Topic 3, L5 - The Immune System II

Question 1

The Adaptive Immune System

Answer 1

• Specific defensive system that eliminates almost any pathogen or abnormal cell in body
• Amplifies inflammatory response & activates complement BUT it must be primed

Question 2

What are characteristics of the adaptive immune system ?

Answer 2

• Involves B and T lymphocytes
• Specific : Recognizes and targets specific antigens
• Is systemic : Not restricted to initial site
• Has memory : Mounts an even stronger attack to “known” antigens (second and subsequent exposures)

Question 3

2 main branches of adaptive immune system

Answer 3

1. Humoral immunity
   - Antibodies, produced by lymphocytes, circulate freely in body fluids
   - Bind & temporarily inactivate target cell
   - Mark for destruction by phagocytes or complement
   - Has extracellular targets
2. Cellular (cell-mediated) immunity
   - Lymphocytes act against target cell
   - Directly —by killing infected cells
   - Indirectly —by releasing chemicals that enhance inflammatory response; or activating other lymphocytes or macrophages
   - Intra / cellular targets

Question 4

What are antigens ?

Answer 4

substances that can mobilize adaptive defenses and provoke an immune response
Targets of all adaptive immune responses
Most are large, complex molecules not normally found in body (non-self)

Characteristics of antigens
Can be a complete antigen or hapten (incomplete)
Contain antigentic determinants (parts of antigen that antibodies or lymphocyte receptors bind to)
Can be a self-antigen

Question 5

Complete Antigens

Answer 5

2 important functional properties :
1. Immunogenicity : Ability to stimulate proliferation of specific lymphocytes

2. Reactivity : Ability to react with activated lymphocytes and antibodies released by immunogenic reactions
   - eg: foreign proteins, polysaccharides, lipids, and nucleic acids; seen on many foreign invaders such as pollen and microorganisms

Question 6

Incomplete Antigens

Answer 6

AKA haptens

Involve molecules too small to be seen so are not immunogenic by themselves

eg: small peptides, nucleotides, some hormones

• May become immunogenic if hapten attaches to body’s own proteins
• Combination of protein + hapten is then seen as foreign
• Causes immune system to mount attack that is harmful to person because it attacks self-proteins as well as hapten
  eg: poison ivy, animal dander, detergents, and cosmetics

Question 7

What are self-antigens [ MHC Proteins ] ?

Answer 7

All cells are covered with variety of proteins located on surface that are not antigenic to self, but may be antigenic to others in transfusions or grafts

1 set of important self-proteins are group of glycoproteins called MHC proteins
- Coded by genes of major histocompatibility complex (MHC) and unique to each individual
- Contain groove that can hold piece of self-antigen or foreign antigen
- T lymphocytes can recognize only antigens that are presented on MHC proteins

Self-marker, labelling bofy’s cells as a “friend” to be tolerated by immune system

Question 8

What are the 3 types of cells of the adaptive immune system ?

Answer 8

Lymphocytes
- B lymphocytes (B cells) - humoral
- T ymphocytes (T cells) - cellular

Antgen-Presenting Cells (APCs)
- do NOT respond to specific antigens
- essential auxiliary roles in immunity

Question 9

Development, maturation & activation of Lymphocytes

Answer 9

T and B lymphocytes share common development & steps in their life cycles

5 general steps :
1. Origin : Both lymphocytes originate in red bone marrow

2. Maturation : Lymphocytes are “educated” in a 2–3-day process and mature in primary lymphoid organs (B cells in bone marrow + thymus)
   - Lymphocytes are educated for 2 reasons :
   – Immunocompetence – Lymphocytes must be able to recognize only 1 specific antigen, B or T cells display only 1 unique type of antigen receptor on surface when mature so bind only one specific antigen
   – Self-tolerance – Lymphocytes must be unresponsive to own antigens
3. Seeding secondary lymphoid organs and circulation : Immunocompetent B and T cells not yet exposed to antigen are called naive
   - Exported from primary lymphoid organs (bone marrow and thymus) to “seed” (colonize) secondary lymphoid organs (lymph nodes, spleen, etc.)
   - Increases chance of encounter with antigen
4. Antigen encounter and activation : Naive lymphocyte’s first encounter with antigen triggers lymphocyte to develop further
   - Lymphocyte is selected to differentiate into active cell by binding to its specific antigen
   - Referred to as clonal selection
   - If correct signals are present, lymphocyte will complete its differentiation into active cell
5. Proliferation and differentiation : Once selected and activated, lymphocyte proliferates
   - Forms army of exact copies of itself
   - Referred to as clones
   - Most clones become effector cells that fight infections
   - A few remain as memory cells
   - Able to respond to same antigen more quickly second time it is encountered
   - B and T memory cells & effector T cells circulate continuously

