The innate immune response

Innate and Adaptive Immunity

Characteristics Vertebrates and invertebrates First line of defense Rapid Non-specific recognition of molecular patterns Induces the adaptive response

Infection Inflammation Immunity Innate immune system

Functions of the (innate) immune system Barriers: Recognition: Remove and destroy: Distinguish self and non-self: Memory? Ask for examples

Functions of the innate immune system Barriers: Physical, chemical, microbial Recognition: PAMPs Remove and destroy:Phagocytes Distinguish self and non-self: NK cells

Barriers to microbial invasion Figure 2-4 Microbiota

Respiratory tract Mucociliary escalator Skin

Infection can occur when mechanical barriers fail Skin wound Pneumonia Cystic fibrosis Primary ciliary dyskinesia (immotile cilia) Snakes Urinary tract infection Obstruction Failure of peristalsis

Antimicrobial peptides Defensins and others Produced by epithelial cells Broad specificity: Bacteria Fungi Viruses Actions: Direct killing Modulation of microbiota Epithelial surfaces

Microbiota The communities of microorganisms on normal mucosal surfaces Bacteria, fungi, viruses, protozoa Mechanisms of protection: Competition Antibacterial products Stimulation of host defenses

Functions of the innate immune system Barriers: Physical, chemical, microbial Recognition: PAMPs, other receptors Remove and destroy:Phagocytes Distinguish self and non-self: NK cells

Toll: A drosophila gene Discovered in 1985: embryology of drosophila 1996: Required for innate immunity 1997: Toll-like genes in mammals Lemaitre, et al, Cell 86:973-983 (1996)

Recognizing pathogens: Pathogen-Associated Molecular Patterns (PAMPs) Characteristic molecules expressed by classes of microorganisms: Bacteria: Cell wall and cell membrane components, capsules Viruses: DNA, RNA, coat proteins Fungi, parasites: Surface molecules Microbe-associated (MAMPs) Pathogen response receptors (PRRs)

Toll-like receptors

} Ligand Recognition domain Receptor Signaling domain Signal transduction Gene expression

Other Pathogen Response Receptors

The inflammasome IL-1 Endogenous pyrogen

Pathogen? Helpful microbe? Non-pathogen? Damaged host cell? Some of each?

Danger signals: DAMPs and PAMPs Damage-associated molecular patterns (DAMPs) Molecules released by damaged cells Extracellular/extranuclear DNA ATP Lysosomal contents Etc. Recognize damaged host cells Distinguish pathogens from non-pathogens

Classes of PAMP and DAMP receptors receptors NOD = Nucleotide-binding oligomerization domain: activation site NOD-like receptors, NLR Intracellular/intracytoplasmic PRRs RIG-like receptors (retinoid acid-inducible gene): RLR Cytosolic DNA and dsRNA PAMP, DAMP receptor RAGE: Receptor for Advanced Glycosylation End-Produces DAMP receptor

Tang D, et al Immunological Reviews. 2012;249(1):158-175.

Functions of the innate immune system Barriers: Physical, chemical, microbial Recognition: PAMPs Remove and destroy: Phagocytes Distinguish self and non-self: NK cells

Phagocyte functions Phagocytes: Neutrophils, Macrophages, Dendritic cells Recognition, removal and killing of pathogens Release of necrotizing enzymes Cytokine and chemokine secretion Induction of an adaptive response

Consequences of pattern recognition by phagocytes Binding, internalization and degradation (killing) Release of toxic products/tissue destruction Cytokine production Inflammation Activation of adaptive immunity

Lysosomal degradation Kill microbes “Collateral damage”

Collateral damage: Frustrated phagocytosis Normal

Reactive Oxygen Species (ROS) Enzymes: Phagocyte oxidase Nitric oxide synthetase (iNOS) Myeloperoxidase Products: Superoxide Hydrogen peroxide Nitric oxide Halides Respiratory burst Myeloperoxidase

Gross photo alert!

Phagocyte toxic products: Microbe killing and tissue destruction

Functions of the innate immune system Barriers: Physical, chemical, microbial Recognition: PAMPs Remove and destroy:Phagocytes Distinguish self and non-self: NK cells

Natural killer (NK) cells: self-recognition “Innate lymphoid cells” Kill cells on contact Pre-programmed Recognize self by the presence of the Major Histocompatability Complex (MHC) Self MHC present: no activation Self MHC absent or abnormal: activation and killing

Natural Killer Cells: recognition of self Foreign cell Virus infected cell

Major Histocompatibility Molecules Principal determinants of self-recognition Surface-expressed Functions: Compatibility of transplanted tissues: Histocompatibility Recognition by Natural Killer cells Antigen presentation to T cells Two classes: MHCI: present on all nucleated cells: recognition of self MHCII: Present on antigen presenting cells

When is self-MHC absent or abnormal? Non-self MHC (example?) Abnormal self-MHC (examples?) Foreign cell (transplant) = non self mhc Tumor cell = abnormal mhc Infected cell = abnormal mhc

Killing by NK cells Kill by contact: “Kiss of death” Pore formation Induce apoptosis Toxic granules secreted directly into target cells Cytokine production

IFNg TNFa

Complement 20+ plasma proteins and cleavage products Proteolytic cascade(s) Designated by C# Innate and adaptive immunity

Complement: History 1890-1900 Bactericidal serum factors Heat-labile: Non-specific, bactericidal Heat-stable: micro-organism specific Heat-labile factor is necessary for (“complements”) activity of the heat stable factor Heat-stable = antibodies Heat-labile = complement

What is complement? Multiple proteins An enzyme cascade Many functions: Entire cascade: Direct killing Components: Activation of phagocytes Chemotaxis Different components have different functions

The complement cascade Adaptive Innate C3 lysis

Actions of complement Innate Adaptive Opsonization = the process of coating particles to make them recognizable by phagocytes

Membrane attack complex

Overview of innate immunity Physical and chemical barriers Phagocytosis: Bacterial killing Lysosomal enzymes Toxic oxygen radicals Cytokine and chemokine secretion Antigen presentation Complement activation: Chemotaxis Membrane attack complex Opsonization Adaptive immunity Adaptive immunity