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IAHI Block 1 > 9 - Humoral Immunity > Flashcards

9 - Humoral Immunity Flashcards

1
Q

Humoral immunity protects against what? What is it mediated by?

A

Extracellular pathogens and noxious stimuli.

Mediated by B lymphocytes and secreted antibodies.

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2
Q

How does the immune system recognize and discriminate between self and non-self extracellular antigens?

A

Immunoglobulins (Ig)

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3
Q

What is an epitope? What is it recognized by?

A

The part of an extracelluler antigen that’s recognized by immunoglobulin.

Membrane Ig - the B cell receptor (BCR).

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4
Q

What is the cardinal structure of membrane Ig (BCRs)? What does this recognize and how does it differ from what TCR’s recognize?

A

Y shaped.

Both the stalk and the branches of the Y have receptor regions that recognize in tact macromolecules.

This differs from TCRs because TCRs only recognize small linear peptides.

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5
Q

What are the regions on an immunoglobulin?

A

Variable regions with hypervariable regions (CDRs)

Constant regions that are variable.

Affinity.

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6
Q

Where do antigens bind to immunoglobulins?

A

Three CDR reasons in the heavy chain and three in the light chain.

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7
Q

What is the structure of an immunoglobulin (Ig)?

A

There’s two heavy chains: a variable and a constant heavy chain

And two light chains: a variable and a constant light chain

Antigen binding site on the tips of the Y branches.

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8
Q

How can B cells within the adaptive immune system change of adapt to differences in self or non-self antigens?

A

They modify the BCR (surface Ig) through somatic recombination of their germ line DNA.

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9
Q

What exons are on the Ig heavy chain locus?

Which are on the light chain locus?

A

Heavy: encodes V, D, and J

Light, ONLY V and J regions

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10
Q

Why are the complementary determining regions (CDRs) on immunoglobulins important? What are they encoded by?

A

Because they are the contact points for antigens.

Encoded by variable Ig heavy and Ig light chains.

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11
Q

What two things contribute to the antigenic diversity of B cell receptors?

A

Combinatorial diversity: variation amongst exon combos

Junctional diversity: removal or nucleotides or addition of nucleotides by TdT enzyme; strand repair.

Only heavy chains have a diversity region.

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12
Q

What are the three checkpoints in B cell development?

A
  1. Pro B cell needs to have at least an Ig heavy chain on the surface to become a Pre C cell
  2. Pre B cell needs to have an intact receptor (light chain and heavy chain together) to be an immature B cell
  3. Go through + and - selection in the bone marrow
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13
Q

How does the + and - selection differ in B cells from in T cells?

A

When immature B cells strongly recognize self antigens, particularly T independent antigens like polysaccharides, lipids, and nucleic acids, the B cell undergoes either negative selection or receptor editing.

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14
Q

What is central tolerance? What is peripheral tolerance?

A

Central: deletion of lymphocytes that recognize self antigens present in generative organs

Peripheral: deletion or anergy of lymphocytes that recognize self antigens in peripheral lymphoid tissues

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15
Q

What does a mature B cell have on it’s membrane?

A

IgM and IgD

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16
Q

IL-7 drives proliferation in the ______, while IL-2 is proliferative in the _______.

A

IL-7: bone marrow

IL-2: peripheral lymphoid tissues

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17
Q

What are the major differences between TCRs and BCRs?

A

TCRs: Only recognize linearized peptides, are MHC restricted and composed of TCRalpha chains, and are membrane-localized

BCRs: recognize numerous chemicals, higher affinity binding, membrane bound or secreted, have IgD, IgM, IgE, IgA, and IgG; composed of heavy and light chains.

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18
Q

What are the Fab and Fc regions on immunoglobulins?

A

Fab: antigen binding region ( branches of Y)

Fc: effector region (stalk)

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19
Q

Howdo B cells protect the body from pathogens or potentially noxious stimuli?

A

Recognition by signaling through the BCR.

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20
Q

What are the four outcomes after a B cell is differentiated?

A
  1. Antibody secretion
  2. Isotype switching
  3. Affinity maturation
  4. Memory B cell
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21
Q

How do B cells first meet antigens in peripheral lymphoid tissues?

A

Antigens are funneled into the follicles of the lymph node through the afferent lymphatic vessels.

