6-1 Introduction to the Lymphatic and Immune Systems

Lymphatic System and Immunity

• Lymphatic system (lymphoid system)
• Organs, vessels, cells, and lymph
• Protects us against disease
• Lymphatic system cells respond to
• Environmental pathogens
• Toxins
• Abnormal body cells, such as cancers
• Lymphocytes
• Part of the immune response
• Identify, attack, and develop immunity to specific pathogens

​

Pathogens

• Microscopic organisms that cause disease:
• Viruses
• Bacteria
• Fungi
• Parasites
• Each can attack in a specific way

Functions of Lymphatic System

• Immunity
• Produce, maintain, and distribute lymphoid cells
• Includes antigen presenting and antibody producing
• Fluids from all capillary beds are filtered
• Immune cells stand ready to respond to foreign cells or chemicals encountered
• Lipid absorption
• Lacteals in small intestine absorb dietary lipids
• Fluid recovery
• Absorbs plasma proteins and fluid (2 to 4 L/day) from tissues and returns it to the bloodstream
• interference with lymphatic drainage leads to severe edema

Lymph and Lymphatic Capillaries

• Lymph
• clear, colorless fluid, similar to plasma but much less protein
• Lymphatic capillaries
• closed at one end
• tethered to surrounding tissue by protein filaments
• endothelial cells loosely overlapped
• allow bacteria and cells entrance to lymphatic capillary
• creates valve-like flaps that open when interstitial fluid pressure is high, and close when it is low
• Known as lacteals in GI system

​

COVERED IN LAB – HERE FOR YOUR REFERENCE

Lymphatic Vessels

• Larger ones composed of 3 layers
• tunica interna: endothelium and valves
• tunica media: elastic fibers, smooth muscle
• tunica externa: thin outer layer

COVERED IN LAB – HERE FOR YOUR REFERENCE

Route of Lymph Flow

• Lymphatic capillaries
• Collecting vessels: course through many lymph nodes
• Lymphatic trunks: drain major portions of body
• Collecting ducts :
• right lymphatic duct – receives lymph from R arm, R side of head and thorax; empties into R subclavian vein
• thoracic duct - larger and longer, begins as a prominent sac in abdomen called the cisterna chyli, receives lymph from below diaphragm, left arm, left side of head, neck and thorax; empties into L subclavian vein

COVERED IN LAB – HERE FOR YOUR REFERENCE

Lymph Flow Without a Pump?

• Lymph flows at low pressure and speed
• Moved along by rhythmic contractions of lymphatic vessels
• stretching of vessels stimulates contraction
• Flow aided by skeletal muscle pump
• Thoracic pump aids flow from abdominal to thoracic cavity
• Valves prevent backward flow
• Rapidly flowing bloodstream in subclavian veins, draws lymph into it
• Exercise significantly increases lymphatic return

COVERED IN LAB – HERE FOR YOUR REFERENCE

Lymphatic Cells

• Lymphocytes
• T lymphocytes
• Mature in thymus
• B lymphocytes
• Activation causes proliferation and differentiation into plasma cells that produce antibodies
• Phagocytic/Antigen Presenting Cells
• Macrophages (from monocytes)
• Microphages – Granulocytes
• Eosinophils & Neutrophils

COVERED IN LAB – HERE FOR YOUR REFERENCE

Lymphoid Organs/Tissues

• MALT – Mucosa Associated Lymphatic Tissue
• Found in mucosa lined passages
• GI system (GALT), Respiratory tract, Urinary, and Reproductive systems
• Tonsils
• Lymph Nodes
• Found along lymphatic vessels
• CT stroma
• Parenchyma contains dividing B cells and plasma cells
• Spleen
• Filters blood, platelet and RBC storage, erythropoesis in infants, RBC removal
• Thymus
• **These are covered in detail in lab**

​

​

COVERED IN LAB – HERE FOR YOUR REFERENCE

Metastasis Through Lymphatic System

• Characteristic of malignant tumors
• Spread of disease from one organ to another
• cancer cells travel via blood or lymphatic system
• cells establish new tumors where lodge
• Secondary tumor sites can be predicted by direction of lymphatic flow from primary site
• Cancerous lymph nodes are firm, enlarged and nontender -- infected lymph nodes are not firm and are very tender

