Immunology Module 1: Immune System Organization

Immunology

The study of the physiological mechanisms used to defend against invasion by microorganisms

the Immune System

• All of the cells, organs, and proteins involved in defending and protecting the body are collectively referred to as….

• Consists of cells, proteins, and structures that defend against pathogens

Commensal Microorganisms

Microorganisms that are symbiotic with the human body (help us) and interdependent with the host, form the human microbiome/microbiota

• Ex. good gut bacteria

Humoral Immunity

An adaptive immune response mediated by antibody-producing B cells that target extracellular pathogens in body fluids

Microbiome (microbiota)

Entire microbial community of the human body

Two major groups of Microorganisms

• Commensal Microorganisms and Pathogens

• microorganisms and host are independent

Pathogens

Microorganisms that can cause disease

True Pathogens

Pathogens that can cause disease in any susceptible host which include:

1. Bacteria

2. Viruses

3. Fungi

4. Parasites

Opportunistic Pathogens

• When normal microbiota (commensal microbes) are disrupted and cause disease only under certain conditions, they are referred to as…

Two branches of Immune Defenses/Pathogen-recognition Mechanisms

• Innate immunity

• Adaptive immunity

Innate Immunity

• Nonspecific responses to pathogens

• Responds quickly exposure to harmful agents (hours)

• Fixed responses (ex. fever, inflammation)

• Includes physical/chemical barriers, various immune cells, immune proteins

• Limited number of specificities

• Constant during the course of response

• Controls pathogen SPREAD

Adaptive Immunity

• Responses against specific pathogens

• Responds more slowly after exposure to harmful agents (days to weeks)

• Recognize/target specific part of pathogen

• Variable

• Numerous highly selective specificities

• Improves during the course of response

• Clears pathogen and creates MEMORY

Three lines of defense provided by the Immune System

• Physical and chemical barriers

• Innate recognition and responses

• Adaptive recognition and responses

Physical and Chemical Barriers provided by the Immune System (line of defense)

• Epithelium (skin, respiratory, digestive)

• Endothelium of the respiratory, digestive, genitourinary systems

• Mucus

• Antimicrobial peptides

• Acidic environments

Epithelium

Layer of cells covering the body’s surface and lining it’s internal cavities and organs

Endothelium

Layer of cells that lines the inside of blood vessels, the heart, lymphatic vessels which can be found in the respiratory, digestive, and genitourinary systems

Innate Recognition and Responses (line of defense)

• Nonspecific immune cells called effectors identify pathogens

• Initiate fixed responses (phagocytosis, inflammation, fever, etc.)

• Involves several chemical mediators

Effectors

• Nonspecific immune cells that help identify pathogens for innate and adaptive recognition and responses

• Activated Lymphocytes

Phagocytosis

Cellular process where specialized immune cells engulf and destroy large particles, foreign bodies, and pathogens

Adaptive Recognition and Responses (line of defense)

• Immune cells called lymphocytes recognize particular parts of specific pathogens

• Initiate response that targets specific pathogen

• Produces immunological memory

Lymphocytes

• Immune cells that can recognize particular parts of specific pathogens

• Only cells found in lymph and pass between blood and the lymphatic system

• Reside in secondary lymphatic tissues

Immunological Memory

Protection against subsequent exposure to pathogen

Immune Cells

• Both innate and adaptive responses are mediated by white blood cells (wbc, leukocytes)

• Replenished using hematopoiesis in red bone marrow

Hematopoiesis

• Continuous process in red bone marrow where hematopoietic stem cells differentiate into specialized blood and immune cells

• 2 main lineages: Myeloid and Lymphoid

• The biological process by which the body creates new blood cells and platelets

Two Leukocyte Lineages (stemming from hematopoiesis)

Myeloid and Lymphoid

Myeloid Lineage

Leukocyte lineage that includes (from hematopoiesis):

• Erythrocytes

• Megakaryocytes/platelets

• Granulocytes (Neutrophils, Eosinophils, Basophils)

