Lecture 5 Inflammation, Hypersensitivities, and Tolerance

Inflammation, Hypersensitivities, and Tolerance

• Innate immune response that develops when our tissues are damaged

• Tissue injury initiates blood-clotting cascades

• Blood clots curb blood loss and limit pathogen spread

Three main goals of inflammation are:

1.Recruit immune defenses to the injured tissue

2.Limit the spread of infectious agents

3.Deliver oxygen, nutrients, and chemical factors essential for tissue recovery

Inflammation has 3 phases:

1. Vascular changes

2. Leukocyte recruitment

3. Resolution

1. Vascular changes

Injury or infection damages tissues then vasoactive molecules (like histamine, prostaglandins, leukotrienes, complement fragments) are released, these molecules cause vasodilation and increased vascular permeablity

Vasodilation Inflammation

more blood flows to the area → redness & heat.

Increased vascular permeability

fluid, proteins, and immune cells (cytokines)leak into tissue → swelling & pain.

2. Leukocyte recruitment

Cytokines attract white blood cells to the site (chemotaxis).

Neutrophils arrive first → they phagocytose (eat) pathogens.

Monocytes arrive later → mature into macrophages.

Both neutrophils and macrophages kill invaders and release more cytokines to recruit other leukocytes.

Margination

• Leukocytes slow as they roll along vessel wall

• Eventually leukocytes adhere to vessel wall

Diapedesis

• Leukocytes change shape

• Leukocytes squeeze out of vessel

3. Resolution

Blood vessels return to normal, Inflammatory signals decrease (Local tissue cells and leukocytes release cytokines and growth factors that shut down inflammation and promote healing)

Neutrophils and macrophages that are no longer needed undergo apoptosis (which forms pus)

Swelling decreases and healing increases

Chronic Inflammation

Response goes on too long past the injury or infection (not useful), it exacerbates tissue injury

Chronic Inflammation results in

• atherosclerosis,

• certain cancers, and

• progressive neurodegenerative disorders

Treatments for inflammation

Nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., aspirin, ibuprofen, naproxen)

Steroidal anti-inflammatory drugs(SAIDs) (e.g., cortisone, prednisolone)

Fever (pyrexia)

Systemic innate immune response

• Pyrogens—fever-inducing agents

- Bacterial toxins (e.g., endotoxin, lipopolysaccharide-LPS)

• Trigger the release of cytokines

• Signal the hypothalamus to raise the body's baseline temperature

Low Grade Fever

Considered protective and can run its course

Sometimes increasing your body temperature can help you fight off certain pathogens and also promotes tissue repair that.

High Grade Fever

Dangerous, reaches 40.5 °C (105 °F)

Essential cellular enzymes and proteins will begin to denature and stop working

Hypersensitivities

are inappropriate immune responses (e.g., allergy and autoimmunity)

• Can be localized and therefore restricted to a given tissue

• Can be systemic and spread through the body and affect multiple tissues and organ systems

Hypersensitivities 4 types ACID

A Type 1 - Allergy, Anaphylaxis

C Type 2 - Cytotoxic

I Type 3 - Immune Complex

D Type 4 - Delayed Onset

-Each type can be triggered by drugs

Allergies type 1 Hypersensitivity

Include all allergies:

• Atopic asthma - allergy-based asthma

• Atopic dermatitis - inflamed and itchy skin condition also known as atopic eczema

Risk is genetic

Inhaled and ingested allergen

Sensitizing exposure

First exposure to allergen activates B cell which turn into plasma cells that produces IgE antibodies which have granules that contain histamine

Doesn't release histamine

Post-sensitization exposure

allergen binds IgE → mast cell degranulation → allergy symptoms

Releases histamine and other chemicals

Induces degranulation

Degranulation

the process where immune cells (like mast cells, basophils, and eosinophils) release the contents of their granules (packets of chemicals) into the surrounding tissue

C Type 2 - Cytotoxic

Two Main Cytotoxic Mechanisms

It occurs when antibodies (IgG or IgM) bind directly to antigens on the surface of host cells.

This “tags” the cells as enemies → leading to their destruction.

Seen in conditions like hemolytic anemia, blood transfusion reactions, Rh incompatibility, some autoimmune diseases.

