Topic 3, L4 - The Immune System

Question 1

• blood components diagram -

Question 2

What is the general structure & functional characteristics of leukocytes ?

Answer 2

ONLY formed elements that are complete cells ( have nucleus + organelles )

Comprise <1% total blood volume [ usu 4800 -10,800 WBCs/μl blood ]

• Function in defense against disease*
• Can leave capillaries via diapedesis (move from within blood capillaries thru spaces to migrate to site of infection / inflammation) → Immune and/or inflammatory response
• Move through tissue spaces by amoeboid motion and positive chemotaxis (attracts WBCs to area)

Question 3

What is leukocytosis ?

Answer 3

Increased WBC count in response to infection / injury, > 11,000 per μl blood

Question 4

2 categories of Leukocytes

Answer 4

Granulocytes : Contain visible cytoplasmic granules (little sacs within cells)
- Neutrophils, eosinophils, basophils)
- spherical, larger than RBCs, lobed nuclei, cytoplasmic granules, Wright’s stain
- all are phagocytic to some degree

Agranulocytes : Do not contain visible cytoplasmic granules
- Lymphocytes, monocytes)
-No visible granules; nuclei spherical or kidney-shaped

Never Let Monkeys Eat Bananas
(n - neutrophils, l - lymphocytes, m - monocytes, e - eosinophils, b - basophils)

Question 5

Neutrophils

Answer 5

Most numerous WBCs (50–70% of WBCs)
GRAN

• Granules stain with both acid and basic dyes
• Granules contain either hydrolytic enzymes OR antimicrobial proteins (defensins)

Called polymorphonuclear leukocytes [ PMNs or polys ]: they contain many differently shaped nuclear lobes ( cell has anywhere from 3 - 6 lobes )

• Most phagocytic –> Arrive first at site of injury / infection
• Referred to as “bacteria slayers” (ingest + destroy)
• Kill microbes by process called respiratory burst –> cell synthesizes potent oxidizing substances (bleach or hydrogen peroxide)
• Defensin granules merge with phagosome to form “spears” that pierce holes in membrane of ingested microbe

Question 6

Eosinophils

Answer 6

Account for 2–4% of all leukocytes
GRAN

• Nucleus has 2 lobes connected by a broad band; resembles ear muffs
• Red-staining granules (acidic) contain digestive enzymes that get released to target large parasitic worms, digesting their surface
• Plays role in allergies and asthma, as well as immune response modulators

Question 7

Basophils

Answer 7

Rarest WBCs, accounting for only 0.5–1% of leukocytes
GRAN

• Nucleus deep purple with 1-2 constrictions
• Large, purplish black (basophilic) granules contain histamine
• Histamine : Inflammatory chemical that acts as vasodilator and attracts WBCs to inflamed sites
• Are functionally similar to mast cells

Question 8

Lymphocytes

Answer 8

Second most numerous WBC, accounts for 25%
AGRAN

• Large, dark purple, circular nuclei with thin rim of blue cytoplasm
• Mostly found in lymphoid tissue (eg. lymph nodes, spleen), but a few circulate in blood / Crucial to immunity

2 types of lymphocytes
- T lymphocytes (T cells) act against virus-infected cells & tumor cells
- B lymphocytes (B cells) give rise to plasma cells, which produce antibodies

Question 9

Monocytes

Answer 9

Largest of all leukocytes; 3–8% of all WBCs
AGRAN

• Abundant pale blue cytoplasm
• Dark purple-staining, U- or kidney-shaped nuclei
• Leave circulation, enter tissues, and differentiate into macrophages
• Actively phagocytic cells; crucial against viruses, intracellular bacterial parasites, and chronic infections
• Activate lymphocytes to mount an immune response

Question 10

What is leukopoiesis ?

Answer 10

All leukocytes originate from hemocytoblast pluripotent stem cell, gives rise to all cells part of hematopoietic systemstem cell that branches into 2 pathways :
- Lymphoid stem cells produces lymphocytes (B & T cells)
- Myeloid stem cells produce all other elements (basophils, neutrophils, monocytes)

Process is hormonally regulated according to body’s need by interleukins (ILs) & colony-stimulating factors (CSFs)

• Bone marrow stores mature granulocytes (not erythrocytes); usu contains 10-20X more granulocytes than in blood
• Reticulocytes released in bloodstream → mature there
• Lifespan of granulocytes = 0.5-9.0 days (most die in line of duty)

