Immunodeficiencies Flashcards
What is the purpose of DNA repair?
Prevent the formation of cancer
Which three immunological processes require DNA repair?
- V(D)J recombination
- SHM
- CSR
What are the different mechanisms of DNA repair? (4)
- Base excision repair (BER)
- Mismatch repair (MMR)
- Nucleotide excision repair (GG- and TC-NER)
- Double strand break repair (NHEJ, homologous)
Which DNA repair mechanism is used for abasic sites?
BER
Which DNA repair mechanism is used for replication errors?
MMR
Which DNA repair mechanism is used for bulky adducts/intrastrand crosslink?
Nucleotide excision repair
Which DNA repair mechanism is used for double strand break/interstrand crosslinks?
NHEJ, HR
For which immune cell types is DNA repair crucial? (2)
- B cells
- T cells
Which DNA repair pathway is involved in the DNA repair during V(D)J recombination?
NHEJ
Which DNA repair pathways are involved in the DNA repair during somatic hypermutation? (2)
- Base excision repair
- Mismatch repair
Which DNA repair pathways are involved in the DNA repair during class switch recombination? (2)
- NHEJ
- UNG
What are the three phases of V(D)J recombination?
- Initiation
- Hairpin opening
- Processing/ligation
Which proteins are involved in the initiation phase of V(D)J recombination? Leads to?
Rag 1/2 (only expressed in B and T cells during VDJ) -> cause DNA damage
Which proteins are involved in hairpin opening phase of V(D)J recombination? (2)
- DNA-PKcs
- Artemis
Which proteins are involved in the processing/ligation phase of V(D)J recombination? (3)
- LIG4
- XLF
- XRCC4
What is the function of the enzyme TdT?
Adds random nucleotides to increase junctional diversity (lymphoid specific)
What disease occurs if there is a defect in the process of V(D)J recombination?
You don’t make antigen receptors -> no T cells -> Severe combined immunodeficiency (SCID)
Describe the clinical presentation of SCID (6)
- Early onset (>3 months of age)
- Repeated/severe/opportunistic infections
- Failure to thrive
- Chronic diarrhea
- Lymphocytopenia
- Hypo-/agammaglobulinaemia
To what does a complete block of V(D)J recombination lead?
T-B-SCID
What are the two types of T-B-SCID?
- Non-radiosensitive
- Radiosensitive
How is non-radiosensitive T-B-SCID caused?
Defect in lymphoid specific initiation phase -> mutation in RAG1/RAG2
Do you see neurological and other abnormalities in patients with RAG deficiency?
No
How is radiosensitive T-B-SCID caused?
Defect in non-homologous end joining -> mutation in component NHEJ
What determines the level of radiosensitivity in radiosensitive T-B-SCID patients?
Which defect you have -> Artemis for example not very sensitive, but ligation defect much more sensitive
Why is it important to know whether patients are sensitive to radiation? (2)
- BTx
- Medical exams
To what does an incomplete block of V(D)J recombination lead?
Spectrum of disease including atypical SCID, Omenn syndrome and primordial dwarfism
Do patients with a defect in NHEJ only have an immunological defect?
No -> all other cells of the body have this problem
What are the steps of the pathway to signaling for broken DNA ends? (3)
- MRN complex
- MRN recruits ATM (signaling hub)
- ATM recruits more factors -> 53PB1
What encompasses ATM as a signaling hub? (2)
- Signals for repair
- Signals for shutdown of proliferation
Which syndromes can occur when you have defects in the pathway to signal for broken DNA ends? (2)
- Nijmegen breakage syndrome
- Ataxia Telangiectasia
What are the clinical characteristics of Nijmegen breakage syndrome? (7)
- Facial appearance
- Microcephaly
- Growth retardation
- Strong predisposition to malignancies
- Immunodeficiency
- High sensitivity for ionizing radiation
- Biallelic mutations in NBN
True or false: Nijmegen breakage syndrome patients have reduced T and B cells, but not as low as SCID patients
True
When you can’t keep the DNA ends together, you get?
Loss of juxtaposition of RAG-induced breaks
What are the clinical characteristics of Alexia Telangiectasia? (6)
- Cerebellar deterioration/ataxia
- Telangiectasia
- Strong predisposition to malignancies
- Variable immunodeficiency
- Severe sensitivity for ionizing radiation
- Biallelic mutations in ATM gene
What is the purpose of somatic hypermutation?
Affinity maturation -> selection for antigen binding
Where do the somatic hypermutations occur in the B cell?
Random mutations in the variable domain of the BCR –> CDRs
What are the two outcomes of somatic hypermutation?
- Antigen-binding disrupted
- Antigen-binding retained/increased
SHM and CSR both depend on..?
AID lesions
What is AID?
Activation-induced Cytidine Deaminase –> enzyme that introduces NICS
True or false: In SHM, DNA is repaired in a sloppy way
True -> few regions, single strand breaks
Which DNA repair pathways occur in SHM?
- Base excision repair
- Mismatch repair
–> depending on the type of mutations
What does AID do to the amino acid C?
Deamination to U –> if you take out the uracil you get an abasic site
How does AID work during CSR?
AID makes lesions in switch regions (repetitive) -> lots of lesions/abasic sites -> dsDNA break
What is UNG deficiency?
Hyper IgM syndrome type 5
What are the characteristics of UNG deficiency? (4)
- Susceptibility to bacterial infections
- Normal or increased IgM
- IgG, IgA, and IgE are low or absent
- Defect in CSR
Why can patients with DNA repair defect also present with non-immunological features?
DNA repair is also important for brain development
