2. Innate Immune System

What are the 3 main functions of the innate immune system

• Controls/Eliminates infection

• Eliminates damaged cell and influences repair

• Stimulates the adaptive immune response

What are the Main “Players” of the Innate Immune System other than cells?

• Physical Barriers

  • Skin and Mucosa

• Enzymatic barriers

  • Lactoferrin, Lysozyme

Explain the 6 types of Physical barriers and the characteristics of each

• Skin

  • Dry

  • Slightly acidic pH (4)

  • Sloughing (skin falls off)

  • Impenetrable when intact

• Mucosa

  • Mucin slides off or traps pathogens

  • Lactoferrin and Lysozyme enzymatic barriers and Defensins

• Muco-ciliary escalator: mucin-trapped particles are moved towards the pharynx to be either swallowed or expelled

• Normal Flora: good bacteria compete with pathogens by

  • Occupying binding sites

  • Using resources/nutrients

  • Producing toxins that kill pathogens by destroying cell wall or causing lysis

• Fever:

  • retards growth

  • speeds hematopoiesis (thus cell production)

• Eye:

  • Tear washes eye

  • Blinking

  • Contains lysozyme

What are the 2 Enzymatic Barriers?

• Lysozyme: Breaks down NAM and NAG linkages on Peptidoglycan

  • Present in tears, saliva and mucus

• Urea: denatures proteins

What are the 4 Protein Effectors?

• Proteases: cleaves proteins on the pathogen

• Defensins:

  • Antimicrobial peptide found in phagolysosomes, granulocytes and mucosal secretion

  • Destroys membranes of pathogens by poking holes

• Iron-sequestering proteins:

  • Prevent bacteria from using iron

  • Present in mucosal secretions

• Complement System: 30 protein cascade that either kills or tags pathogen for destruction

Name the 4 major cells of Innate Immunity and their function

• NK cells

  • Not phagocytes

  • Scan cells for presence of host markers such as MHC markers (determines self and non-self)

  • Kills infected cells or abnormal cells

• Neutrophils:

  • Phagocyte

  • Short-lived

  • Granulocytes: secrete toxic substances (lactoferrin, defensins, lysozyme, ROS and RNS) that kill pathogens

  • Polymorphonuclear cell due to segmented nuclei

  • Circulate in the blood until called to site of infection

• Monocyte

  • Macrophage progenitor cell

  • Circulates in the blood for 3 days and only differentiates once it enters tissues (cytokine regulated)

• Macrophage:

  • Long lived

  • Tissue fixed: “the commander” that patrols the tissue and calls others for backup through cytokines

  • Phagocyte and APC

• Dendritic cells:

  • Phagocytic

  • APC

  • Not tissue fixed: leave tissue with pathogenic cargo and travel to one of the 2 lymphoid organs to present

  • Bridge innate and adaptive

What are the characteristics of the Phagosome/Phagolysosome?

• Acidic environment impedes growth

• Has ROS and RNS that release superoxide to lumen

  • Destroys proteins, nucleic acids and lipids

  • Impairs bacterial metabolism

• Antimicrobial proteins and peptides

  • Lactoferrin

  • Defensins

  • Hydrolysis by lysozyme, phospholipases and proteases

• Who detects pathogens?

• How do phagocytes know when to act?

• Macrophages

• They have Pattern Recognition Receptors (PRR) that recognize pathogen motifs called Pathogen-Associated Molecular Patterns (PAMPS) → PRR binding PAMP causes phagocyte activation

What are types of Pathogen Recognition Receptors (PRRs)?

• Toll-Like Receptors (TLRs)

  • Recognize and bind extracellular PAMPs

  • Located on cell surface

  • TLR2 recognizes Bacterial PG and TLR4 recognizes LPS

• Nod-like Receptors (NLRs_

  • Recognizes and binds intracellular PAMPs

  • Located on cytoplasm

  • Nod1 recognizes ubiquitous gram negative and Nod2 recognizes gram -/+ expressed in Paneth cells

• Mannose-binding lectins (MBLs)

  • Bind structures with high mannose content (easy way to determine non-cell bc human cells do not have mannose)

  • Activate lectin complement pathway

What happens when the phagocyte’s PRR binds the pathogen’s PAMP?

The phagocyte increases its phagocytosis/metabolic activity, releases cytokines to recruit other cells (monocytes and neutrophils) to the site of infection, releases ROS and RNS and other degrative enzymes

A BETTER PHAGOCYTE!!!!

What are the 3 most important Cytokines and what do they do

• IL-1, IL-6 and TNF-alpha

• Pyrogenic

• Increase vascular permeability Increase vasodilation, Increase selectin expression → For extravasation

• Increase differentiation of immune mediators

• Increase production of acute phase proteins

Extravasation

• What is it?

• Steps

• Extravasation is the process through which cells pass from capillaries into tissues

• 1. Rolling: Cytokines dilate blood vessels, which slows blood down. Selectin expression is increased. Cell binds to selectins via their glycoproteins and roll (bind, detach) slowing down.

  2. Activation: Cytokines lead to conformational change in integrin receptors, which allow them to bind to endothelial cells’ ICAM ligand

  3. Firm Adhesion: High affinity of Integrin to ICAM leads to firm adhesion, which completely stops leukocyte movement and now spreads onto vessel wall

  4. Trans-endothelial migration: Due to cytokine induced cell permeability, the leukocyte is able to squeeze between endothelial cells and pass into the tissues

What are the 3 goals of INFLAMMATION?

What are the 4 Symptoms of INFLAMMATION? Why

• Recruiting more cells and effector molecules, provides a physical barrier to prevent spread (swelling/edema/cells), promote tissue repair

• Rubor (redness), Calor (heat), Dolor (pain), Tumor (swelling) → Due to soluble mediators increasing vasodilation, cellular influx and even effects on nerves

• What is the Acute Phase Response?

• What is an example?

• Why do we get a fever?

• It’s a rapid SYSTEMIC response triggered by the innate system by detection of infection

• Fever

• We get a fever due to IL-1, IL-6 and TNF-alpha cytokines, which travel to and act upon the hypothalamus