Innate Immune Responses (2/2)

Pain, redness, heat, swelling

Inflammation is characterized by these 4 signs

release mediators like histamine

Mast cell function in inflammation

TNF-α, IL-1, IL-6, IL-12, IFNy

5 pro-inflammatory cytokines to know

IL-8 (CXCL-8)

Important chemokine involved in inflammation

Small soluble proteins that increase vasodilation, vascular permeability, and smooth muscle contraction

What are kinins?

histamine and serotonin

Platelets secrete these 2 things

Cause arterioles and venules to dilate —> increased blood flow to site

Capillaries become more permeable —> allowing exudate to escape into tissue

Function of components like histamine, leukotrienes, and prostaglandins with respect to vessels

neutrophils

Serotonin released from platelets recruits —

Compared to histamine, which causes constriction of airways and edema formation, the leukotrienes are three to four orders of magnitude more potent and the effects have longer duration.

Potency of leukotrienes vs histamine

arachidonic acid via lipoxygenase pathway

Leukotrienes are generated from — via this pathway

cyclooxygenase

Prostaglandins are generated from arachidonic acid via the — pathway

neutrophils

Leukotrienes are involved in the recruitment of —

neutrophils, then monocytes (to differentiate into dendritic cells or macrophages), then basophils, eosinophils, and lymphocytes

Cells infiltrate the tissue in this order

IL-1B, IL-6, and TNF-a

Acute phase response and fever

Inflammatory cytokines produced by macrophages can induce systemic effects. What are the 3 cytokines and what are the two effects?

Increased metabolism to increase body temperature

Systemic inflammatory effects seen in fat and muscle

the change in the ratio of serum proteins secreted by the hepatocytes in the liver.

Acute phase response is —

C-reactive protein and mannose binding lectin

The two proteins of note that get increased in the acute-phase response

IL-6

This is the primary cytokine that initiates the acute phase response

increases everywhere, leading to decreased blood volume and pressure and lots of edema

vascular permeability in sepsis

Type I interferon and NK cells

The two main innate defenses against viruses

When a virus infects a cell, the cell responds by secreting IFN-B. IFN-B binds in an autocrine fashion, stimulating the same cell to release IFN-a. Interferon alpha and beta both bind to nearby cells to induce the production of antiviral proteins to prevent them from getting infected.

Process of how type 1 interferons (IFNa and IFNB) induce an anti-viral state in response to viral infection

Plasmacytoid dendritic cells are a type of leukocyte found in lymphoid tissue and as a small population of circulating leukocytes (<1%). They secrete interferon at a rate 1000x higher than ordinary cells. When they detect the presence of a virus, they secrete large amounts of interferon, which then circulates and causes systemic anti-viral effects.

How type 1 interferon can lead to systemic inflammation

prevents additional cells from becoming infected

Type 1 interferon doesn’t neutralize virus, rather, it —

Interferon has many abilities, including driving proliferation of NK cells and making them more effective

Connection between interferon and NK cells

NK cells are always ready to kill and don’t need activated, but they can become better at killing

NK: activation?

cytotoxic granules

NK cells kill via their —

CD16 and CD56

NK activity can be identified by the presence of these 2 cytokines

IL-12 —> stimulates more cytokine production by NK cells

IL-15 —> stimulates NK cells to become more cytotoxic

IL-12 vs IL-15 effect on NK cells

–IFNγ, IL-1, GM-CSF, TNFα

Cytokines that NK cells secrete include —

to activate macrophages, which in turn secrete cytokines to activate NK cells. This creates an inflammatory feedback loop.

The purpose of NK secreting cytokines

Ig-like and lectin-like

2 structural categories of NK cell receptors

–Inhibitory

•Engagement prevents killing by NK cells

–Activating

•Engagement allows killing by NK cells

2 functional categories of NK cell receptors

ITAM and ITIM (immunotyrosine activating or inhibitory motifs)

Cytoplasmic motifs of activating vs inhibitory NK cell receptors

normal expression of MHC class I receptors (present on all healthy, nucleated cells)

Major inhibitory signal received by NK cells

They cause it to not be expressed in infected cells

Many viruses have this effect on MHC I expression

2 or more

Signals from this many activating receptors are required to activate NK cells

IgG

In the presence of —, the Fc receptor can activate NK cells without help from another receptor

Using the contents of their granules, which includes:

perforin, which creates a pore in the target cell that assists in delivering other molecules to the target cell

Granzymes like Granzyme B, which is a serine protease, which enters the cell and induces apoptosis via the caspase pathway (prevents viral spread because a virus cannot replicate in a dead cell)

How NK cells kill