Toll-like Receptors: Innate Immunity

Explain how the discovery of Toll in Drosophila melanogaster revolutionized our understanding of the innate immune system in mammals?

What is the structural feature of TLRs that allows them to bind to a diverse array of ligands, and how does this contribute to their function in pathogen recognition?

Contrast the location and function of TLRs found on the cell surface versus those found in endosomes.

Describe the immediate downstream signaling events that occur upon ligand binding to a TLR, and explain how this initiates an immune response.

How does the recognition of PAMPs by TLRs lead to the activation of macrophages, and what are the major downstream effects of this activation on the immune response?

Compare and contrast the mechanisms by which macrophages and neutrophils eliminate pathogens, highlighting the unique roles of NETs and the respiratory burst.

Explain how defects in NADPH oxidase lead to chronic granulomatous disease (CGD), and why patients with CGD are particularly susceptible to certain types of infections.

Propose a targeted therapeutic approach to augment NET formation in immunocompromised individuals with impaired neutrophil function, while mitigating potential off-target inflammatory damage.

Describe the key differences between pattern recognition receptors (PRRs) of the innate immune system and the antigen receptors (T cell receptors and antibodies) of the adaptive immune system, focusing on their mechanisms of antigen recognition and the scope of pathogens they can detect.

Predict how the disruption of phagolysosome formation would impact the ability of macrophages to clear intracellular pathogens, and suggest a potential mechanism by which pathogens could evade this cellular defense.

Describe how the speed of blood flow impacts the initial stages of leukocyte extravasation.

What crucial role do chemokines play in the extravasation of leukocytes, specifically relating to integrin activation?

How might blocking selectin-mediated interactions affect the subsequent steps of leukocyte extravasation, and what implications does this have for inflammation?

Explain the significance of endothelial activation in inflammation. How does it facilitate leukocyte recruitment and contribute to the overall inflammatory response?

How do lipid mediators such as prostaglandins and leukotrienes contribute to the process of endothelial activation during an inflammatory response?

Considering the steps of leukocyte extravasation, how would the absence or dysfunction of integrins on the leukocyte surface specifically impede the process, and what would be the physiological consequences?

Describe how intravital microscopy (IVM) enhances our understanding of leukocyte extravasation beyond what traditional in vitro methods offer.

Describe the mechanism by which cGAS/STING pathway detects cytosolic dsDNA and initiates an immune response, including the specific molecules involved and the ultimate outcome.

Explain how RIG-I discriminates between host and viral RNA, leading to the activation of type I interferon and inflammatory cytokine production.

How does the activation of innate sensors in macrophages and dendritic cells contribute to the development of adaptive immunity?

What role do adjuvants play in vaccines, and how does this relate to the activation of cytosolic PRRs?

In the context of viral infection, what differences between self and non-self nucleic acids are exploited by cytosolic PRRs?

Describe how signaling via STING ultimately results in the transcription of interferon genes.

Explain why the induction of co-stimulatory molecules CD80 and CD86 is essential for effective T cell activation. What happens in their absence?

How do cytosolic PRRs contribute to the elimination of intracellular pathogens that do not directly infect immune cells (e.g., viruses in non-immune cells)?

Inhibitory NK receptors trigger activation signals via immunoreceptor tyrosine-based activation motifs (ITAMs) following ligand binding.

The functional outcome of NK cell activity (cytokine production and cytotoxicity) is solely determined by the strength of activating signals, disregarding the influence of inhibitory signals.

Innate immune effector mechanisms are primarily regulated by receptors generated through somatic recombination, similar to the adaptive immune system.

Pathogen-associated molecular patterns (PAMPs) are exclusively derived from viral pathogens and do not include any bacterial components.

The breaching of epithelial barriers leads to an immediate and direct activation of adaptive immunity, bypassing the steps involving tissue-resident cells and inflammatory mediators.

Danger-associated molecular patterns (DAMPs) are exclusively recognized by B cell receptors to initiate humoral immune responses.

Tyrosine phosphorylation within ITAM motifs of activating NK receptors leads to the direct inhibition of cytotoxic granule release.

Mannose-binding lectin (MBL) and ficolin exemplify free receptors present in the serum, acting as pattern recognition receptors.

The invariable region of T cell receptors directly recognizes and binds to microbial surface patterns during an infection.

Cytoplasmic signaling receptors like NOD receptors are primarily involved in the detection of extracellular pathogens.

Tissue inflammation is solely detrimental and does not contribute to pathogen clearance or tissue repair.

Endothelial activation, induced by inflammatory mediators, results in decreased leukocyte adhesion and transmigration into tissues.

Natural Killer (NK) cells exert their antiviral effects exclusively through the release of antibodies.

Cytokines and chemokines function primarily to suppress the immune response, preventing excessive inflammation post-infection.

The detection of pathogen-associated molecular patterns (PAMPs) by sensor cells leads to the down regulation, rather than the induction, of inflammatory mediators.

Membrane-bound phagocytic receptors such as mannose receptor, are primarily involved in intracellular signaling rather than pathogen engulfment.

NLRP3 inflammasome activation results in the exclusive production of anti-inflammatory cytokines, limiting the extent of pyroptosis.

NLRP3, a crucial component of the inflammasome, contains a CARD domain, similar to NOD2, enabling direct interaction with caspase-1 for cytokine processing.

The CGAS-STING pathway is activated exclusively by extracellular pathogens, triggering a localized inflammatory response via the production of type I interferons.

Uric acid crystals, elevated ATP levels, and disruption of lysosomes inhibit NLRP3 inflammasome.

Endothelial activation, as part of the inflammatory response, exclusively inhibits blood clotting to ensure continuous leukocyte recruitment to the infection site.

The essential roles of inflammation include inhibiting effector molecule delivery, suppressing leukocyte recruitment, and preventing tissue repair.

Cytosolic PRRs, such as NOD-like receptors and RIG-I-like receptors, exclusively recognize pathogen-associated molecular patterns (PAMPs) derived from extracellular bacteria.

Following tissue injury, the primary role of inflammation is to suppress immune cell activity to prevent excessive damage and promote rapid tissue regeneration.

NLRP3 inflammasome activation is exclusively triggered by pathogen-associated molecular patterns (PAMPs), ensuring a specific immune response against infectious agents.