Lymphatic and Immune System- A&P 2

Pathogens

Microscopic organisms that cause disease

• Viruses

• Bacteria

• Fungi

• Parasites

The lymphatic system includes…

…Cells, tissues, and organs responsible for defending the body against:

• Environmental pathogens

• Toxins

• Abnormal body cells, such as cancers

Immunity

Ability to resist a pathogen and mount a defense, infectious response, or counter a pathogen

Nonspecific defenses (Innate defenses)

1st line of defense: Phagocytes, granulocytes, lysozymes, opsins, etc

• Block or attack any potential infectious organism

• Does not distinguish one invader from another

Specific defenses (Adaptive defenses)

Lymphocytes, T-Cells and B-Cells

• Identify, attack, and develop immunity to a specific pathogen

• Extended or lifelong memory for specific pathogen

Lymph

A fluid similar to plasma but much fewer proteins, contains more lipid metabolites

• Originates as interstitial fluid from excess extracellular fluid

Lymphatic vessels (Lymphatics)

Carry lymph from peripheral tissues to the venous system (via the thoracic duct)

Lymphoid tissues

High concentration of lymphocytes, macrophages

Lymphoid organs

High concentration of lymphocytes, macrophages, and NK cells enclosed in fibrous capsule

Lymph Nodes

Are the body’s Police Checkpoints

• Quarantine off pathogens or cancer to a point

• Concentrated at points of vulnerability

• Lymph nodes survey lymph fluid and components in the lymph fluid

Lymphatic System function

To aid in production of lymphocytes

• T-Cells mature in lymphatic tissues and organs

Drain Excess Interstitial fluid and return to the blood

• Maintain blood volume

• Ensure similar composition of interstitial fluid throughout the body

Immunity

• Lymph passes through lymph nodes

• Immune cells activate immune response if needed

Fat Absorption

• Lacteals

• Chyle

Lacteals

In the small intestine absorb dietary fats and fat-soluble vitamins and transport them to the blood as chyle

Chyle

Is a collection of fat particles: Chlyomicrons, Trig, Vit ADEK

Lymphatic capillaries

Differ from blood capillaries in 4 ways:

• Start as pockets rather than tubes

• Have larger diameters

• Have thinner walls

• Irregular outline in sectional view

Overlap

Loosely binds together endothelial cells

• Overlap acts as a one-way valve

• Allows fluids, solutes, lipids, viruses, parasites, and bacteria to enter

• Prevents return into interstitial fluid/intercellular space

• Lymphangiogenesis

Lymphatic vessels

• Lymphatic capillaries flow to lymphatic vessels

• Contain one-way valves

• Travel through body with veins as they head towards trunk by LMCs

Superficial lymphatics

Located in skin, mucous membranes, serous membranes lining body cavities

Deep lymphatics

Larger vessels that accompany deep arteries and veins in the:

• Neck

• Limbs

• Trunk

Lymphatic trunks

The joining of superficial and deep lymphatics together

• Empty into two major collecting vessels: Thoracic duct and right lymphatic duct

Right lymphatic duct

• Collects lymph from the right side of the body, superior to the diaphragm

• Empties into right subclavial vein

Thoracic duct

• The base expands into cisterna chyli which receives lymph from the abdomen, pelvis, and lower limbs.

• Collects lymph from the left arm, left side of head, neck, and chest

• Empties into left subclavial vein

Lymphedema

• Blockage of lymphatic drainage from a limb

• Causes buildup of interstitial fluid, swelling

• Risk of severe infection in the area because it is essentially cut off from the rest of the lymphatic system

• Most commonly a result of removal of damage to lymph nodes during cancer treatment

Elephantiasis

• Lymphatic filariasis (worms)

• Mosquito-borne parasitic disease

• Blocked lymph vessels

• Swelling, skin-thickening, stiffening of limbs

• Tx: Ivermectin + Albendazole + Diethylcarbamazine

Lymphocytes

• Make up 20-30% of circulating leukocytes

• Most lymphocytes are not circulating

• Types: T Cells, B cells, NK cells

T Cells

• Thymus-dependent

• Make up 80% of circulating lymphocytes (Defectives)

Cytotoxic T Cells (Specific Killers)

• CD8 Cells

• Attack foreign cells or cells infected by viruses

Helper T Cells (Generals)