Question 11

Leukemias

Answer 11

Cancerous condition involving overproduction of abnormal WBCs /usually involve clones of single abnormal cell

Named according to abnormal WBC clone involved :
- Myeloid leukemia – Myeloblast descendants
- Lymphocytic leukemia – Involves lymphocytes

• Acute leukemia (quickly advancing – fast developing) derives from stem cells - primarily affects children
• Chronic leukemia (slowly advancing) involves proliferation of later cell stages -more prevalent in older people (cell metastasized further down differentiation pathway, closer to pluripotent stem cell becomes cancerous → more acute disease)

Bone marrow taken over by cancerous cells →
Severe anemia (produce less RBCs), clotting problems (produce less) (also fever, weight loss, bone pain)

WBCs numerous but non-functional - death usu from internal bleeding & overwhelming infections

Question 12

Infectious Mononucleosis

Answer 12

Highly contagious viral disease (“kissing disease”)
Usually seen in young adults

• Caused by Epstein-Barr virus
• Results in high numbers of typical agranulocytes
• Involve lymphocytes that become enlarged
• Originally thought cells were monocytes, so disease named mononucleosis

Symptoms : Tired, achy, chronic sore throat, low fever

Runs course with rest in 4–6 weeks (trickier for immunocompromised)

Question 13

Leukopenia

Answer 13

Abnormally low WBC count - usu due to drugs, esp. glucocorticoids & anticancer agents

Question 14

The Immune System

Answer 14

Provides resistance to disease, 2 intrinsic systems :

Innate (nonspecific) defense system → BORN WITH IT
- Constitutes first & second lines of defense
- First line of defense : External body membranes (skin and mucosae)
- Second line of defense : Antimicrobial proteins, phagocytes, and other cells (inhibit spread of invaders; inflammation most important mechanism)
- Protects against foreign substances/abnormal cells without having to specifically identify them

Adaptive (specific) defense system → ACQUIRED
- Third line of defense attacks particular foreign substances (takes longer to react than innate)
subpopulations of lymphocytes recognize the specific target (usually specific cell surface proteins) and attack the target
- **Does NOT develop until we are exposed to pathogen

Question 15

Innate Defense - Surface Barriers

Answer 15

Surface barriers are skin & mucous membranes, along with their secretions
- Physical barrier to most microorganisms
- Keratin is resistant to weak acids and bases, bacterial enzymes, and toxins
- Mucosae provide similar mechanical barriers

Skin and mucous membranes produce protective chemicals that inhibit or destroy microorganisms :
- Acid: Acidity of skin and some mucous secretions inhibits growth; called acid mantle
- Enzymes: Lysozyme of saliva, respiratory mucus, and lacrimal fluid kills many microorganisms; enzymes in stomach kill many microorganisms
- Mucin: Sticky mucus that lines digestive and respiratory tract traps microorganisms
- Defensins: Antimicrobial peptides that inhibit microbial growth
- Other chemicals: Lipids in sebum and dermicidin in sweat are toxic to some bacteria

Respiratory system also has modifications to stop pathogens
- Mucus-coated hairs in nose trap inhaled particles
- Cilia of upper respiratory tract sweep dust- and bacteria-laden mucus toward mouth

Surface barriers breached by nicks or cuts trigger the internal second line of defense that protects deeper tissues

Question 16

Innate Internal Defense - Cells & chemicals

Answer 16

Innate internal system necessary if microorganisms invade deeper tissues; includes:
- Phagocytes
- Natural killer (NK) cells
- Inflammatory response
- Antimicrobial proteins
- Fever

Question 17

Phagocytes

Answer 17

• WBCs that recognize, ingest and digest (eat) foreign invaders
• Neutrophils: Most abundant phagocytes, but die fighting; become phagocytic on exposure to infectious material
• Macrophages: Develop from monocytes (which leave the blood stream) are chief and most robust phagocytic cells
• Free macrophages
• Fixed macrophages

Question 18

Phagocytosis

Answer 18

Phagocytes recognizes & binds to pathogen’s carbohydrate “signature”

[ Some pathogens hide their surface carbohydrates, helping them evade phagocytosis ]

Opsonization : Immune sys. uses antibodies or complement proteins as opsonins that coat pathogens

Some pathogens are not killed with acidified lysosomal enzymes (eg. TB bacteria) :