​

​

COVERED IN LAB – HERE FOR YOUR REFERENCE

6-2 Innate Immunity

Immunity

• Immunity
• Ability to resist and defend against disease and infections
• Resistance is the ability to ward off disease
• Lack of resistance is termed susceptibility
• Sign
• Objective; detectable by outside observer
• Symptom
• Subjective; described by afflicted individual
• Relies on 3 lines of defense:
1. Physical and chemical barriers
• Skin/mucous membranes, acid mantle, stomach acid, cilia…
2. Nonspecific (Innate) resistance
• Macro/microphages, complement system, fever, inflammation…
3. Specific (Adaptive) resistance
• B and T cell mediated responses

​

Immunity

• Immunity
• Can also be split into innate and adaptive
• Innate (nonspecific) immunity
• Always works the same way
• Works (or attempts) against any invading agent
• Genetically determined
• Adaptive (specific) immunity
• Ability to fight a specific pathogen
• Depends on lymphocytes
• Cell-mediated immunity
• Antibody-mediated immunity
• Only develops after exposure

What is Immunity?

Innate Immunity

• Local
• Nonspecific
• Lack memory
• Relies on 3 approaches
• Protective proteins
• Protective cells
• Protective processes

Innate Immunity - Barriers

• Mechanical protection
• skin (epidermis) closely packed, keratinized cells
• shedding helps remove microbes
• mucous membrane secretes viscous mucous
• cilia & mucus trap & move microbes toward throat
• washing action of tears, urine and saliva
• Chemical protection
• sebum inhibits growth bacteria & fungus
• perspiration lysozymes breakdown bacterial cells
• acidic pH of gastric juice and vaginal secretions destroys bacteria

Innate Immunity - Phagocytes

• Phagocytes
• Attack and remove dangerous microorganisms
• Microphages
• Neutrophils and eosinophils
• Enter peripheral tissues to fight infections
• Macrophages
• Large phagocytic cells derived from monocytes
• Distributed throughout body
• Make up monocyte–macrophage system (reticuloendothelial system)

Innate Immunity - Complement and Interferons

• Antimicrobial proteins discourage microbial growth
• Complement proteins
• inactive proteins in blood plasma
• when activated enhance immune, allergic & inflammatory reactions
• Interferons
• produced by virally infected lymphocytes & macrophages
• diffuse to neighboring cells to induce synthesis of antiviral proteins
• Transferrins
• iron-binding proteins inhibit bacterial growth by reducing available iron

Innate Immunity – Immune Surveillance

• NK cells kill a variety of microbes & tumor cells
• Part of innate system, similar to cytotoxic T cells though will attack a variety of abnormal antigens (not just one)
• NK cells
• Identify and adhere to abnormal cells
• Golgi apparatus produces vesicles containing perforins and granzymes
• Vesicles release perforins by exocytosis
• Perforins form pores in abnormal cell’s plasma membrane, causing lysis
• Granzymes move through pores and destroy proteins/initiate apoptosis

Innate Immunity – Fever/Pyrexia

• Promotes interferon activity
• Accelerating metabolic rate and tissue repair
• Inhibits some pathogen reproduction
• Stages of fever
• onset, stadium, defervescence

​

• Stimulated by Interleukin 1, a pyrogen
• Secreted by macrophages
• Resets body thermostat higher
• > 40.5°C may cause delirium,
• 44-46°C (111°F- 115°F), coma-death

Innate Immunity - Inflammation

• Localized tissue response to injury
• Triggered by any stimulus that kills cells or injures tissue
• Cardinal signs and symptoms of inflammation
• Redness
• Swelling
• Heat
• Pain
• Goal is to (1) limit spread, (2) remove debris, and (3) repair tissue.

