1. Chapter 9
Immunogenetics

2. Immune responses

3. Innate Immune Response I
Types of innate immune response
phagocytes
The complement system
natural killer cells
MBL : mannose-binding lectin
MASP : MBL-associated serine proteases

4. Innate Immune Response II
recognition by cell-surface receptors (eg. the Toll-like receptor)
lipopolysaccharides and peptidoglycans of bacteria
unmethylated CpG motifs of bacterial DNAs
ds RNAs of virus

5. Adaptive immune response

6. Humoral immune system I
Class II MHC molecules in antigen-presenting cells carry foreign peptides to the surface of the cell, where the foreign peptide is recognized by a helper T cell. The T cell secretes cytokines, which stimulate B cells whose immunoglobulins will bind to the foreign peptide. These B cells become plasma cells, which secrete antibodies into the circulation to bind with the microbe, helping to combat the infection. (Modified from Nossal GJ: Life, death and the immune system. Sci Am 1993;269:53-62.)

7. Humoral immune system II

8. Cellular immune system I

9. Cellular immune system II
ABC transporter

10. Cellular immune system III

11. Cellular immune system IV

12. Lymphocyte Activation

13. An antibody molecule

14. Immunoglobulin Genes chromosome 2: κ light chain
chromosome 14 (4 gene segments): heavy chains (γ, μ,α,δ, and ε)

15. Immunoglobulin Genes and Structure
light chain: C, V, J genes
heavy chain: C, V, D, J genes

16. Basis of Immunoglobulin Diversity
multiple germline immunoglobulin genes
more than 80 different V segments
6 different J segments
more than 30 different D segments
somatic recombination (VDJ recombination)
light chain: recombination of V and J
heavy chain: recombination of V, D, and J
deletion by recombinases encoded by RAG1 and RAG2 genes (11p13), and joining by ligases
Junctional diversity
varied amino acid sequences at the junctions
somatic hypermutation
secondary differentiation of B-lymphocytes by stimulation by a foreign antigen
multiple combination of heavy and light chains

17. Immunoglobulin Diversity

18. Somatic VDJ recombination and somatic hypermutation

19. T-cell Receptors similar to immunoglobulins, but not secreted
heterodimers (90% αβ and 10% γδ)
α,δ on chromosome 14
β,γ on chromosome 7
T-cell receptor diversity
multiple germline gene segments
VDJ somatic recombination
junctional diversity
but no somatic hypermutation → tolerance of self peptide and recognition of MHC molecules

20. MHC class I molecules expressed on the surface of nearly all cells
complex formation with foreign peptides → recognized by receptors on the surface of cytotoxic T-lymphocytes

21. MHC class I molecules heterodimers class I loci
a heavy glycoprotein chain α
a light chain (β2-microglobulin, in chromosome 15)
class I loci
HLA-A, -B, and -C: in 1.8 Mb, highly polymorphic, each dozens of alleles
additional genes and pseudogenes

22. MHC class II molecules
expressed on the surface of antigen-presenting cells (phagocytes and B-cells)
association with foreign peptides → recognized by receptors on the surface of helper T cells
heterodimer (α,β)
class II loci
HLA-DP, -DQ, and -DR on chromosome 6
highly polymorphic
cf. TAP1 and TAP2 in class II region: transporter proteins

23. Significance of polymorphic MHC molecules
results of natural selection for allelic variability
providing effective defense against a variety of pathogens
some specific actions of MHC molecules
HLA-B53: protective against malaria
HLA-DRB1 1302: protective against hepatitis B
MHC restriction required for T cell functions and natural killer cells, but not for complement systems
different class I and class II MHC molecules among individuals
same class I and class II MHC molecules within an individuals
different T-cell receptors and immunoglobulins from cell to cell within an individuals

24. Chromosome Location and Function of Major Immune Response Genes

25. MHC-Disease Association
linkage disequilibrium (no causal links)
HLA-A3 ↔ hemochromatosis
HLA-DQA1 and -DQB1 ↔ narcolepsy (the hypocretin type 2 receptor gene nearby)
causal associations
HLA-DQB1: undefined autoimmunity → type 1 diabetes
HLA-B7: infection of a specific microbe and then autoimmunity → ankylosing spondylitis
maybe resulted from cross-reaction in which the immune system mistakes formolecular mimicry of foreign peptides

26. Examples of Major Histocompatibility Complex and Disease Associations

27. ABO system genes: a single gene on chromosome 9 (IA, IB, IO)
N-acetylaminogalactosyltransferase : A enzyme
Galacosyltransferase : B enzyme
A, B antigen expression on erythrocyte surface

28. Rh system genes: D*, C, E on chromosome 1
DD, Dd: Rh positive dd: Rh negative
anti-Rh antibody production by a direct stimulus
Rh maternal-fetal incompatibility (DD, Dd father and dd mother)
erythroblastosis fetalis and anemia resulting from hemolysis (hemolytic disease of the newborn, HDN)
spontaneous abortion or stillbirth
cerebral damage after birth (mental retardation, cerebral palsy, deafness)
prevented by Rh immunoglobulin
cf. A, B, O maternal-fetal incompatibility
a mother with type O/a fetus with type A or B
mild symptoms, protect against Rh incompatibility

29. B-cell immunodeficiency diseases
X-linked agammaglobulinemia (XLA)
mainly male, XR, no B cells, no IgG
by mutations of a B-cell tyrosine kinase (Bruton's tyrosine kinase, BTK)
treated by γ-globulin administration
autosomal B-cell immunodeficiency
by mutations of immunoglobulin chains

30. T-cell immunodeficiency diseases
affecting T-cells → affecting B-cells → severe combined immune deficiency (SCID)
by mutations of γ chains of cytokine receptors (IL 2, 4, 7, 9, 15, and 21) → X-linked SCID
50% of SCID, XR
by mutation of JAK3 gene
autosomal SCID, similar to X-SCID
by adenosine deaminase (ADA) deficiency
15%, autosomal SCID
buildup of purine metabolites
treated by bone marrow transplantation and gene therapy
by mutations of RAG1 and RAG2
abnormal VDJ recombinations of T-cell and B-cell receptors

31. Bare lymphocyte syndromes
BLS I (rare)
by mutations of TAP2 (or TAP1, TAPBP) gene
no MHC I expression → reduced number of functional T and B cells
BLS II (major)
by mutations of transcriptional factors for MHC II expression
class II trans-activator (CIITA)
regulatory factor of the X box 5 (RFX5)
RFX-associated protein (RFXAP)
RFX ankyrin repeats (RFXANK; also known as RFXB)
no MHC II expression on APC → no antibody production

32. Chronic granulomatous disease (CGD)
Abnormal NADPH oxidase (PHOX) in phagocytes
by mutations of a subunit of cytochrome b, XR (gp91 protein, p91-PHOX)
by mutations of some autosomal genes, AR
difficulty forming the reactive oxygen compounds (most importantly, the superoxide radical) used to kill certain ingested pathogens
normal phagocytosis of pathogenes, but no killing → forming granulomas → recurrent severe infections
superoxide

33. Primary Immunodeficiency Diseases