Immunology Lecture 2

Cytokines

immune modulating agents made up of proteins

Chemokines

superfamily of cytokines that mediate chemotaxis

Interferons

a type of cytokine that alerts the immune system

Interleukin

class of glycoproteins made by leukocytes (WBCs) for regulating immune responses

What is the first line of defense against pathogens?

innate immunity

What is the function of innate immunity?

recruit other cells and stimulate inflammation

Innate Cells

mast cells, granulocytes, phagocytes, and natural killer cells

What do granulocytes include?

eosinophils, basophils, neutrophils

What do phagocytes include?

monocytes, dendritic cells, and macrophages

What are Sentinel Cells

Innate immune cells embedded in tissues

What is the function of sentinel cells?

Recognize PAMPS and DAMPS via specialized PRRs

What are examples of Sentinel Cells

Macrophages and Dendritic cells

What are specific macrophages and dendritic cells that are sentinel cells?

Kupffer cells (liver), Langerhans cells (skin and mucosa), alveolar macrophages (lung), and microglia (brain)

Sentinel Cells Major types

Macrophages, dendritic cells, mast cells, epithelial cells, and tissue-resident lymphoid cells

Sentinel Macrophages function

engulfs and digests pathogens, damaged cells, debris, and foreign substances

Sentinel Dendritic Cells function

processes the antigen and presents it to circulating T/B cells (antigen-presenting cells or APC)

Sentinel Cells: Mast Cell Function

resident cell of connective tissues with histamine and heparin granules; roles in allergy

Sentinel Cells: Epithelial Cells function

physical barriers with PRRs

Sentinel Cells: Tissue Resident lymphoid cells Funciton

tissue-resident natural killer cells

Where are innate immune cells strategically placed?

They are placed throughout the body at sites that could come into contact with pathogens (skin and lungs etc)

What are the main sentinel cells in the skin?

Langerhans cells that capture antigens and migrate to draining lymph nodes to prime T cells

What are the main sentinel cells in the lungs?

Alveolar macrophanges patrol airway lumen and phagocytose pathogens

What are the main sentinel cells in the gut?

Dendritic cells and epithelial cells that reside in the Specialized lymphoid tissue called Peyer’s patches

When sentinel cells are activated, they initiate

Cytokine and chemokine Production, Upregulation of costimulatory molecules and adaptive immune cell molecules (T cells), Type 1 IFN response, and Phagocytosis and ROS/ Nitric Oxide Production

What happens during Cytokine and chemokine production

induces local inflammation and neutrophil and monocytes recruit cells to shape magnitude and type of immune response

What cells induce local inflammation in cytokine and chemokine production?

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

What cells help to recruit cells during cytokine and chemokine production?

CXCL8 (neutrophil) and CCL2 (monocyte)

How are type 1 IFN responses triggered?

pro inflammatory response to viral nucleic acid sensing (RIG-I, TLR3)

When Sentinel cells activate phagocytosis what occurs?

macrophages and neutrophils increase phagocytic activity by eating pathogens

When Sentinel cells activate ROS/nitric oxide production, what occurs?

there is a generation of reactive oxygen species (ROS) and nitric oxide (NO) that kill pathogens

What are Pattern Recognition Receptors?

cellular protein receptor that recognizes molecules frequently found in pathogens or molecules released by damaged cells

How are PRRs expressed?

innate immunity and sentinel cells

How are PRRs upregulated?

cytokines (IFN-y enhances TLR expression)

Where are PRRs usually found?

cell surface or in the cytosol (usually in an endosome) which is beneficial for intracellular infections

What do PRRS help to initiate?

phagocytosis, autophagy, apoptosis, inflammasome formation, or recruitment of other cells

What are the different types of pattern recognition receptors?

toll-like receptors, nod-like receptors, RIG-I-like receptors, C-type lectin receptors, and AIM2-like receptors

What PRRs are on the cell surface?

TLR2, TLR4, TLR5, and CLR

Name the PRR: Detects triacyl and diacyl lipopeptides

TLR2

Name the PRR: Detects LPS

TRL4

Name the PRR: detects flagellin

TLR5

**Name the PRR: detects extracellular microbes

TLR2-5

What are the endosomal PRRS?

TLR3, TLR7, TLR8, TLR9

Name the PRR: detects dsRNA

TLR3

Name the PRR: detects ssRNA

TLR7/8

Name the PRR: detects CpG DNA

TLR9

Name the PRR: detects nucleic acids from viruses and bacteria

TLR3, TLR7/8, TLR9

What are your cytosolic PRRs ?

