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MBBS II HIS > L12 – Humoral Immune Responses > Flashcards

L12 – Humoral Immune Responses Flashcards

1
Q

List the 5 Ab isotypes? Which are membrane bound? Which are secretory?

A

IgG, A, M, E, D

A = secretory and mucosal defense
M,D = membrane bound
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2
Q

Compare secondary humoral response time, Ab titre and affinity, Ab class to primary.

A

Secondary:

  • Shorter lag phase with exponential production of Ab from Ag-specific memory B cells
  • Mainly IgG, little IgM
  • Much higher Ab affinity to Ag
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3
Q

Describe the primary humoral response? (cell type, Ig type, time)

A
  • long lag phase (~7-10 days), persistence depends on nature of Ag
  • antigen-specific naïve B cells undergo clonal selection and differentiation into plasma cells and memory cells
  • IgM first**, then IgG
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4
Q

Describe the B-cell receptor composition.

A
  • Ig heavy and light chains

* Ig α/β chain for intracellular signal transduction

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5
Q

Summarize the intracellular signalling events to activate transcription after BCR activation by Ag? ***

A
  1. Antigens (Ag) crosslink B cell receptors (Ig) cluster on B cell surface
  2. Phosphorylate immunoreceptor tyrosine-based activation motifs (ITAM)**
  3. Recruit and phosphorylate tyrosine kinases** (especially LYN, SYK)&raquo_space; initiate intracellular signaling
  4. Activate multiple pathways at the same time:
    (i) Burton’s tyrosine kinase (BTK)
    (ii) Phospholipase Cγ (PLCγ) , increase intracellular [Ca2+]
    (iii) Phosphatidyl inositol-3-kinases (PI3K)/AKT
  5. Activate transcription factors
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6
Q

List the gene transcriptions that occur after BCR signalling? *****

A

Activate genes for:
1) Cell proliferation (e.g. c-fos, cmyc)

2) Receptors for cytokines ** (e.g. IL4R, IL-6R, TGFBR, IFNGR)
3) Surface molecules e.g. MHC class II ** for Th cells
4) Specific enzymes: e.g. Activation induced deaminase (AID) – for somatic hypermutation in Ig

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7
Q

Describe how B cells present antigens after BCR activation/ crosslinking?

A

BCR crosslinking

> > Endocytosis BCR- Ag complex and break down

> > Use MHC - II from activated gene transcription to load Ag

> > Present MHC-II with Ag on surface to interact with Th

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8
Q

Classify Ag by their downstream reaction after binding to BCR?

A

Thymus dependent Ag&raquo_space; Ag require contact help from T helper cell for optimal Ab response

Thymus- independent Ag&raquo_space; no interaction with Th

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9
Q

What are the 2 ways in which T cells can induce B cell proliferation and class switching?

A

Cell-cell contact through CD40 and CD40L binding between Th and B cells

T cells secrete cytokines for Ig class switching and survival

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10
Q

Describe the cell-cell contact between Th and B cells and its purpose?

A

critical for Ig isotype class-switching to IgA, IgG, IgE

Signal 1: antigen binding to BCR increases the expression of MHC-II, CD40 (both constitutively expressed)&raquo_space; IgM pentamer made immediately

Signal 2: MHC-II loaded with Ag bind to TCR on Th&raquo_space;
upregulates CD40L on activated Th

Signal 3: CD40L on Th bind to CD40 on B cell&raquo_space; induce Ig class switching

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11
Q

What disease is caused by CD40L deficiency in Th cells?

A

X-linked hyper IgM syndrome: no CD40/CD40L interaction = no Ig class switching

who also have a defect in macrophage function, immunodeficiency, more infection susceptibility

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12
Q

Describe the interaction between Thymus-independent Ag and B cells? (think TI-2 and TI-1 and their respective functions)

A
  • antibody response without the need of Th cell contact
    1. TI-1 Ag binds to BCR and other receptors (i.e. Toll- like receptors) &raquo_space; Polyclonal B cell activation regardless of antigen specificity**
    2. TI-2 Ag causes extensive Ig crosslinking on B cell&raquo_space; Plasma cell with weaker Ab response (IgM mainly), No memory cells
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13
Q

Compare the source of TI-1 and TI-2 Ag?

A

TI-1 antigens (e.g. lipopolysaccharides (LPS)*** on Gramnegative bacterial cell wall components) = mitogens

TI-2 antigens (carbohydrates/polysaccharide*** with repeating subunits, e.g. pneumococcal polysaccharides, Salmonella polymerized flagellin)

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14
Q

Location of B cell activation and differentiation?

A

Germinal centers of lymphoid follicles of secondary lymphoid organs

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15
Q

List 2 processes that occurs in the dark zone of germinal centers in lymphoid follicles?

A
  • B cell proliferation (clonal expansion)&raquo_space; become centroblasts
  • Somatic hypermutation in Ig gene&raquo_space; change affinity to Ag
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16
Q

Describe the processes that occur in Class switch recombination (CSR)** in immunoglobulin gene to induce Ig class switching? (think about the enzymes involved)

A

Before switching, alternative splicing makes IgM, IgD

involves several enzymes:
1) Activation-induced deaminase (AID)*****: cytosine&raquo_space; uracil

2) UNG: excises uracil from DNA
3) APE: nicks phosphodiester backbone in DNA

> > free ends of the DNA are rejoined by NHEJ

@ C SEGMENT GENES!!! NOT HYPERVARIABLE REGIONS IN SOMATIC HYPERMUTATION

17
Q

Which Ig isotypes are made before and after class switching? Which cells make these isotypes?