• CD4 Cells

• Stimulate function of T cells and B cells

Antigen presentation by Macrophages and Dendritic cells

Pathogens must be processed before cytotoxic and helper T-Cells can recognize an invader

Antigen Presentation; APCs: Dendritic cells, langerhans cells, macrophages, B-Cells

• Engulf pathogen (exogenous)

• Extract antigens and package different pieces (epitopes) for presentation

• Display on cell surface on MHC I and MHC II

• APC “presents” the antigen to Helper T-Cell

• Activated Helper T-Cell to authorize APC to engage CD8 (NO auth, no go)

• Stimulates B-Cells to make antibodies

• Help activate cytotoxic T-Cells by releasing cytokines

• Trigger destruction of pathogens engulfed by Macrophages

Antigen Presentation; Co-stimulation of Cells

Cells display MHC I proteins on cell surface of all nucleated cells

• When antigen on MHC is normal, no response stimulated

• When antigen on MHC is abnormal (virus infected/cancer cells):

• Cytotoxic T-Cells specific for that antigen are activated

• Apoptosis of target cell (and damage to viral DNA)

• Induce Caspase enzymes path

• Proliferation of T-Cells specific for that antigen

Memory T Cells

• Formed in response to foreign substance when T-cells are activated

• Remain in body to give “immunity” to that substance

Suppressor T Cells (Regulatory T Cells / Tregs)

• Limit the immune response - dose dependent expression

• Important in preventing autoimmune diseases

• Express inhibitory cytokines

B Cells

• Make up 10-15% of circulating lymphocytes

• Do not directly attack invaders, but responsible for antibody mediated immunity called humoral immunity

• T-Cell-Dependent Activated B-Cells differentiate into:

Plasma cells: Produce and secrete antibodies (immunoglobulin proteins) – IgG, IgE, IgA, IgM, IgD (require 14-21 days)

Memory B Cells: Remain in lymph nodes after primary infection. Lead to production of antibodies quickly if secondary infection occurs (within 2-3 days)

T Cell- Independent B-Cell Activation

• These B-Cell reside in the Marginal Zone of the Lymph Nodes

• Rapid Response to Non- Protein Antigens

• Bacterial Polysaccharides & Lipopolysaccharides (LPS)

• E-Coli, Salmonella, Staph, Strep, Hib, N. Menin

• Gram- LPS endotoxins & Gram + polysaccharides are Highly repetitive on bacterial membrane

• Cross-link Multiple TLRs

• Antigens bind to several surface IgD’s on B-Cell

• High-intensity surface signaling to trigger low affinity IgM & some Memory B cells

Antigens

• Molecule that triggers an immune response

• Epitope binds to antibodies and CD8 cells

• VERY specific recognition-dependent binding

• Strong affinity at the Antigen Binding Site variable region to the pathogen

• Fc Region recognized by immune cells

• Ex: COVID Spike Proteins

Immunoglobulins (Antibodies)

• Soluble proteins that bind to antigens

• Pathogen is tagged for destruction

• IgG most abundant, affinity, pass placenta

• IgA (mucosal), IgE (allergies), IgM (1st)

Antibody function

Neutralize: Blocking immunogenic regions of antigen

• IgGs bind to Viral capsule proteins

• Tagged for destruction by the other B-cells

Complement fixation

• Antibody binds to antigen

• Complement proteins bind to antibody

• Inflammation, improved phagocytosis, cytolysis

Agglutination (IgG, IgM)

• Antibody binds to multiple antigen molecules

• Clumping prevents spread

• Immobilized Pathogens

Natural Killer (NK) Cells

• Make up 5–10% of circulating lymphocytes

• Apart of the Innate Immune System

• Normal cell express MHC class I

• NK Tolerance with normally expressed receptors

• 1st line defense for virus-infected cells and cancerous cells

• Bind to target cell expressing Stress Signals or No MHC class I receptor

• Cancer cells mutate & STOP expressing MHC class I receptors to evade CD4 surveillance

• NK cells Release perforins and cytokines to perforate plasma membrane on target

• Cytolysis – granzymes B

Lymphopoiesis

Process of producing T cell, B cell, and NK cells

• Stem cell differentiation in progenitor cells then differentiate into effector cells