Two Main Cytotoxic Mechanisms

1. Complement-Dependent Cytolysis

2. Complement-Independent Cytolysis (Antibody-Dependent Cellular Cytotoxicity, ADCC)

1. Complement-Dependent Cytolysis

-Antibodies bound to a host cell activate the complement cascade.

-Complement proteins form the Membrane Attack Complex (MAC) → punches holes in the cell → cell lysis.

-Complement fragments also opsonize the cell → phagocytes eat it

2. Complement-Independent Cytolysis (Antibody-Dependent Cellular Cytotoxicity, ADCC)

-Antibodies bound to a host cell recruit leukocytes (like NK cells).

-NK cells bind to the antibody Fc region.

-NK cell releases perforin & granzymes, triggering apoptosis of the tagged cell.

Type II hypersensitivities are often characterized by cytotoxic reactions

-Goodpasture syndrome: Connective tissues of the kidney and lungs are attacked

-Autoimmune hemolytic anemia: Red blood cells are attacked when bound to drugs like cephalosporins and penicillins

-Rheumatic heart disease: Antibodies made against Streptoccocus pyogenes cross-react with the patient's heart valves

Type II - Blood Groups

Blood types referring to the presence of antigens on the surface of red blood cells• These antigens include:

• Carbohydrates: A, B, O

• Protein: Rh (rhesus factor) - indicated by a "+"

Possible blood types:

A+, A-, B+, B-, AB+, AB-, O+, O-

O blood type antigen

On every blood type, we all have O antigen

Difference between ABO and Rh

ABO are carbohydrates so they are everywhere in your body while Rh (D antigen) is a protein only in red blood cells, itll never be in your body unless you are Rh+

Rh-negative person only develops

this antibody after exposure to Rh-positive blood

• Usually from transfusion, or through placental exposure during a pregnancy

Incompatible transfused red blood cells cause

a hemolytic transfusion reaction

• Lyses red blood cells

• Could kill the patient

• Signs and symptoms occur within hours

• Fever, chills, lower back pain, chest pain, tachycardia, reducedblood pressuree

• No therapy to reverse a transfusion reaction or block it once it starts

• Supportive care to reduce kidney failure

O- blood type

the universal blood type

Rh factor incompatibility during pregnancy

may lead to hemolytic disease of the newborn (HDN)

-no effective way to prevent HDN if mother is already sensitized

To prevent HDN

prevent Rh negative women from ever being sensitized to the Rh factor

• Rh(D) immunoglobulin(RhoGAM) is given

Rh(D) immunoglobulin(RhoGAM)

This is an antibody against the Rh factor (also known as D antigen)

I Type 3 - Immune Complex

Antibodies and soluble antigens bind to form antigen antibody complexes deposit on the tissue which causes inflammation

Examples of Autoimmune Type III Hypersensitivities:

1. Systemic Lupus Erythematosus (SLE)

2.Rheumatoid Arthritis (RA)

3. Poststreptococcal Glomerulonephritis

Systemic Lupus Erythematosus (SLE)

Attacks DNA histones, ribosomes, ribonuclease, proteins the ones with the stars

Systemic (gastrointestinal, lung, kidney, and thyroid issues); often manifests with rash across cheeks and nose, fatigue, joint pain, fever, or hair loss

Rheumatoid Arthritis (RA)

Attacks Rheumatoid factor

Severe arthritis; mainly in wrists and hands; can cause bone erosion that deforms joints

Poststreptococcal Glomerulonephritis

Attacks antibodies against Streptococci cross-react with proteins in the kidney

May develop after untreated Streptococcus pyogenes infection; antibiotics make it rare in developed countries; usually resolves in weeks to months but may progress to renal failure.

D Type 4 - Delayed Onset

Both autoimmune and nonautoimmune

-autoimmune --> Multiple Sclerosis

-nonautoimmune --> Contact dermatitis (poison ivy) and latex reactions

Contact dermatitis

• Caused by drugs, nickel, chromate, poison ivy toxin (pentadecacatechol)

• T cells are sensitized

• Secondary exposure to the same antigen leads to inflammation and generates an extremely itchy (pruritic) red rash

Latex sensitivities

Healthcare workers regularly wear gloves causing dry, cracked skin

• Promotes entry of the latex into the skin to trigger sensitization

Tolerance

The ability of the immune system to recognize “self” and not attack it.

