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I&I WCII > Immunodeficiencies > Flashcards

Immunodeficiencies Flashcards

1
Q

Which 3 immunological processes require DNA repair?

A

V(D)J recombination
Somatic hypermutation
Class switching

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2
Q

Which DNA repair pathway is involved in V(D)J recombination?

A

Non-homologous end-joining

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3
Q

Which DNA repair pathway is involved in somatic hypermutation?

A

Mismatch repair (MMR) and base excision repair (BER)

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4
Q

Which DNA repair pathway is involved in class switching?

A

Non-homologous end-joining

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5
Q

How does non-homologous end-joining work and why does it work in V(D)J recombination?

A

V(D)J recombination occurs in developing B and T lymphocytes to generate diverse antigen receptors. Double-strand breaks occur in this process, and these are repaired by non-homologous end-joining. Non-homologous end-joining doesn’t require a template, which in this case in also not available.

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6
Q

How does non-homologous end-joining work and why does it work in class-switch recombination (CSR)?

A

CSR allows B cells to change antibody isotype by rearranging S regions in the Ig heavy chain locus. While this happens, AID induces single strand breaks in the DNA (called AID lesions), which then develop into double strand breaks. NHEJ repairs these breaks.

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7
Q

What happens when there are defects in V(D)J recombination?

A

You do not get functional T and B cells, leading to SCID (severe combined immunodeficiency)

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8
Q

What happens in non-homologous end joining?

A

A double strand break is detected, leading to the binding of enzymes that recruits DNA-PKcs, which then recruits endonuclease artemis to open up hairpins and removed mismatched or damaged DNA ends. DNA ligase IV among other things processes the DNA back together. TdT can add random nucleotides to increase junctional diversity.

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9
Q

What part of V(D)J is lymphoid specific?

A

Hairpin formation by Rag1 and Rag2

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10
Q

What are the two types of T- and B- SCID?

A

Non-radiosensitive SCID: Defect in lymphoid specific initiation phase (mutation in RAG1/RAG2)
Radiosensitive SCID: Defect in NHEJ (mutation in NHEJ component)

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11
Q

Which SCID defect has a phenotype restricted to lymphocytes?

A

RAG1/RAG2 mutations (part of the lymphoid V(D)J recombination initiation phase)

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12
Q

Which SCID defect has a phenotype affecting all cells?

A

Mutations in NHEJ components

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13
Q

Why is it important to know if a patient is sensitive for ionizing radiation?

A

Non-immune cell defects will not be restored with hematopoietic stem cell transplantation. If someone is not radiosensitive it is an option.

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14
Q

Why do NHEJ defects result in sensitivity to ionizing radiation?

A

There is a general DNA repair defect in all cells.

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15
Q

Where are most (somatic hyper)mutations found in functional BCRs?

A

In the CDR domains, since the rest is necessary for proper structure of the BCR and the CDR domains are important for antigen binding

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16
Q

How does AID work?

A

It replaces C with U in switch regions to create a mismatch and get an AID lesion that needs to be repaired. In somatic hypermutation, this is a single-stranded mutation. However, there are a lot of possible target sites for AID in the switch region for class switching, making it very prone for double stranded breaks. This can then be repaired with non-homologous end-joining.

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17
Q

When does base-excision repair occur?

A

In somatic hypermutation, when there is a mismatch because AID turned C into a U, it is taken out and can be replaced with something else.

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18
Q

When does mismatch repair (MMR) occur?

A

In somatic hypermutation, when there is a mismatch because AID turned C into a U, multiple molecules are attracted to it and take out a longer stretch and fill it back in, as opposed to just the U like in base-excision repair.

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19
Q

What mediates base-excision repair?

A

UNG

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20
Q

What happens when there is an UNG deficiency?

A

Reduced efficiency in somatic hypermutations, but especially not efficient at class switching.

21
Q

What is the phenotype of UNG deficiency?

A

Normal or increased IgM and no IgG, IgA and IgE. This makes patients especially susceptible to bacterial infections.

22
Q

Why do patients with DNA repair defects also present with non-immunological features? (2)

A

DNA is also important for brain development and normal DNA repair in all tissues

23
Q

Wat are the most important classes of PRRs?

A

TLRs, C-type lectin receptors, NOD-like receptors, RIG-I

24
Q

Why do c-type lectin receptors recognize?