Question 10

T cells mature in the ___________, under negative and positive selection pressures

Answer 10

thymus

Positive selection process
- Selects T cells capable of recognizing self-MHC proteins (MHC restriction); those that can’t are destroyed by apoptosis

Negative selection
- Prompts apoptosis of T cells that bind to self-antigens displayed by self-MHC
- Process, called clonal deletion, ensures self-tolerance

Question 11

Antigen-Presenting Cells (APCs)

Answer 11

Engulf antigens and present fragments of antigens to T cells for recognition

Dendritic cells
- Found in connective tissues & epidermis / act as mobile sentinels of boundary tissues
- Phagocytize pathogens that enter tissues, then enter lymphatics to present antigens to T cells in lymph node
- Most effective antigen presenter known / key link between innate & adaptive immunity

Macrophages
- Widely distributed in CT + lymphoid organs
- Present antigens to T cells, which not only activates T cell, but also further activates macrophage
- Activated macrophage becomes voracious phagocytic killer
- Also trigger powerful inflammatory responses and recruit additional defenses

B cells
- Do not activate naive T cells
- Present antigens to helper T cell to assist their own activation

Question 12

The Humoral Immune Response

Answer 12

Provoked when B cell encounters target antigen & antibodies specific for that particular antigen will then be produced

B cells : Activated when antigens bind to surface receptors, cross-linking them
- Triggers receptor-mediated endocytosis of cross-linked antigen-receptor complexes (clonal selection), leading to proliferation and differentiation of B cell into effector cells

Most clone cells become plasma cells, antibody-secreting effector cells
- Secrete specific antibodies at rate of 2000 molecules per second for 4 to 5 days, then die
- Antibodies circulate in blood or lymph, binding to free antigens, marking them for destruction by innate or other adaptive mechanisms

Clone cells that do not become plasma cells become memory cells
- Provide immunological memory
- Mount an immediate response to future exposures to same antigen

Question 13

Immunological Memory (Primary vs Secondary Immune Responnse)

Answer 13

Primary immune response : Cell proliferation & differentiation upon exposure to antigen for the first time
- Lag period: 3 to 6 days
- Peak levels of plasma antibody are reached in 10 days
- Antibody levels then decline
- VACCINES

Secondary immune response : Re-exposure to same antigen gives faster, more prolonged, more effective response
- Sensitized memory cells provide immunological memory
- Respond within hours, not days
- Antibody levels peak in 2 to 3 days at much higher levels
- Antibodies bind with greater affinity
- Antibody level can remain high for weeks to months

Question 14

Active Humoral Immunity

Answer 14

B cells encounter antigens and produce specific antibodies against them

2 types of active humoral immunity
1. Naturally acquired : Formed in response to actual bacterial or viral infection
2. Artificially acquired : Formed in response to vaccine of dead or attenuated pathogens
- Provide antigenic determinants that are immunogenic and reactive
- Spare us symptoms of primary response

Question 15

Passive Humoral Immunity

Answer 15

Ready-made antibodies are introduced into body

• B cells are not challenged by antigens; Immunological memory does not occur
• Protection ends when antibodies degrade

2 types of passive humoral immunity :
1. Naturally acquired : Antibodies delivered to fetus via placenta or to infant through milk
2. Artificially acquired : Injection of serum, such as gamma globulin
- Protection immediate but ends when antibodies naturally degrade in body

Question 16

What are antibodies ?