​

​

Innate Immunity - Inflammation

Mobilization of defenses

• Vasoactive chemicals promote hyperemia
• Histamine, leukotrienes, bradykinin
• Increased permeability
• Leukocyte deployment
• Margination
• Leukocytes adhere to endothelium
• Diapedesis
• Leukocytes squeeze between endothelial cells
• Chemotaxis
• Leukocytes follow chemical signals to damage/infection
• Promoted by ATP/ADP, bradykinin, leukotrienes

Innate Immunity - Inflammation

Containment

• Leaked fibrinogen clots
• Heparin at site of injury prevents clotting here but allows it in surrounding tissue
• Edema resulting from increased permeability isolates area and increases lymph flow
• Colony stimulating factors from T cells and macrophages promotes neutrophilia & eosinophilia

Innate Immunity - Inflammation

Repair

• Cellular debris removed
• Platelet/endothelial derived growth factors promote mitosis (esp. of fibroblasts)
• Hyperemia leads to increased temperature
• Pain reduces use

Adaptive (Specific) Immunity

• Immunity is body’s ability to defend itself against specific foreign material or organisms
• bacteria, toxins, viruses, cat dander, etc.
• Not present at birth
• Differs from nonspecific defense mechanisms
• Specificity 🡪 recognize self & non-self
• Memory 🡪 2nd encounter produces even more vigorous response
• 4 properties
1. Specificity
2. Versatility
3. Memory
4. Tolerance
• 2 kinds
• Cell mediated (T lymphocytes)
• Antibody mediated (B lymphocytes)

Cell vs Antibody Mediated Immunity

7-1 Adaptive Immunity

Adaptive (Specific) Immunity

• Immunity is body’s ability to defend itself against specific foreign material or organisms
• bacteria, toxins, viruses, cat dander, etc.
• Not present at birth
• Differs from nonspecific defense mechanisms
• Specificity 🡪 recognize self & non-self
• Memory 🡪 2nd encounter produces even more vigorous response
• 4 properties
1. Specificity
2. Versatility
3. Memory
4. Tolerance
• 2 kinds
• Cell mediated (T lymphocytes)
• Antibody mediated (B lymphocytes)

Cell vs Antibody Mediated Immunity

Lymphocytes

Maturation of T and B Cells

• T cell mature in thymus
• cell-mediated response
• killer cells attack antigens
• helper cells co-stimulate T and B cells
• effective against fungi, viruses, parasites, cancer, and tissue transplants
• B cells in bone marrow
• antibody-mediated response
• plasma cells form antibodies
• effective against bacteria

Antigens

• Molecules or bits of foreign material
• Entire microbes, parts of microbes, bacterial toxins, pollen, transplanted organs, incompatible blood cells
• Usually proteins
• Simple, repeating units usually not antigenic (i.e. Teflon in joint repair)
• Epitope: small part of antigen that triggers immune response
• Must have:
• immunogenicity = ability to provoke immune response
• reactivity = ability to react to cells or antibodies it caused to be formed
• A hapten is smaller substance that can’t trigger an immune response unless attached to body protein
• lipid of poison ivy

​

Major Histocompatibility Complex Antigens

• All our cells have unique surface markers (1000s molecules)
• integral membrane proteins called HLA antigens
• MHC-I molecules are built into cell membrane of all cells except red blood cells
• Pick up peptides and carry them to cell surface
• T cells ignore normal peptides but recognize abnormal (cancer) or viral peptides
• MHC-II markers seen only on membrane of antigen presenting cells (macrophages, B cells, thymus cells)
• If antigen presenting cells (macrophages or B cells) ingest foreign proteins, they will display as part of their MHC-II

​

MHC I �most cells����MHC II�APCs

Pathways of Antigen Processing

7-2 T Lymphocytes

T Lymphocytes

• 4-ish classes of T cells
1. Cytotoxic (killer) T cells (CD8)
• React with MHC I antigens
• Directly kill infected and cancerous cells
2. Helper T cells (CD4)
• Help promote T cell and B cell activation and nonspecific defense mechanisms
• Respond to MHC II (APC) antigens
3. Regulatory T cells
• Important for maintaining immunological tolerance
4. 4A Memory T_H cells
• help activate T and B cells (cytokines) if future exposure

4B Memory T_C cells

• ready to fight immediately if antigen ever presents itself again

​

Activation, Proliferation & Differentiation of Cytotoxic T Cells

• Receptor on T_C CD8 cell binds to foreign antigen fragment part of MHC-I
• Costimulation from stimulating cell or activated T_H CD4 cell (IL-2)
• prevents accidental immune response
• Proliferates & differentiates into population (clone) of Tc cells and memory Tc cells
• Occurs in secondary lymphatic organs such as lymph node

