Immuno - genetic method of medical genetics

Содержание

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What is Immuno-Genetics? Immunogenetics or immungenetics is the branch of medical

What is Immuno-Genetics?

Immunogenetics or immungenetics is the branch of medical genetics that explores the relationship

between the immune system and genetics. The term ‘immunogenetics’ refers to the scientific discipline that studies the molecular and genetic basis of the immune response.
Genetic conditions that affect either the development or function of components of the immune system lead to an inability to control infectious pathogens or a susceptibility to autoimmunity or cancer.
These primary immunodeficiency disorders have dramatically increased our understanding that certain components of the immune system are essential for controlling specific pathogens in humans.
They have also informed our understanding of basic mechanisms involved in immune tolerance (autoimmunity) and immune surveillance (tumor immunity) under normal conditions.
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Overview of the Immune System Immune System Innate (Nonspecific) 10 line

Overview of the Immune System

Immune System

Innate
(Nonspecific)
10 line of defense

Adaptive
(Specific)
20 line of

defense
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Innate immunity vs Adaptive Immunity Innate Immunity (first line of defense)

Innate immunity vs Adaptive Immunity

Innate Immunity

(first line of defense)

Adaptive Immunity

(second line

of defense)

No time lag
Not antigen specific
No memory

A lag period
Antigen specific
Development of memory

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The innate immune System Innate Immune System External defenses Internal defenses

The innate immune System

Innate Immune
System

External
defenses

Internal
defenses

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Innate immune system External defenses

Innate immune system
External defenses

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Anatomical Barriers - Mechanical Factors Skin Mucociliary escalator Flushing action of saliva, tears, urine

Anatomical Barriers - Mechanical
Factors

Skin

Mucociliary escalator

Flushing action of
saliva, tears, urine

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Anatomical Barriers – Chemical factors Antimicrobial Peptides in sweat HCl in stomach Lysozyme in tears /saliva

Anatomical Barriers – Chemical
factors

Antimicrobial
Peptides in sweat

HCl in stomach

Lysozyme in tears /saliva

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Anatomical Barriers – Biological factors Normal flora – microbes in many

Anatomical Barriers – Biological
factors

Normal flora – microbes in many parts of

the body
Normal flora – > 1000 species of bacteria
Normal flora – competes with pathogens for nutrients and sp
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Innate immune system internal defenses

Innate immune system
internal defenses

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Innate immune system: components of Blood Complement proteins Coagulation proteins Cytokines Extracellular WBCs

Innate immune system: components of Blood

Complement proteins
Coagulation proteins
Cytokines
Extracellular
WBCs

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White blood cells (WBCs) B- lymphocytes T- lymphocytes Natural killer(NK) cells Mast cells Macrophages

White blood cells (WBCs)

B- lymphocytes
T- lymphocytes
Natural killer(NK) cells

Mast
cells

Macrophages

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Neutrophils in innate immune response Most abundant WBCs (~50-60%) Efficient phagocytes

Neutrophils in innate immune
response

Most abundant WBCs (~50-60%)
Efficient phagocytes
Most important cells of

the innate immune system
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Monocytes Monocytes (~5% of WBCs) Migrate into the tissues and become Macrophages

Monocytes

Monocytes (~5% of WBCs)
Migrate into the tissues and become Macrophages

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Macrophages “Big eaters” Phagocytosis of microbes in tissue (neutrophils are present only in blood) Antigen presentation

Macrophages

“Big eaters”
Phagocytosis of microbes in tissue
(neutrophils are present only in

blood)
Antigen presentation
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Natural killer cells Not B-lymphocytes / T lymphocytes Important part of

Natural killer cells

Not B-lymphocytes / T lymphocytes
Important part of the innate

immune system
Kill virus /bacteria infected cells (Intracellular pathogens)
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Toll-like receptors (TLRs) Transmembrane proteins Present on macrophages / few other

Toll-like receptors (TLRs)

Transmembrane proteins
Present on macrophages / few other cells
Conserved across

vertebrates
Important part of innate immune system
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Summary: innate response – internal defenses – Cellular (WBCs) Come into

Summary: innate response – internal
defenses – Cellular (WBCs)
Come into play when

the external defenses are breached
• Neutrophils
• Monocytes /macrophages
• NK cells
• TLRs
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Cytokines Small proteins – secreted bycells of the immune system Affect

Cytokines
Small proteins – secreted bycells of the immune system
Affect the behaviour

of other
cells
Signalling molecules
Key players in innate and
acquired immunity
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Examples of cytokines Interferons Interleukins Tumour necrosis factor (TNF)

Examples of cytokines
Interferons
Interleukins
Tumour necrosis factor (TNF)

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Interferons (IFN) Signalling proteins produced by by virus infected monocytes and

Interferons (IFN)
Signalling proteins produced by by virus infected monocytes and lymphocytes
Secreted

proteins – Key anti-viral proteins
“Interfere” with virus replication
Warn the neighbouring cells that a virus is around..
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Interleukins Interleukins – 1-37 Not stored inside cells Quickly synthesized and

