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Chapter 23
Immunogenetics
The immune response in mammals
involves three steps:
1. Recognition of the foreign substance
2. Communication of this recognition to the
responding cells
3. Elimination of the invading agent
Nonspecific immune
responses:
-Inflammation of the infected
tissues resulting in increased
blood flow
-Recruitment of phagocytes to
ingest and destroy
microorganisms
Figure 23.1 A phagocyte stalking a
rod-shaped bacterium.
Antigen:
A substance that is bound by an antibody or T cell receptor is
called an antigen (antibody-generating substance)
Immunogen:
An antigen that elicits an immune response is called
immunogen
B lymphocyte (B cell):
Lymphocyte that differentiate in the bone marrow
T lymphocyte (T cell):
Lymphocyte that differentiate in the thymus
B lymphocyte (B cell):
-Upon receiving signal, B cells differentiate into plasma cells
which produce antibodies
-Upon receiving signal, B cells differentiate into memory B cells
which facilitate a more rapid production of antibodies during a
later exposure to the same antigen
T lymphocyte (T cell):
-Cytotoxic (killer) T cells carry T cell receptor on their cell surface
and kill cells displaying the appropriate antigen
-Helper T cells stimulate B and T cells to differentiate
-Suppressor T cells assist in down-regulating the activity of
plasma cells and cytotoxic T cells
-Memory T cells “remember” the antigen and provide for a rapid
production of cytotoxic T cells subsequent encounters with the
same antigen
The mammalian immune response has two
major components:
1. The antibody-mediated or humoral response
-Production and secretion of antibody into circulatory system
-The antibody/antigen complex are ingested and destroyed by a special
class of white blood cells
-response to foreign cells (e.g. bacteria and fungi) and free viruses
before they infect host cells.
2. T cell-mediated or cellular response
-Production of T cell receptor that coat the surfaces of cytotoxic T cells
-The cytotoxic T cells recognize and kill infected cells of the host
organism
-Responsible for protecting mammals from viral infection
Figure 23.2 The most important cells of the immune
system are derived from bone marrow stem cells by
three separate cell lineages.
Lock-and-key
interaction between
an antigen and an
antibody
Effector function
domain: interaction
of the antibody with
other immune
components
Human IgG molecule
Figure 23.3 (a) Diagram and (b) space-filling
model of antibody structure.
Five Classes of Antibodies
Complement:
-about 20 soluble proteins that circulate in the bloodstream and form large
protein complexes in response to antibody/antigen complexes
-Kill cells by a variety of mechanisms, e.g. punching holes in the cell membrane
-The proteins called complement because it complements the activity of
antibodies in fighting pathogenic foreign cells
Cytotoxic T cell
Helper T cells
Figure 23.5 Structure of a T cell receptor
anchored in the cell membrane.
Major Histocompatibility Antigen:
Distinguishing Self from Non-self
-Major histocompatibility complex (MHC) proteins
are cell surface macromolecules
-In human, MHC proteins are called HLA antigen
(human leukocyte-associated antigen)
-Initial studied in the immune rejections of
transplanted tissues
-Primary function is to distinguish self from non-self
antigens to protect pathogenic microorganisms
-Highly polymorphic, with some genes having up to
100 or more different alleles
Three different classes of MHC proteins
MHC (HLA) class I genes
-Transplantation antigens
-Glycoproteins present on virtually all cells of an organism
-Provide cytotoxic T cells with a mechanism for distinguishing
“foreign” from “self’
MHC (HLA) class II genes
-Polypeptides present on surface of B cells and macrophages
-Binding and present antigens to helper T cells
MHC (HLA) class III genes
-Complement proteins
-Interact with antibody/antigen complex and help destroy them
by proteolysis
Figure 23.6 Organization of the major histocompatibility
complex (HLA) on human chromosome 6.
Figure 23.7
Summary of the immune
response in mammals.
Clonal selection: stimulation
of a B cell producing an
antibody that recognize the
antigen to multiply and
differentiate into plasma
cells all producing the same
antibody.
Clonal
selection
Cytotoxic T cells secrete
perforins to kill the target
Naïve cells:
B and T cells that have
never encountered a
foreign antigen
Figure 23.8 Antibody/antigen complexes
are eliminated by two major pathways.
T cell
Target
cell
Figure 23.9 Lysis of a target cell displaying a foreign
antigen by a killer T cell
Genome Rearrangements during B
Lymphocyte Differentiation
•Lambda light chain genes assembled from two different segments
LlVl (leader peptide and variable region), 51 LlVl (30 functional)
JlCl (joining segment and constant region), 7 JlCl (4 functional)
•Kappa light chain genes assembled from three different segments
LkVk (leader peptide and variable region), 76 LkVk (40 functional)
Jk (joining segment), 5 Jk
Cl (constant region), 1 Ck
•Heavy chain genes assembled from four different segments
LHVH (leader peptide and variable region), 123 LHVH (44 functional)
DH (diversity), 27 DH (25 functional)
JH (joining segment), 6 JH
CH (constant region), 9 CH
51 LlVl (30 functional)
7 JlCl (4 functional)
Figure 23.10 The genetic control of human antibody lambda light chains.
Figure 23.11
The genetic control human antibody heavy chains.
Figure 23.12 Abbreviated
model of Vk-Jk joining.
Sequence-specific recombination:
complementary RSS sequences
RSS,
Recombination signal sequences
Heptamer-spacer-nonamer
RAG,
recombination-activating gene,
endonuclease
Artemis,
repair DNA double strand break
Figure 23.13 Antibody
diversity at the Vk-Jk
junction is produced by
variation in the exact
position of the joining
reaction.
Additional Diversity of Antibody:
•Variable joining sites
VkJk
VlJl
VHDHJH
•Somatic hypermutation
Variable region (2%)
Antibody Class Switching
- B cells can switch from the
production of one class of
antibody to another class
- Genome rearrangement
(Figure 23.11)
- Alternative splicing
(Figure 23.14)
Figure 23.14 Antibody class switching
may occur by alternate pathways of
transcript splicing.
Allelic Exclusion:
Only One Functional Rearrangement per Cell
•Each plasma cell produces only one type of antibody
•One of the allele is excluded from being expressed in
the diploid B cells
•Only one productive genome rearrangement of light
chain and heavy chain coding sequences occur
during the differentiation of each B cell.
•Both alleles are sometimes arranged in the same cell,
but only one allele has undergone a productive
rearrangement to a functional gene.
Heavy Chain Gene Transcription:
A Tissue-Specific Enhancer
Figure 23.15 Activation of heavy chain gene transcription by
movement of a heavy chain gene promoter into proximity with a
tissue-specific enhancer during gene assembly in B lymphocytes.
Figure 1
The production
of monoclonal
antibodies by
hybridoma cell
clones.
In 1975,
Dr. Cesar Milstein
Dr. Georges Kohlor