MIMM 214 Lecture Notes - Lecture 26: Recombination-Activating Gene, Chromosome, V(D)J Recombination

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tealduck852

7 Jun 2018

School

McGill University

Department

Microbiology & Immunology

Course

MIMM 214

Professor

Claire Trottier

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Lecture 27 – March 13, 2017

What makes the V region variable?

Problem

- Antibodies and TCRs can be produced for an enourmous variety of different specific antigens

- How do 20-25 thousand protein coding genes result in ~5x1013 different Ig and ~1018 TCR

Primary Diversity

- Raccal that Ig proteins consist of

o Two identical heavy chains

o Two identical light chains

Ig gene diversity

- B cells use groups of PARTS of genes to create different possible antibodies using recombination

- Like shuffling a deck of cards, dealing out different hands

- Tightly regulated machinery controls recombination processes

- There are variable (V), diversity (D), joining (J), and constant © region gene segments

- D segments are used in antibody heavy chains only

- Variable region of both heavy and light chain is composed segments from recombined V, D (only

in H chain), and J genes

- There are many different V, D, J segments in germline DNA

- During B cell development → V(D)J recombination occurs to chose one of each to make up the

carriable region

Light chain

- Two different loci with different constant regions

- Each locys includes many different V and J regions

- Constant regions in light chain

o Kappa chain has one constant region

o Gamma has more than one constant region

Heavy chain

- One locus

- Includes many different V, D, and J regions

- Many different constant regions represents the different isotypes

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Document Summary

Antibodies and tcrs can be produced for an enourmous variety of different specific antigens. How do 20-25 thousand protein coding genes result in ~5x1013 different ig and ~1018 tcr. Raccal that ig proteins consist of: two identical heavy chains, two identical light chains. B cells use groups of parts of genes to create different possible antibodies using recombination. Like shuffling a deck of cards, dealing out different hands. There are variable (v), diversity (d), joining (j), and constant region gene segments. D segments are used in antibody heavy chains only. Variable region of both heavy and light chain is composed segments from recombined v, d (only in h chain), and j genes. There are many different v, d, j segments in germline dna. During b cell development v(d)j recombination occurs to chose one of each to make up the carriable region. Each locys includes many different v and j regions.

Related Questions

Which of the following statements is TRUE?

The germline organization of Ig and TCR genes is different in a liver cell as in a mature B or T lymphocyte.

Positive selection is a checkpoint during lymphocyte maturation that ensures the survival of functionally useful lymphocytes.

In the Ig heavy chain gene locus there is found a cluster of V genes and a cluster of J genes.

Only the TCR-alpha gene locus contains D gene segments.

Developing T cells that have a high affinity for self-proteins survive the negative selection checkpoint.

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True / False Questions

01. _____ Antibody is composed of 2identical long heavy chains and 2 identical shorter lightchains.

02. _____ Variable (V) and constant(C) regions are part of both heavy and light chains.

03. _____ Variable regions for heavyand light chains from the same antibody molecule are alwaysidentical.

04. _____ Variable region of lightchains are encoded by the DNA sequences that contain rearranged V,D, and J segments.

05. _____ Fc part of the antibody isnot important, F(abâ)₂ fragment has the same binding andeffector capacity.

06. _____ Fab fragments are generatedby alternative splicing.

07. _____ J chain is used as asurrogate light chain during pre-B cell receptor testing forsuccessful V(D)J rearrangement.

08. _____ Binding of the antigen byantibody is stabilized by disulfide bonds.

09. _____ RAG1/2 are always expressedin B cells at high level, because B cells need RAG1/2 to constantlyrearrange their V regions.

10. _____ âNâ (non template)nucleotides are added by TdT.

11. _____ The 12/23 rule is appliedduring class switching.

12. _____ For B cells, V(D)Jrecombination occurs only in the bone marrow.

13. _____ The process of somatichypermutation helps to improve specificity of the antibody.

14. _____ In late pro-B cells, Vsegment is rearranged with DJ segments.

15. _____ Failure to eliminateself-reactive B cells may lead to serious autoimmune diseases.

16. _____ Mature, naÃ¯ve B cellsexpress IgD and any of the other classes of antibody (IgM, IgG,IgA, or IgE) on their surfaces.

17. _____ B1 cells are present in theperitoneal cavity, pleural spaces and brain.

