Immunobio test 1 lecture 6 Flashcards

Types of humoral immune responses and functional diversification of antibodies

division of labor among 3 mature B cell types

• T cell dependent antibody responses
  • Follicular (Fo) B cells
    • IgM + IgD
    • most abundant
• T cell independent ab responses
  • marginal zone (MZ) B cells
    • IgM
    • about 1/10 of splenic B cells
  • B1 B cells
    • IgM
    • reside in fluidic parts of the body

BCR can activate B cells with non-T help (TLR and BAFFR ligands)

• TI type 1
  • IgM aggregation + additional act sig
  • simultaneous activation of BCR and other receptors on B cells (like TLRs) induce the B cells to proliferate and differentiate
  • BAFFR - B cell activating receptor
  • IgM + IgG

BCR can activate B cells without T cell help or other help

• TI type 2
  • IgM aggregation (extensive receptor aggregation)
  • strong cross linking of BCRs by repetitive polysaccharide or protein epitopes
  • IgM

CR2 complement receptor and CD19 are part of BCR as a whole

BCR do not function in isolation - have coreceptors

another component like complement can help even in T cell independent antibody response

important to keep in mind that T and B cells NEVER work in isolation

2 situations where have coreceptors -> help with B cell activation

• either with TLR or BAFF receptor

so:

• B cells not independent from T cells in function (know from before)
• and B cells can have help even when T cell independent - but still not as powerful as when T cell work with B cell

need 2 signals in order to activate and undergo B cell proliferation + differentiation

• safe guard
• more tan 1 signal needed for activation, bc if not then easy for autoimmunity to occur
• so safe guard bc it keeps accidental self run from occurring bc need more than 1 signal to activate B cell

where T cell help is important bc changes in antibodies are much more potently helped by T cells

activation of B cells and migration of B/helper T cell complex into germinal center

-> B cell proliferation

-> somatic mutation and affinity maturation; isotope switching

-> exit of high affinity antibody secreting cells and memory B cells

1. and 2.
2. (steps 1 and 2): T and B cells recognize epitopes of the same antigen in diff locations
3. T-B migrate to each other and B cell present antigen to T cells in the extra follicular space
4. initially Ab are produced in the extrafollicular space
5. activated Th and activated B cells migrate and form GC (germinal center) and are termed Tfh T cells and GC B cells

B cell can be anywhere in the body

B and T cell must have same specifications to work together to make potent immune response

must find each other for tangle to happen

this interaction (activation of B cell) not happening to germinal center (interaction occurs outside of germinal center)

make antibodies

bc new relationship, B cells make IgM isotype

antibodies produced help bridge gap btw initial exposure and have not refined binding site of antbodies

some T follicular and B cells move to germinal center (like discussed last class) which is important for maturation of B cells and memory cells

germinal center does not exist without infection

1. B and T cell activated independently

2. They find each other, B cell can start making antibodies early to cover the gap in time

TD

• plasma cells made by T cell help can be long lived
• antigen = protein
• isotope switching
  • IgM -> IgE, IgG, IgA
• yes affinity maturation
• secondary response (memory B cells)

TI

• plasma cells made independent of T cell help are short lived
• antigen = polymeric antigens, especially polysaccharides, glycolipids, nucleic acids
• isotopes:
  • TI2 = IgM
  • TI1 = IgG
• little to no affinity maturation
• secondary response/memory B cells only with some polysaccharide antigens

see pic

• bacterial capsular polysaccharide conjugated to protein recognized by B cell
• -> process the protein
• presents peptide to helper T cell
• B cell activation and differentiation
• -> long lived plasma cells and memory B cells

shows that can make T cell independent immune response into a T cell dependent immune response, bc B cell can attach to the pathogen (made of biomolecules)

complex of molecules has sugars, etc. so there is a mix of things, which B cell can bind bc they see shapes

what the B cell interact w/ gets internalized, and the protein in the pathogen gets processed by B cell, which is then presented to T cell -> now will produce long lived plasma cells (very used/handy in vaccine design, to provide longer time of resistance / better immunity)

they attach protein piece to a structure, can trick the T cell to help

pause for activity

see pic

from google:

Activation-induced cytidine deaminase (AID) is an enzyme that is predominantly expressed in germinal center B cells and plays a pivotal role in immunoglobulin class switch recombination and somatic hypermutation for antibody (Ab) maturation.