RIG-1, MDA5, NOD2, AIM2

What are the functions of your cytosolic PRRs?

detect intracellular infections and cellular damage

What Are PAMPS

conserved molecular motifs found on or made by microorganisms, but not host cells

**What is the PAMP and what recognizes it from gram negative bacteria?

Lipopolysaccharide and TLR4 recognizes it

What is the PAMP for gram-positive bacteria and what recognizes the PAMP?

Lipoteichoic acid and peptidoglycan and it is recognized by TLR2

What is the PAMP for viruses and what recognizes the PAMP?

Double stranded RNA (dsRNA), 5’ triphosphate ssRNA and it is recognized by TLR3, RIG-1, and MDA5

What is the PAMP for FUNGI and what recognizes the PAMP?

B-glucose and mannans and they are recognized by Dectin-1 (CLR) and TLR2

What is the PAMP for Mycobacteria and what recognizes the PAMP?

Lipoarabinomannan (LAM) recognized by TLR2 and TLR1

What is the PAMP for Bacterial flagellin and what recognizes the PAMP?

flagellin recognized by TLR5

What is the PAMP for unmethylated CpG DNA and what recognizes it?

Found in bacteria and some viruses and is recognized by TLR9

What does PAMPS stand for?

Pathogen- Associated Molecular Pathways

What are DAMPs?

host-derived molecules released from stressed, injured, or dying cells

Name the source and receptor/pathway for the DAMP High Mobility Group Box 1 (HMGB1)

Source is chromatin-associated protein released during necrosis and the receptor/pathway is TLR2, TLR4, AND RAGE

Name the source and receptor/pathway for the DAMP Extracellular ATP

Source is released from dying cells and the receptor/pathway is P2X7 receptor and NLRP3 inflammasome

Name the source and receptor/pathway for the DAMP Uric acid crystals

Source is byproduct of purine metabolism and the receptor/pathway is NLRP3 inflammasome

Name the source and receptor/pathway for the DAMP Mitochondrial DNA

source is released during cell stress and resembles bacterial DNA while the pathway is TLR9, and cGAS-STRING pathway

Name the source and receptor/pathway for the DAMP heat shock proteins (HSP60 + HSP70)

released from stressed cells and the pathway is TLR2 and TLR4

Name the source and receptor/pathway for the DAMP s100 proteins (S100 A8/A9)

source is damaged neutrophils and the pathway is TLR4 and Rage

DAMPS often alert immune system in the _______ of infection

absence

Where do DAMPs originate?

from host cells, especially after necrosis

PAMPS are non-self which means

infection

DAMPS are “altered self”, meaning,

injury

Does Apoptosis trigger inflammation?

No but necrosis or lytic viral replication does

What triggers inflammation?

necrosis or lytic viral replication

Why would a system designed to detect infection also respond to “sterile” damage?

It primes the tissues for repair, clears debris, and protects against opportunistic infections

What are clinical disorders that are linked to PRR dysregulation?

Sepsis and Systemic Inflammatory response (SIRS), Autoimmune and Autoinflammatory Diseases, and Viral infections and Immune Evasion

What is SIRS)

it is an overactivation of TLRs by PAMPs leading to a cytokine storm

What is Autoimmune and Autoinflammatory response to PRR dysregulation?

Chronic DAMP exposure activates PRRs that trigger sterile inflammation, Systemic Lupus Erythematosus, Gout, and Atherosclerosis

What happens during systemic lupus erythematosus?

TLR9 and 7 activation by self nucleic acids

What happens during gout?

NLRP3 inflammasome activation by urates

What is happening during Atherosclerosis?

DAMPs form oxidized LDL activate TLRs and inflammasomes in plaques

How can we use PRRs in a therapeutic and diagnostic application?

Use PRRs as drug targets that are used for autoimmune diseases, cancer immunotherapy, and chronic infections

How can we use PAMPS in a therapeutic and diagnostic application?

Vaccine Adjuvants are PAMP mimics that activate PRRs to enhance immune responses and memory formation

What are example of vaccine adjuvants?

MPL (monophophoryl liquid A) TLR4 agonist in HPA and HBV vaccines

How can DAMPS be used in therapuetic and diagnostic applications?

biomarker discovery where circulating DAMPs serve as biomarkers for tissue injury, cancer, and autoimmune flares

How can cytokine be useful in biomarker discovery?

profiles which helps monitor disease activity and therapeutic responses