Lec 45: Adaptive Immunity III

Question 1

Explain the differences in the mechanisms of TD and TI antigens.

Answer 1

TD antigen (Thymus-Dependent)

TI Antigen (Thymus Independent)

An antigen with a protein component that can be presented by MHC

Activates B cells without TH cell involvement (Polysaccharides, lipids, and other nonprotein antigens)

Dendritic cells transport antigen from peripheral tissues to 2* lymphoid organs

Antigen is encountered in lymph nodes or spleen

Antigen is encountered in lymph nodes or spleen on Th cells (CD4+)

Passive transport: antigens migrate from site of infection to the lymph node via lymphatics (native antigen B Cell activation)

BCRs crosslinked by antigens and also cluster (similar to TCR)

BCR crosslinking leads to phosphorylation of Iga and Igb ITAMs → syk kinase activation

syk kinase -> transcription factors (NFAT, NK-bk, AP-1)

transcription factors -> secretion of IgM (autocrine cytokine)

BCR efficiently cross link with carbohydrate coats of encapsulated bacteria because of the highly repetitive carbohydrate structure

(higher signal than TD antigen induced phosphorylation)

• BCR crosslinking leads to phosphorylation of Iga and Igb ITAMs → syk kinase activation
• syk kinase -> transcription factors (NFAT, NK-bk, AP-1)
• transcription factors -> secretion of IgM (autocrine cytokine)
• IgM binds to polysaccharide capsule
• Activation of complement cascade
• Opsonization of capsulated bacteria

Crucial for elimination of encapsulated bacteria because T cells cannot respond to pure carbohydrate antigen (carbs can’t be presented by MHC, peptide only)

Activates T-cell via CD40L expression → cytokine secretion ->activation of B cell

Does not stimulate CD40 (no T cell assistance)

CD40+cytokine required for B cell differentiation - Ig class switching to IgG, IgE, IgA)

TI antigens are IgM isotope only (no class switching)

CD40+cytokine required for B cell differentiation - somatic hypermutation (affinity maturation)

Antibodies to TI antigens are low affinity because there isn’t somatic hypermutation or affinity maturation

Differentiates to B effector and B memory cells

Does not produce memory B cells; no secondary TI response (2d response has same kinetics as primary response)

Question 2

What is a TD Antigen?

Answer 2

An antigen with a protein component that can be presented by MHC

Question 3

What is a TI antigen?

Answer 3

An antigen that activates B cells without TH cell involvement (Polysaccharides, lipids, and other nonprotein antigens)

Question 4

Where and and on what are TD antigens encountered?

Answer 4

Antigen is encountered in lymph nodes or spleen on Th cells (CD4+)

Question 5

Where do TI antigens activate B cells, and in what form?

Answer 5

Passive transport: antigens migrate from site of infection to the lymph node via lymphatics (native antigen B Cell activation)

Question 6

What type of antigen is crucial for the elimination of encapsulated bacteria?

Why?

How does this happen?

Answer 6

TI antigen

Crucial for elimination of encapsulated bacteria because T cells cannot respond to pure carbohydrate antigen (carbs can’t be presented by MHC, peptide only)

BCR efficiently cross link with carbohydrate coats of encapsulated bacteria because of the highly repetitive carbohydrate structure

(higher signal than TD antigen induced phosphorylation)

• BCR crosslinking leads to phosphorylation of Iga and Igb ITAMs → syk kinase activation
• syk kinase -> transcription factors (NFAT, NK-bk, AP-1)
• transcription factors -> secretion of IgM (autocrine cytokine)
• IgM binds to polysaccharide capsule
• Activation of complement cascade
• Opsonization of capsulated bacteria

Question 7

Do TI antigens stimulate CD40?

Answer 7

No.

Question 8

What type on antigen (TI/TD) enables Ig class switching, and why?

Answer 8

TD antigens

CD40+cytokine required for B cell differentiation - Ig class switching to IgG, IgE, IgA)

Question 9

Compare the secondary response to TI antigens.

Answer 9

There usually isn’t one because primary response doesn’t produce memory cells. If there is one, it is much slower.

Question 10

Describe the difference in affinity maturation of antibodies to TI and TD antigens.

Answer 10

TI: Antibodies to TI antigens are low affinity because there isn’t somatic hypermutation or affinity maturation

TD: CD40+cytokine required for B cell differentiation - somatic hypermutation (affinity maturation)

Question 11

Compare and contrast the process of B cell activation to T cell activation through the BCR and TCR.

Question 12

What forms of antigens are recognized by BCRs? TCRs?

Answer 12

BCR:

• Macromolecule (protein, polysaccharide, lipds, nucleic acids)
• small chemicals

TCR:

-Peptides displayed on MHC molecules on APCs

Question 13

Compare and contrast the difference in antigen recognition for TCRs and BCRs.

Answer 13

BCR:

Antigen recognition mediated by V region of heavy and light chains of membrane Ig

TCR:

Antigen recognition is mediated by V region of a and b chains

Question 14

Compare and contrast effector function of BCR and TCR

Answer 14

BCR: C region of secreted Ig

TCR: no effector function

Question 15

Compare and contrast signaling function mediation of BCR and TCR.

Answer 15

BCR: Proteins (Igα and Igβ) associated with Ig

TCR: Proteins (CD3 and ξ) associated with TCR

Question 16

Describe antigen receptor mediated signal transduction in B cells.

Answer 16

BCR crosslinking by antigen leads to phosphorylation of Iga and Igb “ITAMs, activates syk kinase

Activation signal is transduced by Immunoglobulin Signal cascade: Syk -> NFAT, NF-kB, AP-1

Question 17

Describe antigen mediated signal transduction in T cells

Answer 17

Activation signal is transduced by the CD3 complex

Phosphorylates ZAP-70, causes cascading effects that yield transcription factors NFAT, NF- κβ, AP-1,

Transcription factors activate IL2 which induces T cell proliferation

Question 18

Explain the molecular basis of isotype class switching and affinity maturation.

Answer 18

Th activation of B cells via CD40 + cytokines is required for B cell differentiation

Ig class switching

secretion of IgG, IgE, IgA isotypes

somatic hypermutation

Question 19

Explain the mechanistic basis of all differences between the primary and secondary antibody response to antigen.

Answer 19

• Primary response lags and only produces modest antibodies;
  
  • Lags because has to differentiate, then needs TCell help
• Secondary response respond to antigens with production of antibody at higher level and have a higher affinity to antigen than primary antibody response
  
  • shorter response time and higher antibody titer (especially IgG)

Question 20

Explain the molecular basis of differential distribution of antibody isotypes in the body

Answer 20

• IgM: only in blood and circulatory system b/c there is no transporter to move it anywhere else
• IgG and monomeric IgA: blood and extracellular spaces
• IgA transported across epithelial surfaces by poly-Ig receptor; becomes associated with mucosal secretions
• IgG is specifically transported across placenta by the FcRB receptor
• Dimeric IgA: mucosal spaces (specific transporter = Poly-Ig receptor)
• IgE: epithelial surfaces