Process where constant region can be switched to other constant region

Can switch constant regions without changing binding site

Why change binding site of antibody? So constant regions get switched

- each clone w/ same specificity has potential to change constant region, so have the same specificity

see pic

IgM - standard

if have T cell help: can switch to IgG, IgE, IgA

IgM - complement activation

IgG - Fc receptor dependent phagocyte responses; complement activation; neonatal immunity (placental transfer)

IgE - immunity vs helminths; mast cell degranulation (immediate hypersensitivity)

IgA - mucosal immunity (transport of IgA through epithelia)

overview of isotypes

• IgM, then can be switched into IgE, IgG, IgA
• framework: in T cell dependent immune response, the T cell produce cytokines, which influence what type of isotope is produced in the immune response
• initial pathogen which immune response is made. The isotope made against it should be made to be more effective vs the pathogen
  • ex: infection in gut -> the immune response will make IgA, so isotope matches the pathogen type to help protection, bc it is in gut, so mucosal area which IgA is best for

IgM - primary antibody

IgG - class switching CH

he didn't say anything

changing the DNA/genome of B cells to accomplish switch that constant region is changing

initially making IgM (constant region mu)

• this is what is normally made

same specificity can be juxtaposed to another constant region

constant regions can be switched and keep same specificity

HOWEVER, the genome itself obviously changes a LOT with these switches

see pic

initial transcription of VDJ recombination

turned out to be DNA recombination

extremely long distances between Ig constant regions

longtranscripts or DNA recombination?

• turned out to be DNA recombination

DNA sequences before each constant regions can be joined together by an enzyme (cuts to where line goes)

result - same specificity now to make diff antibody isotype

T cell help w/ cytokines can each target DNA areas in chromosomes to make it available for recombination

if recombine to alpha, make IgA antibody, etc.

remaining DNA sequences are chopped out of genome, so then the isotope change is irreversible (permanent change in B cell clone)

rearranged DNA in IgM producing cells

-> signals from helper T cells -> AID

signal can make regions switch

carried out by AID

IgM -> AID

-> recombination os Su with Sy -> deletion of intervening C (constant) genes

-> transcription; RNA splicing

-> translation

= IgG

region not used -> deleted as a circle = now diff constant region

showing middle regions of C region being cut out during class switch recombination

already said this

in isotype switching, lose big chunks of genome

same info

genes in heavy chain locus of an IgM expressing B cell

transcript for IgM

-> removal of DNA segment by enzyme activity between switch regions

-> non homologous end joining of DNA at switch regions

-> genes in heavy chain locus of an IgG expressing B cell

transcript for IgG1

SHM (somatic hybrid mutation)

• in variable regions of gene (learned a long time ago)

and CSR

• at constant region of antibody

are BOTH carried out by the same enzyme, AID

pause for activity

*******EXAM QUESTION!!!!*******

answer: diversity, affinity, constant region (isotype, IgG, IgA, etc.)

cytokines

• T helper cell can make IL4 - cytokine made by T follicular helper cell can open constant regions
  • cytokine specializes in opening constant region Y1 (gG) and E (IgE)
    • IgE important vs parasites and mucosal surfaces to protect skin
    • IgG1 is good for most things
• TGF-b opens Y2b and a locus constant regions

diff type cytokines made by helper cell allow switching to diff regions (have gone over this a lot already this lecture)

Summary to help remember

Which cytokines important for what

IL4 – IgE important for allergic rxns

Interferon gamma produced in immune response by T cells when pathogen is cross cellular

- result – antibodies produced help killing of target cells by T cells

Cytokines guide switching of antibody

1. Exquisite specificity of Antibody for its cognate Antigen

• When antigen comes, choosing out of all b cell clones until fits lock and key

2. Adaptability of the Antibody to change its effector functions by changing Ig isotype by Class switch recombination (CSR)

3. Ability of antibodies to increase binding affinity (affinity maturation) by Somatic Hyper mutations (SHM)

• Can adapt to become better in binding by affinity maturation

4. CSR and SHM take place in specialized structures called Germinal Centers

• Geminal centers formed after B and T cell have been activated, meet, and form geminal center - before this is made, the B/T cell complex can make antibodies early which don’t generate memory (this is to fill gap btw innate response and when the better antibodies are made)

5. GCs are formed after T and B cells activated by the same antigen meet in extrafollicular spaces

6. GCs produce antibody-secreting plasma cells and memory B cells that produce recall antibody response upon reexposure with the same antigen (pathogen)

• Affinity btw antibody and antigen has tightest binding possible