Question

A mother has a germ line mutation in Toll Like Receptor 4. Will her children carry this mutation? Will her children be affected by this mutation? Briefly explain your reasoning. Part b. Briefly explain the functional importance of TLRs within the context of an immune response.

Answer 1

(a)

Germline mutations or Hereditary mutations are the genetic changes observed in a body’s reproductive cell (sperm or egg) that gets incorporated into the DNA of every cell in the body of the offspring. These mutations are passed on from parents to offspring.

Therefore, if a mother has a germ line mutation in Toll-like receptor 4, the children will carry this mutation.

The Children will not be affected by mutation in Toll-like receptor 4 because this mutation is not present in other cells of the body (somatic cells). Based on family studies, the risk of getting the children affected by mutation may be low (< 1%), moderate (< 7%) or high (45%). The high risk of the children getting affected by the mutation of Toll-like receptor 4 mutation occurs when it’s Autosomal dominant mutation.

(b) Importance of TLRs in Immune response

The Innate immunity is a first line of defense against many pathogens. Toll-like receptor 4 (TLR4), which belongs to Pattern recognition receptor (PRR) family, plays an important role in Innate immunity against bacteria (Gram-negative bacteria), and TLR4 are activated by Lipopolysaccharides that are present on the outer membrane of Gram-negative bacteria. Thus, in short, the TLRs activation leads to an intracellular signaling pathway NF- and inflammatory cytokine production, which is responsible for activation of Innate immunity system. The mechanism of TLR4 in Innate immunity is given below -

1. Firstly, TLR4 recognises Lipopolysaccharides, captured by LPS binding protein, followed by binding with CD14, a protein present in the membrane of Innate immune cells. The CD14 helps in the transport of TLR4 to lipid rafts regions of the cell membrane.
2. This is followed by recruitment of co-receptor myeloid differentiation actor 2 (MD-2), thus forming CD14/TLR4/MD2 complex, which facilitates the endocytosis of this complex.
3. The complex activates two alternative signaling pathways – MyD88 dependant and MyD88 independent signaling pathways.
4. MyD88 dependant signaling pathway – Myeloid Differentiation Primary Response Gene 88 (MyD88) and TIR Domain-containing Adaptor protein (TIRAP) protein complex is activated by CD14/TLR4/MD2 complex. The MyD88/TIRAP protein complex activates Mitogen Activated Protein Kinase (MAPK) and IKK (I Kinase). IKKs signaling pathway is responsible for NF- transcription factor induction and MAPKs leads to the activation of AP-1 transcription factor. The AP-1 and NF regulates the production of Pro-inflamatory cytokines, eg, IL-12.
5. MyD88 independant signaling pathway - This pathway involves the recruitment of TRIF (TIR domain containing adaptor inducing Interferon ) and TRAM (TRIF related adaptor molecule) adaptor proteins, which activate the transcription factor IRF3 (Interferon regulatory factor-3), thus controls the production of Type- 1 Interferons (IFN-).

Thus, TLRs activation leads to an intracellular signaling pathway NF- and inflammatory cytokine production, which is responsible for activation of Innate immunity system