Lymphopoiesis maturation and activation sites

• Bone marrow – B cells maturation

• Thymus – T cells mature in the Thymus after leaving the bone marrow

• Peripheral lymphoid tissues

• Lymphoid follicles have B cells that rapidly proliferate in Germinal Centers when activated

• T-cell Zones (paracortex) of the lymph nodes

Hemocytoblasts

In bone marrow, divide into two types of lymphoid system cells

• Group 1: Remains in bone marrow, produces B cells and NK cells

• Group 2: Migrates to thymus, produces T cells into environment isolated by blood-thymus barrier

T Cells and B Cells location

• Are located throughout the periphery, especially in lymphoid tissue

• Retaining their ability to divide is essential to immune system function

• B cells differentiate with exposure to a type of hormone called a cytokine (interleukin: IL-4, IL-6, IL-21, BAFF)

• T cells differentiate with exposure to several thymic hormones (thymosin) as well as interleukin (IL-2, IL-7, IL-12, IL-15, IL-18)

Lymphoid tissues

• Connective tissues dominated by lymphocytes

• Do not have a fibrous capsule surrounding them

Lymphoid Nodules

• Areolar tissue with densely packed lymphocytes

• MALT, tonsils, Peyer’s Patch

• Germinal center contains dividing lymphocytes

• Transient in most tissues

Diffuse Lymphoid Tissue

Constant in lymph nodes, tonsils, appendix, along GI, urinary, and reproductive tracts

Mucosa-Associated Lymphoid Tissue (MALT)

Collection of lymphoid tissues that protect the epithelia of the Mucus Membranes of the respiratory (BALT), digestive (GALT), urinary, and reproductive tracts for 1st line of defense protection.

• Aggregated Lymphoid Nodules “Peyer’s patches”

• Organized GALT clusters of nodules deep to Small Intestines epithelial lining

• Appendix (Vermiform Appendix)

• A mass of fused lymphoid nodules where the small and large intestines meet

• Tonsils

• Large nodules in the walls of the pharynx

Tonsilitis

• Most common reasons for pediatric medical visit

• Inflammation of the tonsils

• Usually caused by Viruses (flu, EBV mono) or Group A Strep infection

• Treatment: Fluids, ibuprofen, acetaminophen, Amoxicillin, tonsillectomy

Lymphoid Organs

• Are separated from surrounding tissues by a fibrous connective tissue capsule

Lymph fluid pass through

• Lymph nodes

• Thymus

• Spleen

Lymph Nodes

Small lymphoid organs concentrated in the neck, armpit, and groin for 1st line of defense

Trabeculae

• Bundles of collagen fibers

• Extend from capsule into interior of lymph node

Hilum

A shallow indentation where vessels and nerves reach the lymph node

Afferent lymphatics

• Carry lymph from peripheral tissues to lymph node

• Vessels on opposite side from the hilum

Efferent lymphatics

• Carry lymph from the node to venous circulation

• Leave lymph node at hilum

Lymph Flow

Flows through lymph node in a network of sinuses

Subscapular space (contains macrophages and dendritic cells cDC & FDC) → Outer cortex (contains B Cells within germinal centers) → Deep cortex (dominated by T Cells) → Through the core (medulla)(contains B Cells and plasma cells) → Hilum and efferent lymphatics

Lymph Node Function

• A filter that purifies lymph before returning it to venous circulation

• Removes: Debris, pathogens, 99% of antigens

• Site of B-Cell and T-Cell activation

• Stop pathogens before they reach vital organs of trunk

• Carries dietary fats and utilizes these lipids for energy, structural integrity, and signaling.

• LEC use fatty acid beta-oxidation (FAO) as a primary energy source for growth

• Proliferating T and B cells within lymph nodes utilized significant FAO

• LMC utilize FAO as a critical component of their mitochondrial bioenergetics

Lymphadentitis

Inflammation of a lymph node

• When a node is fighting an antigen, pathogen, or cancer it may swell

• Increase in the number and size of germinal centers within cortex

• PMN infiltration can lead to abscess formation and swollen node that are often painful

• Can be palpated on PE

Lymphoma

Cancer of a lymph node

• • Cancerous cells destroy the normal structure and

  breach the capsule

  • Lymphatic capillaries are highly permeable

  • Lymph nodes are common sites of metastasis

  • Lymph Node are critical in determining Dx and Tx

Thymus

• Located in mediastinum

• Academy of the Immune System – central tolerance

• Thymus is divided into 2 lobes (Bilobed)

