Random immunology

Question 1

how do superantigens work?

Answer 1

they directly cross link the MHC class II to the beta chain of the T-cell-receptor

they cause a massive stimulatory response

Question 2

what type of bacteria are complement MAC important in stopping?

Answer 2

C5-C9 is important for Gram neg cocci, such as Neisseria

hence the whole MAC deficiency leading to Neisseria susceptibility.

Outside of this, MAC isn’t really that important for things like Gram + management

Question 3

What are Toll-Like Receptors (TLRs)? On which cells are they found? What is their function?

Answer 3

TLRs are found on all eukaryotic cells, but different cell types will have different TLR type (TLR1-10).

TLRs are part of the INNATE immune system.
TLR = receptor
PAMPs (pathogen-associated molecular patterns) = ligands

Binding of ligand to TLR → activation → triggers downstream signalling → transcription factors → gene expression → inflammatory protein production (eg. TNF, IL-1beta, IL-6, IL-8, IL-12).

Can induce:

• Phagocytosis
• Apoptosis (of infected cells)
• Activation of APCs to produce co-stimulatory signals (eg. dendritic cells in skin)
• Production of antimicrobial peptide production (eg. defensins in GI / resp tracts).

Question 4

Give some examples of involvement of Toll-Like Receptors in disease states:

Answer 4

Excess action:
Excessive / systemic TLR signaling underlies the pathophysiology of sepsis (shock in gram negative sepsis)

Deficiency:

1. TLR3 pathway deficiency in some children with HSV encephalitis
2. IRAK4 deficiency (IRAK4 is downstream of TLR7-9) → recurrent infections with pyogenic bacteria in some children

Question 5

Give some examples of Toll-Like Receptors in therapeutics:

Answer 5

1. TLR7 agonists: useful in slowing the growth of malignancies and inhibiting viral replication. Precise MOA unknown.
   Eg. Imiquimod = synthetic agonist of TLR7 – effective as topical monotherapy for BCC.
2. Immmune Modulation:TLR ligands such as CpG nucleotides can be co-administered with vaccination → enhances Th1 immune response.

Eg. to enhance response to HBV vaccination (human trials underway).

Eg. studies of CpG + CEA in CRC.

Eg. studies of CpG + rituxmab in NHL.

Eg. Allergen immunotherapy: co-administer with antigen to shift T cell cytokine response from Th2 (allergic) to Th1 (non-allergic)

Question 6

Anti-TNF immunotherapy has revolutionized the treatment of some inflammatory diseases, such as RA. However, a major concern is that patients receiving this therapy have an increased risk of fungal and bacterial infection, particularly of reactivating latent tuberculosis.
What is the reason for reactivation of LTBI with anti-ANF agents, such as infliximab?

Answer 6

Due to decreased cytotoxic T-cell antimicrobial function.

Subsets of effector memory CD8+ T cells that contribute to the killing of intracellular M. tuberculosis are depleted in vivo by infliximab.

There is reduced expression of perforin and granulysin in CTLs, which are important for antimicrobial actions of CTLs.

Furthermore, TNF-alpha is important for macrophage activation, phagosome activation, differentiation of monocytes into macrophages, recruitment of neutrophils and macrophages, granuloma formation, and maintenance of granuloma integrity.
Mycobacteria are not killed readily by host defense mechanisms, but instead are sequestered within granulomas, which are comprised of a central core of macrophages, multinucleated giant cells, and necrotic debris surrounded by macrophages and lymphocytes.
TNF-alpha is required for the orderly recruitment of these cells and for continued maintenance of the granuloma structure

Question 7

Live vaccines are relatively contraindicated in those who are immunocompromised.
Which vaccines should be avoided?

Answer 7

Live Vaccines = “MOBY-VRT”:

• MMR
• Oral polio (Inactivated Polio Vaccine is ok)
• BCG
• Yellow fever
• Varicella (and varicella zoster)
• Rotavirus
• Oral Typhoid (Inactivated Parenteral Typhoid Vaccine is ok)

Question 8

When are live vaccines contraindicated?

Answer 8

> 20mg prednisolone / day

HIV positive with CD4<200

anti-TNF meds

+ Some primary immunodeficiencies (vaccines avoided varies by deficiency).
+ Consider risk in haematological malignancy.

Other immunosuppressants (eg. azathioprine, MTX) - risk unclear.
Suggest being off all these Rx for at least one month (best 3 months) before giving

Note: other inactivated vaccines may be safe but ineffective - patient may not make protective antibody response

Question 9

Which Ig class crosses the placenta?
Which Ig class is present in breast milk?

Answer 9

IgG crosses the placenta.
Levels start to wane at 3 months of age. Therefore, primary immunodeficiency commonly presents after 6 months of age (except CVID, which often presents later).

IgA is present in breast milk.

Note: IgA may not be detectable in infant’s serum in first 6 months of life, but may not necessarily indicate IgA deficiency.

Question 10

What do high IgE levels indicate?

Answer 10

High serum IgE levels in a clinical context of recurrent cold abscesses due to Staphylococcus
aureus may suggest a diagnosis of hyper-IgE syndrome (rare and usually has other associated features, eg. typical facies).

However, elevated IgE is most commonly observed with atopic disorders such as atopic dermatitis, and is also seen with systemic helminth
infections.