• Mast Cells

• Dendritic Cells

• Monocytes/macrophages (agranular)

Granulocytes

Leukocyte lineage including Neutrophils (40-75%), Eosinophils (1-6%), and Basophils (<1%)

Lymphoid Linage

Leukocyte lineage that includes (from hematopoiesis:

• NK cells

• Lymphocytes (T cells, B cells; agranular)

• Dendritic cells

Agranular Cells

• Cells with no noticible microscopic granules (tiny spots/sacs) in their cytoplasm

• Under a microscope, their fluid look smooth and clear, unlike "granular" cells which look spotted.

Innate Immune Cells (Leukocytes)

• Neutrophils (Granulocyte)

• Eosinophils (Granulocyte)

• Basophils (Granulocyte)

• Mast Cells

• Dendritic Cells

• Natural Killer Cells

• Monocytes (Precursor)

• Macrophages

Neutrophils

• Granular leukocyte

• Effective in killing and phagocytizing bacteria

• Most numerous leukocyte (40-75% total wbc)

• First responder to injury/inflammation

• Phagocyte that targets bacteria (granules filled with H₂O₂)

• Innate

Eosinophils

• Granular leukocyte

• Targets parasites

• Comprise 1-6% of total wbc

• Granules released to kill parasitic worms

• Also phagocytize allergens and antigen-antibody complexes

• Kills antibody-coated parasites through the release of toxic granule contents

• Innate

Basophils

• Granular leukocyte

• Mediate inflammation and is highly involved in allergies

• Comprise less than 1% of total wbc

• Granules contain histamine and heparin released during inflammation

• Controls immune responses to parasites

• Innate

Histamine

Vasodilator (involved in allergies); Stimulates smooth muscle contraction leading to pathogen clearance

Blood thinners; Prevents blood clots ex. Heparin

Anticoagulant

Mast Cells

• Antigen-presenting cell

• Granular leukocyte that resides in connective and mucosal tissues

• Contains granules of histamine and heparin

• Expulsion of parasites from the body by the release of granules containing histamine and other active agents

• Innate

Dendritic Cells

• Acts as MAIN/PRIMARY antigen-presenting cell (APC)

• Agranular leukocyte/phagocyte that reside in various tissues

• Gathers antigens and presents them to adaptive immune cells

• Activates T cells to initiate the adaptive immune response

• Innate

Natural Killer (NK) Cells

Granular lymphocytes that destroy abnormal self-cells, viral-infected cells, and cancer cells using perforins and granzymes that disrupt the abnormal cell’s plasma membrane (kiss of death); Innate

Monocytes

• Agranular leukocyte

• Surveys the body and can become a macrophage

• Comprises 2-10% of total wbc

• Become macrophages when they identify pathogens

• Circulating agranular PRECURSORS that differentiate into macrophages

• Innate

Macrophages

• Engulf/degrade pathogens and release inflammatory cytokines

• Large, primary tissue phagocytes within body (free or fixed)

• Can be Free or Fixed

• Phagocytosis and killing of microorganisms

• Innate

• Antigen-presenting cell (APC)

Free Macrophages

Activated monocytes

Fixed Macrophages

Permanent residents of nearly all tissues

Adaptive Immune Cells (leukocytes)

• Lymphocytes (B and T)

• Memory Cells

Lymphocytes

• Make up 20-50% of total wbc in the blood

• Mostly reside in lymphatic tissues

• Morphologically indistinguishable

• B cells make antibodies, T cells help B cells kill infected cells

• Agranular

Two main classes of Lymphocytes

• B Lymphocytes and T Lymphocytes

• Both B and T cells have about 100,000 receptors on their cell surface

B Lymphocytes (cells)

• Use Y-shaped B cell receptors (BCRs) in plasma membrane to detect pathogens in extracellular fluid; differentiates into plasma cells (effector B cells) that secrete antibodies and into memory B cells

