1: Intro to the Immune System

Defense against infections

• What it does: Protects your body from viruses and bacteria.

• Real-world effect: If your immune system is weak (like with AIDS), you get sick much easier. Vaccines help train it to fight off these germs better.

Defense against tumors

• What it does: Hunts down and destroys cancerous cells.

• Real-world effect: Doctors can use cancer treatments (immunotherapy) that train your own immune system to target and destroy tumors

The immune system can injure cells and induce pathologic inflammation

• What it does: Sometimes overreacts or attacks the body by mistake.

• Real-world effect: This overreaction is what triggers allergies, autoimmune conditions, and harmful inflammation.

The immune system recognizes and responds to tissue grafts and newly introduced proteins

• What it does: Spot and attack anything foreign, like transplanted organs or new gene treatments.

• Real-world effect: Because it treats foreign tissue as an invader, it can reject organ transplants or block gene therapies unless controlled

Roles of the immune system

• Defense against infections

• Defense against tumors

• The immune system can injure cells and induce pathologic inflammation

• The immune system recognizes and responds to tissue grafts and newly introduced proteins

Innate (native) Immunity

• Nonspecific and fast

  • Reacts immediately to fight off any intruder, regardless of the type of germ it is

• First line of defense (e.g., skin, mucous membranes, sebaceous secretions, pinocytosis, or phagocytosis)

  • Physical barriers like skin, mucus, oils, etc./generic defenders that swallow up invaders

Pinocytosis

“Cell drinking”

• Pinocytosis is a process in which a cell takes in liquids and tiny dissolved particles from its surrounding environment.

Phagocytosis

“Cell eating”

• Process in which a cell surrounds and engulfs large solid particles, such as bacteria, viruses, or dead cell debris.

Adaptive (acquired) immunity

• Specific

• Memory

  • Creates custom-tailored weapons for specific germs and remembers them so you don’t get sick from the same thing twice

• Adaptive by infection or vaccination

  • Body learns how to fight a germ on its own once you get infected or receive a vaccine

• Passive by placental transfer or injection of specific antigen

  • Body receives ready-made antibodies from an outside source, rather than making its own

Organisms of innate immunity

• Epithelial barriers

• Dendritic cells

• Mast cells

• Phagocytes

• Complement proteins

• NK and ILCs

Epithelial barriers

Skin/lining of organs

• blocks microbes from entering in the first place

Dendritic cells

Swallow and display pieces of an invader to alert the adaptive immune system

Mast Cells

Alarm raisers!

• Release chemical signals to trigger inflammation and call for backup when tissues are damaged or invaded

Phagocytes

Engulf and digest microbes

Complement Proteins

Proteins in the blood that tag microbes or punch holes directly in their membrane to destroy them

NK cells and ILCs

Search and destroy your body’s own cells if they notice it’s become infected or abnormal

How long doe sit take from innate immunity to kick in?

Kicks in within minutes or hours to block and fight generic invaders

Lymphocytes

A specialized type of white blood cell that acts as the main defender in the immune system

How do B lymphocytes work?

• B cell receptors recognize the specific antigen on a pathogen

• B cells multiply into an army of clone B cells

• The clone cells turn into plasma cells

• The plasma cells pump out antibodies (proteins) that latch onto microbes, neutralizing them (blocking them from entering and infecting healthy cells) or marking them for destruction

How do T cells work?

• Dendritic cells present pieces of the pathogen to T cells

• T cells recognize the match and multiply into effector T cells

• There are 2 types of effector T cells

  • Cytotoxic T cells (CD8+): These "killer" cells find and destroy cells infected with viruses or transformed by cancer by releasing toxic molecules like perforin and granzymes.

  • Helper T cells (CD4+): These cells do not kill directly; instead, they release chemical signals called cytokines to coordinate and boost the rest of the immune system, including activating B cells and macrophages.

What kind of receptors are there in innate immunity?

Innate cells are born with a small set of pre-made, hard-wired receptors

• Every person gets the exact same basic sensors to spot generic microbe patterns

“A limited number of hard-wired pattern recognition receptors”

What kind of receptors are in adaptive immunity?