Answer 16

Immunoglobulins (Igs) — Proteins secreted by plasma cells / make up gamma globulin portion of blood
- Capable of binding specifically with antigen detected by B cells

Basic antibody structure : Overall T- or Y-shaped antibody monomer consists of four looping polypeptide chains linked by disulfide bonds

4 chains consist of:
- 2 identical heavy (H) chains with hinge region at “middles”
- 2 identical light (L) chains

–> Variable (V) regions at one end of each arm combine to form two identical antigen-binding sites
–> Stems makeup constant (C) regions
- Area that determines antibody class
- Considered effector region of antibody

Question 17

5 Ig classes

Answer 17

IgM - Pentamer (larger than others); first antibody released
IgA (secretory IgA)- Monomer or dimer; found in mucus & other secretions
IgD - Monomer attached to surface of B cells / B-cell receptors
IgG - Monomer; 75–85% of antibodies in plasma
IgE - Monomer active in some allergies reactions and parasitic infections

Question 18

T/F : Plasma B cells can switch from making one class of antibodies to another

Answer 18

TRUE

• Retain specificity for same antigen
• IgM is released during primary response, but plasma cell can switch to IgG for secondary response
• Almost all secondary responses are IgG
• Switching from IgM to IgA or IgE can also occur

Question 19

Antibodies do NOT destroy antigens ; they _____________ and ______ them to form ________________________________________

Answer 19

inactivate, tag

antigen-antibody (immune) complexes

Question 20

Mechanisms of Antibody Action

Answer 20

Neutralization : Simplest, but one of most important defensive mechanism
- Antibodies block specific sites on viruses or bacterial exotoxins /Prevent antigens from binding to receptors on tissue cells
- Antigen-antibody complexes undergo phagocytosis

Agglutination : Antibodies can bind same determinant on two different antigens at the same time
- Allows for antigen-antibody complexes to become cross-linked into large lattice-like clumps - process referred to as agglutination eg clumping of mismatched blood cells

Precipitation : Soluble molecules (instead of cells) are cross-linked into complexes which precipitate out of solution → easier for phagocytes to engulf

Complement fixation : Main antibody defense against cellular antigens (bacteria, mismatched RBCs)
- When several antibodies are bound close together on same antigen, complement-binding sites on their stem regions are aligned → complement fixation, which leads to cell lysis, as well as other complement functions eg: amplification of inflammatory response, opsonization

Question 21

The Cell-Mediated / Cellular Immune Response

Answer 21

Antibodies can handle only obvious antigens (outside cells) - cannot, eg, fight TB bacillus or viruses that multiply INSIDE cells

Involves various types of T-cells - don’t respond to free antigens; « see » only processed antigen fragments displayed on body’s own cells

• Direct attack against body cells infected by viruses, bacteria; also abnormal or cancerous cells, cells of infused/transplanted foreign tissues
• Some T cells directly kill cells; others release chemicals that regulate immune response

Question 22

T cells

Answer 22

T cells are more complex than B cells both in classification and function
Two populations of T cells are based on which cell differentiation glycoprotein receptors are displayed on their surface
CD4 cells usually become helper T cells (TH) that can activate B cells, other T cells, and macrophages; direct adaptive immune response
Some become regulatory T cells, which moderate immune response
Can also become memory T cells
CD8 cells become cytotoxic T cells (TC) capable of destroying cells harboring foreign antigens
Also become memory T cells
Helper, cytotoxic, and regulatory T cells are activated T cells
Naive T cells are simply termed CD4 or CD8 cells

Question 23

MHC Proteins & Antigen Presentation

Answer 23

T cells respond only to processed fragments of antigens displayed on surfaces of cells by major histocompatibility complex (MHC) proteins

Antigen presentation is vital for activation of naive T cells and normal functioning of effector T cells

Question 24

2 CLASSES OF MHC PROTEINS

Answer 24

Class I MHC proteins : Displayed by all cells except RBCs
- Bind with short fragment (8–9 amino acids) of endogenous antigen
- Endogenous antigen can be:
- Self-antigen / non-self antigen: abnormal proteins in infected or abnormal cell

–> Class I MHC crucial for CD8 cell activation
- Act as antigen holders; form “self” part that T cells recognize
- Inform cytotoxic T cells of microorganisms hiding in cells (cytotoxic T cells ignore displayed self-antigens)

Class II MHC proteins : Displayed by APCs
- Bind with longer fragments (14–17 aa) of exogenous (extracellular) antigens that have been engulfed and broken down in a phagolysosome by APC
- Class II MHC proteins recognized by helper T cells
–> Signal CD4 cells that help is required

