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Immunology Jenny > 8. B-cells and humoral immune response > Flashcards

8. B-cells and humoral immune response Flashcards

1
Q

Negative selection

A

Aim: elimination of self-specific B-cells

  • In bone marrow
  • Guided by autoantigens of bone marrow
  • Receptor editing: autoreactive B cells can reactivate their RAG genes to create not self-reactive BCR
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2
Q

Development before antigen

A

Bone marrow: gene rearrangement

Immature B cell (IgM) -> mature B cell (w/BCR - IgM and IgD)

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3
Q

Development after antigen (what happens after encounter antigen)

A

Periphery

  • Antigen presentation to Th cells
  • B cell ctivation, proliferation
  • Affinity maturation
  • Differentiation to plasma and memory cells
  • Isotype switch
  • Effector action
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4
Q

Gene rearrangement

A

Variable region
- V(D)J recombination
- Either in H-chain or L-chain
Constant region
- Antibody isotype (alpha, delta, gamma, mu, epsilon)
*BCR: either IgD or IgM, while secreted form can be anyone

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5
Q

Mechanisms responsible for full diversity of BCRs

A

V(D)J rearrangement

1) Germline diversity
2) Combinatory diversity
3) Junctional diversity

Post- V(D)J rearrangement

4) Receptor editing
5) Somatic hypermutation
6) Receptor revision

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6
Q

Types of B cells

A

1) Follicular B cells
- In spleen or other lymphoid organs
- TD-response (Thymus dep.) - protein antigen+Th cell
- Isotype-switched, high affinity antibodies (IgG, IgA, IgE). Long-living plasma cells
2) Marginal zone B cells
- In spleen or other lymphoid organs
- TI-response (Thymus indep.) - polysacch, lipids etc
- Mainly IgM. Short-living plasma cells
3) B-1 B cells
- Mucosal tissues, peritoneal cavity
- TI-response (Thymus indep.) - polysacch, lipids etc
- Mainly IgM. Short-living plasma cells

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7
Q

Life-span of B cells

A

Only a few days

- Many die without meeting their antigen

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8
Q

B-cell activation

A
  • In secondary lymphoid organs

- Meeting appropriate antigen

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9
Q

Primary lymphoid follicle (in lymph node)

A

Mostly B cells

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10
Q

Paracortical area (in lymph node)

A

Mostly T cells

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11
Q

Antigen presentation to Th cells

A 
By dendritic cells
- MHC II-peptide complex => TCR+CD4
- CD80/CD86 => CD28
- CD40 => CD40L
Th0 becomes Th2 (IL-4, -5 and -13)
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12
Q

T-cell/B-cell reciprocal activation

A
  • B cells are APCs: endocytose, process and present appropriate antigen to Th2
  • Antigen-specific B cells interact with antigen-activated Th2 cells to form a primary focus
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13
Q

Intracellular signaling pathways in B cells when encountering antigen

A

Initiated by cross-linking of BRCs by multivalent antigen (Between IgM and IgD på bildet) - required for activation

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14
Q

Activation signals

A

1) BCR => antigen
2) Costimulation by Th cell (TCR+CD4 => MHC II+peptide on B cell)
“Co-recognition”: same antigen recognized by B- and T-cells (but diff. epitopes)

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15
Q

B cell activation by help of Th cell (steps)

A

1) B-cell antigen recognition (1st signal) + Th2 cell antigen recognition
2) Th cell activation => CD40 ligand expression => CD40-CD40L interaction (2nd signal)
3) Th2 cytokine production - IL-4, -5, -6 (3rd signal)
4) B- cell activation (kan også bli direkte aktivert av 2 tror jeg)
* 4th signal: CR2 on B cell bind to complement fragment on antigen

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16
Q

What immunoglobulin is produced first

A

IgM

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17
Q

Antibody class switching

A
  • Germinal center reaction
    Follicular DC - IL-6 => Follicular Th cell - IL-21 => B cell (isotype switch) => Plasma cells (long-lived) and memory B cells
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18
Q

Functional results of interaction between CD40 and CD40L

A
  • Generation of germinal centers, proliferation, secretion of antibodies
  • Affinity maturation
  • Isotype-switch
  • Generation of memory cells
19
Q

Affinity maturation

A

Happens with the clonal expansion
- BCRs with high affinity for the antigen also have a higher chance of survival
- Somatic hypermutation generate variability of Ig genes variable domain (BCRs have diff. affinity to antigen)
“Repertoire diversification”

20
Q

Key enzymes in somatic hypermutation

A

1) AID (activation-induced cytidine deaminase)
- Expressed in activated germinal center B cells
- Cytosine => uridine
- “Transition mutations”
2) UNG (uracil-N-glycosylase)
- Uridine => abasic
- Removes uracil to form apyrimidinic residue
- “Transversion mutations”