Adaptive cells can cut, shuffle, and paste different gene pieces together to build custom receptors

• They have the ability to create millions of unique sensors to sense almost every antigen

“An enormous number of somatically generated receptors via gene rearrangement”

Repeated exposure and the innate immune system

The innate immune system reacts to a given stimulus with a consistent intensity, regardless of how many times it has been exposed to that stimulus

• Responds with the exact same speed & strength regardless of the number of encounters

Repeated exposure and the adaptive immune system

The adaptive immune system can adapt and modify its response after each exposure to a given stimulus.

• Learns from the past! Grows quicker and stronger with every exposure

Humoral immunity

Targets invaders floating freely outside your body’s cells (like fluids of bloodstream)

What are the responding lymphocytes in humoral immunity?

B lymphocytes

What is the target in humoral immunity?

Microbes

What is the effector mechanism of B lymphocytes?

B lymphocytes transform into plasma cells that secrete antibodies and bind to the microbe, physically blocking it from entering cells and marking it for destruction

What are the functions of humoral immunity?

Block infections and eliminate extracellular microbes

Cell-mediated immunity

Targets microbes that have already invaded your body’s cells

• There are two strategies depending on where the microbe is hiding

What are the targets in cell-mediated immunity?

• Phagocytosed microbes that can live within macrophages

  • Swallowed by macrophages (phagocytosed) but managed to live inside them

• Intracellular microbes (e.g., viruses) replicated within the infected cell)

  • Actively replicated inside infected body cells

What are the responding lymphocytes in cell-mediated immunity?

Helper T lymphocyte & Cytotoxic T lymphocyte

How does the Helper T lymphocyte work?

helper T cells release chemical signals to activate the macrophage, giving it the extra push destroy the trapped microbe

How to cytotoxic T lymphocytes work?

“Killer T cells”

• killer T cells recognize the infected host cell and destroy it entirely to prevent the virus inside for multiplying further. To do so, they punch holes in the target cell membrane, using proteins called perforins and inject toxic enzymes to trigger cell death.

what is the function of helper T cells in cell – mediated immunity??

elimination of phagocytosed microbes

what is the function of killer T cells in cell-mediated immunity?

Kill infected cells and eliminate reservoirs of infection

What are the properties of adaptive immune responses?

• Specificity

• Diversity

• Memory

• Clonal expansion

• Specialization

• Contraction and homeostasis

• Non-reactivity to self

what does specificity mean as a property of the adaptive immune system?

Ensures that distinct antigen's illicit specific responses

• Body sends the right to weapon to attack

• Targets unique features on specific germs (Antigens)

What does diversity mean as a property of the adaptive immune system?

Enable immune system to respond to a large variety of antigens

• There are millions of different receptors, so the immune system can recognize almost every invader

What does memory mean as a property of the adaptive immune system?

Leads to enhanced response responses to repeated exposures to the same antigens

• Makes future responses faster and stronger

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What does clonal expansion mean as a property of the adaptive immune system?

Increases number of antigen specific lymphocytes from a small number of naïve lymphocytes

• When a matching immune cell finds a microbe, it rapidly duplicates itself, building an army to fight

What does specialization mean as a property of the adaptive immune system?

Generates responses that are optimal for defense against different types of microbes

• Immune system adapts tactics depending on the threat

What does contraction and homeostasis mean as a property of the adaptive immune system?

Allows immune system to respond to newly encountered antigens, rather than remaining cluttered with old cells

• after infection is cleared, the army of immune cells, die off, returning the body to homeostasis

What does non-reactivity to self mean as a property of the adaptive immune system?

Prevents injury to the host during responses to foreign antigens

• Immune system learns to ignore your own cells

• Stop the body from attacking itself!

Process of clonal selection:

1. Precursor cells in organs divide into mature immune cells (lymphocytes)

2. Each mature lymphocyte develops a unique receptor on its surface through gene rearrangement

3. Lymphocyte receptors will only bind to the matching antigen

4. Once they meet the matching antigen, the lymphocyte rapidly divide to make identical clones of itself

5. Clones, then attack the threat by producing specific antibodies for the antigen

What happens to cells that target your body’s healthy tissue?