A

Carbohydrates such as those on fungi, bacteria, viral glycoproteins (glycosylation), but also host DAMPs

25
What do NOD-like receptors recognize?
Intracellular PAMPs and DAMPs including flagellin and mitochondrial DNA
26
What does RIG-I detect?
double stranded RNA (like in viruses)
27
What influences the outcome of a response to PAMPs and DAMPs?
The cell type expressing the PRR influences the signaling outcome. This leads to there being multiple lines of defense against the same patterns.
28
Newcastle disease virus has ways to supress type I interferon. How does cross-talk between PRRs still help supress the virus?
NDV can infect macrophages, which can detect dsRNA from the virus using RIG-I. NDV can supress the production of Type I IFN in these macrophages. As a backup, peripheral DCs can take the virus up in its endosomes, which express TLR7 which recognize ssRNA and can in that way lead to the production if type I IFN.
29
Why are elderly people more vulnerable to Influenza A infections?
Type I IFN production in monocytes and macrophages is significantly reduced. This is due to degradation of TRAF3 (downstream of RIG-I), which plays a role in signal transduction in the primary phase of IFN induction (during which IFN is quickly produced), and IRF8 induction is also impaired in the secondary (feedback amplification) phase (where produced IFN in the primary phase is amplified). However, IL-1ß is still there, which leads to susceptibility of bacterial infection and thus recruitment of large numbers of neutrophils which undergo NETosis and cause significant tissue damage.
30
What causes DAMP-induced inflammation in SLE?
There is defective clearance of self-nucleic accids, leading to elevated type I IFN
31
Why do grafts from living donors survive longer than those from deceased donors? (4)
- Cold ischemia time is much longer in deceased donor organs, leading to tissue damage, necrosis, and DAMP release. - HMGB1, a nuclear DAMP, is only detected in deceased donor organs, triggering inflammation. - TLR4 is upregulated in deceased donor grafts; blocking it reduces inflammatory markers. Some donors with TLR4 mutations show less inflammation and better transplant outcomes. - TLR2 is upregulated post-transplant, attracting granulocytes, monocytes, and macrophages, worsening inflammation. Knocking it out leads to better graft function.
32
Why is it important to better understand PRR activation?
To be able to develop better treatments or even vaccines. Knowledge on which "molecular patterns" lead to a specific type of T and/or B cell response can be implemented in vaccine design to induce a desired type of immunity, for examples as adjuvants.
33
What is the issue with viruses in immunocompromised patients?
It leads to latency of common viruses and can cause unique syndromes.
34
What is the seroprevalence of CMV in adults?
70%
35
How is CMV transmitted?
Saliva, urine, blood, breast milk, sperm, and solid organ transplantation
36
What is CMV primo-infection?
CMV infection in a CMV-negative person
37
What is CMV reactivation?
Replication of latent CMV in a previously infected person
38
What is CMV reinfection?
A CMV positive person getting infected with a new CMV strain.
39
What is CMV end-organ disease
Organ dysfunction due to CMV replication in that organ.
40
What are the symptoms of CMV syndrome in transplant recipients?
Fever and bone marrow suppression (neutropenia/thrombopenia)
41
What are common CMV-related diseases in immunocompromised patients?
Encephalitis, retinitis, pneumonia, gastroenteritis (which can lead to perforation)
42
What pathology finding is associated with CMV?
Owl eye inclusion bodies
43
What are the main diagnostic methods for CMV?
Histopathology and qPCR (blood)
44
What are the treatment strategies for CMV?
Prophylaxis (before CMV DNA is detected) Pre-emptive therapy (when CMV DNA is detected) CMV disease treatment (when disease is present)
45
What is a CMV-IGRA test? What do the results indicate?
CMV-interferon gamma release assay measures T cell response to CMV by detecting IFNy production. If positive, it may indicate a functional T cell response and thus a lower likelihood of developing disease after stopping prophylaxis in transplant patients. The results can be used to determine whether prophylaxis can safely be stopped.
46
Why is immune response detection difficult in immunocompromised patients?
Immune response detection is sometimes used to assess whether someone is positive or not for CMV. Immunocompromised patients may not mount a strong T cell or antibody response, leading to false negatives.
47
Why is serology not useful for diagnosing Parvovirus B19 in immunocompromised patients?
They may not produce antibodies, leading to undetectable IgM/IgG or false positives due to IVIg treatment.
48
What is the main clinical consequence of Parvovirus B19 in immunocompromised patients?
Chronic infection and severe anemia due to its tropism for erythroid progenitor cells
49
What viral diagnostic test is less sensitive in immunocompromised patients?
Serology-based tests due to poor antibody responses.

I&I WCII (8 decks)

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