Unit 2 - Innate Immunity

Types of Mucosa Membrane

• Ocular mucosa

• Gastrointestinal mucosa

• Respirtory mucosa

• Urogenital Mucosa

Buccal Mucosa

Has a skin-like epithelium to absorb abraisons when eating with lamin propria underneath

Ingetinal Mucosa

Single layer of epithelia cells to maximize absorption with lamina propria underneath

Commensal Microbes

Microorganisms that lives on/inside an animal host with no harm

Intrinsic Barriers

• Mechanical

• Chemical

• Microbiological

Mechanical Barriers

Physically stops pathogens from touching our cells

Chemical Barriers

Molecules made by body system that damage/destroy pathogens/toxins while supporting commensal microbes

Microbiological Barriers

Natural microbiota out competes bad microbes, forming biofilms, fighting bacteria with proteins

Human Microbes provide

Immune defenses and create hormones to regular mood/choices/etc

Where is the one places with a lack of microbial diversity?

Vagina, dominated by lactobacilli

Dysbiosis

Improper composition or diversity in wrong place of bacteria

Forms of Mechanical Barriers

• Tight junctions

• Shedding epithelium

• Flow of air & fluid

• Tears

• Cilia

What do chemical barriers do to pathogens?

• Disrupt membrane

• Stop metabolism

• Denature proteins

• Increase commensal microbiome

What can a decrease in pH do to pathogens?

Stops folded proteins to prevent attachment, and phospholipid denaturing

Surfactants

Decreases surface tension and denatures proteins/interrupt membrane

Antimicrobial Peptides (AMPs)

Very positively charged, short peptides that destroy negatively charged membrane pathogens

Defensins

AMP molecule that embeds itself into cell membrane to create a pore with other defensins

Cathelicidins

AMP always amde by epithelial cells at all barrier (LL37)

V. Chloerae evasion method

Digests mucus layer

H. pylori evasion method

Makes NH₃ to neutralize HCl

P. aeruginosa evasion method

Secretes elastase that destroys LL37

S. flexneri evasion method

Digests tight junctions

B. pertussis evasion

Destroys cilia

Zymogens

Pre-proteins that need to be cleaved

Convertases

Enzymes that cut inactive precursor proteins into their active forms

Complete Cascade performs via

• Recruitment

• Opsonization

• Direct Killing

Recruitment

Cleaved proteins bind to neutrophil and macrophage receptors to bring them to infection

Opsonization

Proteins coats pathogen to signal for killing by immune cells

Direct Killing

Proteins form a membrane attakc complex

Ways to start the Completment Cascade

1. Alternative pathway

2. Lectin pathway

3. Classical pathway

Alterantive Pathway (1st)

Pathogen surfacve spontaneously cleaves complement

Lectin Pathway (2nd)

Mannose binding lectin detects glycans that are unique to pathgens, then cleaves complement

Classical Pathway (3rd)

Antibodies bind to pathogen and cleaves complement

Self/Non Self Discrimination Hypothesis

Immune system recognizes self and attacks foreign molecules based on characteristics

Danger Hypothesis

Immune always looking for danger and only respond when danger occurs

Pattern Recognition Receptors (PRR)

Fixed receptors that sense evolutionary conserved molecules, critical for pathogen survival

Types of PRRs

• Toll like receptors

• C-type lectin receptors

• NOD like receptors

• RIG-I-like receptors

Toll Like Receptors

Localized receptors that targets conserved bacteria and viral products outside and inside cell

Where are bacterial PRRs

Outside, on the plasma membrane

Where are viral PRRs

Inside endosomes, as viruses are camouflaged before entering

C-Type Lectin REceptors

Targets unusual carbohydrates, especially fungal pathogens by binding to its glycan and induces the cell to eat/destroy their targets

NOD Like Receptor

Targets bacterial products in cytosol that are shed, causing activated receptors to drive inflammation via NF-kB

RIG-I-Like Receptor

Targets viral nucleic acid sensors in cytosol, looking for uncapped, exposed triphosphate ends

RIG-I-Like Receptor Activation Process

1. RIG-I binds to RNA, inducing MAVS association

2. TRAF activates IRFs & IRF7

3. Interferons are produced to stop protein synthesis

MDA5 Interferon

Looks for long dsRNA

LGP2 Interferon

Looks for dsRNA

MyD88

Activates NF-kB that turns on cytokines, movement, activate adaptive immunity

TRIF

Activates IRFs that secrete type 1 interferons

PAMPs

Ligands/structures that PRRs detects

DAMPs

Binds to PRRs from out of place molecules and signals inflammatory response

HMGB1

DNA transcription factor that’s released into cytosol and binds to TLR4 to indicate stress

