Immunogenetics Marie Cern

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Immunogenetics Marie Cerná
Lecture No 635-T
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Immune system

• belongs to basic homeostatic mechanisms of
  organism
• Its function is maintaining the integrity of
  organism by recognition of harmful from harmless,
  and by this way it protects organism against
  injurious matter of external and internal origin.

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Immunogenetics

• Study characters of heredity laws of antigen
  recognitions.

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• An antigen is any substance
• biological / chemical, natural /
  artificial,
• self / nonself
• that elicits an immune response.

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Immunity

• Innate immunity
• First line integrity of the skin and the mucosa
• Second line nonspecific defense itself
• - cellular components
• - humoral components
• Acquired immunity
• - cellular components
• - humoral components

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Innate immunity

• First line
• integrity of the skin and the mucosa
• defense mechanisms
• mechanical (movement of cilia)
• chemical (fatty acids, pH 3-5, lysozyme)
• microbial (normal microbes)

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Innate immunity

• Second line nonspecific defense itself
• - cellular components
• phagocytic cells
• natural killer (NK) cells
• - humoral components
• complement system
• interferons

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Acquired immunity

• Specific defense only in vertebrates
• - cellular components
• T - lymphocytes
• B - lymphocytes
• - humoral components
• antibodies produced by B - lymphocytes
• Induction of immunological memory

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Acquired immunity
antibodies T effector cells plasma cells foreign antigen lymphoblasts B lymphocytes T lymphocytes humoral immunity cell immunity
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Acquired immunity

• Vertebrates react selectively against a
  broad spectrum of foreign antigens.
• Large variability of specific immune reactions is
  encoded in the genome.
• Specific selective respond results from somatic
  recombination and rearrangement of genes (antigen
  receptors TCR and Ig) and also huge gene
  polymorphism (antigen-presenting molecules
  HLA).

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Accessory chains
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Antigen receptors

• Immunoglobulins (Ig) humoral (cellular)
• L light chain 2 isotypes ? ?
• H heavy chain 5 isotypes µ, d, ?, e, a
• T cell receptors (TCR) cellular
• a chain (or d chain)
• ß chain (or ? chain)
• Each chain contains
• - constant region C
• - variable region with V, (D), J subregions
• - region for antigen binding

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Immunoglobulins (Ig) 2 heavy, 2 light chains
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Genetic Diversity

• Genes are rearranged, during activation of
  lymphocytes, differently and specifically for
  every cell somatic recombination
• Allelic exclusion
• Each antibody (receptor of T lymphocyte)
  contains the combination of 2 chains (HL, aß)
  of one type - active genes only on 1 chromosome
• (transcription from 1 allele/haplotype)

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Genetic Diversity

• The combinations of V, D and J segments
• V 1-100 variable segment
• D 1-20 diversity segment
• J 1-10 joining segment
• Inaccuracy in lining these segments
• Random insertion of nucleotides at the joints
  between the segments
• Somatic mutations in the J segment

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Somatic recombination
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T cell receptors (TCR)
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T cell receptors (TCR)
a chain and d chain loci V-J combinations
ß chain locus V-D-J combinations (IgH locus)
? chain locus V-J combinations locus
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Genetic diversity in Ig and TCR genes
Mechanism Immunoglobulin H chain L chain TCR a b
Variable domains 250 1 000 250 75 25
Number of D segments 12 0 0 2
Number of J segments 4 4 50 12
Segment Combinations 65 000 - 250 000 1 825
Total diversity 1011 1016

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Antigen presenting systembinding to TCR

• Major histocompatibility complex (MHC) a
  group of genes on one chromosome. This gene
  complex was discovered after observation that
  histocompatibility, i.e. the ability to accept
  graft (transplant), depends on fact if the donor
  and recipient share the same MHC haplotype.
• MHC antigens of man
• Human leukocyte antigens
• - first detected on leukocytes

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HLA complex

• contains three classes of genes (I, II, III)
• one of the most polymorphic loci in human genome
• (5 500 alleles)
• is inherited en bloc as a haplotype

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HLA complex
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HLA class I and class II

• transmembrane proteins
• presenting antigens to TCRs on T- lymphocytes
• - TCRs recognize antigens only in context with
  MHC molecules
• part of cellular immune response
• class I - serologicaly defined antigens
• contains genes, each gene encodes one alpha
  chain
• classical A, B, C on all nucleated cells
• recognized by cytotoxic CD8 T-lymphocytes
• non-classical E, F, G on certain tissues
  (placenta)
• recognized by NK cells (inhibition effect on NK
  cells)
• class II region D - cellularly defined antigens
• loci DP, DQ, DR, each locus contains alpha
  beta chains
• on antigen-presenting cells (macrophages, B
  lymphocytes)
• recognized by helper CD4 T-lymphocytes
  

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HLA class III

• mostly serum proteins
• part of humoral immune response
• other genes without any function in
  immune responsiveness
• Complement system molecules C2, C4, Factor B
• Cytokines tumor necrosis factor (TNF)
• Heat shock proteins (HSP)
• Enzyme 21-hydroxylase
• (mutation cases congenital adrenal hyperplasia)
• The gene for hemochromatosis

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HLA class I

• The extracellular part of the alpha chain
  contains 3 domains ?1 ?2 ?3
• (ß2 microglobulin is coded on chromosome 15)
• Polymorphic ?1 and ?2 domains bind antigenic
  peptides.

