Adaptive Immunity

Question 1

What are the two main types of lymphocyte ?

Answer 1

T and B cells

Question 2

What do B cells do ?

Answer 2

Produce soluble antibodies
-defense against extracellular pathogens

Question 3

What are T cells ?

Answer 3

T cells play a key role in defense against intracellular pathogens

Two main types:
-CD4+ T cells: Key regulators of the entire immune system (“helper T cells”) - using cyotkines
-CD8+ T cells: Kill virally infected body cells (“Cytotoxic T cells”) - also kill cancers

Question 4

What are the main parts of the acquired immune response ?

Answer 4

B cells, antibodies
T cells

Question 5

Where are lymphocytes developed and what does this involve ?

Answer 5

Lymphocytes, along with other immune cells, develop from haemopoetic stem cells in the bone marrow (and subsequently, in the case of T cells, in the thymus)

As they develop, B cells and T cells learn to distinguish self from non-self
-If they react strongly to self-antigens, they are (usually!) destroyed or inactivated

Primary Lymphoid tissues are anatomical sites where white blood cells (leukocytes) are produced:

Bone marrow and thymus are the primary lymphoid tissues

WBCs, RBCs, platelets come from haemopoetic stem cells

Question 6

How do T cells and B cells recognise and respond to invading microorganisms in secondary lymphoid tissues?

Answer 6

Innate cells express PRRs for many different PAMPs, most pathogens have many different PAMPs, lymphocytes specific for one antigen

Why do our cells not have PAMPs/no body response to self PAMPs???

Innate cells produce a generalised response, adaptive cells produce tailored response

Question 7

What are antigens ?

Answer 7

Specific molecules which iduce adaptive immune responses
-Antigen: any substance which can cause an adaptive immune response by activating B cells and T cells
-Antigenic epitope is a small part of an antigen to which an antibody (or an antigen receptor) binds

Antigens are not just proteins/polypeptides

Question 8

What are antibodies ?

Answer 8

An antibody (also known as an immunoglobulin) is a protein that binds to one specific antigenic epitope
-An antibody is produced in response to a specific antigen during acquired immune responses

Question 9

How many antigens can a pathogen have ?

Answer 9

Pathogens express multiple antigens, each of which have multiple epitopes
-A single pathogen can activate and be affected by several different immune cells/antibodies

Question 10

How do B cells recognise antigens ?

Answer 10

B cells use membrane-bound antibodies as their antigen receptor → recognises and bind to membrane-associated or soluble antigens
Collectively, B cells (and their BCRs) can recognise and respond to a huge variety of different types of antigens:
Proteins, polysaccharides, fatty acids, nucleic acids, metals etc

Question 11

What different types of substance can antigens be ?

Answer 11

Proteins, polysaccharides, fatty acids, nucleic acids, metals etc

Question 12

How are antibodies generated ?

Answer 12

By production of heavy chain (HC) and light chain (LC) polypeptides that are synthesized from two separate immunoglobulin (Ig) genes
-HCs and LCs held together by disulphide bridges
-Body of antibody is constant
-Variable regions of light and heavy chain come together to form unique 3d shape to bind a unique antigenic epitotpe, each antibody has two binding regions

Question 13

How to T cells recognise antigens ?

Answer 13

T cells use a membrane-associated dimer of two proteins (TCRα and TCRβ chains) as their antigen receptor

These TCRs can only recognise and bind to short peptide antigens presented by Major Histocompatibility Complex (MHC) molecules

TCR + T cell receptor

Question 14

What are MHC molecules ?

Answer 14

Major Histocompatibility Complex (MHC) molecules
-MHC molecules are expressed on all nucleated cells in the body and can present thousands of different peptide antigens to T cells so collectively, T cells (and their TCRs) can recognise and respond to a huge variety of protein antigens

MHC molecules are also known as HLA (Human Leucocyte Antigen) molecules in humans

Question 15

Compare which antigens B cells and T cells can recognise

Answer 15

B cells (as a population) can recognise peptides, polysaccharides, nucleic acids etc
T cells can only recognise peptides presented on MHC molecules

Question 16

What are the two major types of MHC ?

Answer 16

Class I and Class II MHC

Question 17

What is Class I MHC ?

Answer 17

Expressed on all nucleated cells
Present peptide antigens to CD8+T cells

CD8 protein helps stabalise interaction

Question 18

What is Class II MHC ?

Answer 18

Expressed on specialised ‘Antigen Presenting Cells’ in addition to class I MHC
→ Dendritic cells
→ (also activated macrophages and B cells)
Present peptide antigens to CD4+T cells, activating them

CD4 protein helps stabalise interaction

Question 19

Where do T cells and B cells encounter antigens ?

Answer 19

Mature B cells and T cells constantly recirculate in the body through blood, secondary lymphoid tissues (e.g. lymph nodes), and the lymphatic system
-Secondary Lymphoid tissues are anatomical sites where T cells and B cell become activated

Question 20

How do different immune cells access secondary lymphoid tissues ?

