Cell mediated immunity and lymphocyte ontogeny

Question 1

Review:

C3a and C3b

Answer 1

C3a for vasodilation and chemotaxis

C3b for opsonisation and focus for late component assembly into membrane pore

Question 2

Why do we have different antibody classes

Answer 2

each carry out slightly different roles

all made at slightly different times in our development

Question 3

IgM

Answer 3

Largest antibody molecule (pentamer) 
Mostly blood and lymphatics 
About 10% of the antibody pool 
First in primary antibody response 
Very effective agglutinator 
Efficient complement activator 
Important defence against blood- bonre spread of infectious organisms such as bacteria

Question 4

Primary vs secondly response IgM, IgG

Answer 4

IgM composes the first component of the primary response and often a major component of the primary response, and docent change much (in amplitude) in the secondary response 
IgG comes up later in the primary response and comprises most of the secondary response 
There is a class switch when the B cells go from making IgM to IgG, but there is no change in specificity, still the same antigen binding sites

Question 5

IgG

Answer 5

Small monomer 
70-75% of the immunoglobulin pool 
Diffuses into extravascular spaces 
Potent antitoxin antibody 
Effective barrier against virus infections 
Actively transported across placenta 
Good complement activator 
Strongly bound by phagocytic cells 
Enhancement of phagocytosis (opsonisation)

Question 6

IgA

Answer 6

15-20% of human blood antibodies
Predominant class in seromucous secretions
Main role is protection of external body surfaces
Surface protection of gut, respiratory and GU tracts

Question 7

IgD

Answer 7

Trace amounts in blood and other body fluids (because should only be on the surface to B cells)
Found on the surface of antigen sensitive naive B cells
receptor for antigen binding to activate naive B cells

Question 8

IgE

Answer 8

Generally only trace amounts in blood
Binds strongly to mast cells (differentiated basophils)
Important in parasitic infections and allergies
Allergens binding to mast cell associated IgE, activates processes that lead to symptoms of allergy or asthma

Question 9

How antibodies are used diagnostically and therapeutically

Answer 9

good stable molecules
High specificity against particular shapes
could be used as a detection test molecule

Question 10

The problems with antisera antibodies

Answer 10

they’re always polyclonal, so you get heterogenous population and heterogeneous range of affinities, and a relatively small amount of what you are after
Can be used diagnostically but not therapeutically

Question 11

Treating B-CLL

Answer 11

Indolent 
if aggressive 
RFC chemotherapy
R = rituximab (anti-CD20 Mab) 
F = fludarabine (purine analog) 
C = cyclophosphamide (alkylating agent)

Question 12

Responses to grafts

Answer 12

initially CD8 cytotoxic responses

Question 13

T cell colonel activation

Answer 13

In secondary lymphoid organs theres a large repitore of CD8 bearing T cells
Like all other lymphocytes they’re specific for a certain antigen, by their TCR
an antigen presented by either HLA-A,B or C will select out of this repitore the small number of CD8 bearing T cells that have high enough affinity to bind and get the first activation signal and then the additional signals will trigger the cell to respond or not
Proliferation and differentiation = clone of cytotoxic effector cells which move out of the secondary lymphoid organs go around the body looking for the same peptide presented on the same MHC and having the ability to use their TCR’s to bind to that and then to kill those targets, producing a memory cell population, larger in number and more longer circulating than the virgin cell from which they’re derived

Question 14

The killing mechanisms

Answer 14

1. release perforin + enzymes for polymerisation (similar to the late components)
2. Hydrolytic enzymes (granzymes)
3. cytokines TNFalpha, IFNbeta and gamma, that induce apoptosis

Question 15

B cell ontogeny

Answer 15

Uncommitted stem cell
Pre-B cell (cytoplasmic mu chains)
Immature B cell (surface IgM)
Mature Bcell (surface IgM anf IgD)

Question 16

Immunoglobulin genes

Answer 16

we have two sets of genes that code for antibodies, one set that codes for the heavy chain and two other similar sets that code for the light chains (kappa and lambda)
V, D and J axons, which combine to give the variable region and then downstream a series of Constant region axons that will code for the heavy chains. In the bone marrow there is random reassortment of Ib, Id and Ij cutting out the intervening material, this is a random process that happens independently of antigens what we can do is generate a coding region that contains VD and J that is going to code for the variable region of the heavy chain, the way we mix the axons gives us diversity

Question 17

B cell ontogeny and immunoglobulin genes - important points

Answer 17

• Development in the bone marrow (primary lymphoid organ)
  Multiple V,D and J exons recombine –> V region
  Recombination independent of antigen
  variable region diversity arises from this
  B cells become committed to one Vh and one Vl
  Single constant region axons for each class
  Negative selection to remove strong self reactivity
  Class switching retains V region, changing C region

Question 18

Important points

Answer 18

Development in the thymus (primary lymphoid organ)
Multiple V,D and J axons recombine - Vregion
Recombination indépendant of antigen
T cells become committed to one Valpa and one Vbeta
Positive selection for HLA class I or II recognition
Negative selection against strong self reactivity