Chapter 2: Innate Immunity

Inflammation {Purpose}

• Accumulations of leukocytes and proteins at infection site or tissue injury (non-infection)

• Kills microbes and eliminates damage tissues

Antiviral Defense {Methods}

Target intracellular viruses via

• NK cells: eliminate infected cells with reduced MHC I

• Type I Interferons

Type I Interferons

Infected cell release interferons (alert) to neighboring cells so they can enter antiviral state

Innate Immunity {Sites}

• Recognize PAMP that are shared by many microbes but not present in mammalian cells (self cells)

• Present at

  • Epithelia: portals of entries that are reinforced with antimicrobial molecules & lymphoid cells (B, T, & NK cells)

  • Tissues

  • Blood: complement system

Mammalian Cells {Recognize}

Self cells that have pattern-recognition receptor (PRR) that recognize

• Viral double-stranded ribonucleic acid (dsRNA)

• Microbial unmethylated oligonucleotides that are uncommon in regular cell DNA

Pathogen-Associated Molecular Patterns (PAMPs) {Examples}

• Structures that are essential for pathogen survival and effectiveness, but also get recognize by PRR such as lipopolysaccharide (LPS), and peptidoglycans

• Around 1000 patterns

Damage-Associated Molecular Patterns (DAMPs)

Released by damaged mammalian cells or tissue such as infarction (tissue damaged from lacked of oxygen

Germline

PRR is encoded by inherited genetic DNA

Innate vs Adaptive Receptors

	Innate receptors	Adaptive receptors
Main receptors	PRRs	B & T cells receptors
Recognize	PAMPs / DAMPs	Specific antigens/epitopes
Genetic origin	Germline-encoded	Somatic V(D)J rearrangement
Diversity	Limited	Extremely diverse
Specificity	Recognize common molecular patterns	Highly antigen-specific
Memory	No classic antigen-specific memory	Yes
Found on	Many innate immune cells	B and T lymphocytes

Toll-Like Receptor (TLR)

A subset of PRR that is homologous to Drosophila Toll protein that protect flies against infections

NOD-Like Receptors Pyrin(NLRP-3) {Conditions, Release}

• A cytosolic receptors (reside in the inside cytoplasm) that recognize PAMP & DAMP

• Triggers cytokine interleukin-1β (IL-1β) when:

  • ATP released

  • Uric acid crystal derived from DNA/RNA

  • Change in intracellular potassium concentration

  • Endogenous substances deposited in cells (e.g. cholesterol)

Interleukin-1β (IL-1β)

• Primary pro-inflammatory cytokine of innate system, and triggers fever (systemic effect)

• activate caspase-1 that convert pre-IL-1β to the active version

Inflammasome

Multiprotein complex that activate inflammation response via production of interleukin-1 (IL-1)

• NLRP-3: sensor

• Adaptor protein: trigger

• Caspase-1: inactive enzyme

RIG-Like Receptor (RLR)

Sense viral RNA and produce type 1-IFN

Cytosolic DNA Sensor (CDS)

Sense microbial/viral DNA (ds-DNA) and produce type 1-IFN

Autophagy

When cell detects that its own cellular components are damaged, send to the lysosome for degradation

Intraepithelial Lymphocytes (IELs) {Receptor}

• Carry gamma-delta T-cell receptor (γδ-TCR) that recognize shared microbial components.

• T cells (several kinds) reside within the epithelial layer

• Specitivity and functionality are still unknown

Defensins & Cathelicidins

antimicrobial peptides released by endothelial cells that disrupt the microbes membranes

Opsonization

• Process where foreign pathogens or dead cells are coated with opsonins to make them stand out for immune cells

• Microbes are coated with C3b to be phagocytized via complement receptor type 1 on phagocytes

Classical Pathway {Trigger Condition}

1. Triggers when Igs bind to microbial Ags and the Fc region is opened

2. C1q binds Fc region to activate C1r & C1s

3. C1s cleaves both C4 & C2

Lectin Pathway {Trigger Condition}

1. Initiates by mannose-bind lectin (MBL) attaches to mannose of microbes

2. MBL-associated serine proteases (MASP-1 & MASP-2) becomes activated

3. MASP-1 & MASP-2 performs similar job as C1s by cleaving C4 & C2

Alternate Pathway {Trigger Condition}

• Triggers when C3b (hydrolyze from C3) opsonizes the microbe (binds to factor b)

• Factor D then cleaves it into C3 convertase (C3bBb) and Ba

• Properdin stabilizes the C3 convertase

Chemoattractants {Functions}

• Chemokines

• Smaller fragments 3a, 5a from complement system that induces inflammatory response

Proteolytic Enzymes {Functions}

Cleave proteins into active fragments, with 3 main functions

• Inflammatory chemoattractants (e.g. C3a)

• Opsonization & phagocytosis (e.g. C3b)

• Cell lysis (e.g. MAC)

Membrane Attack Complex (MAC) {Mechanism}

• Form from the final protein C9 polymerizes

• Creates pore in the cell membrane, which ions/water enter that leads to cell lysis

• Effective against microbes with thin cell walls

Complement System Function

• Inflammation: C3a, and C5a induce inflammation by recruiting neutrophils. Act on endothelial cells to enhance migration of leukocytes & plasma proteins from blood → tissue

• C3d acts as a molecular “tag” that enhances B-cell activation through complement receptor type-2 on the B cells

Acute-Phase Protein (APP) {Promote, Released Conditions}

• Plasma proteins produced by liver in response to cytokines from Nф, Mф

• Promote sepsis (uncontrolled response to infection that leads to organ dysfunction) & increase erythrocyte sedimentation rate

C-Reactive Protein (CRP) {Function}

• An acute-phase protein that opsonizes microbes for Mф

• Activate classical complement proteins

Acute Phase Response

Increase production of plasma proteins in response to system dissemination (spread) of inflammatory cytokines

Source of Cytokines in Innate Immunity

• Mast cells, DC, Mф

• Secrete due to stimuli recognition of microbial components (e.g. LPS, dsRNA)

• Secrete in small amounts bind to high-affinity receptors

  • Triggers fever when act on hypothalamus

  • Swelling, pain around infection site

Recruiting Blood Neutrophils Cytokines

• Chemokines

• Tumor necrosis factor (TNF)

• Interleukin-1

Tumor Necrosis Factor

• Combine with IL-1 in hypothalamus triggers fever

• Combine with IL-6, and IL-1 stimulates acute-phase proteins for microbial killing and walling off infection sites

• Promotes thrombosis on endothelium

• Reduce blood pressure

Septic Shock

• Due to severe bacterial infections that leads to high TNF level

• Cause low blood pressure and organ failure, disseminated intravascular coagulation (depletion of coagulation factors)