immunology

• Phagocytic cells are macrophages, neutrophils and dendritic cells in tissues while monocytes in blood
• monocytes differentiate into macrophage
• Innate immunity: pattern recognition, cytokines and inflammation
• Maria Yurchenko, PhD, is a researcher at IKOM, Center of Molecular Inflammation Research, NTNU.
• Innate immunity consists of layers of defence, with the first line of defence being anatomical barriers to infection such as physical/mechanical and chemical barriers.
• The second line of defense in innate immunity is the induced innate response, which includes cellular innate immune responses like phagocytosis, PRR signaling, and inflammation.
• Understanding how innate immunity works is crucial as pathogens have evolved various strategies to evade innate immune detection, such as inhibiting phagocytosis/pathogen uptake, turning off cytokines production, masking their genetic material, or interfering with function of recognition receptors.
• The lecture includes an introduction to phagocytic cells and phagocytosis, patterns recognition receptors: classes, structure, signaling, cytokines, cross-talk with immune system, and basic knowledge about innate immune cells.
• When the invader breaches the anatomical barriers, the cellular responses are activated.
• There are four main types of innate immune cells: neutrophils, monocytes, dendritic cells, and macrophages.
• Phagocytic cells (macrophages, neutrophils and dendritic cells in tissues, and monocytes in blood) are able to “eat” particulate material (e.g. bacteria), which is a key mechanism for the elimination of pathogens.
• Elie Metchnikoff (Ilia Mechnikoff) discovered in 1882 that certain white blood cells could engulf and destroy harmful bodies such as bacteria.
• Functional characteristics indicative of pathogen presence include NLRPs/Inflammasomes, pore-formation (bacterial pore-forming toxins, viroporins), and the elimination of the need for specific receptors for each virulence structure.
• Recognition of functional features in combination with Pattern Recognition Receptors (PRRs) informs the immune system that the microbe is a pathogen.
• Toll-like receptors (TLRs) are transmembrane proteins with an ectodomain that is horseshoe-like with tandem copies of Leucine-rich repeat (LRR) motifs that bind to ligands.
• The cytoplasmic signaling domain of TLRs is homologous to the IL-1R, termed the Toll/IL-1R homology (TIR) domain.
• Ligand binding induces conformational changes in preformed TLR dimers that initiate downstream signaling.
• Signaling through TLRs utilizes “common pathways”, such as NF-κB, which is activated by signaling from several TLRs.
• Virus recognition activates IRFs that turn on type I IFNs, crucial antiviral mediators.
• The particular signaling pathway that is activated is determined by the adaptors that bind to the TIR domain.
• Two key adaptors in TLR signaling are MyD88, used by most TLRs, and TRIF, used by TLR3.
• Sorting adaptors in TLR signaling include TIRAP/Mal for MyD88 and TICAM-2/TRAM for TRIF.
• TLRs recognize nucleic acids such as dsRNA, polyIC, flagellin, B DNA, CpG, and ssRNA.
• Nucleic acid recognition by RLRs includes recognition of RNA viruses.
• Elie Metchnikoff's discovery was met with skepticism from other scientists.
• Pasteur and Behring won the Nobel prize in 1908 for their work on leukocytes and microbes.
• Leukocytes migrate to the infected area.
• The leukocytes move into the tissue through a process called extravasation.
• Microbes are recognized, ingested, and killed by phagocytes.
• Ingested materials are taken into phagosomes.
• Phagosomes are fused with lysosomes or granules.
• Destruction occurs through enzyme degradation, antimicrobial proteins, and toxic effects of reactive oxygen and reactive nitrogen species (ROS and RNS).
• G-protein-coupled receptors on phagocytes link microbe recognition with increased efficiency of intracellular killing.
• Neutrophil Extracellular Traps (NETs) are a type of extracellular DNA that is green.
• Charles Janeway predicted in 1989 that activation of the adaptive immune response is controlled by the innate immune system.
• He proposed a general theory based on Pattern recognition receptors (PRRs), which are soluble or membrane bound receptors that recognize Pathogen-associated molecular patterns (PAMPs) and Damage-associated molecular patterns (DAMPs).
• Secreted PRRs function as opsonins by binding microorganisms and promote complement activation and recognition by phagocytes.
• Endocytic PRRs are expressed on phagocytes and efficiently bind PAMPs, triggering clearance by internalization and lysosomal destruction.
• Signaling PRRs activate signal transduction pathways and induce expression of a variety of immune response genes.
• Transmembrane PRRs span the cellular membranes and include Toll-Like Receptors (TLRs), C-type Lectin Receptors (CLRs), and NOD-Like Receptors (NLRs).