Random Dermatology MCQ - Toll-like Receptors

A researcher is studying the innate immune defense of the skin. He notes that a specific class of pattern recognition receptors (PRRs) is highly expressed on keratinocytes and recognizes microbial components such as lipopolysaccharide (LPS) and viral double-stranded RNA. Activation of these receptors leads to the production of antimicrobial peptides (e.g., defensins) and proinflammatory cytokines. A genetic defect in the intracellular signaling pathway of these receptors would predispose an individual to severe skin infections with which of the following pathogens?

A) Staphylococcus aureus
B) Mycobacterium leprae
C) Human papillomavirus (HPV)
D) Candida albicans
E) All of the above

Correct Answer: E) All of the above

Explanation

The question describes Toll-like Receptors (TLRs), which are a fundamental component of the innate immune system in the skin.

Key Concepts of Toll-like Receptors (TLRs) in Skin:

• Function: TLRs are Pattern Recognition Receptors (PRRs) that recognize conserved Pathogen-Associated Molecular Patterns (PAMPs) from microbes and Damage-Associated Molecular Patterns (DAMPs) from host cells.

• Location: Expressed on various skin cells, including keratinocytes, Langerhans cells, and dermal dendritic cells.

• Signaling: Upon ligand binding, TLRs (except TLR3) signal primarily via the MyD88-dependent pathway, leading to the activation of NF-κB and the production of:

  • Proinflammatory cytokines (e.g., TNF-α, IL-1, IL-6)

  • Type I interferons (especially via TLR3, TLR7, TLR8, TLR9)

  • Antimicrobial peptides (AMPs) like defensins and cathelicidin

TLR Specificity and Clinical Relevance:

A defect in the core signaling pathway (e.g., MyD88 or IRAK-4 deficiency) would impair the function of multiple TLRs, leading to broad susceptibility. Here's how the listed pathogens are relevant:

• TLR2: Recognizes lipopeptides from Staphylococcus aureus and other Gram-positive bacteria.

• TLR2/TLR1 Heterodimer: Recognizes lipopeptides from Mycobacterium leprae.

• TLR3: Recognizes double-stranded RNA (dsRNA), a replication intermediate for many viruses, making it crucial for antiviral defense.

• TLR4: Recognizes Lipopolysaccharide (LPS) from Gram-negative bacteria.

• TLR5: Recognizes flagellin (bacterial flagella).

• TLR7/TLR8: Recognize single-stranded RNA (ssRNA) from viruses.

• TLR9: Recognizes unmethylated CpG DNA from bacteria and viruses.

Crucially, the induction of antimicrobial peptides (AMPs) is a key downstream effect of TLR activation that provides broad-spectrum defense against bacteria, viruses, and fungi.

Why the Answer is "All of the Above":

A defect in the intracellular signaling pathway (e.g., MyD88) would cripple the response from multiple TLRs. This would lead to:

1. Impaired defense against bacteria like S. aureus (via TLR2).

2. Impaired defense against intracellular bacteria like M. leprae (via TLR2/1).

3. Impaired defense against viruses like HPV (via TLR3, TLR7, TLR8, TLR9 for viral nucleic acids).

4. Impaired defense against fungi like C. albicans (recognized by TLR2 and TLR4, leading to AMP production).

Clinical Correlation:
Patients with inherited defects in the TLR3 signaling pathway are predisposed to herpes simplex encephalitis. This question highlights the non-redundant and critical role of TLRs in providing a first-line defense against a wide array of pathogens in the skin.

Note: TLRs bridge the gap between innate and adaptive immunity by activating dendritic cells, which then prime pathogen-specific T-cells. Their role is fundamental in psoriasis, atopic dermatitis, and host defense against cutaneous infections.