18. _____ AID (activation inducedcytidine deaminase) is expressed only in B cells and it canintroduce breaks in double stranded DNA.

19. _____ Different classes (isotypes)of antibodies have different effector functions, which aretriggered by special receptors expressed by a variety of cells.

20. _____ Plasma cells are terminallydifferentiated cells that produce large quantities ofantibodies.

21. _____ Repeated exposure to thesame antigen eventually leads to immunological exhaustion and lackof immunity, because there is no room for new plasma cells in thebone marrow.

22. _____ Germinal centers arespecialized sites within the bone marrow where Ig genes ofactivated B cells undergo affinity maturation.

23. _____ B cells can present antigensto T helper cells.

24. _____ Co-stimulatory molecules arerequired for efficient generation of memory B cells.

25. _____ Lymphocytes migrate to thelymphoid tissues in response to chemokines.

26. _____ Class switching duringgerminal center reaction is a random process.

27. _____ T cell independent responsescan generate strong and long lasting B cell memory.

28. _____ Fc receptors that arepresent on many different cell types are crucial for removal of thepathogens.

29. _____ The ideal vaccine should bedesigned to mimic the natural course of infection without causingsymptoms of the disease.

30. _____ The protective immunity canbe generated against any pathogen because there is virtuallyunlimited number of possible V regions, thus any antigen can berecognize by an antibody.

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Topic A

1. Indicate to which branch(es) of theimmune system the following statements apply.

Explain your answer.

a) Involves macrophages

b) Responds to viral infection

c) Involves T cells

d) Responds to bacterial toxins

e) Most likely responds following an organ transplant

f) Involves cytotoxic T cells

g) Involves B cells

h) Involves complement

i) Responds to extracellular bacterial infection

j) Involves secreted antibody

k) Kills virus infected self cells

I) Involves the thymus

m) Involves the bone marrow

2. You are given two solutions, one containing protein A and theother the antibody to this protein both at about 5mg/ml. When youadd 1 ml of anti-A to 1 ml of protein A, a precipitate forms.However, when you dilute the antibody solution 20 fold and then mix1 ml of the diluted anti-A with 1 ml protein A, no precipitateforms.

Explain why no precipitate formed with the diluted antibody.

3. An energetic immunology student has isolated protein X.

The student believes it is a new isotype of humanimmunoglobulin.

a)What structural features would protein X have to have in orderto be classified as an immunoglobulin?

b) You prepare rabbit antibodies to (i) whole human IgG, (ii) tohuman ÃÂ» chain and (iii) to human ÃÂ³ chain.

Assuming protein X is in fact a new immunoglobulin isotype,which of these antibodies will bind to protein X? Explain why?

TOPIC B

4. a) Describe the time course of a typical antibody response totetanus toxoid

b) Outline a vaccination schedule that makes effective use ofthis information.

5. a) Tetanus immunoglobulin from the horse can be used toprotect an individual against tetanus. How is the treatmentadministered and what are the advantages/disadvantages of this formof immunisation? 2

b) Is it possible to confer cell mediated immunity on anunsensitised recipient by transferring cells?

c) Would this be a practical method of immunisation, and whatproblems may be encountered in this type of experiment?

6. If you inject a rabbit with a large protein antigen X andsubsequently harvest the antiserum from the animal, would youexpect the antibodies to X in the antiserum to be monoclonal orpolyclonal?

TOPIC C

7. a) Why, if the immune system is so efficient, do we continueto suffer from infectious diseases?

b) Speculate on the consequences if the immune system were tolose its ability to distinguish self-antigens from foreignones.

c) If a child is born without a thymus gland, what will be thenature of the child's illness

d) If a child were born with a defect in the complement system,say a deficiency in function C3, what would be theconsequences?

8 Considering only combinational joining of gene segments andassociation of light and heavy chains, how many different antibodymolecules potentially could be generated from germ line DNAcontaining 500VL and 4JL gene segments and 200VH. 10DH and 4JH genesegments?

9 During an immune response to antigen, the antibodies producedduring a secondary and subsequent responses have a greater affinityfor antigen than those produced during a primary response toantigen

Explain what is meant by "affinity"

Explain in principle the mechanism which explains the aboveobservation re increasing antibody affinity for antigen insecondary and subsequent responses

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MIMM 214 Lecture Notes - Lecture 26: Recombination-Activating Gene, Chromosome, V(D)J Recombination

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