2: Innate Immunity

General Characteristics of Innate Immunity

•Action is immediate

•Response is non-specific

•Response is not enhanced on repeated exposure to pathogen (No memory)

•Diversity: Limited 

What does it mean for diversity to be limited in innate immunity?

-Means that they have fewer receptors!

-Receptors are hardwired

-All the receptor needs to do is identify the pathogen; it does not need to specifically identify what the pathogen is.

How are receptors made up in B and T cells?

In B and T cells, receptors are made by a combination of genes

Interconnectedness of the Immune System

•Provides early defense against microbes

• The innate system acts as your first line of shield, fighting off invading germs right away before they can spread.

•Induction of adaptive immune responses

• While fighting the threat, the innate system sends signals and alarm bells to wake up and activate the adaptive immune system

•An effector function of adaptive immune response

• Once active, the adaptive system sends powerful signals back to the innate system, giving it specialized tools to finish off the germs effectively.

What must be activated in order for adaptive immunity to be activated?

Innate immunity has to be activated in order for adaptive immunity to be activated!

• Special forces go to the site of infection and help the macrophages that are fighting, so they help innate immunity.

Receptor-Ligand Interactions

Shape Specificity: Receptors only bind to ligands of the appropriate shape. If the shape doesn't match, they won't fit together.

Affinity (Binding Strength): The strength of the interaction between a ligand and a receptor is called affinity. A different affinity can lead to a different response!

Strong binding (high affinity)

The ligand fits perfectly, creating a tight bond. This triggers a specific signal or cellular response.

Weak binding (low affinity)

The fit is partial or loose, resulting in a different level of signaling or an entirely different cellular outcome.

How do receptor-ligand interactions influence an outcome?

• Cells release chemical messengers like cytokines and chemokines (the ligands).

• These ligands attach to specific receptors on the surface of receiving cells.

• A cell often receives multiple signals at once. The overall combination of these signals determines the specific outcome (e.g., Response A, No response, Response B, or Response C)

How does the innate immune system identify a foreign pathogen?

-Has to identify a foreign pathogen based on a structure that many pathogens have (find patterns)

-Look at PAMPs (Pathogen-associated molecular patterns)

-PAMPs are detected by PRRs receptors

PAMPs

Pathogen-associated molecular patterns

• Molecules associated with groups of pathogens

• Recognized by cells of the innate immune system.

• These molecules can be referred to as small molecular motifs conserved within a class of microbes

MUST BE SOMETHING ONLY ANTIGENS HAVE!

How do macrophages identify PAMPs?

Macrophages have receptors called PRRS that look at and identify PAMPs

How are PAMPs recognized?

• Toll-like receptors (TLRs)

• Other pattern recognition receptors (PRRs)

What do PAMPs do?

They activate innate immune responses, protecting the host from infection, by identifying some conserved non-self molecules, e.g.

Examples of PAMPs

•Bacterial Lipopolysaccharide (LPS)

•Bacterial flagellin

•Bacterial lipoteichoic acid from Gram positive bacteria

•Nucleic acid variants normally associated with viruses, such as double-stranded RNA (dsRNA) or unmethylated CpG motifs.

Extracellular Receptors

These sensors sit directly on the plasma membrane (the cell's outer skin), pointing outward. They scan the fluid surrounding the cell to catch invaders before they break inside.

• Toll-like Receptors (TLRs)

• C-type Lectin Receptors (CLRs)

Toll-like Receptors (TLRs)

Bind to outer microbial components, such as bacterial cell wall lipids.

C-type Lectin Receptors (CLRs)

Recognize sugar molecules (polysaccharides) found on the surface of fungi and bacteria.

Cytosolic Receptors

INSIDE THE CYTOPLASM

If a pathogen successfully invades or injects its genetic material directly into the cell's main fluid (the cytoplasm), these internal sensors detect the threat and sound the alarm.

• NOD-like Receptors (NLRs)

• RIG-like Receptors (RLRs)

• Cytosolic DNA Sensors (CDS)

NOD-like Receptors (NLRs)

Detect bacterial cell wall pieces and molecules released by damaged host cells.

