Immunogenetics

1
• Immune response represents a system of
recognition of foreign molecules.
• Foreign molecules (proteins, glycoproteins,
carbohydrates, ssDNA, viruses) or parts of foreign
molecules are called antigens.
• When foreign molecules enter in bloodstream
immune system starts specific recognition of
antigens and their destroying.

2
• Components responsible for immune response:
– B lymphocytes (bone)
– T lymphocytes (thymus)
– macrophages
• Each type of lymphocytes ensures synthesis of
different proteins responsible for immune
response.

3
 Immunodeficiency
Type Origin Consequence

Deficiency of B- Genetic defects in Viral infections

lymphocytes maturing of B-
lymphocytes

Deficiency of T- Genetic defects in Intracellular infections

lymphocytes maturing of T-
lymphocytes

Deficiency of B- and T- Mutations in genes for SCID (Severe Combined

lymphocytes interleukins, deficiency of Immune Deficiency) –
ADA (adenosin- any pathogen
desaminase), absence of
MHC
4
Macrophage Mutations in genes Chronic
deficiency coding subunits of granulomatosis
cytochrome B (intracellular digestion
absent)

Complement Affected complement High susceptibility for

deficiency infections

5
6
 Immune response

Humoral Cellular
• Determined by B-  Determined by
lymphocytes; T-lymphocytes;
• Mediated by  Mediated by
antibodies. TcR.

7
 Humoral response
• Production of Ab responsible for recognition of Ag.
• Ag interact in bloodstream with Ab and produce complexes Ab-
Ag;
• Complexes Ab-Ag interact with other components of immune
system:
– Ab-Ag is recognized by complement - 20 proteases, which
destroy complexes, or
– Ab-Ag is recognized by macrophages, which destroy
complexes.
• For secretion of Ab an interaction between B-cells with specific
type of T-cells, called T-helper is required.

8
 B-cell

Secretion of antibodies, mediated

by T-helpers

Antibody Antigen

Antibody-antigen
complex

9
Macrophage Complement
 Cellular response
• Determined by T-lymphocytes, called cytotoxic T-
cells (T-killer).
• Takes place in case of:
– Infections
– Reaction of tuberculine
– Rejection of tissues.
• Viral Ag are exposed on surface of the cell by, MHC
(major histocopatibility complex).
• Complexes MHC-Ag are recognized by T-cell
receptors (TcR).

10
 Infected cell

Antigen + MHC TcR

T-killer cell

11
• !!! both Ig, and TcR never attack self
protein – tolerance.
• If organism loose tolerance – autoimmune
disease.

12
Main principles of immune response
• After contacting an Ag, organism become immune. It is
resistant to repeated attack..

• Organism contains 106-108 T and B immature lymphocytes.

Each type of lymphocyte is able to produce a single type of
antibody or TcR.

• Under antigenic attack Ab orTcR of some clones interacts with

foreign molecules:

– These clones rapidly proliferate producing immune

molecules (primary immune response);

– After antigen is destroyed, these cells are transformed in

memory cells. Under repeated attack of the same antigen,
memory cells are activated rapidly and produce secondary 13
 Antigen X

Clone selection

Antibodies anti-X
14
• Ab orTcR interact with a fragment of
antigen (5-6 amino acids).
• May be several types of lymphocytes
against the same antigen; among them
one is the most effective.

15
• Genes for immune system represent a superfamily
of immune genes:
– Genes for Ab
– Genes for TcR
– Genes for complement
– Genes for MHC ...

• These genes developed by repeated duplications

of an ancestral gene.

16
 Structure of antibody
• There are 106-108 types of antibody in organism.
• Each antibody represents an immunoglobuline which
consists of:
– 2 identical L-chains
•  (60%)
• λ (40%)
– 2 identical H-chains.
• Each chain contains:
– N variable end (V)
– C constant end (C).

17
18
• There are numerous gene segments (V and C) for each
type of polypeptide dispersed in chromosomes 2, 14
and 22.

• For synthesis of polypeptides junction of V and C

segments is required during somatic recombination
between sister chromatids.

• Arrangement of different V and C segments is

different among different lymphocyte clones as well
as STEM cells and somatic cells.

19
 Segments of immunoglobulin genes

Family Chrs. % V J D C

κ(Kappa) 2p12 60 300 5 0 1

λ(Lambda) 22q11 40 300 6 0 6

H (Heavy) 14q32 100 300 6 20 9

20
 Genes for immunoglobulin
contain:
• Many segments for variable region (V),
• Junction segments (J),
• Diversity segments (D)
• Segments for constant region(C).

21
1 2 125 299 300 1 2 6
L V L V L V L V L V J C J C J C

Recombination
1 2 125 2 6
L V L V L VJ C J C

Transcription
125 2
L VJ C
5’ 3’

RNA processing
5’ AAAAAAA

Translation

Polypeptide processing

IgL Lambda 22
1 2 99 299 300 1 2 3 4 5 6
L V L V L V L V L V J J J J J J C

Recombination
1 2 99 2 3 4 5 6
L V L V L VJ J J J J C

Transcription
99 2 3 4 5 6
L VJ J J J J C
5’ 3’

RNA processing
2J
5’ AAAAAAA

Translation

Polypeptide processing

IgL Kappa 23
1 2 300 1 2 3 20 1 2 3 4 5 6
L V L V L V DDD D J J J J J J C C C

1st recombination
1 2 300 1 2 35 6
L V L V L V D D DJ J C C C

1 2 2nd recombination
L V L V C C C

Transcription
C C C
5’ 3’

RNA processing

5’ AAAAAAA

Translation

Polypeptide processing 24
IgH
• Antibodies activate in different environment.
• Type of antibody is determined by variant of
C segment in H-chain.
• There are 5 types of CH, so 5 classes of
antibodies.

25
 Main classes of antibodies

Type IgM IgD IgG IgA IgE

H-chain μ δ γ α ε

% 5% 1% 80% 14% <1%

Tolerance
Activates the Activates the Allergic
Function complement
(in
complement
In secrets
response
membrane)

26
 Mechanisms of antibody
diversity

• Existence of many gene segments

• Somatic recombination
• Alternative splicing
• Polyallelism
• Allelic exclusion
• Erorrs of recombination
• Somatic mutations

27
 MHC
(Major Histocompatibility Complex)
• Multigenic, polymorphic system
• Located on 6p
• important in activation of cellular immune
response
• Important for transplantation
• There are 3 types of genes

28
• 1st Class
– HLA A, B, C genes which encode Ag on surface of all
cells
• 2nd class
– Surface Ag HLA D on macrophages, activated B, T-
lymphocytes
• 3rd class
– Seric proteins, membrane receptors involved
immune reactions (Bf, C2, C4 factors)
– Heterogeneous proteins(HSP, TNF,β)

29
 Interferon
• Variable proteins, M=15-30 kDa
• Synthesis induced by antigens
• Have nonspecific antiviral activity, inhibition of viral
proteins, but not self
• Activate macrophages

30
 Immune tolerance

• Inability to recognize as foreign antigens,

which are not self

• Interaction with Ag during foetal

development

31
 Immunodeficiency

• Absence or abnormal activity of

components of immune system
• May be primary or secondary
• Primary may be hereditary or acquired

32
 Immunodeficiency

• Increased susceptibility to some

pathogens
• Severe infections
• Tumorogenesis
• Autoimmune diseases

33
 Autoimmune diseases
• Absence of tolerance to self antigens
• Production of self-antibody

34