Helper T cells trigger macrophage to produce respiratory burst, which kills pathogens resistant to lysosomal enzymes by:
- Releasing cell-killing free radicals /producing oxidizing chemicals (e.g., H2O2) / increasing pH & osmolarity of phagolysosome
- Defensins (in neutrophils) also help by piercing membrane of pathogen

Question 19

Natural Killer (NK) Cells

Answer 19

Nonphagocytic, large granular lymphocytes that police blood & lymph

• DONT identify invaders; just recognize abnormalities on surface of body cells such as loss of self-antigens – recognize cells that are “stressed”
• Contact target + inject toxins inducing it to undergo apoptosis
• Secrete potent chemicals that enhance inflammatory response

NK population greatly reduced in people with AIDS

Question 20

Inflammation

Answer 20

Tissue response triggered by injury

Question 21

What are the benefits of inflammation ?

Answer 21

• Prevents spread of damaging agents to nearby tissues
• Disposes of cell debris & pathogens
• Sets the stage for repair processes
• Alerts the adaptive immune system

Sometimes a 5th sign, impairment of function, is seen if movement or use of area is hampered

Question 22

What are the stages of inflammation ?

Answer 22

• see table -

1. Inflammatory chemical release
- Chemicals (eg. histamine released by mast cells) are released into ECF by injured tissues or immune cells
- Involves kinins, prostaglandins (PGs), cytokines ( & complement if pathogens involved )
- All make capillaries leaky / many attract phagocytes to area

2. Vasodilation & increased vascular permeability
- Vasodilation causes hyperemia — Which leads to redness & heat
- Increased capillary permeability causes exudate(fluid containing clotting factors + antibodies) to leak into tissue
- Results in local swelling (edema)
- Swelling also pushes on nerve endings, resulting in pain

3. Phagocyte mobilization
- Neutrophils flood area first; macrophages follow
- If inflammation is due to pathogens, complement is activated; adaptive immunity elements arrive

Question 23

Steps for 3. Phagocyte mobilization

Answer 23

1. Leukocytosis : Release of neutrophils from bone marrow in response to leukocytosis-inducing factors from injured cells
2. Margination: Endothelial cells of capillaries in inflamed area project cell adhesion molecules (CAMs) into vessel lumen that grab onto passing neutrophils, causing them to slow and roll along, clinging to vessel wall
3. Diapedesis: Neutrophils flatten and squeeze between endothelial cells, moving into interstitial spaces
4. Chemotaxis: Inflammatory chemicals act as chemotactic agents that promote positive chemotaxis of neutrophils toward injured area

Question 24

Antimicrobial Proteins

Answer 24

Enhance innate defense by :
- Attacking microorganisms directly, or
- Hindering microorganisms’ ability to reproduce

Most important antimicrobial proteins :
- Interferons
- Complement proteins

Question 25

Interferon (IFN)

Answer 25

Family (α, β, γ) of immune modulating proteins
secreted by virus-infected cells to warn healthy neighboring cells (only produced after infection)

• Enter nearby non-infected cells stimulating production of proteins that block viral reproduction & degrade viral RNA (α & β)
• NOT virus-specific

Also activate macrophages & mobilize natural killer cells (α & β), allowing for some anti-cancer effects as well

INF-γ secreted by lymphocytes, activates macrophages, widespread immune mobilizing effect

Question 26

Complement

Answer 26

Consists of ~20 blood proteins that circulate in blood in inactive form

• Includes proteins C1–C9, factors B, D, and P, and regulatory proteins
• Provides major mechanism for destroying foreign substances
• Activation enhances inflammation + directly destroys bacteria (enhances both innate and adaptive defenses )

Question 27

Complement System Activation

Answer 27

1. Classical Pathway
- Antibodies first bind to invading organisms and then bind to complement components, activating them –> double binding, called complement fixation
- Once initial complement proteins are activated, an activation cascade is triggered

2. Lectin Pathway
- Lectins are produced by innate system to recognize foreign invaders
- When lectin is bound to specific sugars on foreign invaders, it can also bind + activate complement

3. Alternative Pathway
- Complement cascade is activated spontaneously when certain complement factors bind directly to foreign invader
- Lack of inhibitors on microorganism’s surface allows process to proceed

Question 28

Fever

Answer 28

Abnormally high body temperature that is a systemic response to invading microorganisms

• Body’s thermostat normally set at 37 C +/- 5
• Reset by pyrogens released by leukocytes & macrophages exposed to bacteria & other foreign substances

HI fever dangerous - denatures body’s own proteins, cell injury / death