Cells that target your own bodies, healthy tissues are deleted or shut down before entering the active pool (the repertoire)

• This ensures self tolerance!

Repertoire

Total collection of unique disease fighting receptors found on your body's B and T cells

Types of lymphocytes

• B lymphocytes

• T lymphocytes

Principal function of B lymphocytes:

Produce targeted antibodies that circulate and bodily fluids to neutralize invaders

Principal function of T lymphocytes:

Directly attack infected host cells or instruct other immune cells to do so

Types of antigen presenting cells:

• Dendritic cells

• macrophages

• B cells

• Follicular dendritic cells

Principal function of dendritic cells

Initiation of T cell responses

• Present captured antigens to infected T cells

Principal function of macrophages

Effector phase of cell mediated immunity

• Present antigen during execution phase of cell immunity

Principal function of follicular dendritic cells

Display of antigens to B lymphocytes in humoral immune responses

• Present antigens to B cells during humoral immune responses in lymph nodes

Types of effector cells

• T lymphocytes

• Macrophages

• Granulocytes

Principal function of T lymphocytes

Activated of phagocytes (engulfing cells), killing infected cells

Principal function of macrophages

Phagocytosis and killing of microbes

• engulfs and digests/ kills the microbe

Principal function of granulocytes

Killing microbes

• Releases chemical granules to directly kill the microbes

How do Helper T cells work?

• Helper T cells inspect antigens presented to them on the surface of an antigen-presenting cell

• Once they detect an antigen, they become activated and release chemical signals called cytokines

• These cytokines can lead to the activation of macrophages (cell eating), inflammation (protection and healing), and the activation of B cells (to produce antibodies)

How do cytotoxic T lymphocytes work?

• Infected cells express a microbial antigen, which the CTL detects

• Once detected, the CTL latches onto the infected cell

• CTLs release perforin and Granzymes to kill the infected cell

Perforin

Protein that punches holes into a infected cell

Granzymes

Enzymes that enter through the holes caused by perforin and trigger apoptosis (programmed cell death).

How do regulatory T lymphocytes work?

• Tregs notice that the immune system is overreacting or attacking healthy cells.

• They travel to the area and lock onto the active immune cells.

• Tregs soak up the chemicals that active T cells need to keep growing, starving them out.

• They release "calm down" chemicals that tell surrounding cells to stop fighting.

• They directly turn off active cells—or destroy them if they won't stop—bringing the attack to an end.

SUPPRESSION OF IMMUNE RESPONSE!

Helper T cell phenotypic markers

CD3+

CD4+

CD8-

Killer T cell phenotypic markers

CD3+

CD4-

CD8+

Regulatory T cell phenotypic markers

CD3-

CD4-

CD25+

FoxP3+ (most common)

B cell phenotypic markers

CD19

CD23

Maturation of B lymphocytes (process)

• All lymphocytes start from a single precursor cell originating in the bone marrow

• Some lymphocytes stay in the bone marrow to fully mature into B cells

• Once mature, B cells enter circulation (blood vessel systems) to travel around the body

• They continuously recirculate back and forth between the blood and the peripheral lymphoid organs until they find a pathogen to fight

Maturation of T lymphocytes (process)

• All lymphocytes start from a single precursor cell originating in the bone marrow

• Some lymphocytes leave the bone marrow and travel to the thymus to mature into T cells

• Once mature, T cells enter circulation (blood vessel systems) to travel around the body

• They continuously recirculate back and forth between the blood and the peripheral lymphoid organs until they find a pathogen to fight

Peripheral lymphoid organs

• Lymph nodes

• Spleen

• Mucosal and cutaneous lymphoid tissues

Ageing T Cell Repertoire

The thymus is most active early in life, producing a lot of new, naive T cells. As you get older, thymic output decreases as you are exposed to more pathogens. This results in a decrease in naive T cells and an increase in memory T cells.

