Basics if Immunogenetics by Prof. Mohamed Labib Salem Prof. of Immunology, Tanta University

1. IMMUNOGENETICS
Mohamed Labib Salem
Prof. of Immunology
Faculty of Science, Tanta University

2. Talk Agenda
1. Definition of immunogenetics
2. Basic of immune responses
o Innate immunity
o Adaptive immunity
3. Diversity for specificity
o BCR
o TCR
o HLA
4. Diseases associated with
immunodeficiency

3. How are re we different and why?

4. How are re we different and why?

5. Talk Agenda
1. Definition of immunogenetics
2. Basic of immune responses
o Innate immunity
o Adaptive immunity
3. Diversity for specificity
o BCR
o TCR
o HLA
4. Diseases associated with
immunodeficiency

6. Immunogenetics as a discipline
The study of the genetic control
of the cells and molecules that
shapes immune responses
against infectious
microorganisms

7. Immunogenetics as a discipline
It focuses on:
1. Structure and organizations of genes
mediating immune responses
2. HLA antigens and their association
with disease
3. Generation of antibody diversity
4. Generation of T cell diversity

8. Immunogenetics: Specificity
1. Specificity: Is a key feature of the
adaptive immune system
2. Ability of the immune system to
distinguish between antigens
3. It ensures that distinct antigens
elicit specific responses

9. Polymorphism
• The human genome contains an estimated 32,000 genes
that encode mRNAs for proteins.
• To protect us, our immune system has the ability to
produce about 1010-1011 different antibodies.
• How can our immune system produce so many different
antibodies with so few genes?
• How is Ig diversity specified genetically?
Polymorphism→ diversity

10. Immunogenetics
• Specificity and polymorphism
– specificity is attributed to highly variable
lymphocyte receptors ( BCR and TCR ) and
immunoglobulins
– Unique specificity of antigen receptors and the
ability to react selectively against a very broad
range of foreign antigens is a result of
polymorphism
– Polymorphism means existence of two or more
alternative forms or variants of expressed proteins
in a population

11. Talk Agenda
1. Definition of immunogenetics
2. Basic of immune responses
o Innate immunity
o Adaptive immunity
3. Diversity for specificity
o BCR
o TCR
o HLA
4. Diseases associated with
immunodeficiency

12. Because of too many
antigen we need to too
many specificities
“Diversity”

18. Antigens

19. Antigen
Recognition • Antigens
 Processed, Unprocessed
 Endogenous, exogenous
 Self, Foreign
• Receptors
 Ag-specific adaptive
 PRRs ->innate

20. Innate
&
Adaptive
Immune
Cells

21. Levels of immune response

23. Talk Agenda
1. Definition of immunogenetics
2. Basic of immune responses
o Innate immunity
o Adaptive immunity
3. Diversity for specificity
o BCR
o TCR
o HLA
4. Diseases associated with
immunodeficiency

25. MHC restriction of immune response
TCR/BCR TCR/BCR

26. Immunogenetics
• Immunoglobulin superfamily
Polymorphic immune molecules belong
to a large family of proteins that contain a
globular structure motif - Ig domain.
they all possess a domain known as an
immunoglobulin domain or fold
This group of proteins is called
immunoglobulin super family

27. • There are about 40 members of immunoglobulin
superfamily:
– Recognition and regulation molecules:
• Ig, BCR, TCR, MHC molecules, CD2, CD3, CD4, CD8
molécules, Fc receptors
– Adhesion molecules (e.g. ICAM-1, ICAM-2,
VCAM-1, PECAM-1)
– Receptors for PDGFR (= platelet growth factor
receptor)
– Transporter associated with antigens (TAPI and TAO2)
Immunogenetics

28. • Immunoglobulin gene superfamily
– Genes that encode immunoglobulins (antibodies) ;
BCR, TCR on cell surface molecules ; and MHC
molecules
– Appear to be evolutionary related genes
– Members of a family share a certain degree of
sequence homology
– Are likely to have been derived from a common
precursor gene
Immunogenetics