RIG-like Receptors (RLRs)

Specifically look for foreign viral RNA floating in the cytoplasm

Cytosolic DNA Sensors (CDS)

Detect unusual microbial DNA present in the cytoplasm where host DNA shouldn't normally be

• Recognize the microbe in the cytoplasm

Endosomal Receptors

Inside Internal Compartments

When an immune cell eats or engulfs a pathogen to break it down, it traps the invader inside an internal bubble called an endosome. As the pathogen is digested, its hidden inner contents are exposed.

• Endosomal TLRs

-Pathogens are getting digested here!!!!

Endosomal TLRs

Sit on the inner membrane of digestive bubbles (endosomes) to detect exposed viral or bacterial genetic material (nucleic acids like DNA and RNA).

What TLR recognizes gram-positive bacterial lipopeptides?

• TLR-1

• TLR-2

• TLR-6

  • Surface TLRs

What TLR recognizes gram-positive bacterial peptidoglycan?

TLR-2

• Surface TLRs

What TLR recognizes gram-negative LPS

TLR-4

• Surface TLRs

What TLR recognizes bacterial flagellin?

TLR-5

• Surface TLRs

What TLR recognizes dsRNA?

TLR-3

• Endosomal TLR

What TLR recognizes ssRNA?

TLR-7 & TLR-8

• Endosomal TLR

What TLR recognizes CpG DNA?

TLR-9

• Endosomal TLR

How do Toll-Like Receptors (TLRs) send signals inside a cell?

• A bacterial or viral molecule binds to the extracellular part of the TLR because it recognizes its PAMPs (made of Leucine-rich repeats).

• The internal part of the receptor (TIR domain) triggers the recruitment of adaptor proteins inside the cell.

• The signal branches into two distinct transcription factor pathways:

1. NF-κB Pathway

2. IRF Pathway

NF-κB Pathway of TLR signaling

Activates the NF-κB transcription factor, which travels into the nucleus to turn on genes for inflammatory cytokines, adhesion molecules, and costimulators.

• Acute inflammation

• Stimulation of adaptive immunity inflammation

IRF Pathway of TLR signaling

Activates IRFs (Interferon Regulatory Factors), which move to the nucleus to trigger the production of Type 1 Interferons (IFN-α, IFN-β)

• Antiviral state

What are Type 1 Interferons?

IFN-α and IFN-β are essential defensive proteins (cytokines) produced by your body's cells when they detect a viral invasion.

• They act as an early-warning alarm system to stop viruses from multiplying and spreading to nearby healthy cells.

What are the inflammatory cytokines?

Il-1

IL-6

TNFα

IL-12

How is a phagolysosome formed?

Phagocytosis: An immune cell swallows a pathogen (such as a bacterium), enclosing it inside an internal bubble called a phagosome.

Fusion: The phagosome fuses with a lysosome—a cellular organelle filled with acidic digestive enzymes and toxic oxygen species—to form the phagolysosome.

What is a phagolysosome?

A phagolysosome is a specialized membrane-bound structure formed inside an immune cell (like a macrophage or neutrophil) to destroy engulfed microbes and cellular debris.

What is signal transduction?

Signal transduction is the process by which a cell converts an external signal into a specific functional response inside the cell.

What is an inflammasome?

An inflammasome is a group of proteins inside an immune cell that acts like an alarm system.

• Senses a microbe in the environment

• Can sense that a macrophage is dying and that there is mitochondrial damage.

• Activates inflammatory proteins, triggering inflammation

What is IL-1β?

A cytokine that signals to the body that something is wrong and to start inflammation

What are the two signals of an Inflammasome?

Signal 1: causes the cell to make pro-IL-1β

Signal 2: Activates NLRP3 → forms the inflammasome → activates caspase-1→ turns pro-IL-1β into IL-1β

How does Signal 1 (creation of pro-IL-1β) in an inflammasome work?

