Transcript Document

Immunogenetics
Marie Černá
Lecture No 635-T
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.
Immunogenetics
Study characters of heredity laws of
antigen recognitions.
An antigen is any substance:
biological / chemical,
natural / artificial,
self / nonself
• that elicits an immune response.
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
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)
Innate immunity
Second line – nonspecific defense itself
- cellular components:
phagocytic cells
natural killer (NK) cells
- humoral components:
complement system
interferons
Acquired immunity
Specific defense only in vertebrates
- cellular components:
T - lymphocytes
B - lymphocytes
- humoral components:
antibodies produced by B - lymphocytes
Induction of immunological memory
Acquired immunity
antibodies
plasma cells
T effector cells
foreign antigen
B lymphocytes
humoral immunity
lymphoblasts
T lymphocytes
cell immunity
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).
Accessory chains
Antigen receptors
Immunoglobulins (Ig) – humoral (cellular)
• L – light chain – 2 isotypes  + 
• H – heavy chain – 5 isotypes μ, δ, γ, ε, α
T cell receptors (TCR) – cellular
• α chain (or δ chain)
• β chain (or γ chain)
Each chain contains:
- constant region C
- variable region with V, (D), J subregions
- region for antigen binding
chromosome No:
Immunoglobulins (Ig)
2 heavy, 2 light chains
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
(H+L, α+β) of one type - active genes only
on 1 chromosome
(transcription from 1 allele/haplotype)
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
Somatic recombination
IgH locus: V-D-J combinations
C- for M,D,G,E,A constant region - defines Ig class
V1
V100
D1
D20
IgL locus: V-J combinations
Ig L kappa
Ig L lambda
J1 J2 J3 J4 J5
V D
V100
J1 J2 J3 J4J5
V100
J1-10 C1-10
J
C1
C
C
T cell receptors (TCR)
T cell receptors (TCR)
α chain and δ chain loci: V-J combinations
β chain locus: V-D-J combinations (IgH locus)
γ chain locus: V-J combinations locus:
Genetic diversity in Ig and TCR genes
Mechanism
Variable
domains
Immunoglobulin
H chain
L chain
250 – 1 000
a
TCR
b
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
Antigen presenting system
binding 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
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
HLA complex
6
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
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
HLA class I
The extracellular part
of the alpha chain
contains 3 domains:
a1 a2 a3
(β2 microglobulin is
coded on
chromosome 15)
Polymorphic a1 and
a2 domains bind
antigenic peptides.
HLA class II
The extracellular parts
of the beta and alpha
chains contain 2
domains:
β1 β2 and a1 a2
Polymorphic β1 and
a1 domains bind
antigenic peptides.
Allele polymorphism of HLA complex
region
class I
classical
gene
No of
alleles
A
B
class II
nonclassical
C
965 1543 626
G
DR
D
R
A
E
F
9
21 46 3
DR
B
DQ
DP
DR DQ DQ DP
B1 A1 B1 A1
855 762
35
107
28
DP
B1
138
• 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 =>
alleles are transmitted together
• Alleles are codominant
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
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 =>
T lymphocytes of donor react against cells of recipient
Transplantation laws
• 1. H1H1
H1H1
• 2. H1H1
X
H2H2
• 3. H1H1
x
H2H2
X
F1:
X
H1H2
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
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
Transplantation and HLA
• Register of bone marrow donors
• Waiting list of kidney recipients
Predictive Medicine
HLA association with autoimmune diseases
Anthropology
Population 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
Blood groups systems
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
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
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
N
MN
genotypes: MM
NN
MN
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
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