Interleukins
Interleukins – 1-37
Not stored inside cells
Quickly synthesized and secreted in response

to infection
Key modulators of behaviour of immune cells
Mostly secreted by T-lymphocytes & macrophages
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Complement (C`) a large number of distinct plasma proteins that react

Complement (C`)
a large number of distinct plasma proteins that react with

one another (C1 thro’ C9)
Complement can bind to microbes and coat the microbes
Essential part of innate immune response
Enhances adaptive immune resposne (taught later)
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Coagulation proteins Coagulation: mechanism to stop bleeding after injury to blood

Coagulation proteins
Coagulation: mechanism to stop bleeding after injury to blood vessels
Complex

pathway involves
Platelets
Coagulation factors
Vitamin K
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Coagulation and innate immunity Pathogens and cytokines Anticoagulants Coagulation proteins

Coagulation and innate immunity

Pathogens and
cytokines

Anticoagulants

Coagulation
proteins

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Summary: innate response – internal defenses Cellular • Neutrophils • Monocytes

Summary: innate response – internal
defenses
Cellular
• Neutrophils
• Monocytes /macrophages
• NK cells
• TLRs
Extracellular
•

Cytokines
• Complement
• Coagulation
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Inflammation Complex biological process by which body responds to pathogens and

Inflammation
Complex biological process by which body responds to pathogens and irritants
Associated

with swelling of tissue
Key player in innate immune repsone
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Summary: role of Inflammation in innate immunity Initiation of phagocytosis –

Summary: role of Inflammation
in innate immunity
Initiation of phagocytosis – killing of

pathogen
Limiting the spread of infection
Stimulate adaptive immune response
Initiate tissue repair
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Immunogens and antigens Immunogen / antigen: a substance that elicits an

Immunogens and antigens
Immunogen / antigen: a substance that elicits
an immune response

[i.e. a humoral (antibody
response) or cell-mediated immune response]
Immune response generator
Though the two terms are used interchangeably – there are differences between the two
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Epitope Epitope: the portion of an antigen that is recognized and

Epitope
Epitope: the portion of an antigen that is recognized
and bound by

an antibody (Ab) or a T-cell receptor
(TCR)
epitope = antigenic determinant
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Isoantigens Isoantigens: Antigens present in some but not all members of

Isoantigens
Isoantigens: Antigens present in some but not all members of a

species
Blood group antigens – basis of blood grouping
MHC (major histocompatibility complex)- cell surface glycoproteins
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Autoantigens Autoantigens are substances capable of immunizing the host from which

Autoantigens
Autoantigens are substances capable of immunizing the host from which they

are obtained.
Self antigens are ordinarily non-antigenic
Modifications of self-antigens are capable of eliciting an immune response
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Haptens Haptens are small molecules which are non immunogenic, thus could

Haptens
Haptens are small molecules which are non immunogenic, thus could never

induce an immune response by themselves.
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What is an antibody? Produced by Plasma cell (B-lymphocytes producing Ab)

What is an antibody?
Produced by Plasma cell (B-lymphocytes producing Ab) •

Essential part of adaptive immunity
Specifically bind a unique antigenic epitope (also called an
antigenic determinant)
Possesses antigen binding sites
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The molecular genetics of immunoglobulins A single C region gene encoded

The molecular genetics of immunoglobulins

A single C region gene encoded in

the GERMLINE and separate from the V region genes
Multiple choices of V region genes available
A mechanism to rearrange V and C genes in the genome so that they can fuse to form a complete Immunoglobulin gene.

Dreyer & Bennett (1965)
For a single isotype of antibody there may be:

How can the bifunctional nature of antibodies be explained genetically?

This was genetic heresy as it violated the then accepted notion that DNA was identical in every cell of an individual

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Genetic models of the 1960’s were also unable to explain: How

Genetic models of the 1960’s were also unable to explain:

How B

cells shut down the Ig genes on just one of their chromosomes.
All other genes known at the time were expressed co-dominantly. B cells expressed a light chain from one parent only and a heavy chain from one parent only (evidence from allotypes).
A genetic mechanism to account for increased antibody affinity in an immune response
How a single specificity of antibody sequentially switched isotype.
How the same specificity of antibody was secreted and simultaneously expressed on the cell surface of a B cell.
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Further diversity in the Ig heavy chain Heavy chain: between 0

Further diversity in the Ig heavy chain

Heavy chain: between 0 and

8 additional amino acids between JH and CH
The D or DIVERSITY region

Each light chain requires two recombination events:
VL to JL and VLJL to CL

Each heavy chain requires three recombination events:
VH to JH, VHJH to DH and VHJHDH to CH

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Diversity: Multiple Germline Genes

Diversity: Multiple Germline Genes

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Diversity: Multiple germline genes

Diversity: Multiple germline genes

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Genomic organisation of Ig genes (No.s include pseudogenes etc.)

Genomic organisation of Ig genes
(No.s include pseudogenes etc.)