-Achieved through two main mechanisms: central tolerance and peripheral tolerance

- Central (thymus and bone marrow) and Peripheral (lymph nodes and other lymph tissue)

Apoptosis

cell programmed death and is the mechanism for both central and peripheral

Central Tolerance (thymus) T cell

Happens during lymphocyte development (in the bone marrow for B cells, thymus for T cells).

-Immature lymphocytes are tested:

a. If they recognize self-antigens strongly, they are deleted (via apoptosis = negative selection).

b. Only cells that don’t strongly react to self survive.

-Apoptosis here prevents autoimmunity early on.

Peripheral Tolerance T cell

Happens after lymphocytes mature and enter circulation/tissues.

Some self-reactive cells escape central tolerance → peripheral tolerance controls them:

-Anergy

-Regulatory T cells (Tregs) suppress self-reactive cells

- Apoptosis

Anergy

cells become inactive if they recognize antigen without proper co-stimulation

Central tolerance Summary T cell

(in thymus/bone marrow) deletes self-reactive cells by apoptosis during development

Peripheral Tolerance Summary T cell

controls escaped self-reactive cells in tissues using anergy, Tregs, or apoptosis

Regulatory T cells (Tregs)

A special subset of CD4⁺ T cells, supress directly by starving effector T cells

Their main job is to suppress or "turn down" immune responses so the system doesn't overreact or attack self.

Central tolerance B cells

Occurs in bone marrow

Immature B cells tested against self-antigens.

If B cell receptor (BCR) strongly recognizes self:

-Apoptosis (clonal deletion), OR

-Receptor editing → B cell rearranges its receptor genes to try making a non-self-reactive receptor.

Outcome: Prevents release of highly self-reactive B cells.

Peripheral Tolerance B cells

If self-reactive B cells escape:

-Anergy: they become unresponsive.

-Apoptosis: repeated stimulation by self-antigen without T cell help leads to cell death.

-Regulation by T cells: lack of proper T cell signals prevents them from becoming active.

Kinetics of an Immune Response

1. Pathogen invasion & innate detection

2. Innate immunity is overwhelmed

3. Adaptive immunity kicks in

4. Adaptive immunity kicks in

Kinetics of an Immune Response Summary

The immune response begins with innate defense, gets overwhelmed, then adaptive immunity clears the infection, and finally memory ensures future protection.

1. Pathogen invasion & innate detection

-Pathogen enters, colonizes, and replicates.

-Innate immunity (barriers, phagocytes, complement, K cells) detects it.

-Early inflammation begins.

2. Innate immunity is overwhelmed

-Pathogen numbers grow faster than innate defenses can control.

-Symptoms may appear here (fever, inflammation).

3. Adaptive immunity kicks in

-B cells → plasma cells make antibodies.

-T cells (cytotoxic & helper) eliminate infected cells and coordinate response.

-Pathogen numbers drop as adaptive effectors clear infection.

4. Adaptive immunity kicks in

After infection is resolved, memory B and T cells remain.

They provide long-lasting protection and mount a faster, stronger response on re-exposure.

Different stages of infection

1. invasion of pathogen and immune response

2. APC activation

3. immune clearance of pathogen

4. Resolution of immune response

1. invasion of pathogen and immune response

-Pathogen enters, colonizes, and begins replicating.

-Innate immunity responds first: barriers, complement, phagocytes, NK cells.

-Inflammation is triggered to slow pathogen spread.

2. APC activation

-Dendritic cells and macrophages engulf pathogen.

-They process antigens and present them on MHC molecules.

-They travel to lymph nodes to activate T helper cells and stimulate B cells.

3. immune clearance of pathogen

Adaptive immunity takes over:

-B cells → plasma cells → antibodies (neutralization, opsonization, complement activation).

-Cytotoxic T cells (CD8⁺) kill infected host cells.

-Helper T cells (CD4⁺) release cytokines to coordinate the immune attack.

Pathogen numbers decline.

4. Resolution of immune response

Once pathogen is cleared:

-Pro-inflammatory signals drop.

-Tregs, IL-10, TGF-β suppress immune activity.

-Apoptosis removes extra neutrophils and effector T cells.

-Macrophages clear debris and promote tissue repair.

Memory B and T cells remain → faster, stronger response on re-exposure

Resolution summary

Every immune response must be followed by resolution, where inflammation stops, immune cells clear out, and tissues repair — otherwise chronic disease can develop.