Complement Activation Quiz

Innate Immune Recognition

• Innate immunity directly recognizes microbial infections through conserved molecular structures.
• PAMPs, MAMPs, and DAMPs are defined as pathogen-associated molecular patterns, microbe-associated molecular patterns, and damage-associated molecular patterns, respectively.
• Soluble factors like the complement system are important for activating and mediating host defense.
• Major classes of pattern recognition receptors (PRRs) have specific functions and locations.
• Professional phagocytes have receptors that bind pathogen surfaces, internalizing them through phagocytosis.
• Pathogens are subsequently destroyed by multiple effector mechanisms within the phagolysosome.
• The innate immune system rapidly recognizes pathogens, unlike adaptive immunity, which requires time and information to respond.

Clinical Correlate

• A breeding colony of Brittany spaniels exhibited increased susceptibility to infections (sepsis, pneumonia, surgical site infections), primarily caused by Pseudomonas, E. coli, Clostridia, and Klebsiella.
• Prolonged antibiotic treatments were required for recovery in the majority of dogs.

Learning Objectives

• The innate immune system directly recognizes microbial infection through conserved molecular structures.
• PAMPs, MAMPs, and DAMPs.
• Soluble factors play critical roles in activating and mediating host defense.
• Major classes of pattern recognition receptors, their functions, and locations.

Layers of Host Protection

• Anatomical barriers (skin, oral mucosa, respiratory epithelium, and intestine).
• Complement/antimicrobial proteins (C3, defensins, RegIII).
• Innate immune cells (macrophages, granulocytes, natural killer cells, epithelial cells).
• Adaptive immunity (B cells, antibodies, and T cells).

The Complement System

• Complement proteins are constitutively present in blood and interstitial spaces.
• Complement protein C3 is crucial within the complement cascade.
• C3 is cleaved into C3a and C3b.
• C3b covalently binds to bacterial surfaces, acting as an opsonin, enhancing phagocytosis.
• The complement system can be activated via the alternative, lectin, or classical pathways.
• Complement activation leads to altered membranes, bacterial lysis, opsonization, phagocytosis, mast cell degranulation, neutrophil chemotaxis, inflammation, immune regulation, angiogenesis, and removal of apoptotic cells.

Three Ways to Activate Complement

• Alternative pathway: an innate pathway, common in complement activation
• Lectin pathway: another innate pathway triggered by mannose on microbial surfaces.
• Classical pathway: triggered by antibody binding, part of the adaptive response.

Complement Pathway Outcomes

• Membrane attack complex (MAC) formation: leads to cell lysis.
• Opsonization: enhances phagocytosis.
• Inflammation: associated with complement activation.

Why Host Cells Aren't Lysed

• Host cells have protective complement control proteins, like decay-accelerating factor (DAF), which prevent the complement cascade from attacking host cells.

Three Shared Outcomes of Complement C3

• Opsonization: Enhancement of phagocytosis by complement components.
• Inflammation: Complement activation facilitates inflammation at the site of infection.
• Cell lysis: via the formation of the membrane attack complex (MAC).

Pattern Recognition Receptors (PRRs)

• Toll-like receptors (TLRs): innate signaling receptors recognizing pathogen-associated patterns.
• TLR ligands: variety of patterns present in microbes (e.g., LPS, DNA, RNA, flagellin).
• TLR function: activate antigen-presenting cells, induce inflammatory cytokines (TNF, IL-1), induce antiviral cytokines, and induce phagocytosis and killing.

Toll-like Receptor Signaling and Outcomes

• Ligand binding to TLR activates intracellular signaling pathways leading to NF-κB activation.
• NF-κB upregulates the expression of inflammatory cytokines (e.g., TNF, IL-1, IL-6), involved in the host response.

IL-1 and IL-18 Secretion

• These cytokines require a secondary step involving inflammasomes and caspase cleavage for secretion.

Danger-Associated Molecular Patterns (DAMPs)

• DAMPs are products of damaged host cells or from intracellular components released upon cellular damage.
• DAMPs activate immune signaling pathways similar to pathogen-associated molecular patterns (PAMPs), triggering inflammation at the site of injury or infection.
• DAMPs include mitochondrial DNA, uric acid, chromatin, heat shock proteins, adenosine, galectins, S100 proteins, cathelicidins, defensins, N-formyl peptides, and lactoferrin.

Consequences of PRR Signaling

• Inflammation: cytokines cause blood vessel permeability, enabling effector cells and fluid containing soluble effector molecules to enter the infected tissue.
• Recruit immune cells: cytokines like chemokines direct neutrophils, macrophages, and other immune cells to the site of infection.
• Increase body temperature at the infection sites(induced by cytokines): enhances immune response.

Summary

• Soluble factors enhance cell recruitment, tagging microbes for phagocytosis or direct killing.
• The complement cascade covalently attaches C3b, acting as an opsonin.
• Soluble PRRs mark microbes and enhance phagocytosis.
• Membrane-bound PRRs activate cells and induce cytokine production, also directly contributing to phagocytosis.
• PRR activation results in cytokine secretion, affecting both local and system-wide responses.