Innate Immune Response Quiz

Innate Immune Response

• Innate immunity is a crucial part of any immune response.
• It reacts quickly to invading microbes, keeping the host alive while adaptive immunity develops a specific response.
• Innate defenses are present at birth, ready to fight infections.
• They have limited diversity in antigen recognition and attack microbes with consistent vigor regardless of encounter frequency.
• Innate immunity acts fast, immediately within minutes to hours after infection.
• The response doesn't retain memory, so repeated exposure doesn't enhance it.

Learning Objectives

• Identify innate immune components/barriers.
• Identify cells of innate immunity and their functions.

Innate Immune Components/Barriers

• Physical (anatomic) barriers:
  • Skin: Most pathogens cannot penetrate intact skin; its pH is slightly acidic, hindering pathogen growth.
  • Respiratory tract: Lined with cilia that help remove microbes, along with saliva and mucus (rich in antimicrobial enzymes and chemicals).
  • Gastrointestinal (GI) tract: Also a mucous membrane, requiring pathogens to survive a highly acidic stomach environment. Sticky mucus traps foreign material.
• Physiologic barriers:
  • Temperature: Many microbial pathogens cannot survive human body temperature.
  • pH: The acidic pH of the stomach prevents pathogen growth and transmission. Skin pH also hinders pathogen growth.
  • -Chemical: Lysozyme in secretions (tears, saliva, breast milk, mucus) breaks down bacterial cell walls. Defensins in phagocytes form pores in bacteria and fungi. Interferons (IFN-α and IFN-β) are antiviral.

Skin and Mucous Membranes

• Stratified epithelium (skin, lining of mouth)
• Embedded keratin
• Columnar epithelium (respiratory and reproductive systems)
• Cilia
• Mucus-producing cells

Innate Cellular Response

• Phagocytic cells (monocytes/macrophages, neutrophils, dendritic cells) are part of the first line of defense against invading pathogens.
• They recognize shared pathogen molecules (PAMPs) not found on host cells.
• Receptors of the innate immune system are called Pattern Recognition Receptors (PRRs).
• PRRs recognize pathogen-associated molecular patterns (PAMPs). Examples are molecules shared by pathogens (e.g., bacterial LPS)
• Innate receptors are built into the germline genes. They are not created by recombination in lymphocytes.
• Innate immunity can recognize up to 1000 pathogen patterns. Adaptive immunity recognizes over 1 billion or more.

Cells of Innate Immunity

• Neutrophils: Circulating phagocytes with a short lifespan, providing rapid but not prolonged defense.
• Eosinophils: Circulating phagocytes.
• Monocytes/Macrophages: Circulate in blood and become macrophages in tissues, promoting prolonged defense. Produce cytokines (inflammation), phagocytose pathogens, and clear dead tissue, aiding in tissue repair.
• Dendritic cells (DCs): Found throughout tissues, processing and presenting antigens. Initiate inflammatory responses and stimulate adaptive immunity.
• Mast cells: Found in skin and mucosa, playing a role in innate immunity via two activation pathways (innate TLRs and antibody-dependent, IgE).
• Natural killer cells (NK cells): Found in blood and periphery. Directly lyse cells and secrete IFN-γ.

Killing Mechanisms

• 1-NK cell mechanism: NK cells make close contact with target cells, releasing granules containing substances to cause lysis and activate apoptosis.
• 2- Antibody-dependent cell-mediated cytotoxicity (ADCC): IgG antibodies bind to target cells and to Fc receptors on NK cells, directing NK cells to kill the target cell.

Phagocytosis

• Process of engulfment and destruction of particles (bacteria, cellular debris, etc.).
• Involves chemotaxis, attachment, engulfment (phagosome formation), fusion with lysosomes (phagolysosome formation) and intracellular killing. Killing involves a variety of mechanisms.
• Microorganisms are exposed to a potent array of microbicidal proteins and oxidizing agents, eventually killing and digesting the microbe.
• Oxygen dependent killing and oxygen independent killing.

Chemotaxis

• Phagocytes move purposefully towards microorganisms following a chemoattractant.
• Source of chemoattractants from microorganisms and injured tissues.
• Chemotatic factors attract phagocytic cells to the infection site.

Attachment

• Phagocytes have receptors on their surface that recognize and bind pathogen-associated molecular patterns (PAMPs).
• PAMPs are shared by microorganisms and not present on host cells. These provide a target for phagocytes.

Engulfment

• Phagocytic membrane surrounds and encloses the organism in a vacuole termed a phagosome.
• Phagosome moves inside the cell.
• Phagocytosis is a specific membrane fusion event.

Fusion of phagosomes with lysosomes

• Fusion of phagosomes with lysosomes (containing enzymes and killing substances) creates phagolysosomes.
• The contents of phagolysosomes are mixed.
• These enzymes and killing factors are responsible for killing ingested microorganisms.

Killing

• Once ingested, microorganisms are exposed to potent microbicidal proteins and oxidizing agents, causing their death and digestion.
• Intracellular killing involves both oxygen-dependent and oxygen-independent pathways.

Intracellular Killing

• Respiratory burst (a metabolic process) generates reactive oxygen metabolites (important in killing).
• Reactive nitrogen intermediates also play a role.
• Lysosomal contents (e.g., lysozyme, defensins, lactoferrin, hydrolytic enzymes) have degradative effects.

Evasion of Phagocytosis

• Some microorganisms lack pattern molecules or coat themselves to evade recognition.
• Attachment can still occur if these microorganism become coated with opsonins (proteins like antibodies or complement).
• The coating makes them more desirable targets for phagocytosis.

Cytokines

• Important in mediating innate immune response.
• Pro-inflammatory cytokines (e.g. IL-1, IL-6, and TNF-α) produced by macrophages are involved in fever, cachexia and production of acute phase proteins.
• IL-12 secreted by macrophages promotes the activation of NK cells and type II interferons (IFN-γ). This promotes more class I MHC gene expression in general, as well as NK cell activation.
• IFN-α and IFN-β, secreted by virus infected cells, block viral replication.
• IFN-γ, secreted by T lymphocytes and NK cells, can interfere with virus replication in uninfected cells. Interferons also increase the MHC I and II expression in different cells.

Interferons

• Group of proteins with antiviral activity.
• IFN-α and IFN-β are part of innate immunity. Produced by virus-infected cells.
• IFN-γ is part of adaptive and innate immunity. Produced by T lymphocytes and NK cells.
• Mechanism of action: Interferons block viral replication by stimulating the production of cellular antiviral proteins.

Acute Phase Proteins

• Proteins that increase in the blood during infections, often in response to cytokines (IL-6).
• Examples include C-reactive protein.
• Mechanism of action: Acute phase proteins can bind to bacteria, promote microbial elimination through different effector mechanisms, and increase the killing ability of phagocytes.

Complement

• Group of proteins that is normally inactive, but gets activated resulting in elimination of the organism.
• Activation leads to elimination of the organism.
• Complement plays a role in inflammation, phagocytosis and target cell lysis.

Inflammation

• Process of inflammation that leads to leukocytes and plasma proteins for defense.
• Important and needed in the battle against infection.
• Inflammation is accompanied by local swelling, pain and redness.

Innate Immunity Conclusion

• Innate immunity is effective and sufficient to kill invading microbes.
• When initial innate mechanisms fail, they activate adaptive immunity which takes over to provide a specific defense.