• Mediate humoral immunity

B cell receptors

• Antigen-presenting cell bound to plasma membrane

• Detect extracellular pathogens, trigger release of soluble antibodies

• Y-shaped immunoglobulin (antibody)

• Recognize pathogens by their antigens

T Lymphocytes

Use T cell receptors (TCRs) in plasma membrane to detect intracellular pathogens;

Differentiate into several effector cells:

• helper T (T_H) cells

• cytotoxic T (T_c) cells

• regulatory T (T_reg) cells

T cell receptors

• Detect intracellular pathogens

• Recognize pathogens by their antigens

Antigens (def)

• Pathogenic or foreign molecules (ex. capsids, cell walls, toxins) recognized by lymphocytes leading to immune responses

• Often a protein or large polysaccharide

Examples of Antigens

• Protein capsid of viruses

• Cell wall of bacteria or fungi

• Bacterial toxins

• Abnormal proteins or tumor antigens

Memory Cells

• Produced by B cells and T cells as well as effector cells

• Immunological memory protects your from subsequent infection with the same pathogen

Antigen Receptor Diversity

Each B cell and T cell can only recognize one antigen which leads to…

Self-antigens

The antigens that our cells contain; the body's own molecules, proteins, and cellular structures that the immune system normally learns to tolerate without launching an attack

Major Histocompatibility Complexes (MHC)

• Glycoproteins where antigens are displayed

• MHC I and MHC II

MHC I

Glycoprotein found on all nucleated cells displaying self or intracellular antigens (ex. proteins) to Cytotoxic T (T_C) cells

MHC II

Glycoproteins found on antigen-presenting cells (APCs) (ex. macrophages, dendritic cells, B cells) displaying pathogenic antigens to Helper T (T_H) cells

Helper T cells (T_H)

• Activate cytotoxic T cells (T_C) or B cells when shown an antigen by an APC

• Recognize pathogenic antigen on MHC II of an APC

• Responds by dividing rapidly, the clones differentiate into effector T_H cells and memory T_H cells

Effector T_H Cells

Activate T_c cells or B cells to destroy the pathogen

Cytotoxic T cells (T_C)

• Recognize abnormal self-antigen on MHC I of an APC to destroy/target viral-infected/abnormal self-cells and cancer cells

• Requires coactivation by antigen and T_H cell

• Responds by dividing rapidly with the clones differentiating into effector T_C cells and memory T_C cells

Regulatory T Cells (T_reg)

Modulate/suppress immune responses

Effector T_C Cells

Target self-cells displaying the abnormal antigen

Self-cells

The body's own normal, healthy cells that express specific molecular markers indicating they belong to the host

Effector B Cells (plasma cells)

Produce and secrete antibodies against the antigen

Lymphocyte Locations

• Small fraction found in the blood despite being the second-most abundant wbc

• Most reside in lymphatic (lymphoid) tissues; primary and secondary

Primary Lymphoid Tissues

Sites where immune cells originate and mature

• Bone Marrow (hematopoiesis and B cell maturation)

• Thymus (T cell selection/maturation)

Secondary Lymphoid Tissues

Sites where mature lymphocytes encounter antigens and coordinate immune responses

• Tonsils, adenoids

• Lymph nodes

• Lymph vessels

• Spleen (tissues: Red and White Pulp)

• Appendix (A lot of Lymphoid tissue in this organ)

• Peyer’s patches in small intestine

• MALT

Lymphatic System Mechanism

Lymphatic Capillaries drain excess interstitial fluid from our tissues and return any leftover fluid from capillary exchange, returning it to venous circulation

• the fluid is now called lymph

Lymph is then carried through lymphatic vessels to lymph nodes where it is filtered/cleaned

Lymphocyte Recirculation

• Lymphocytes reside in secondary lymphatic tissues → Exit Lymphatic Tissues → Goes to capillaries → Goes to venous circulation → Reenters lymphatic tissues from blood capillaries and lymphatic vessels

• Spleen is the only exception to this pattern

• Allows traveling lymphocytes to monitor the secondary lymphoid tissues for any evidence of infection

What Happens When Tissues are Infected?