Answer 20

The endothelium of post-capillary HEVs is specialised to allow constitutive transendothelial migration of mature T cells and B cells into secondary lymphoid tissues
-High Endothelial Venules have thicker endothelia than normal venules

Dendritic cells (and soluble antigens) enter secondary lymphoid tissues via the lymphatic system

Question 21

How do B cells encounter antigens ?

Answer 21

Question 22

How do T cells encounter antigens ?

Answer 22

Antigen-presenting dendritic cells
1) In infected, inflamed tissues Dendritic cells recognise and internalise microbial debris particles via phagocytosis (using their PRRs)
2) Dendritic Cells digest ingested microbial proteins and display small peptides derived from these on their cell surface in complex with MHC-I and MHC-II molecules
3) Pro-Inflammatory TNFα stimulates maturation of tissue-resident Dendritic cells → migrate towards lymph nodes via the afferent lymphatics

Question 23

What happens when T cells and B cells encounter their partner antigen?

Answer 23

Both specific antigen and co-stimulation needed to fully activate lymphocyte

Question 24

What happens when B cells are activated ?

Answer 24

B cells clonally proliferate and differentiate into two different types of effector cells:
Plasma cells - produce and secrete soluble, antigen-specific antibodies; most are short-lived
Memory B cells - long lived cells that continue to circulate around the body

Question 25

What do B cells need to recieve to become fully active and clonally proliferate and differentiate ?

Answer 25

Need two signals: 1) Antigen 2) Co-stimulation

Question 26

Which antibodies are produced initially and later on ?

Answer 26

Initially antigen-specific IgM antibodies are secreted by plasma cells Later, Ig class switching occurs → antigen-specific antibodies of other classes are secreted (e.g. IgG, IgE, IgA) -Pre plasma cell B cells class switch

Question 27

Describe CD4+ helper T cell co-stimulation of B cells

Answer 27

CD4+ helper T cells -Both B cells and CD4+ T cells respond to antigenic epitopes on the antigen -Protein antigens involved (only peptides trigger cd4+/cd8+ T cell responses) T cell co-stimulation occurs within specialised areas of secondary lymphoid tissues (the Germinal Centre) → optimal antibody responses: -High affinity antibodies -Ig class switching -Long-lived plasma cells -Memory B cells

Question 28

Describe co-stimulation of B cells in secondary lymphoid tissue

Answer 28

1) Protein antigen bound to BCR is internalised by the B cell. The antigen is degraded and peptides derived from it are presented on the B cell surface in complex with MHC-II molecules 2) Effector TFH cells move into B cell zone of the lymph node where they are re-stimulated by B cells in an antigen-specific manner 3) Re-activated effector TFH cells stimulate the B cell to clonally proliferate and differentiate into plasma cells that secrete high affinity, class switched antibodies (Germinal Centre reaction)

Question 29

What can TFH cells can help in the Germinal Centre ?

Answer 29

Can help antigen-activated B cells mutate their antibody (IgH and IgL chain) genes to produce higher affinity antibodies:

Question 30

What can provide co-stimulation in the full activation and clonal proliferation of B cells in response to antigens ?

Answer 30

CD4+ Helper T Cells Antigenic epitopes (less potent)

Question 31

Describe co-stimulation of B cells by antigens

Answer 31

B cells respond to antigenic epitopes on any antigen type (protein, fatty acid, polysaccharides, nucleic acids etc) -T cells are NOT involved -NO Germinal Centre reaction Less potent (but still effective) antibody responses: -Low-medium affinity antibodies -Ig class switching -Short-lived plasma cells -No Memory B cells

Question 32

How do antigen-specific antibodies kill and eliminate invading microorganisms?

Answer 32

Recognition function -Binding to antigen mediated by variable region sites of the antibody Effector function -Clearance mechanisms mediated interaction of the heavy chain constant region (Fc region) with effector molecules such as Complement and Fc receptors

Question 33

What differentiates antibodies ?

Answer 33

Classified into five classes (or isotypes) according to their Ig heavy chains, which provide each isotype with distinct characteristics and biological functions:

Question 34

What does IgM do ?

Answer 34

In membrane-bound monomeric form, IgM serves as the B cell antigen receptor (BCR) In its secreted, pentameric form, IgM is the first Ig type produced during adaptive immune responses -Present in blood (serum) and lymphatic fluids -Key functions: Agglutination, Complement system activation

Question 35

What is agglutination and what does it do ?

Answer 35

Immune complex formation -Mediated by specific antigen binding to IgM and IgG classes of antibody -Agglutination increases the efficacy of pathogen elimination by phagocytic cells -Agglutination also prevents viruses from binding to and infecting host cells

Question 36

Which antibodies can active the classical complement pathway ?

Answer 36

IgM and IgG

Question 37

What is IgG ?

Answer 37

Most abundant normal serum, is monomeric -The dominant Ig type produced during a secondary (memory) immune response Key functions: -Agglutination -Complement system activation -Opsonisation -Neutralisation -Natural Killer cell activation (ADCC) -Foetal immune protection | Only antibody which can cross placenta

Question 38

How does IgG opsonise ?