Both types are synthesized in ER and bind to peptide fragments

Question 25

MHC Restriction

Answer 25

CD4 and CD8 cells have different requirements for MHC protein that presents antigens to them
- CD4 cells that become TH are restricted to binding to only class II MHC proteins typically on APC surfaces
- CD8 cells that become cytotoxic T cells are restricted to binding only class I MHC proteins found on every cell surface, including APC surfaces

Once activated, cytotoxic T cells seek out same antigen on class I MHC proteins on any cell

Question 26

T Cell Activation

Answer 26

T cells can be activated only when antigen is presented to them

Activation is a 2-step process
1. Antigen binding
- T cell antigen receptors (TCRs) bind to antigen-MHC complex on APC surface
- TCR must perform double recognition by recognizing both MHC & foreign antigen it displays

2. Co-stimulation
   - T cell also bind to one or more co-stimulatory signals on surface of APC
   - Without co-stimulation, anergy occurs, in which T cells:
   –> Become tolerant to that antigen
   –> Are unable to divide
   –> Do not secrete cytokines

Both occur on surface of same APC & are required for clonal selection of T cell

Question 27

T Cell Proliferation / Differentiation

Answer 27

• Activated cells enlarge, proliferate, differentiate & perform functions according to their T cell class / response peaks within 1 wk
• Apoptosis (cell death) occurs btwn 7 – 30 d.
• Memory cells remain & mediate 2o responses

Question 28

What is the function of cytokines ?

Answer 28

• Chemical messengers of immune system
• Mediate cell development, differentiation, and responses in immune system
• Include interferons and interleukins

Question 29

T Helper Cells (T h cells)

Answer 29

Play central role in adaptive immune response
– Activate both humoral and cellular arms
– Once primed by APC presentation of antigen, helper T cells:
- Help activate B cells and other T cells
- Induce T and B cell proliferation
- Secrete cytokines that recruit other immune cells

Without TH, there is NO IMMUNE RESPONSE

Activation of B cells
- Helper T cells interact directly with B cells displaying antigen fragments bound to MHC II receptors
- Stimulate B cells to divide more rapidly and begin antibody formation
- B cells may be activated without TH cells by binding to T cell–independent antigens
- Response is weak and short-lived
- Most antigens are T cell–dependent antigens that require TH co-stimulation to activate B cells

Activation of CD8 cells
- CD8 cells require TH cell to become activated into destructive cytotoxic T cells
- Cause dendritic cells to express co-stimulatory molecules required for CD8 cell activation

Amplification of innate defenses
- Amplify responses of innate immune system
- Activate macrophages, leading to more potent killers
- Mobilize lymphocytes and macrophages and attract other types of WBCs

Question 30

Cytotoxic T Cells (T c cells)

Answer 30

• Directly attack & kill other cells
• Activated Tc cells circulate in blood/lymph /lymphoid organs

TC cells target:
- Virus-infected/ cancer cells
- Cells with intracellular bacteria or parasites
- Foreign cells (transfusions or transplants)

Deliver lethal hit using 2 mechanisms :
- Releases perforins & granzymes by exocytosis
- Binds specific membrane receptor on target cell and stimulates apoptosis

Question 31

Natural killer cells recognize other signs of abnormality that cytotoxic T cells do not look for, such as …

Answer 31

• Cells that lack class I MHC proteins
• Antibodies coating target cell
• Different surface markers seen on stressed cells
• NK cells use same key mechanisms as TC cells for killing their target cells

Immune surveillance: NK and TC cells prowl body looking for markers they each recognize

Question 32

Regulatory T Cells (T reg)

Answer 32

Dampen immune response by direct contact or by secreting inhibitory cytokines such as IL-10 and transforming growth factor beta (TGF-β)

Important in preventing autoimmune reactions :
- Suppress self-reactive lymphocytes in periphery (outside lymphoid organs)
- Research into using them to induce tolerance to transplanted tissue

Question 33

Natural killer cells recognize other signs of abnormality that cytotoxic T cells do not look for, such as …

Answer 33

• Cells that lack class I MHC proteins
• Antibodies coating target cell
• Different surface markers seen on stressed cells
• NK cells use same key mechanisms as TC cells for killing their target cells

Immune surveillance: NK and TC cells prowl body looking for markers they each recognize