Lecture 2.2 - The innate immune system

Immune System and Infectious Disease

• The immune system consists of cells and organs that contribute to immune defenses against infectious and non-infectious conditions, distinguishing between self and non-self.
• Infectious disease occurs when a pathogen succeeds in evading and/or overwhelming the host's immune defenses.

Innate Barriers

• Innate barriers include microbiota (commensals) that live on the skin and in the nasopharynx, such as Staphylococcus aureus, Streptococcus pneumoniae, and Candida albicans.
• These microorganisms can become pathogenic under certain conditions.

Clinical Problems

• Clinical problems arise when:
  • Normal flora is displaced from its normal location to a sterile location.
  • The skin integrity is breached, e.g., through skin loss, IV lines, surgery, skin diseases, or injection drug use.
  • The fecal-oral route or fecal-perineal-urethral route is compromised, leading to infections such as foodborne infections or urinary tract infections.
  • There is poor dental hygiene or dental work, resulting in infections such as dental extraction or gingivitis.
  • Patients are at high risk, e.g., asplenic or hyposplenic patients, or those with damaged or prosthetic valves.

The Immune Response

• The initial immune response occurs when a pathogen overcomes the innate barriers and enters the body.
• Macrophages recognize pathogen-associated molecular patterns (PAMPs) and phagocytose them, releasing cytokines that recruit other cells to the site of infection.
• Cytokines also cause inflammation, leading to vasodilation, vascular permeability, mast cell degranulation, and clotting system activation.

Microbes and PAMPs

• Microbes have PAMPs that interact with pattern recognition receptors (PRRs) on innate cells.
• This interaction leads to the activation of macrophages, monocytes, and neutrophils, which release cytokines such as TNF alpha, IL-1, IL-6, and IL-8.

Phagocytosis and Opsonins

• Phagocytosis is the process by which phagocytes (e.g., macrophages and neutrophils) internalize and destroy pathogens.
• Opsonins, such as complement proteins, antibodies, and acute phase proteins, enhance phagocytosis by marking pathogens for destruction.
• Examples of opsonins include C3, C4, IgG, IgM, CRP, and MBL.

Clearance of Opsonized Pathogen

• Complement proteins can "punch holes" in the pathogen's cell membrane, leading to death.
• Phagocytes recognize opsonized pathogens through Fc receptors, internalize them, and produce reactive oxygen species to destroy the pathogen.

Phagocyte Intracellular Killing Mechanisms

• Oxygen-dependent pathway: respiratory burst produces toxic oxygen products (e.g., hydrogen peroxide, hydroxyl radical) that kill pathogens.
• Oxygen-independent pathways: lysozyme, lactoferrin or transferrin, cationic proteins, proteolytic and hydrolytic enzymes, and NETs (neutrophil extracellular traps).

NETosis

• NETosis is the process by which neutrophils externally trap pathogens using decondensed chromatin and granule contents.
• This mechanism can be used as a means of neutrophil cell death and is commonly used to deal with pathogenic insults.

Summary of the Innate Immune Response

• The innate immune response is a crucial defense against pathogens, involving the recognition of PAMPs, activation of macrophages and neutrophils, and the production of cytokines and opsonins.
• Phagocytosis and intracellular killing mechanisms are essential for eliminating pathogens.