RIG-I binds to

dsRNA/improper RNA to signal stress

NLRP3

Looks for disturbances and forms inflammasome

Inflammasome

Creates active IL-1B causing inflammatory response

Pyropoptosis

Inflammatory cell death, where stored IL-1 activates caspase, leading to pore formation and stored IL-1B to be released which recruits immune cells to clean up

Proton Sensitive Ion Channel

Monitors pH

Piezo 1 and 2

Monitors mechanical stress

Purinergic Receptors

Monitors ATP

Mononuclear Phagocytes

Single lobed nucleus phagocytes

Types of Mononuclear Phagocytes

• Monocytes

• Macrophages

• Dendritic cell

Granulocytes

Multi-nuclei cells with granules

Types of Granulocytes

• Neutrophil

• Eosinophil

• Mast Cell

• Basophil

Innate Lymphoid Cells

Lack rearranged antigen receptors but help regulates immunity, inflammation, tissue repair

Types of Innate Lymphoid Cells

• Innate Lymphoid Cells (type 1,2,3)

• NK Cells

Hematopoiesis

Production of all blood cells

Yolk Sac

Makes immune cells at conception

Fetal Live and Spleen

Takes over immune production quickly at the beginning of gestation

Bone Marrow

Takes over hematopoiesis before birth

Which immune cell is derived from the yolk sac/liver/spleen?

Macrophages, maintains itself via self renewal

Self Renewal

Stem cell asymmetrically divides to make an immune cell and a copy of itself

Common Lymphoid Precursor (CLP)

Gives rise to adaptive and innate immune lymphocytes

Macrophage

Yolk sac/liver derived that’s present in all tissues and makes cytokine/phagocyses them when induced by monocytes

Macrophage Phagocytosis

1. Bacteria binds to PRR causing engulfment

2. Bacteria enters phagosome

3. Phagosome fuses with lysosome to make phagolysosome

4. phagolysosome degrades bacteria

Macrophage Cytokine Production

1. Bacterial component is sensed

2. Receptor endocytosed

3. Inflammatory cytokine is transcribed

Chemokines

Macrophage molecules that bring immune cells to infection and vesicles become permeable for induced immunity

Systematic Release of Cytokine

Induces more immune proteins and fever

Polarization

Asymmetric organization of cell to create specialized subcellular domain

Killer (M1) Macrophage

Has increased capacity to detect, engulf and kill pathogens

Healers (M2) Macrophage

Increased ability to detect cellular debris and makes molecules that promotes wound healing

Dendritic Cells

Lives in barrier tissues and lymphoid organs that activates adaptive immunity by binding to bacteria with PRR to present it on its MHC to T cells

Homeostatic Function of Dendritic Cells

Constantly sampling our own cells to present in the lymph nodes

CD80 & CD86

Co-stimulatory molecules that activates T-cells

Monocytes

Resides in blood and recruited into tissues through inflammation response to differentiate into different cell types and phagocyte based on context

Hematoxylin

Positively charged molecule that stains negatively charged molecules purple

Eosin

Negatively charged molecules that stains positively charged molecules pink

NETosis

Neutrophil pack caustic proteins in DNA and shoots it outwards that catches pathogens and destroys them

Neutrophil

Circulates in the blood and enters tissues to phagocyse and NETosis

Neutrophil Killing

1. Neutrophil engulfs bacterium

2. Endosome fuses with granules

3. Bacteria killed and degraded

4. Neutrophil apoptose and eaten by macrophage

Eosinophil

Circulates blood and in mucosal tissue that degranulates parasites

Eosinophil Homeostatic Function

Uses granules to remove tissues, helps digestion absorption, supports VEGF (angiogensis)

Mast Cells

Circulates in blood as a progenitor then differentiates in tissues to degranulate

Mast Cell Granules Content

Vasoactive products, histamine, heparin, CPA3, chymase, tryptases

CPA3

Within mast cell granules that destroy and targets venom enzymes

Allergies Activation

Allergen binds to IgE antibodies on mast cell causing degranulation of histamines

Basophil

Circulates blood, rarely recruited to tissues for parasitic infection, to degranulate and also related to allergies

Innate Lymphoid Cells (ILC)

In every tissue, especially barrier tissues

Major Effectors Modules

• Cytotoxicity

• Intracellular Immunity (Type 1)

• Muscosal and Barrier Immunity (Type 2)

• Extracellular Immunity (Type 3)

Cytotoxicity Module

Removes virally infected and metabolically stressed cells

What is the Innate Cell for Cytotoxicity Modules

NK cells

What is the Adaptive Cell for Cytotoxicity Modules

CD8 T Cells