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HLA class II

• The extracellular parts of the beta and alpha
  chains contain 2 domains
• ß1 ß2 and ?1 ?2
• Polymorphic ß1 and ?1 domains bind antigenic
  peptides.

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Allele polymorphism of HLA complex
region class I class I class I class I class I class I class II class II class II class II class II class II class II
classical classical classical non-classical non-classical non-classical DR DR DR DQ DQ DP DP
gene A B C E F G DRA DRB DRB1 DQA1 DQB1 DPA1 DPB1
No of alleles 965 1543 626 9 21 46 3 855 762 35 107 28 138

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• One haplotype haploid genotype
• group of alleles on one chromosome
• - each parent has two haplotypes and transmits
  one of them to his child
• Genes are closely linked gt
• alleles are transmitted together
• Alleles are codominant

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JEAN DAUSSET (1916-2009) 1980 Nobel Prize for
HLA discovery in Physiology and Medicine

• 1952 - white cell agglutination
• induced by serum antibodies
• 1958 - the first leukocyte antigen
• the cardinal words of HLA
• transplantation
• cellular immunology
• predictive medicine
• anthropology

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Transplantation and MHC

• MHC match - graft is accepted
• donor recipient have the same MHC
  antigens/alleles
• MHC mismatch - graft is rejected
• donor recipient have different MHC
  antigens/alleles
• Graft versus host reaction
• (in bone marrow transplantation with MHC
  mismatch)
• Immunosuppression of recipient gt
• T lymphocytes of donor react against cells of
  recipient

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Transplantation laws

• 1. H1H1 H1H1
• 2. H1H1 X H2H2
• 3. H1H1 x H2H2
• X X
• F1 H1H2

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Transplantation and HLA

• Organs or tissue
• Immunology examination
• virology (HIV,HBV,CMV)
• ABO and Rh compatibility
• crossmatch testing antibody detection
• - recipient HLA antibodies (after
  transfusions or deliveries) against donor HLA
  molecules

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Transplantation and HLA

• Bone marrow
• full HLA match for all genes
• (A,B,C, DR,DQ,DP)
• Kidney (and pancreas)
• crossmatch - negative
• half HLA match for 3 genes
• (class I - A, B, class II - DR)
• Liver, lung, heart
• crossmatch - negative

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Transplantation and HLA

• Register of bone marrow donors
• Waiting list of kidney recipients

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Predictive Medicine HLA association with
autoimmune diseases
 
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AnthropologyPopulation studies

• American Indians have remarkable degree of
  restriction of the HLA polymorphism
• North American Caucasians - 27 DR alleles
• North American Indians - 20 DR alleles
• Argentinean Indians - 8 DR alleles
• Brazilian Indians - 5 DR
  alleles

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Blood groups systems
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Blood groups A, B, AB, O chromosome 19 -
antigen H precursor (hh Bombay allele)
chromosome 9 - antigens A, B
group genotype agglutinin in serum
A AA, Ai anti B
B BB, Bi anti A
AB AB -
0 ii anti A, anti B
subgroups A 1-5 subgroups B 1-2
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Blood Group Antigens Antibodies Donor for Recipient from
AB A and B none AB AB, A, B, 0
A A B A and AB A and 0
B B A B and AB B and 0
0 none A and B AB, A, B, 0 0
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Rh system chromosome 1 Rh antigens
DD, Dd, dd (C, E) Rh 83 Rh -
17 Maternal-fetal incompatibility
mother Rh- (dd) father Rh (DD, Dd)

baby Rh (Dd) Antibodies (IgG) from maternal
serum cross the placenta and lyse the red cells
of fetus! MN system Blood
groups M genotypes MM
N
NN
MN
MN
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Literature

• Genetics in Medicine, sixth edition, revised
  reprint
• Thompson Thompson
• Saunders, 2004
• Chapter 14 Genetics of the Immune System
• The Major Histocompatibility Complex,
  Immunoglobulins, The T-Cell Antigen Receptor
  pages 277 285

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Literature

• Medical Genetics at a Glance, second edition,
• Dorian J. Pritchard Bruce R. Korf
• Blackwell Publishing, 2008
• Part 2 Medical genetics 42
• pages 102 103