Immunology: Innate Immune Response Overview

Advanced Lectures of Molecular Medicine, Part I: Immunology

• The lecture series is on molecular medicine, focusing on immunology
• The professor is Christian Bogdan, a professor of medical microbiology and infectious disease immunology
• The lectures are given at Friedrich-Alexander University Erlangen-Nürnberg and the university clinic Erlangen in Erlangen, Germany.

Innate Immunity - Agenda

• The agenda covers dermal and epithelial barriers.
• The agenda includes myeloid cells and leukocyte chemotaxis receptors.
• The agenda covers soluble factors: complement, chemokines, and cytokines.
• The agenda includes pattern recognition receptors.
• The agenda covers antimicrobial effector functions of phagocytes.
• The agenda covers natural killer cells and innate lymphoid cells (ILCs).
• The agenda includes principals of innate antiviral responses.

Innate Immune Response: Stages

• Tissue damage triggers an epithelial response, which is not strictly an immune response but plays a part
• Leukocytes, such as PMNs and natural killer cells, are attracted and migrate to the site of damage.
• Pathogens are recognized by recruited PMNs and resident myeloid cells (macrophages and dendritic cells).
• Recruited PMNs and resident myeloid cells are activated, which includes phagocytosis, antimicrobial effector mechanisms, cytokine production, and initiating the adaptive immune response.
• The final goal is pathogen elimination, infection control, and tissue repair.

Innate Immune Response: Epithelial Barrier

• A physical barrier is the primary defense, with skin and epithelial layers providing inherent antimicrobial protection.
• Microbes are killed by antimicrobial peptides, such as defensins and cathelicidin that are produced by epithelial cells.
• Intraepithelial lymphocytes (IELs) play a role in regulating the immune response, activating macrophages and lysing infected cells. α/β or γ/δ intraepithelial T cells and innate lymphoid cells (ILCs), such as ILC2s, are components of this response.

Myeloid Cells

• Granulocytes (neutrophils, eosinophils, basophils) and circulating blood monocytes are myeloid cells
• Resident tissue macrophages are in the CNS (microglia), liver (Kupffer cells), gut (intestinal macrophages), lung (alveolar macrophages), spleen (red pulp macrophages, marginal zone macrophages, metallophilic macrophages)
• Conventional dendritic cells (CDCs) and plasmocytoid dendritic cells (pDCs) are also myeloid cells.

Professional Phagocytes

• Polymorphonuclear granulocytes (neutrophils)
• Blood monocytes
• Tissue macrophages (alveolar macrophages, Kupffer cells, osteoclasts)
• Immature dendritic cells

Neutrophils

• Neutrophils produce cytokines and chemokines
• During phagocytosis, neutrophils release reactive oxygen intermediates and antimicrobial factors.
• Nets: neutrophil extracellular traps are produced by neutrophils for killing microbes.

The Classical View on Macrophages (until 2000)

• Tissue macrophages are derived from circulating monocytes and are non-replicating tissue cells
• They are professional phagocytes with strong phagocytic activity, ingesting pathogens and cellular debris.
• They degrade material with enzymatic and oxidative antimicrobial activity, acting as a "garbage man" in the body.
• They are activated by lymphocyte products.
• Macrophages are important in tissue repair and homeostasis.

Changes of Paradigms in Macrophage Research (2000-2016)

• Macrophage ontogenesis is more complex; some derive from the yolk sac or fetal liver, others from circulating monocytes that transmigrate as inflammatory macrophages in the postnatal period.
• Macrophages can replicate ("self-renewal").
• Macrophage markers and activation statuses are more complex than previously thought, displaying a range of responses based on stimuli.
• Macrophage plasticity is higher than previously thought.
• Myeloid cells have "trained immunity", a memory-like function with epigenetic remodelling.

Cytokines and Chemokines

• Cytokines (e.g., interleukins, interferons, growth factors) are cell signaling molecules.
• Chemokines are cytokines which primarily attract leukocytes.
• Cytokines have autocrine and paracrine functions.

Cytokine Families

• Type I cytokine receptors are typically dimers or trimers with a single ligand-binding chain and one or more signal-transducing chains. They have conserved tryptophan-serine-X-tryptophan-serine (WSXWS) motifs.
• Type II cytokine receptors are commonly dimers with a single ligand-binding chain and one signal-transducing chain. They lack WSXWS motifs.

Complement System: Pathways of Activation

• The complement system has three pathways (classical, lectin, and alternative) to activate complement enzymes.
• The classical pathway is triggered when antibodies bind to antigens.
• The lectin pathway is a response to pathogen carbohydrates.
• The alternative pathway is triggered by pathogen surfaces and spontaneously activates.

Complement System: Functions

• Complement activation is initiated in different ways (classical, lectin, alternative), but later steps are similar across all three pathways.
• The results include chemoattraction, inflammation, opsonization, and phagocytosis, and also forming the membrane attack complex (MAC) for cell lysis.