• Each lobe is divided into many lobes by trabeculae

• Large in infants/children, atrophies after puberty

• Diminishing effectiveness of immune system making elderly more susceptible to disease

• Pivotal in immune cell education of self

• Heavily implicated in the development of various autoimmune disease

• T1 DM, SLE, MG

Thymic Lobule

Contains a dense outer cortex and a pale central medulla

T-Cells in Thymus

• Divide, differentiate in the cortex

• Migrate into medulla where they are tested

• Mature T cells leave thymus by medullary blood vessels

Thymus: Secrete thymic hormones (thymosin)

• WBC recruitment (chemotaxis), directs movement, and proliferation

• T Cell differentiation

• Enhances NK and DC activity

Thymus: Reticular Epithelial Cells

Framework for lymphocytes in thymus

• Cortex

• Surrounded T-Cells and vessels to create blood-thymus barrier

• Promiscuous gene expression — Molecular mirror of 20,000+ proteins

Thymus: Medulla

• No blood–thymus barrier

• T cells can enter or leave bloodstream

Spleen

Spleen is the largest lymphatic organ, blood rich, lies between lateral border of stomach and diaphragm

Functions of Spleen

• Removal of aged and abnormal blood cells, platelets, and other blood components by phagocytosis (macrophages)

• Initiation of immune responses by B cells and T cells

• Macrophages and Lymphocytes monitor the blood for antigens

• Activate T-Cells and B-Cells when antigen present, esp. IgM

• Pathogen Clearance esp. encapsulated bac.

• Maintain blood volume

• Stores red blood cells and platelets

• Mobilizes in case of hemorrhage & hypoxia

• Iron recycling to bone via transferrin

Histology of the Spleen: Red Pulp

Contains many red blood cells

• Removal of old blood cells by macrophages

• Destroy antibody coated cells and virus or bacterial infected cells

Histology of Spleen: White pulp

Resembles lymphoid nodules

• T-Cell activation

• Immune surveillance

• Initiation of immune responses

Splenectomy

• Spleen is very fragile and capsule ruptures easily

• If capsule ruptures, massive internal bleeding is possible, leading to circulatory shock

• Spleen cannot usually be repaired because structure is so delicate

• Treatment is to remove the spleen (splenectomy)

• Increased risk of infection post splenectomy

• Risk of Overwhelming Post-Splenectomy Infection (OPSI)

• Decreased immunity against encapsulated pathogens; Strep Pneumonia, HiB, N. Meningitis

• Prophylactic and acute antibiotic treatment: Pen V, Vanc, Ceftriaxone, or Levofloxacin

Innate (Nonspecific) defenses

• Present at birth

• Always work the same way against any type of invading agent

• Nonspecific resistance

Adaptive (Specific) defenses

• Protect against specific pathogens

• Depend on activities of lymphocytes

• Specific resistance (immunity) develops after exposure to pathogen/antigen (accidental or intentional)

• APC-mediated and antigen-receptor binding responses

Physical Barriers

Keep pathogens outside of the body

• Epidermis (Vit C aka Ascorbic Acid) is needed for skin and gums

• Scurvy- Severe Vit C deficiency

• Mucous membranes

• Hair/cilia

• Secretions that flush away materials (Perspiration, lacrimal apparatus, mucus, urine, vaginal secretions, defecation/vomiting)

• Secretions that kill or inhibit microorganisms (saliva, sweat, sebum, and stomach acid)

Phagocytes (Leukocytes)

Engulf and degrade cellular debris, foreign compounds, pathogens

Basophil (Non phagocytic leukocyte)

• Aid in mobility and action of other WBC

• Leukotrienes: attract WBC to the area

• Histamine: Dilates blood vessels bring WBC into tissue quickly

• Heparin: Prevents blood clots that may impede entry of WBC

• Allergic Responses, parasitic defenses

• Immune Regulation

Microphages

• Neutrophils and eosinophils

• Circulate in the blood

• Enter peripheral tissues that are injured or infected

• Once activated and phagocytize pathogens they usually die within hours to days.