29. • The most polymorphic molecules of the human immune
system
Immunoglobulins
[antibodies]
MHC molecules
[membrane
glycoproteins]
TCR
(T-Cell Receptor)
BCR
(B-Cell Receptor)
Members of the
immunoglobulin
superfamily
Immunogenetics

30. GENES encoding Ig, BCR and TCR: germline
organization
Cell and Xsome carrying the genes
Ig (BCR) Heavy chain locus B-cell, Chromosome # 14
Ig (BCR) Light chain locus B-cell, Xsome # 2 (k), 22 (l)
TCR b chain T-cell, Xsome # 7
TCR a chain T-cell, Xsome # 14
MHC class I genes All nucleated Xsome # 6
MHC class II genes APC, Xsome # 6

31. BCR, TCR

32. BCR, TCR

33. Antibody Molecules
• The molecule has a "Y" shape,
with the two ends of the fork
• 2 heavy chains plus 2 light
chains, joined together by
disulfide bridges.
• Variable (V) regions form antigen
binding sites which specifically
bind particular antigens
• Each Ab molecule has 2 identical
Ag binding regions, and thus the
Ab molecules can bind together
large groups of Ag's.

34. • Each light (L) chain has 2 domains, a variable (V) region and
a constant (C) region.
– There are only a small number of C regions in each
person, but there are very many different V regions.
– Note that the V and C regions are together on the same
polypeptide chain!
• Each heavy (H) chain has 4 domains, a V domain followed
by 3 C domains.
• The C domains determine the 5 classes of antibodies: IgM
(early response), IgG (main blood Ig), IgA (in body
secretions), IgE (allergic response), and IgD (mostly a cell
surface molecule in the early response).
• In many cases, the constant class-specific regions of the H
chains bind to receptors on the surface of specific cells.
For instance, IgA binds to secretory cells so it gets secreted
into tears, mucus, etc.
Antibody Molecules

35. • Genes for immunoglobulin (antibodies)
– Expression of genes for Ig occurs in B-cells
– Antibody genes are composed of segments
– Gene of Ig heavy chain …chromosome 14
– Genes for Ig kappa and lambda on chromosome 2
and 22 respectively
Antibody Molecules

36. BCR genetics
D-diversity, J-joining, V-variability, C-constant
Chromosome 14

37. – During B-cell maturation in the bone marrow, Ig gene
segments are rearranged and generated into more
than 1010 combinations of V region.
– Each B cell has a unique combination and is
antigenically committed to a specific epitope.
– After antigenic stimulation, further rearrangement of
C-region gene segments can generate changes in
isotypes without changing the specificity of Ig.
– Genomic rearrangement is an essential feature of
lymphocyte differentiation, and no other vertebrate
cell type has been shown to undergo this process.
Antibody Molecules

38. Generation of diversity
• Antigens – 1011 (100 billion)
• Mechanisms – before and after contact with antigen
 V(D)J recombination
 Junctional diversity
 Combinations of receptor chains
 Somatic hypermutation (affinity maturation)

39. TCR genetics
chain chromosome V D J C
α 14 50 - 70 1
β 7 57 2 13 2

40. Major Histocompatibility Complex
(MHC)
• The MHC is a closely linked complex of genes that govern
production of histocompatibility between individuals and
species.
• In humans, MHC resides on the short arm of
chromosome 6
• Class I MHC (HLA) proteins are coded in 3 genes (HLA-A,
HLA-B, HLA-C)
• Class II MHC (HLA-D) proteins are code in several loci
(DP, DQ and DR)
• HLA genes are very diverse (polymorphic) i.e. there are
many alleles of the class I and II genes

41. MHC Molecules
• Between the class I and class II gene loci,
there is a third locus (Class III)
• This locus contains genes encoding tumor
necrosis factor, lymphotoxin and two
complement components (C2 and C4)
• Class III antigens do not participate in MHC
restriction or graft rejection

42. Gene structure

43. Location and components
Class I MHC
Class II MHC
RBCs
Professional
APCs
Nucleated cells
A, B, C DP, DQ, DR
Class III codes for other proteins eg complement components, cytokines