Answer 38

IgG antibodies are excellent opsonins (→ promote phagocytosis) Phagocytes express Fc receptors that binds specifically to the constant region of the IgG heavy chain

Question 39

Which are the Neutralizing antibodies ?

Answer 39

High affinity IgG and secretory IgA (sIgA) -Bind to viruses, blocking infection by preventing binding to host cells and reducing their infectious capacity -Similar role in preventing bacterial toxins from entering host cells

Question 40

Which antibody actives NK cells (ADCC) and how is this achieved ?

Answer 40

Antibody-Dependent Cellular Cytotoxicity Antibody binding to specific antigens on a target cell, allows effector cells like Natural Killer (NK) cells to recognize and bind to the antibody's Fc region → killing of the target cell

Question 41

Which antibodies do neonates have ?

Answer 41

sIgA antibodies are transported into colostrum and breast milk to protect the GI tract of neonates IgG from placenta more a less gone by 6 months

Question 42

What does IgE do ?

Answer 42

Promotes mast cell activation & degranulation → defence against large extracellular parasites → allergy, asthma, anaphylaxis

Question 43

What does IgD do ?

Answer 43

Accounts for less than 1% of human immunoglobulins -Membrane-bound monomeric form, IgD can serves as an a B cell antigen receptor (BCR) -The function of secreted IgD is unknown

Question 44

How do dendritic cells activate T cells ?

Answer 44

Co-stim extensions arent CD4/CD8 proteins T cells which are being co-stimulated

Question 45

What do CD4+ cells do once activated ?

Answer 45

1) Activated CD4+ T cells start to secrete a mitogenic cytokine (for CD8+), Interleukin 2 (IL-2) 2) They also upregulate expression of the IL-2 receptor on their cell surface; triggers autocrine-mediated cell division -self proliferative stimulation 3) CD4+ T cells also provide IL-2 for antigen-activated CD8+ T cells

Question 46

What do Th1 cells do ?

Answer 46

1) CD4+ effector TH1 cells migrate out of secondary lymph nodes to sites of infection/inflammation 2) Re-activated by macrophages -Antigen-specific manner; macrophages express microbial peptide antigens on their cell surface with MHC-II after phagocytosis 3) Re-activated TH1 cells secrete pro-inflammatory cytokines (IFNγ), which enhances macrophage-mediated killing of internalised microbes: ↑ production of reactive oxygen species (ROS) in lysosomes

Question 47

What do TFH cells do ?

Answer 47

1) CD4+ effector TFH cells migrate to B cell follicles in secondary lymph nodes 2) Re-activated by antigen-presenting B cells -B cells express peptide antigens on their cell surface with MHC-II after internalisation of BCR/antigen complexes 3) Re-activated TFH cells secrete cytokines and express cell surface co-stimulatory molecules → full B cell activation

Question 48

What do CTL cells do ?

Answer 48

CD8+ effector CTLs (Cytotoxic T Lymphocytes) migrate out of secondary lymph nodes → enter sites of infection/inflammation to kill infected or abnormal (cancerous) host cells

Question 49

How do CTL cells kill ?

Answer 49

Killing of infected host cells occurs in an antigen-specific manner → secretion of the contents of cytotoxic granules → e.g. perforin and granzyme

Question 50

Overview the adaptive immune response

Answer 50

Question 51

How are innate and adaptive immune responses resolved ?

Answer 51

Invading pathogen eliminated; no inflammatory immune stimulus -↓ activation of new innate and adaptive immune cells -Existing pro-inflammatory mediators/cytokines as well as activated Complement system proteins have short half-lives -Anti-inflammatory cytokines and growth factors are secreted by macrophages -Secreted antibodies have relatively short half-lives (days-weeks) -Effector T cells and B cells are relatively short-lived (days-weeks) * ## Footnote *exceptions: long-lived plasma cells and memory lymphocytes (B cells / CD4+ T cells / CD8+ T cells)

Question 52

What is Immunological Memory ?

Answer 52

Once the adaptive immune system has recognised and responded to a specific antigen, it exhibits life-long immunity to that antigen; -Memory CD4+ T cells -Memory CD8+ T cells -Memory B cells -Long-lived Plasma cells

Question 53

What are the major vaccine types ?

Answer 53

Live, attenuated pathogens; e.g. MMR, polio Inactivated pathogens (Heat killed; Irradiated) e.g. pertussis, polio Toxoid vaccines e.g. diptheria, tetanus Subunit vaccines e.g. HepB, neisseria meningidites Conjugate vaccines e.g. HiB, MenC mRNA vaccines e.g. SARs CoV2

Question 54

What do the best vaccines achieve ?

Answer 54

The best vaccines generate both T cell- and B cell-mediated immunological memory

Question 55

What are Conjugate vaccines ?

Answer 55

Used for pathogens with polysaccharide (sugar) capsules -T cells cannot regnoise sugars of capsule so only B cells can respond to pathogen alone; sub-optimal -Vaccine consists of antigenic polysaccharide with carrier protein linked; B cell binds sugar and internalises complex, presents protein peptide fragments on MHC-II to CD4+ cells, engaging T cell response and co-stimulation | e.g. HiB, Streptococcus pneumoniae, Neisseria meningitidis.