Myeloid Cells and the Innate Immune Response

Overview of the Innate Immune System

Myeloid Cells

• Myeloid cells are a subset of leukocytes (white blood cells) that play a crucial role in the innate immune system.

• Major types of myeloid cells include granulocytes (neutrophils, eosinophils, basophils, mast cells) and monocytes/macrophages.

• Dendritic cells are also included in the myeloid cell category, acting as antigen-presenting cells.

• Granulocytes are characterized by the presence of granules in their cytoplasm, which contain enzymes and other substances important for immune responses.

• Each type of granulocyte has specific functions: neutrophils primarily target bacteria, eosinophils are involved in combating parasites, and basophils play a role in allergic responses.

Recognition of Pathogens

• The innate immune system is the first line of defense, responding quickly (within minutes to hours) and non-specifically to pathogens.

• It recognizes pathogens through patterns and repeating elements, utilizing Pattern Recognition Receptors (PRRs).

• PRRs trigger immediate immune responses and are expressed by all cells of a particular type, ensuring a broad recognition of pathogens.

• Toll-like receptors (TLRs) are a key type of PRR that detect bacteria and viruses, while NOD-like receptors (NLRs) detect intracellular bacteria, and C-type lectin receptors (CLRs) detect fungi.

• TLRs recognize Pathogen-Associated Molecular Patterns (PAMPs) such as LPS, dsRNA, and flagellin, leading to the activation of NF𝚱B, a master transcription factor for inflammatory mediators.

Key Components of the Innate Immune System

• The innate immune system serves as the first line of defense against pathogens, utilizing various cells and proteins to recognize and eliminate invaders.

• Major cell types include macrophages, neutrophils, eosinophils, basophils, and mast cells, each playing distinct roles in immune response.

• Antimicrobial proteins such as lysozyme, defensins, and histatins are crucial for direct pathogen elimination.

• Granulocytes contain inflammatory mediators that enhance the immune response and facilitate pathogen destruction.

Mechanisms of Pathogen Recognition

• Pathogen recognition is primarily mediated by pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs), NOD-like receptors (NLRs), and C-type lectin receptors (CLRs).

• These receptors detect specific pathogen-associated molecular patterns (PAMPs) and initiate immune signaling pathways.

• Activation of NFκB leads to the production of pro-inflammatory cytokines and chemokines, recruiting additional immune cells to the site of infection.

Mechanisms of Pathogen Elimination

Phagocytosis

• Phagocytosis is the process by which innate immune cells, such as neutrophils and macrophages, engulf and destroy extracellular material.

• Phagocytes internalize pathogens into phagosomes, which then fuse with lysosomes to degrade the material.

• The main phagocytic cells include neutrophils, eosinophils, basophils, monocytes, macrophages, and dendritic cells.

• This process is essential for clearing infections and involves various receptors that recognize and bind to pathogens.

Production of Reactive Oxygen Species (ROS)

• Activated phagocytes produce toxic oxygen species through the activation of NADPH oxidase, leading to a respiratory burst.

• This transient increase in oxygen consumption results in the production of hydrogen peroxide (H2O2), a reactive oxygen species that can damage pathogens.

• While ROS are effective in killing pathogens, they can also cause collateral damage to surrounding tissues.

• Chronic Granulomatous Disease (CGD) is a condition where patients have a deficiency in NADPH oxidase, leading to an inability to produce ROS and increased susceptibility to infections.

Antimicrobial Proteins and Their Functions

Types of Antimicrobial Proteins

• Lysozyme: Found in tears and saliva, it breaks down bacterial cell walls, providing a first line of defense.

• Defensins: Secreted by phagocytes and epithelial cells, these small peptides disrupt microbial membranes.

• Histatins: Produced in the oral cavity, they exhibit antifungal activity, particularly against Candida species.

Role of Granulocytes in Immune Response

• Granulocytes, including neutrophils, eosinophils, and basophils, contain granules filled with antimicrobial agents and enzymes.

• Upon activation, these cells release their granules, which contain histamine, prostaglandins, and other inflammatory mediators.

• Neutrophils can form NETs (neutrophil extracellular traps) to capture and kill pathogens, utilizing nuclear chromatin and antimicrobial proteins.

The Complement System

Overview of the Complement System

• The complement system consists of over 30 proteins that enhance the ability of antibodies and phagocytic cells to clear pathogens.

• It operates through three pathways: classical, lectin, and alternative, all converging on the activation of C3 convertase.

• Activation leads to opsonization, inflammation, and direct lysis of pathogens via the Membrane Attack Complex (MAC).

Pathways of Complement Activation

• Classical Pathway: Triggered by antibody-antigen complexes, leading to the formation of C3 convertase and MAC.

• Lectin Pathway: Initiated by mannose-binding lectin (MBL) binding to carbohydrates on pathogens, activating complement.

• Alternative Pathway: Activated spontaneously on pathogen surfaces, amplifying the complement response.

Clinical Implications and Applications

Importance of Complement in Disease

• Deficiencies in complement components can lead to increased susceptibility to infections, particularly with encapsulated bacteria like Neisseria meningitidis.

• Pathogens such as Staphylococcus aureus can evade the immune response by inhibiting complement activation.

• Understanding complement pathways is crucial for developing therapies for autoimmune diseases and infections.

FACS Practice and Immune Cell Analysis

• Flow cytometry (FACS) is used to analyze immune cell populations and their activation states.

• Specific markers such as CD18, TLR4, CCR1, and CCR5 can be used to identify and study macrophage migration and activation.

• Analyzing differences in cell counts and surface markers can provide insights into immune responses during infections.