• Leave behind Pus that is composed of active and dead leukocytes, mainly leukocytes

Macrophages

Large phagocytic cells derived from monocytes

Phagocyte Functional Characteristics

• Move through capillary walls (emigration)

• Are attracted or repelled by chemicals in surrounding fluids (chemotaxis)

• Phagocytosis:

• Begins when phagocyte attaches to target (adhesion)

• Then surrounds it with a vesicle (Endocytosis)

• Finally digests target

Immunological Surveillance

Constant monitoring of normal tissues searching for abnormal cells

• Is carried out by natural killer (NK) cells & CD8 T-cells, esp. seeking out tumors

• But NK cells respond more quickly than T-cells or B-cells

• Can attack bacteria, cancer cells, and cells infected with viruses

• NK Cells kill abnormal cells by releasing vesicles containing perforins and granzymes.

• Perforins are proteins that create pores in the abnormal cell’s plasma membrane

• Granzymes enter cell and induce apoptosis

Interferons (IFNs)

Proteins released by activated lymphocytes and form virus infected cells

• Chemical messengers that trigger production of antiviral proteins in healthy cells

• Antiviral protiens: Do NOT kill viruses or block entry, they DO block viral replication in cell

• Slow the spread of viral infections and stimulate activity of macrophages and NK cells

Nonspecific Defenses: Complement

• Plasma contains 11 complement (C) proteins that form the complement system

• Made in Liver

• Assists antibodies in destruction of pathogens (“complement” antibody action)

• Complement activation

• Complement proteins work together in cascades

Three pathways activate the complement system

• Classical pathway →

• Alternative pathway → Membrane Attack Complex

• Lectin pathway →

All pathways end with the splitting of C3 to the active C3a and C3b

Effects of Complement Activation

• Pore formation to destroy target’s plasma membrane

• Complement proteins form membrane attack complex, MAC

• Enhancement of phagocytosis by opsonization

• Histamine release

• Increases the degree of local inflammation and blood flow

• Increased Vascular Permeability

Inflammation “inflammatory response”

• A local tissue response to injury

• Triggered by any stimulus that kills cells or injures tissue

• Tends to limit the spread of injury or infection

• Cardinal Signs and Symptoms of Infection

• Swelling

• Redness

• Heat

• Pain

Fever

An abnormal elevation of body temp (>100.4 degrees F)

• Increases body metabolism

• Intensifies effects of interferons

• Inhibits some viruses and bacteria

• Pyrogen raises the hypothalamic set point

• Hypothalamus releases prostaglandin

• Body thinks it is too cold and initiates mechanisms to raise body temperature

• Shivering

• Constriction of cutaneous vessels

• Body temp rises, fever is now present

• Aspirin, ibuprofen, and naproxen inhibit the COX-2 enzyme to prevent prostaglandin synthesis

Pyrogens

• Any material that causes the hypothalamus to raise body temperature

• Exogenous pyrogens: From foreign pathogens (glycolipids from bacteria, viruses)

• Endogenous pyrogens: Released by active macrophages and neutrophils

• Interleukin Initiated by IL-1氰 & IL-1氠 (most potent), IL-6 (maintain fever), TNF氠 (stimulate release of IL-1s)

• Induce the COX-2 and microsomal Prostaglandin E Synthase 1 (mPGES-1)

HIV: Human Immunodeficiency Virus

• Spread through infected bodily fluids (blood, semen, vaginal secretions, breast milk, exposed cuts, direct contact with immune cells)

• Binds to, Invades, and Replicates in Helper T-Cells (CD4), Dendritic Cells, Macrophages

• Destroys CD4 T-Helper Cells, inhibits immune system function

• Initial symptoms are flu-like but worsen as CD4 count drops

AIDS: Acquired Immunodeficiency Syndrome

• CD4 count < 200 cells/microliter

• Patient succumbs to opportunistic infections and cancer (Kaposi Sarcoma)

• Experience Oral Thrust (Candidiasis), PCP Pneumonia, TB, CMV, HSV, HPV, PML

Lupus

• Chronic, widespread, autoimmune disease

• Immune system forms Autoantibodies against healthy, self, cells

• Antibody-antigen complexes accumulate and lead to widespread inflammation

• Symptoms can be present in skin, joints, kidneys (lupus nephritis), hair loss, deep breathing chest pain (pleurisy), and other organs

• Malar “Butterfly” rash

• Photosensitivity & Joint Pain

• Organ failure

• Not contagious (Genetic, 90% Women, Epstein Barr Virus)

• Positive Antinuclear Antibody test

• No cure