44. Class I MHC
• α chain (43kDa), β2 microglobulin (12 kDa)
• β2-microglobulin – genes on chromosome 15
• Can accommodate 10 amino acids
b2-M
a-chain
Peptide

45. Class II MHC
a-chain
b-chain
Peptide
• α chain (34kDa), β chain (29 kDa)
• Can accommodate ~15 amino acids

46. Class I MHC and Class II MHC
MHC Class I MHC Class II
Nomenclature HLA-A, HLA-B, HLA-C HLA-DP, HLA-DQ,
HLA-DR
Found on All nucleated somatic cells Macrophages, B-cells,
Dentritic cells, langerhans
cells of skin and activated
T cells
Recognized by CD8 TC cells CD4 TH cells
Functions Presentation of Ag to TC
cells leading to elimination
of tumor or infected host
cell
Presentation of Ag to TH
cells which secrete
cytokines

47. Polymorphism

48. Application of HLA in medicine
Transplantation
Forensic medicine
Anthropological studies
Regulating immune responses
Disease association

49. Talk Agenda
1. Definition of immunogenetics
2. Basic of immune responses
o Innate immunity
o Adaptive immunity
3. Diversity for specificity
o BCR
o TCR
o HLA
4. Diseases associated with
immunodeficiency

50. impaired function of the immune system (immunodeficiency) resulting in increased
susceptibility to infection.
IMMUNODEFICIENCY
Primary immunodeficiency-PID
intrinsic defect of a component of the immune Most by defects in single genes and are hence
heritable.. rare
Secondary or acquired
secondary to another pathological condition, which adversely affects immune function,

51. CAUSES
1. DNA DAMAGE

52. From a clinical perspective, immuno- deficiencies can be classified into eight categories

53. T AND B CELL IMMUNODEFICIENCIES
Next slide

54. SCID; CLASSIFICATION
About 15 percent of SCID cases are caused by deficiency of adenosine deaminase (ADA), an enzyme
required for the salvage of nucleotides within lymphoid cells. The lack of ADA causes the accumulation of
toxic metabolites of adenosine (deoxy- adenosine and deoxy-ATP) within lymphoid cells, resulting in their
demise.
NO STEM CELLS

55. Mutations of the tyro-sine phosphatase,
CD45, which helps to initiate signaling by the
TCR, results in T−B+ SCID in humans. Mutation
of components of CD3-complex (CD3 γ, ε, and
δ) result in a SCID phenotype. During signal
transduction via TCRs, the protein tyrosine
kinases Lck and ZAP70 are required for
phosphorylation of ITAMs on the intracy-
toplasmic segment of the TCR. Deficiency of
either of these kinases results in rare forms of
SCID.

56. T AND B CELL IMMUNODEFICIENCIES

59. Defects in Leucocyte Migration
protein lymphocyte function-associated antigen-1(LFA-1) LFA- 1 expressed on the
leucocyte surface and its ligand intercellular adhesion molecule- 1 (ICAM-1)
expressed on the luminal surface of activated endothelial cells.
•a common β chain (CD18) with three separate α chains called CD11a, b, and c.
•CD18-CD11a heterodimers form LFA-1,
LAD1 n LAD2

60.  CD18/CD11b Heterodimers form complement receptor 3, (CR3)
 CD18 combined to CD11c forms complement receptor 4 (CR4).
Mutation of the gene encoding CD18 (resulting in the lack of expression of LFA-1,
CR3, and CR4) results in an inherited primary immunodeficiency called leukocyte
adhesion deficiency type 1(LAD1).
sialyl LewisX, which is expressed on the surface of leucocytes,
LAD1
LAD2

61. ANTIBODY DEFICIENCY DISEASES
Brutons tyrosine kinase

62. Ab switch, memory b cells, somatic hypermutation, dendritic cells to prime t
cells,CD80 n 86 upregulation
HYPER IgM SYNDROMES

63. Disease association

64. 6-Feb-21 PEH 210 67