Immune Cell Receptors

• Immune cells have receptors for cell-cell communication, pathogen recognition (pattern recognition receptors), and signal transduction.
• Immune cell receptors are used for cell positioning and adhesion.
• The receptors include cell adhesion receptors, chemokine receptors, cytokine receptors, and endocytic receptors.

Pathogen Recognition Receptors

• Pathogen-recognition receptors (PRRs) recognize microbial products, also named PAMPs.
• The PRPs can be located on the cell membrane, cytoplasm, or endosome/lysosome.

Inflammation via TLR and Inflammasome Activation

• Pathogens and their products stimulate TLRs and the inflammasome, leading to inflammation.
• PAMPs and DAMPs stimulate inflammation pathways.
• PAMPs are associated with microbes/pathogens.
• DAMPs are associated with damage/ danger molecules.

Toll-Like Receptors (TLRs)

• TLRs are transmembrane proteins with extracellular and intracellular domains.
• TLRs recognize pathogen-associated molecular patterns (PAMPs).
• Different types of TLRs are located in different cellular compartments (plasma membrane, endosomes).
• TLR activation leads to intracellular signaling pathways to mediate inflammation.

Anti-microbial Effector Mechanisms of Phagocytes

• Phagocytes destroy pathogens with oxygen-independent (constitutive/rapidly available) and oxygen-dependent (inducible) mechanisms.
• Oxygen-independent mechanisms include enzymes (e.g., lysozyme), antimicrobial peptides (defensins, BPI), anti-microbial proteins (histones), and iron chelators (lactoferrin).
• Oxygen-dependent mechanisms include NADPH oxidase, myeloperoxidase, reactive oxygen species, catalytic antibodies, and DNA webs.

Phagocytosis

• Phagocytosis is the cellular uptake and destruction of pathogens
• Phagocytosis can be receptor-mediated or fluid phase
• Mechanisms for phagocytosis include formation of the phagosome, lysosomal fusion, and degradation of the pathogen.

Opsonization

• Opsonization is the coating of pathogens with antibodies or complement proteins to increase their phagocytosis.

Antimicrobial Activity of Phagocytes

• Phagocytes use various methods to kill microbial cells: direct ROI/RNI-mediated killing, enzymatic digestion, pore formation, trapping, and depletion (nutritional).

Neutrophil Extracellular Traps

• Neutrophils produce and release NETs which contain antimicrobial factors (DNA, proteins).
• Nets are involved in pathogen containment and killing.

NETosis of Neutrophils

• Neutrophils undergo NETosis in response to infection, which involves the extrusion of nuclear DNA into the extracellular environment.
• NETosis is associated with the formation of NETs which trap pathogens and contain and eliminate them.

NOS - Chemical Reaction

• The chemical reaction of NO synthase produces nitric oxide.
• Nitric oxide is a crucial component in the direct and indirect antimicrobial activities
• The reaction pathway involves various molecules and steps.

Regulation of iNOS Expression

• Expression is controlled by various factors including mRNA synthesis, mRNA stability, and protein synthesis.
• The regulatory effect of various cytokines (e.g. IFNγ, TNF) is influenced by factors such as L-arginine and LPS.

Role of Antibodies in Innate Immunity

• Antibodies enhance phagocytosis (opsonization).
• Antibodies neutralize pathogens by blocking pathogenic receptors.
• Antibodies initiate acute inflammation.
• Complement activation can occur as a result of antibody binding to pathogens.

Innate Lymphoid Cells (ILCs)

• ILCs are a group of innate immune cells with diverse functions, including responding to pathogens, extracellular bacteria, and parasites.
• ILCs have unique subtypes and functions, such as: cytotoxicity, producing inflammatory cytokines, antimicrobial peptides (produced by innate cells).

Activation and Function of Natural Killer (NK) Cells

• NK cells are activated by activating receptors and inhibited by inhibitory receptors (e.g., MHC class 1-related proteins).
• Activation leads to killing of target cells through granule exocytosis and cytotoxicity.
• Antibody-dependent cell-mediated cytotoxicity (ADCC) also occurs in NK cells.

NK Cell - Target Cell Interaction

• Activation of NK cells depends on whether target cells express normal or abnormal self-markers and self-marker downregulation.
• The interactions involve both activating and inhibitory signals.
• Viral proteins and tumor markers can also affect interaction resulting in alteration in self-markers.

Target Cell Lysis by NK Cells

• NK cells kill target cells (e.g., virus infected, tumor) through either granule exocytosis causing membrane pore formation and subsequent apoptosis.
• Granule exocytosis introduces perforin and granzymes for target cell lysis and death.
• Fas ligand and Fas interactions can also cause apoptosis.

Dual function of NK Cells in Innate Immunity

• NK cells can have a dual function, both directly killing infected, virus-infected or other abnormal cells and also regulating macrophage activity by activating them.

Complement System Pathways

• complement activation is involved in many of the pathways of inflammation.

Explore the key concepts of innate immunity through this quiz based on advanced lectures in molecular medicine. Learn about the structure and functions of dermal and epithelial barriers, myeloid cells, various soluble factors, and the antimicrobial functions of phagocytes. Test your understanding of the innate immune response and its stages in this comprehensive assessment.