21
Q

Selection of surface BCR

A
  • By antigens on surface of follicular DCs
  • Folicular DC have FcR and CR3
    => binds to antibody and C3b on antigen
  • B cells bound to other side of antigen
    ??
22
Q

Germinal center

A
  • Formed by antigen-specific dividing B cells
  • All B cells in each germinal center is derived from only one founder cell
  • Where DC keeps Ag’s for B cells
23
Q

Polyclonal antibodies

A

Many different B cell clones (antibodies) created due to 1 pathogen containing many different epitopes

24
Q

Class (isotype) switch

A
  • Occur in peripheral lymphoid tissues
  • Constant region of H-chain change, variable region remains the same
  • IgM (and IgD) is produced first
  • IFNγ => IgG
  • IL-5 => IgA
  • IL-4 and IL-13 => IgE
  • Switch regions: S
  • AID contributes
25
Q

Negative costimulation (antibody feedback)

A
  • FcγR (low affinity for Ab) on B cell

- Feedback inhibition of B cell division

26
Q

B memory cells

A
  • Localization: mantle zone - direct contact w/antigen
  • BCR: IgG, IgA or IgE (w/high affinity)
  • Higher affinity -> more rapid differentiation to plasma cell
  • Higher amount and more specific Ab secretion
  • Secondary immune response (more rapid and effective)
27
Q

Primary and secondary immune response lag time (after immunization/infection)

A

Primary: 5-10 days
Secondary: 1-3 days

28
Q

Antibody dependent effector mechanisms

A
  • Neutralization of microbes and toxins
  • Opsonization and phagocytosis of microbes (Fcγ R)
  • Antibody-dependent cellular cytotoxicity
  • Complement activation (lysis, phagocytosis of opsonized microbes, inflammation)
  • Mediated by Fc region of antibody (effector region)
29
Q

Effector functions IgM

A

Complement activation (mainly IgM in classical complement pathway - staple form)

30
Q

Effector functions IgG

A
  • Fcγ R-dependent phagocyte responses (opsonizing)
  • Complement activation
  • Neonatal immunity (placental transfer)
31
Q

Effector functions IgE

A
  • Immunity against helminths

- Mast cell degranulation (immediate hypersensitivity)

32
Q

Effector functions IgA

A 
Mucosal immunity (transport of IgA through epithelia)
"Neutralizing antibody"
33
Q

J chain

A

Connects dimeric (or pentameric) antibodies

34
Q

Antibody isotype produced in largest amounts

A

IgA

35
Q

Difference FcγRI and FcγRIIA

A 
FcγRI (CD64):
- High affinity (for IgG)
- On macrophages, neutrophils and eosinophils
FcγRIIA (CD32):
- Low affinity for antibody
- Also on platelets (in addition to ^)
36
Q

FcγRIIIA (CD16)

A
  • ADCC: antibody dependent cellular cytotoxicity (function)
  • IgG-NK-ADCC
  • Low affinity
  • On NK cells
37
Q

FcεRI

A
  • IgE-Eosinophil-ADCC
  • High affinity (for IgE)
  • On mast cells, basophils and eosinophils
  • Function: activation (degranulation) of mast cells and basophils (must have cross-linking of antigen)
38
Q

Selective transport of antibodies

A

1) Passive immunization of fetus
- Transplacental transport of IgG by FcRn
2) Passive immunization of infants
- Transcytosis of IgA by polyIgR to lumen of mammary glands (and small amounts IgG)

39
Q

TI-1 (B2 cells)

A
  • If high conc. of TI-1 antigen: Polyclonal B cell activation => non-specific antibody response
  • If low conc: TI-1 antigen-specific antibody response
40
Q

TI-2 (MZB cells, B1 cells)

A
  • TI-2 antigens alone can signal B cells to prod. IgM

- Activated DCs release BAFF (cytokine) => induce class switching

41
Q

MZB cells (marginal zone B cells)

A
  • Specific group of conventional (B2) B cells(, but TI-2)
  • Recognize generally TI-sugar antigens
  • Secrete mainly IgM (no isotype class switch)
  • Probably no somatic hypermutation
42
Q

B1 cells

A
  • CD5+
  • In first line defence
  • Binds bacterial capsular polysaccharide or cell wall components
  • Recieve signal (IL-5) from accessory cells
  • Secrete IgM antipolysaccharide Ab => binds to bacterial cell wall => activate complement system
43
Q

Compare B1 and B2 cells

A

B1 have more primitive and less adaptive immune response

44
Q

Summary B1, B2 and MZB cells

A

Se bilde ipad!!

Immunology Jenny (16 decks)

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