Innate Immunity (Pathology)

• It is a protective response to pathogens that does not require any previous exposure to the pathogen in question

• It is rapid

• It is relatively non-specific - it depends upon the recognition of conserved/invariant features of pathogens

• It utilises germ line-encoded host receptors

• It does not generate memory

TRUE

PAMPs (Pathogen-Associated Molecular Patterns):

Definition: PAMPs are molecular motifs or patterns that are conserved within a class of microbes but are not present in the host organism.

Examples: Glycans, lipopolysaccharides, bacterial flagellin, lipoteichoic acid, peptidoglycan, and nucleic acid variants associated with viruses (e.g., double-stranded RNA).

Function: PAMPs are recognized by Pattern Recognition Receptors (PRRs) on immune cells, triggering immune responses. They act as signals indicating the presence of potential pathogens.

DAMPs (Pathogen-Associated Molecular Patterns):

Definition: Damage-Associated Molecular Patterns (DAMPs) are endogenous molecules that are typically sequestered within cells.

Example: One example of a DAMP is High Mobility Group Box 1 (HMGB1). HMGB1 is a nuclear protein that is normally present inside cells, where it functions in the regulation of DNA structure.

Function of DAMPs: DAMPs are like alarm signals released by damaged or stressed cells. When cells are in trouble (due to injury, infection, or stress), DAMPs act as signals to alert the immune system. Their main jobs are to kick-start inflammation, which helps the body get rid of damaged cells, and to promote the repair of tissues. DAMPs essentially guide the immune system to areas where there's a problem, ensuring a quick and targeted response to potential threats.

Gram-positive bacteria:

Cell Wall Structure: Gram-positive bacteria have a thick layer of peptidoglycan in their cell walls. Peptidoglycan is a complex molecule made of sugars and amino acids.

Staining Reaction: When subjected to the Gram staining process, Gram-positive bacteria retain the crystal violet dye and appear purple under a microscope.

Outer Membrane: Gram-positive bacteria lack an outer membrane outside the peptidoglycan layer.

Examples of Gram-positive bacteria include Staphylococcus, Streptococcus, and Clostridium.

Gram-negative bacteria:

Cell Wall Structure: Gram-negative bacteria have a thinner layer of peptidoglycan in their cell walls, and they also have an outer membrane outside the peptidoglycan layer. This outer membrane contains lipopolysaccharides (LPS).

Staining Reaction: During Gram staining, Gram-negative bacteria do not retain the crystal violet dye well and appear pink or red under a microscope.

Outer Membrane: Gram-negative bacteria possess an outer membrane, which is not present in Gram-positive bacteria.

Examples of Gram-negative bacteria include Escherichia coli (E. coli), Salmonella, and Pseudomonas.

Pattern recognition receptors (PRRs)• Host factors that specifically recognise a particulartype of PAMP• They are germ-line encoded• There are several classes of PRR, but functionally theyare either:• Extracellular – they recognise PAMPs outside of a cell andtrigger a co-ordinated response to the pathogen• Intracellular (cytoplasmic) – they recognise PAMPs inside acell and act to co-ordinate a response to the pathogen• Secreted – they act to tag circulating pathogens forelimination (e.g. complement)

• Phagocytes– Monocytes/granulocytes/neutrophils• Cytokines/chemokines• The inflammatory response• Complement• Natural Killer cells

• Material to be “eaten” is recognised in a number ofways:• By detecting phosphatidylserine on exterior membranesurface (cells undergoing apoptosis)• By detecting “atypical sugars” (e.g. mannose, fucose, b-glucan) on cell surfaces• By detecting complement proteins bound to thepathogen surface• By Scavenger receptors• By “passive sampling

Cytokines and Chemokines

Cytokines:

Definition: Cytokines are like messenger proteins that cells use to talk to each other.

Functions: They help cells in the immune system communicate and coordinate their actions. Some cytokines promote inflammation, while others calm it down.

Examples: Interleukins, interferons, tumour necrosis factors (TNF), and growth factors.

-In simple terms, cytokines help cells in the immune system communicate, while chemokines guide immune cells to where they're needed in the body. Both are crucial for a healthy immune response.

Chemokines:

Definition: Chemokines are a specific type of cytokine that acts like a GPS, guiding immune cells to where they're needed in the body.

Functions: They attract immune cells to places with infections, inflammation, or injuries, helping the body fight off threats.

Examples: MCP-1, IL-8, RANTES.

-In simple terms, cytokines help cells in the immune system communicate, while chemokines guide immune cells to where they're needed in the body. Both are crucial for a healthy immune response.

The Inflammatory Response

• Triggered by the release of pro-inflammatorycytokines and chemokines at the site of infection• A generic defence mechanism whose purpose is tolocalize and eliminate injurious agents and toremove damaged tissue components• Enhanced permeability and extravasation• Neutrophil recruitment• Enhanced cell adhesion• Enhance clotting

-A system of secreted proteins (these are PRRs/pattern recognition receptors) made in theliver that recognise PAMPs on the surface of microbes and“decorate” or “tag” them.

-The microbes are then cleared byphagocytosis, “opsonised” or they have holes punched in them

Three ways of activating:

(i). Recognition of LPS and other PAMPs by the C1q component of “classical” pathway

(ii). Non-host glycosylation is recognised by MBP and otherlectins to activate the “lectin” pathway

(iii). Membranes that are recognised as “non-self” activate the “alternative” pathway

Proteolytic

Natural Killer (NK) cells(Large granular lymphocytes):

• Makes up 4% of white blood cells• Lymphocyte-like but larger withgranular cytoplasm• Kill certain tumour & virallyinfected cells• Target cell destruction is caused bycytotoxic molecules calledgranzymes & perforins

• NK cells possess the ability to recognise and lyse virallyinfected cells and certain tumour cells.• Selectivity is conferred by LOSS of "self" MHC moleculeson target cell surfaces, AND up-regulation of activatingligands

• Complement – core defects (e.g. C3) linked to development ofautoimmune diseases such as lupus• Complement – non-core defects linked to susceptibility tospecific types of pathogens such as Neisseria• Macrophage deficiencies - Chronic granulomatous disease(CGD); No oxidative burst for bacterial killing• Macrophage deficiencies – IRF8 mutations linked tosusceptibility to TB• Aicardi–Goutières syndrome associated with constitutiveproduction of inflammatory cytokines• Lack of interferon-responsiveness – sensitivity to viralinfection (e.g. measles)