Elimination of Invaders

• Cytotoxic T cells migrate to site of infection or tumor formation
• Recognize, attach & attack
• secrete granules containing perforin that punch holes in target cell
• secrete lymphotoxin that activates enzymes in the target cell causing its DNA to fragment
• secrete gamma-interferon to activate phagocytic cells
• Tumor necrosis factor kills cancer cells in 2-3 days

Cytotoxic T Cell Function

• Cytotoxic T cell binding to cancer cell�

Destruction of Cancer Cell

Immunological Surveillance

• Cancerous cell displays weird surface antigens (tumor antigens)
• Surveillance = immune system finds, recognizes & destroys cells with tumor antigens
• done by cytotoxic T cells, macrophages & natural killer cells
• most effective in finding tumors caused by viruses

Activation, Proliferation & Differentiation of Helper T Cells

• Receptor on CD4 cell binds to foreign antigen fragment associated with MHC-II
• Costimulation with Interleukin-1
• Proliferates & differentiates into population (clone) of TH cells and long-lived memory TH cells

Helper T Cells

• Display CD4 on surface so also known as T₄ cells or TH cells
• Recognize antigen fragments associated with MHC-II molecules & activated by APCs
• Function is to costimulate all other lymphocytes by releaseing cytokines
• Autocrine function in that it costimulates itself to proliferate and secrete more interleukin (positive feedback effect causes formation of many more helper T cells)
• Other cytokines promote B cell activation, B and T mitosis, attract innate immune system cells, and suppressing adaptive immunity (but at a slower rate so it ’turns on’ later)

7-3 B Lymphocytes

Antibody-Mediated Immunity

• Millions of different B cells that can recognize different antigens and respond
• B cells sit still and let antigens be brought to them
• stay put in lymph nodes, spleen or peyer’s patches
• Once activated, differentiate into plasma cells that secrete antibodies
• Antibodies circulate in lymph and blood
• combines with epitope on antigen similarly to key fits a specific lock

​

Activation, Proliferation, & Differentiation of B Cells

• B cell receptors bind to antigen -- response more intense if on APC
• Helper T cell costimulates
• Rapid cell division & differentiation occurs
• long-lived memory cells
• clone of plasma cells
• produce antibody at 2000 molecules/sec for 4-5 days
• secrete only one kind antibody
• Antibody enters the circulation to attack antigen

​

​

Antibody Structure

• Glycoproteins called immunoglobulins
• 2 heavy & 2 light chains
• Hinged midregion lets assume T or Y shape
• Tips are variable regions -- rest is constant region
• 5 different classes based on constant region
• IgG, IgA, IgM, IgD and IgE
• tips form antigen binding sites

Antibody Classes - MADGE

• IgA: Mostly found in/on skin, mucus, saliva, tears, milk, intestinal secretions, prevents adherence to epithelia. Can be monomer (plasma) or dimer (excretions)
• IgD: B cell membrane antigen receptor

​

• IgE: Mast & Basophil cell membrane receptor; stimulates release of histamines, attracts eosinophils

​

• IgG: 80% of circulating, crosses placenta to fetus (anti-Rh), 2° immune response, binds complement
• IgM: Monomer on B cell membrane, antigen receptor; pentamer in plasma, 1° immune response, agglutination of RBCs

​

Antibody Actions

• Neutralization of antigen by blocking effects of toxins or preventing its attachment to body cells
• Immobilize bacteria by attacking cilia/flagella
• Agglutinate & precipitate antigens by cross-linking them causing clumping or making them insolbule
• Complement activation
• Attraction of phagocytes
• Opsonization: enhances phagocytosis
• Promotion of inflammation
• Prevent viral and bacterial adhesion

Immunological Memory

• Primary immune response
• first exposure to antigen�response is steady, slow
• memory cells may remain for�decades
• Takes 1-2 wks to peak
• Secondary immune response�with 2nd exposure
• 1000’s of memory cells proliferate & differentiate into plasma cells & cytotoxic T cells
• antibody titer is measure of memory (amount serum antibody)
• Recognition & removal occurs within days
• Symptoms may not even be felt

Typical Response to Bacterial Infection

7-4 Immunocompetence etc.

