates to the Immuno Polymorphism Database-MHC (IPD-MHC) website SLA haplotypes (http://www.ebi.ac.uk/ipd/mhc/sla/) which serves as the repository for maintaining a list of all SLA Swine MHC recognized genes and their allelic sequences. It reviews the expression of SLA proteins on cell subsets and Transplantation their role in antigen presentation and regulating immune responses. It concludes by discussing the role of Genetic control of immunity SLA genes in swine models of transplantation, xenotransplantation, cancer and allergy and in swine Vaccination Class I MHC production traits and responses to infectious disease and vaccines.
    [Show full text]
  • (CYP21A2) Gene and a Non-Functional Hybrid Tenascin-X (TNXB) Gene P F J Koppens,Hjmsmeets,Ijdewijs, H J Degenhart
    1of7 ELECTRONIC LETTER J Med Genet: first published as 10.1136/jmg.40.5.e53 on 1 May 2003. Downloaded from Mapping of a de novo unequal crossover causing a deletion of the steroid 21-hydroxylase (CYP21A2) gene and a non-functional hybrid tenascin-X (TNXB) gene P F J Koppens,HJMSmeets,IJdeWijs, H J Degenhart ............................................................................................................................. J Med Genet 2003;40:e53(http://www.jmedgenet.com/cgi/content/full/40/5/e53) n the human genome, the major histocompatibility complex Key points class III region on chromosome 6p21.3 stands out as an area of remarkably high gene density.12 Within this region, a I • Defectiveness of the CYP21A2 gene causes steroid section of particular complexity centres around the C4 genes, 21-hydroxylase deficiency, a recessively inherited which encode the fourth component of complement.3–7 disorder of adrenocortical steroid biosynthesis. Centromeric to C4 lies the CYP21A2 gene, which encodes ster- oid 21-hydroxylase, a key enzyme in the biosynthesis of corti- • CYP21A2 is part of a tandemly repeated structure sol and aldosterone.489 The TNXB gene, which encodes the known as the RCCX module, which may misalign during extracellular matrix protein tenascin-X, lies centromeric to meiosis. CYP21A2 and is transcribed from the opposite strand.10–12 Telo- • A paternal de novo deletion of CYP21A2 contributed to meric to C4 lies the RP1 gene, encoding a putative simple virilising steroid 21-hydroxylase deficiency in a serine/threonine kinase.13–15 A typical chromosome 6 carries a patient who inherited the I172N mutation from his duplication of an area of approximately 30 kb encompassing mother.
    [Show full text]
  • Notes C-9: Immunology
    C-9: IMMUNOLOGY UNIT-III Major Histocompatibility complexes class I & class II MHC antigens, antigen processing and presentation. NOTES Major Histocompatibility Complex MHC complex is a large genomic region or group of genes found in most vertebrates on a single chromosome that codes the MHC molecules which plays a vital role in immune system. Major histocompatibility antigens (also called transplantation antigens) mediate rejection of grafts between two genetically different individuals. HLA (human leukocyte antigens) were first detected on leukocytes and so they are called MHC antigens of humans. H-2 antigens are their equivalent MHC antigens of mouse. A set of MHC alleles present on each chromosome is called an MHC haplo-type. Monozygotic human twins have the same histocompatibility molecules on their cells, and they can accept transplants of tissue from each other. Histocompatibility molecules of one individual act as antigens when introduced into a different individual. George Snell, Jean Dausset and Baruj Benacerraf received the Nobel Prize in 1980 for their contributions to the discovery and understanding of the MHC in mice and humans MHC gene products were identified as responsible for graft rejection. MHC gene products that control immune responses are called the immune response genes. Immune response genes influence responses to infections. The essential role of the HLA antigens lies in the induction and regulation of the immune response and defence against microorganisms. The physiologic function of MHC molecules is the presentation of peptide antigen to T lymphocytes. There are two general classes of MHC molecules – Class I and Class II. Class I MHC molecules are found on all nucleated cells and present peptides to cytotoxic T cells.
    [Show full text]
  • Major Histocompatibility Complex (MHC) Markers in Conservation Biology
    Int. J. Mol. Sci. 2011, 12, 5168-5186; doi:10.3390/ijms12085168 OPEN ACCESS International Journal of Molecular Sciences ISSN 1422-0067 www.mdpi.com/journal/ijms Review Major Histocompatibility Complex (MHC) Markers in Conservation Biology Beata Ujvari and Katherine Belov * Faculty of Veterinary Science, University of Sydney, RMC Gunn Bldg, Sydney, NSW 2006, Australia; E-Mail: [email protected] * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +61-2-9351-3454; Fax: +61-2-9351-3957. Received: 11 May 2011; in revised form: 27 June 2011 / Accepted: 5 August 2011 / Published: 15 August 2011 Abstract: Human impacts through habitat destruction, introduction of invasive species and climate change are increasing the number of species threatened with extinction. Decreases in population size simultaneously lead to reductions in genetic diversity, ultimately reducing the ability of populations to adapt to a changing environment. In this way, loss of genetic polymorphism is linked with extinction risk. Recent advances in sequencing technologies mean that obtaining measures of genetic diversity at functionally important genes is within reach for conservation programs. A key region of the genome that should be targeted for population genetic studies is the Major Histocompatibility Complex (MHC). MHC genes, found in all jawed vertebrates, are the most polymorphic genes in vertebrate genomes. They play key roles in immune function via immune-recognition and -surveillance and host-parasite interaction. Therefore, measuring levels of polymorphism at these genes can provide indirect measures of the immunological fitness of populations. The MHC has also been linked with mate-choice and pregnancy outcomes and has application for improving mating success in captive breeding programs.
    [Show full text]
  • BMC Genomics Biomed Central
    BMC Genomics BioMed Central Research article Open Access A genome-wide survey of Major Histocompatibility Complex (MHC) genes and their paralogues in zebrafish Jennifer G Sambrook1, Felipe Figueroa2 and Stephan Beck*1 Address: 1Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge CB10 ISA, UK and 2Max-Planck-Institut für Biologie, Abteilung Immunogenetik, 72076 Tübingen, Germany Email: Jennifer G Sambrook - [email protected]; Felipe Figueroa - [email protected]; Stephan Beck* - [email protected] * Corresponding author Published: 04 November 2005 Received: 05 June 2005 Accepted: 04 November 2005 BMC Genomics 2005, 6:152 doi:10.1186/1471-2164-6-152 This article is available from: http://www.biomedcentral.com/1471-2164/6/152 © 2005 Sambrook et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: The genomic organisation of the Major Histocompatibility Complex (MHC) varies greatly between different vertebrates. In mammals, the classical MHC consists of a large number of linked genes (e.g. greater than 200 in humans) with predominantly immune function. In some birds, it consists of only a small number of linked MHC core genes (e.g. smaller than 20 in chickens) forming a minimal essential MHC and, in fish, the MHC consists of a so far unknown number of genes including non-linked MHC core genes. Here we report a survey of MHC genes and their paralogues in the zebrafish genome.
    [Show full text]