Comes from the innate immune system

• TLRs (Toll-like receptors) detect a signal

• These signals travel to the cell’s nucleus and tell it that a danger is present and that it must be ready to respond

  • This causes the nucleus to turn on the gene for pro-IL-1β

How does signal 2 (IL-1β → inflammation) in an inflammasome work?1

• NLRP3 can be activated by sensing Pathogenic bacteria, Extracellular ATP, Bacterial products, Crystals, K⁺ efflux, Reactive oxygen species

• Once the NLRP3 inflammasome forms, caspase-1 becomes active

• Capase-1 cuts/cleaves and processes pro-IL-1β into IL-1β

• The active IL-1β is released from the cell.

• IL-1β helps promote inflammation by signaling to nearby cells and tissues.

Cytosolic DNA

Normally, your cell's own DNA is mainly found in the nucleus.

• DNA suddenly found floating around in the cytoplasm is a warning sign that something foreign is in the cell

STING Pathway

CYTOSOLIC DNA SENSORS

• cGAS (cytosolic DNA sensor) detects DNA floating in the cytosol

• Once activated, cGAS produces molecules called Cyclic dinucleotides

• The cyclic dinucleotide signal binds to STING, activating it

• STING activates TBK1

• TBK1 phosphorylates IRF3, activating it

• IRF3 enters the nucleus and tells the cell to turn on genes that produce Type I interferons

• Type I interferons (alpha and beta) → induction of antiviral state

  • This means the cell and nearby cells become better prepared to fight viral infection

Type I interferons

IFN-α and IFN-β

• antiviral state

Functions of Epithelia in Innate Immunity

Epithelia present at portals of entry of microbes

1. provide physical barriers,

2. produce antimicrobial substances

• Secrete peptide antibiotics. These natural chemical compounds directly attack and destroy pathogens at the surface before they can infect cells.

3. Harbor lymphocytes that are believed to kill microbes and infected cells

• Intraepithelial lymphocytes live directly inside the epithelial layer. They act as frontline guards to identify and quickly eliminate

Platelets

Essential for blood clotting and tissue repair to prevent excessive bleeding after injury.

Erythrocytes (Red Blood Cells)

Transport oxygen from the lungs to tissues throughout the body and carry carbon dioxide back for exhalation.

Eosinophils

Protect against parasitic infections and play a key role in allergic reactions.

Basophils

Release histamine during inflammatory and allergic responses to aid immune cell recruitment.

Neutrophils

Act as the primary first-responders to infection by rapidly engulfing and destroying invading bacteria

Monocytes / Macrophages

Clean up cellular debris and engulf pathogens, while also presenting antigens to trigger adaptive immune responses.

Dendritic Cells

Capture antigens and present them to lymphocytes, bridging the innate and adaptive immune systems

Natural Killer (NK) Cells

Detect and destroy virus-infected host cells and tumor cells without requiring prior sensitization

• Solely there for fighting viruses and tumors

T Cells

Drive cell-mediated immunity by directly killing infected cells or coordinating overall immune system responses.

B Cells

Target pathogens by developing into plasma cells that secrete antigen-specific antibodies.

Plasma Cells

Function as specialized antibody factories that secrete large volumes of targeted antibodies to neutralize pathogens.

Phagocytes: Cells

• Neutrophils

• Monocytes

  • type of large white blood cell

Antigen Presenting Cells

• Dendritic Cells (Present to T cells)

• Follicular Dendritic Cells (present to B cells)

• Macrophages

• B cells (present to T cells)

Inflammation Cells

• Basophils

• Eosinophils

• Mast Cells

Monocytes & Macrphages

• Monocytes circulate in the blood

• When they leave the circulation to enter the tissues, they are called macrophages

  • They have other names in different tissues, e.g., Kupffer cells (liver), microglial cells (CNS), osteoclasts, alveolar macrophages, etc

Macrophages in the innate immune system:

•Phagocytosis

•Production of cytokines that recruit other inflammatory cells

Macrophages in the adaptive immune system:

•Antigen presentation to T cells

•In cell-mediated immune response

•In humoral-mediated immune response