Primary lymphoid organs

• Bone marrow

• Thymus

Secondary lymphoid organs and tissues

• Adenoid

• Tonsil

• Lymph node

• Appendix

• Spleen

• Peyer’s patch in the small intestine

• Large Intestine

Vascular and Lymphatic Network

• Right subclavian vein

• Left subclavian vein

• Thoracic duct

• Lymphatics

Acts as a highway system, connecting tissues to major blood vessels

Afferent lymphatic vessel (lymph node)

WHERE THE ANTIGEN ENTERS

• Brings lymph fluid containing antigens (pathogens) into the node from surrounding body tissue

Efferent Lymphatic vessel (lymph node)

Carries filtered lymph fluid and activated immune cells out of the lymph node, returning them back toward general blood circulation alongside blood vessels (artery and vein)

Medulla (lymph node)

Where fluid drains toward the exit

High Endothelial Venule (HEV) (lymph node)

Special blood vessels where B & T cells exit the bloodstream to enter the lymph node

• Has gaps between them so that the B & T cells can enter!

Subcapsular sinus (lymph node)

Beneath the outer protective shell of the lymph node, where the incoming lymph fluid drains

B cell zone (follicle) (lymph node)

The B cell zone (lymphoid follicle) is a specialized microenvironment designed specifically to orchestrate B cell maturation and antibody production.

T cell zone (lymph node)

The T cell zone is the distinct region within secondary lymphoid organs designed for antigen presentation and adaptive T cell activation

Process of B and T cells moving through the lymph node:

• B & T cells enter the lymph node to look for an antigen

• If they find an antigen, they use their special force. If they don’t find an antigen, they leave the lymph node through the efferent lymphatic vessels & move to the next lymph node

Marginal sinus & marginal zone (spleen)

Specialized macrophages and B cells live here to trap blood-borne pathogens, and blood flows out of the arterioles

B cell zone (spleen)

ATTACHED TO PALS

• Form germinal centers (factories) when actively producing antibodies

T cell zone (spleen)

PERIARTERIOLAR LYMPHOID SHEATH (PALS)

• T cells gather here to inspect antigens in the blood

Red Pulp (spleen)

RICH IN VASCULAR SINUSOIDS (special blood vessels built like "leaky tunnels” with gaps)

• Makes up most of the spleen

• Filters blood to remove old, damaged, or defective red blood cells

How does blood travel through the spleen?

Blood enters through the trabecular artery —> central arteriole —> follicular arterioles —> marginal sinus —> drains into red pulp

What makes up the white pulp in the spleen?

• B cell zone (follicular)

• T cell zone (Periarteriolar Lymphoid Sheath)

Gut Associated Lymphoid Tissue

• Very vast, so it’s hard to have designated spaces

• More diffused

• Not arranged as nicely as lymph nodes

• Peyer’s Patch

Peyer’s Patch

• Sits right beneath the intestinal lining, scanning the contents of the gut for potential pathogens

• M (microfold) cells on the surface grab antigens from the gut interior and deliver them to waiting immune cells inside the patch

• Helps distinguish between pathogens and harmless everyday materials

• Main sites where B cells are instructed to become antibody-producing plasma cells that secrete immunoglobulin A (IgA)

Immunoglobulin A (IgA)

Secreted by plasma cells

• Neutralizes viruses and harmful bacteria before they can breach the intestinal wall

What is the purpose of chemokines in peripheral lymphoid organs?

Chemokines are for the movement of B and T cells!

• B & T cells are drawn to different areas of the node by chemokines that are produced in these areas and bind selectively to their cell type

Chemokine and Receptor for B cells

Chemokine: CXCL13

Receptor: CXCR5

Chemokine and Receptor for T cells

Chemokines: CCL19 & CCL21

Receptor: CCR7

Migration of T lymphocytes

• Naive T cells migrate from the blood through the high endothelial venules (HEV)

• They go into the T cell zones of the lymph nodes, where they are activated by antigens

  • If they don’t find an antigen, the cells exit

• Activated T cells exit the nodes through the efferent lymphatic vessel, enter the bloodstream, and migrate preferentially to peripheral tissues and sites of infection & inflammation