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Ig light chain gene rearrangement by somatic recombination

Ig light chain gene rearrangement by somatic recombination

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Ig light chain rearrangement: Rescue pathway There is only a 1:3

Ig light chain rearrangement: Rescue pathway

There is only a 1:3 chance

of the join between the V and J region being in frame
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Ig heavy chain gene rearrangement Somatic recombination occurs at the level

Ig heavy chain gene rearrangement

Somatic recombination occurs at the level of

DNA which can now be transcribed

BUT:

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The constant region has additional, optional exons h

The constant region has additional, optional exons

h

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The constant region has additional, optional exons h

The constant region has additional, optional exons

h

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The Heavy chain mRNA is completed by splicing the VDJ region

The Heavy chain mRNA is completed by splicing the VDJ region

to the C region

RNA processing

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V, D, J flanking sequences Sequencing up and down stream of

V, D, J flanking sequences

Sequencing up and down stream of V,

D and J elements Conserved sequences of 7, 23, 9 and 12 nucleotides in an arrangement that depended upon the locus
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Recombination activating gene products, (RAG1 & RAG 2) and ‘high mobility

Recombination activating gene products, (RAG1 & RAG 2) and ‘high mobility

group proteins’ bind to the RSS

The two RAG1/RAG 2 complexes bind to each other and bring the V region adjacent to the DJ region

The recombinase complex makes single stranded nicks in the DNA. The free OH on the 3’ end hydrolyses the phosphodiester bond on the other strand.
This seals the nicks to form a hairpin structure at the end of the V and D regions and a flush double strand break at the ends of the heptamers.
The recombinase complex remains associated with the break

Steps of Ig gene recombination

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A number of other proteins, (Ku70:Ku80, XRCC4 and DNA dependent protein

A number of other proteins, (Ku70:Ku80, XRCC4 and DNA dependent protein

kinases) bind to the hairpins and the heptamer ends.

Steps of Ig gene recombination

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Junctional diversity: P nucleotide additions The recombinase complex makes single stranded

Junctional diversity: P nucleotide additions

The recombinase complex makes single stranded nicks

at random sites close to the ends of the V and D region DNA.

The 2nd strand is cleaved and hairpins form between the complimentary bases at ends of the V and D region.

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Heptamers are ligated by DNA ligase IV V and D regions juxtaposed

Heptamers are ligated by DNA ligase IV

V and D regions juxtaposed

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Endonuclease cleaves single strand at random sites in V and D

Endonuclease cleaves single strand at random sites in V and D

segment

Generation of the palindromic sequence

In terms of G to C and T to A pairing, the ‘new’ nucleotides are palindromic.
The nucleotides GA and TA were not in the genomic sequence and introduce diversity of sequence at the V to D join.

The nicked strand ‘flips’ out

(Palindrome - A Santa at NASA)

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Junctional Diversity – N nucleotide additions Terminal deoxynucleotidyl transferase (TdT) adds

Junctional Diversity – N nucleotide additions

Terminal deoxynucleotidyl transferase (TdT) adds nucleotides randomly to

the P nucleotide ends of the single-stranded V and D segment DNA

CACTCCTTA

TTCTTGCAA

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Junctional Diversity TTTTT TTTTT TTTTT Germline-encoded nucleotides Palindromic (P) nucleotides -

Junctional Diversity

TTTTT
TTTTT
TTTTT

Germline-encoded nucleotides

Palindromic (P) nucleotides - not in the germline

Non-template (N)

encoded nucleotides - not in the germline

Creates an essentially random sequence between the V region, D region and J region in heavy chains and the V region and J region in light chains.

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Why do V regions not join to J or C regions?

Why do V regions not join to J or C regions?

IF

the elements of Ig did not assemble in the correct order, diversity of specificity would be severely compromised

Full potential of the H chain for diversity needs V-D-J-C joining - in the correct order

Were V-J joins allowed in the heavy chain, diversity would be reduced due to loss of the imprecise join between the V and D regions

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Antibody isotype switching Throughout an immune response the specificity of an

Antibody isotype switching

Throughout an immune response the specificity of an antibody

will remain the same (notwithstanding affinity maturation)
The effector function of antibodies throughout a response needs to change drastically as the response progresses.
Antibodies are able to retain variable regions whilst exchanging constant regions that contain the structures that interact with cells.
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Switch regions The Sμ consists of 150 repeats of [(GAGCT)n(GGGGGT)] where

Switch regions

The Sμ consists of 150 repeats of [(GAGCT)n(GGGGGT)] where n

is between 3 and 7.
Switching is mechanistically similar in may ways to V(D)J recombination.
Isotype switching does not take place in the bone marrow, however, and it will only occur after B cell activation by antigen and interactions with T cells.

Upstream of C regions are repetitive regions of DNA called switch regions. (The exception is the Cδ region that has no switch region).

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Switch recombination At each recombination constant regions are deleted from the

Switch recombination

At each recombination constant regions are deleted from the genome
An

IgE - secreting B cell will never be able to switch to IgM, IgD, IgG1-4 or IgA1
- Предыдущая
My professional formation
Следующая -
Общественное движение 80 - 90-х гг

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