A
  • IgM or IgD are transcribed before switching by ALTERNATIVE SPLICING in naïve B cells
  • IgM switched to other classes e.g. IgG, IgA or IgE by C GENE REARRANGEMENT in activated B cells and plasma cells
18
Q

Which gene segment is involved in somatic hypermutation of Ig gene?

A

Hotspots of SHM = complementarity determining regions (CDRs)/ hypervariable region of V domains of H and L chains

= the antigen binding site

19
Q

List the 4 processes that occur in the light zone of the germinal centers in secondary lymphoid organs?

A

1) Centroblasts&raquo_space; centrocytes
2) Ig affinity maturation
3) Ig class switching
4) Differentiation of plasma cells and memory cells

20
Q

Describe the maturation process that selects B cells with the correct Ig against the specific Ag?

A

Affinity maturation:

  • Somatic hypermutation rearrange HV gene segment without changing overall specificity
  • B cells making Ig with the highest Ag specificity are selected, the rest die
21
Q

List the 2 cells responsible for B cell development and maturation

A

T cells (follicular T helper cells)

Follicular Dendritic cells

22
Q

Describe how Follicular T helper cells help B cells maturation?

A

 Cell-cell contact via CD40-CD40L&raquo_space; Ig class switching

 Make cytokines e.g. IL-4/IL-5/IL-13&raquo_space; Critical of B cell survival and Ig class switching

23
Q

Describe how Follicular dendritic cells help B cells maturation?

A
  • Compete with B cells for antigen presentation
  • Outcompete B cells with low affinity Ig

> > only B cells with high affinity Ig survive by expression of survival protein BCL-2&raquo_space; Plasma and memory cells

24
Q

Describe how antigen re-exposure causes increased humoral response and antigen specificity. (think about mutations in Fab)

A
  1. IgM made in primary response has little mutation in Fab, no effect on Ag binding
  2. IgG in late primary response has increased mutation in hypervariable region of Fab > increase binding affinity (low Kd)
  3. IgG in secondary/ tertiary response has increased somatic hypermutation in Fab&raquo_space; much higher binding affinity
25
Q

Isotype class switching affects Ig affinity or specificity. T or F?

A

False

Does not affect Ig affinity or specificity but biological effector activities varies

26
Q

How do T cell cytokines contribute to Ig class switching?

A

Ig class switching involves CYTOKINE-DEPENDENT TRANSCRIPTION in the rearranged constant region

e.g. IL-4 promotes IgE, TGFβ promotes IgA, interferon-gamma promotes IgG1 and IgG3

27
Q

Describe the processes in somatic hypermutation in Fab? (Not Class Switch Recombination)

A

1) Involves activation-induced (cytidine) deaminase (AID): during cell replication: cytosine&raquo_space; uracil (= error in DNA)
2) Uracil removed
3) Replaced by another nucleotide by **error-prone DNA polymerase*

> > introduce high rate of random mutations in DNA

28
Q

Location of memory B cell formation and which Ag stimulates diff. of B cells?

A

Germinal centres, light zones of lymphoid follicles

T-dependent antigens

29
Q

Describe the isotypes of Ab made from memory B cells?

A

Mostly isotype switched (e.g. IgG+ , IgE+ or IgA+)

Higher affinity for the inducing antigens

30
Q

What immune cells offer long term protection or immune responses against specific antigens

A

Memory B cells

31
Q

Compare the C segment genes that make the different isotypes of Ig?

A 
IgG (Cγ) : IgG1, IgG2, IgG3 and IgG4 
IgM (Cμ) 
IgD (Cδ) 
IgA1 (Cα) 
IgE (Cε)
32
Q

Which Ig is the Major Ab for secondary responses?

A

IgG

33
Q

4 Functions of IgG?

A
  • Major Ig for secondary response
  • Neonatal immunity
  • Complement activation
  • Opsonization and sensitization of NK cells via FcγR
34
Q

Which Ig is the major one for primary responses?

A

IgM

35
Q

Which type of Ag induces the most IgM.

A

TI-2 antigens (crosslinking, carbohydrate based)

36
Q

Binding affinity, diffusion capacity and function of IgM?

A
  • Lowest binding affinity
  • Cannot diffuse across vascular wall
  • Potent agonist of complement system
37
Q

Proposed functions of IgD?

A
  • maintain the quiescent state of autoreactive B cells

- secreted IgD appears to enhance mucosal homeostasis

38
Q

2 functions of IgE? how is it transported in blood?

A

Found on surface of mast cells, basophils and eosinophils (express high affinity Fc receptor for IgE, FcεRI)

Helminthic parasite

hypersensitivity reactions

39
Q

Isoforms of IgA and function?

A

monomers and dimers connected by a J-chain

Secretory dimer&raquo_space; trans-epithelial transport&raquo_space; mucosal immunity

e.g. saliva, milk, colostrums, urogenital and tracheobronchial secretions

MBBS II HIS (30 decks)

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