Innate Immune System, Abridged

Leukocyte extravasation
Neutrophils, eosinophils and mast cells exit the blood and enter tissues by extravasation. This begins when endothelial cells of the blood vessel express surface proteins selectin (SEL) and intercellular adhesion molecule (ICAM) in response to local cytokines IL-1 and TNF, which are produced by macrophages at the site of inflammation.

Extravasating immune cells possess ligands selectin ligand (SLIG) and integrin (INT). INT is expressed in response to inflammatory signals (for the neutrophil, the signals are LPS and complement protein C5a).

1. SEL and SLIG contribute to rolling adhesion. 
2. ICAM and INT is a strong interaction, causing the immune cell to stop rolling. 
3. Extravasation to the battle site. 

Major histocompatibility complex
MHC class I molecules are found on non-immune cells, which present cellular proteins to killer T cells. MHC class II molecules are found on immune cells, which present foreign proteins to helper T cells.

Macrophage hyperactive state 
Inputs
IFN-γ received from Th cells or NK cells prime the macrophage to upregulate MHC II molecules. This lets the macrophage become an active antigen presenter to Th cells. A primed macrophage becomes hyperactive when it detects the presence of LPS or mannose.

Outputs
Hyperactive macrophages produce alarm signals IL-1 and TNF, and NK cell-activating IL-12.

• TNF kills tumor cells and virus-infected cells, and activates immune cells, including the macrophage to produce IL-12. 
• Neutrophils also produce TNF, as they are one of the first responders to inflammation. 

Natural Killer cell
Inputs
The detection of LPS causes NK cells to produce IFN-γ; the production of IFN-γ is increased by signals IL-12 and TNF. TNF also influences the upregulation of IL-2R in NK cells.

Outputs
NK cells produce the growth factor IL-2. When there is an increase of IL-2 receptors, NK cells will proliferate. 

• NK cells destroy virus-infected cells if a combination of signals exists: MHC I and an unusual surface protein or carbohydrate. However, if there is a high balance of MHC I, the NK cell determines that the cell is healthy and does not destroy the cell. 

Dendritic cell
Inputs
DC cells become activated in response to TNF or antigen recognition by their toll-like receptors (TLR). Chemokines encourage extravasation.

• The activated DC cell uptakes tissue antigens to load onto MHC II molecules, and expresses MHC II on the cell surface. When it travels to the nearest lymph node, it upregulates surface protein B7 and MHC I (in the event the DC cell may be infected). 
• In the lymph node, DC cells act as antigen presenters and T cell activators. B7 pairs with CD28 on the T cell, and MHC pairs with T cell receptors (TCRs).  

Complement pathways

Alternate (non-discriminate binding)

1. C3 made by liver to blood. 
2. Spontaneous: C3 → C3a + C3b
3. C3b binds to cell surface. 
4. C3b + B → C3bB
5. C3bB + D (cleaver) → C3bBb
• Propagation: C3 + C3bBb (cleaver) → C3b → → C3bBb
6. C5 + C3bBb (cleaver) → C5b
7. C5b + C6 + C7 + C8 + C9 → MAC

Classical (occurs with two units of IgG or IgM; only the pathogen is targeted)

1. Antibody binds antigen. 
2. Two activated subunits C1s form a C1 complex at the Fc tail. 
• C2 + C1s (cleaver) → C2a + C2b
• C4 + C1s (cleaver) → C4a + C4b
3. Forms on pathogen surface: C4b + C2b → C4b2b
4. C3 + C4b2b (cleaver) → C3a + C3b
5. Step 3 of Alternate. 

Lectin (MBL only binds pathogenic carbohydrate)

1. MBL made by liver to blood. 
2. MBL + MASPs
3. MBL/MASP complex binds to pathogen surface. 
4. C3 + MASP (cleaver) → C3a + C3b 
5. Step 3 of Alternate.