1. Pathogens from infected tissues travel through lymph to the nearest lymph node via afferent vessel ex. APC with pathogenic antigen travels via lymph

2. Encounter innate and adaptive cells in lymph node as lymph passes through and gets filtered to prevent pathogens from entering blood stream; antigen recognition leads to the activation of lymphocytes

3. Clean lymph, naive lymphocytes, activated lymphocytes leave lymph node via efferent vessel

Naive Lymphocytes

Mature white blood cells that have left primary lymphoid organs but have not yet encountered their specific matching antigen

Efferent Vessel

The outbound channel that transports filtered lymph fluid and recirculating lymphocytes out of a lymph node and back toward the bloodstream

APC

Antigen-presenting Cell

Afferent Vessel

Carry unfiltered interstitial fluid, antigens, and immune cells from peripheral tissues into draining lymph nodes

What Happens When Blood is Infected?

Pathogens in the blood enter the spleen via splenic artery

Spleen

• The largest secondary lymphoid organ in the body and acts as a specialized blood filter that launches immune responses against blood-borne pathogens

• Contains red pulp and white pulp

Red Pulp

Monitors Erythrocytes (rbcs), removes old/damaged rbc; In spleen

White Pulp

Secondary Lymphoid Tissue similar to lymph nodes that monitors blood for systemic pathogens; in Spleen

Mucosa-Associated Lymphoid Tissue (MALT)

• Secondary lymphatic tissue similar to lymph nodes

• Two types: Gut-associated lymphoid tissue (GALT) and Bronchial-associated lymphoid tissue (BALT) in respiratory and digestive tracts

• Located directly at mucoidal barriers; pathogens cross mucosal epithelia guided directly by microfold (M) cells to encounter immune cells inside GALT

• Have similar microanatomy to one another, although distinct from other lymphoid tissues

• Most are found within the gut (GALT)

Gut-Associated Lymphoid Tissue (GALT)

• Tonsils and adenoids

• Appendix

• Peyer’s patches in small intestine

• Most MALT

Bronchial-Associated Lymphoid Tissue

Less organized aggregates within the respiratory mucosa

Mucosa (Mucous Membrane)

The moist epithelial lining of the body's internal tracts that acts as the primary interface and defensive barrier against external pathogens

Clearing Intestinal Infections

1. Pathogens cross the mucosa and directly encounter GALT, guided by microfold (M) cells

2. Lymphocytes then enter GALT via tissue capillaries

3. Naive lymphocytes leave via efferent lymphatic vessels

4. Activated lymphocytes (effectors) can combat infections locally in surrounding tissue or recirculate into blood and return to GALT

Microfold (M) Cells

Specialized intestinal epithelial cells that sample gut antigens and transport them to underlying immune cells to trigger mucosal immunity

TCR on helper T cells recognize…

MHC II with the help of the CD4 co-receptor

TCR on cytotoxic T cells recognize…

MHC I with the help of the CD8 co-receptor

Pathogens from infected tissues and lymph are cleared by the…

Lymph Nodes

Pathogens within the blood are cleared by the…

Spleen

Three Lines of Immune Defense

1. Physical and Chemical Barriers

2. Innate Recognition and Responses

3. Adaptive Recognition and Responses

Phagocyte

an immune cell—such as a macrophage, monocyte, or neutrophil—that engulfs and digests microorganisms, foreign particles, and dead cells.

How Lymph Nodes Process Infections

Filter fluid (lymph) arriving via afferent lymphatic vessels; enable APCs to present antigens to recirculating lymphocytes

How the Spleen Processes Infections

Filters blood entering via the splenic artery

• Red Pulp: Monitors and removes old/damaged RBCs

• White Pulp: Secondary lymphoid tissue that monitors blood for systemic pathogens