Immunocompetence

• B and T cells are not immediately able to be activated
• Cells gradually become immunocompetent (able to be activated)
• Following birth maternal IgG’s no longer available
• IgA’s available in breast milk
• 2-6 months post partum infant must make most of its antibodies
• Bewtwen 6 months and 12 years we are exposed to a new antigen every 6 weeks

T Cells: Development of Self-Recognition and Self-Tolerance

B Cells: Development of Self-Recognition and Self-Tolerance

Stress and the Immune System

• ACTH is released by cytokines
• Glucocorticoids suppress immune function
• May be important ‘check’ on immune system
• Chronically release:
• Depresses inflammation
• Reduced abundance and activity of phagocytes
• Inhibition of interleukins

​

Hypersensitivity (Allergy)

• Allergy: Excessive immune response against antigen
• 4 kinds (transfusion reaction is Type II)
• Type I (acute) hypersensitivity (most common)
• Occurs in sensitized people
• Allergen and IgE interact with mast cells and basophils
• Release inflammatory chemicals, cause local edema, mucus hypersecretion, congestion; hives, watery eyes, runny nose are typical
• Asthma (most common chronic illness in children)
• inhaled allergens, histamines, bronchiole constriction
• Can lead to anaphylactic shock: bronchiolar constriction, dyspnea, vasodilation, shock, death; treatment- epinephrine

Autoimmune Diseases

• Failure of self tolerance
• cross-reactivity
• abnormal exposure of self-antigens
• changes in structure of self-antigens
• Production of autoantibodies
• Antibodies that target own body’s cells/tissues
• Thyroiditis
• Rheumatoid arthritis

​

Immunodeficiency Diseases

• Severe Combined Immunodeficiency Disease
• hereditary lack of T and B cells
• vulnerability to opportunistic infection

Immunodeficiency Diseases

• Human Immunodeficiency Virus
• HIV structure (next slide)
• invades CD4 (helper) T cells, macrophages and dendritic cells by “tricking” them to internalize viruses by receptor mediated endocytosis
• reverse transcriptase (retrovirus), uses viral RNA as template to synthesize DNA, new DNA inserted into host cell DNA, may be dormant for months to years
• Can lead to Aquired Immunodeficiency Syndrome (AIDS) as CD4 population dwindles and hinders the immune response

HIV Structure

AIDS

• Signs and symptoms
• early symptoms: flulike chills and fever
• progresses to night sweats, fatigue, headache, extreme weight loss, lymphadenitis
• normal T_H count is 600 to 1,200 cells/μL of blood but in AIDS it is < 200 cells/μL
• person susceptible to opportunistic infections (Toxoplasma, Pneumocystitis, herpes simplex virus, CMV or TB
• thrush: white patches on mucous membranes may appear
• Kaposi sarcoma: cancer originates in endothelial cells of blood vessels causes purple lesions in skin
• Caused by opportunistic virus

Kaposi Sarcoma

HIV Transmission

• Through blood, semen, vaginal secretions, breast milk, or across the placenta
• Most common means of transmission
• sexual intercourse (vaginal, anal, oral)
• contaminated blood products
• contaminated needles
• Not transmitted by casual contact
• Undamaged latex condom is an effective barrier to HIV especially with the spermicide nonoxynol-9

Treatment Strategies

• Prevent binding to CD4 proteins of T_H cells, disruption of reverse transcriptase action or inhibiting assembly of new viruses or their release from host cells
• Pre-exposure prophylaxis aims to prevent transmission in at-risk individuals
• Infection can be prevented if PreP provided within 72 hours
• HIV is evolving resistance to the “triple cocktail”
• Vaccine is in development but no successes yet

Aging�

• More susceptible to all types of infections and malignancies
• Response to vaccines is decreased
• Produce more autoantibodies
• Reduced immune system function
• T cells less responsive to antigens
• age-related atrophy of thymus
• decreased production of thymic hormones
• B cells less responsive
• production of antibodies is slowed