Within the follicle the antigens meet naive B lymphocytes.

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22
Q

What are the two B cell subsets? What type of molecule does each recognize? What type of cells are in each subset?

A

T dependent B cells: recognize antigen thats a protein. Memory B cells and long-lived plasma cells.

T independent B cells: recognize polysaccharide antigens (LPS). Short-lived plasma cells.

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23
Q

What is the first signal that must occur for a BCR to be activated?

A

Two or more BCRs must be cross-linked by an antigen to be activated.

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24
Q

What are the second signals required for BCR activation?

A
  1. Bound C3d (compliment protein) signals through CD21 and CD19
  2. PAMP from microbe binds to the TLR
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25
Q

Upon B cell activation, what three things occur?

A

Entry into cell cycle: mitosis

Increased expression of cytokine receptors

Low-level IgM secretion (five Ig linked when secreted)

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26
Q

What dictates the B cell response?

A

The structure of the stimulating antigen.

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27
Q

What occurs when the protein Ag does not provide sufficient BCR cross-linking or 2nd signal? Describe this process.

A

Need Th cells help

Antigen enters follicle and recognized by IgM or IgD of BCR.

  • Ag endocytosed by naive B cell and B cell becomes professional APC
  • Activated B cell goes from follicle to T cell zone to interact with T cell.
28
Q

What happens in a T dependent B cell reaction after the B cell has interacted with the recently activated T cell?

A

B cell will undergo clonal proliferation and some of the cells become plasma cells that secrete IgM.

Tfh cells and B cell clones migrate back into the follicle

29
Q

What structure is observed during a T dependent B cell activation? Where does this happen and what is the result?

A

Germinal center occurs in the follicle: T cells and activated B cells make long-lived plasma cells that produce IgG, IgA, or IgE

30
Q

How do B cells process and present an antigen in T dependent activation? What help do T cells provide?

A
  1. B cell recognition of naive protein antigen via IgM and IgD (this is only the first signal)
  2. Receptor mediated endocytosis of antigen
  3. Antigen processing and presentation of linear peptide on Class II molecule
  4. T cell recognition of antigen and binding via CD40 ligand. (This is the second signal that makes it T dependent).
31
Q

In T dependent activation of B cells, what else activates the B cells besides the CD40 ligand?What is the result?

A

Cytokines.

CD40 and Cytokines cause proliferation, initial antibody production, and the germinal center reaction.

32
Q

What happens when the naive B cell undergoes activation and clonal expansion? during which antibody response does this occur?

A

It releases IgM and IgG during the primary antibody response.

33
Q

There is more ____ after the secondary antibody response. Vaccination boosters take advantage of this.

A

Memory.

34
Q

What three changes in antibody structure that occur as the B cell undergoes differentiation? Which allows an increase in affinity between antibody and antigen?

A
  1. Affinity maturation: somatic mutations in variable regions (increases affinity)
  2. Switch from membrane to secreted form
  3. Isotype switching
35
Q

What is the structure of an antibody?What is the isotype dictated by? What is the idiotype?

A

Five isotypes, each with two heavy and two light chains.

Isotypes: IgG, IgM, IgD, IgA, and IgE dictated by the Fc (stalk and a little bit of the branches) portion of the molecule made of constant heavy chains.

Idiotype: specifically located on the tips of the Y; the variable regions.

36
Q

What is the structure of IgA and IgM when they are secreted? What do they have in common?

A

IgA is secreted as a dimeric molecule

IgM is secreted as a pentameric molecule.

Both are linked by the same protein called J chain, which attaches to the Fc region of each molecule.

37
Q

What is T dependent isotype switching that occurs during B cell differentiation?

A

In response to T cell signals of CD40 ligand and cytokines, the AID protein recombines Smew with S from a different isotype.

38
Q

What is T independent isotype switching that occurs during B cell differentiation? What happens with this cell after differentiation?

A

B cells make that make IgM and do NOT have memory.

NO isotype switching occurs and antibody stays combined.

After differentiation, naive B cells is a plasma cell that secretes IgM

39
Q

Does VDJ change after T dependent B cell isotype switching?

A

NOOOOO.

Antigen bound to the Fab on the antibody on the B cell stays the same.

All we have changed is the constant chain that VDJ is attached to. (same light chain remains associated with the VH region).

40
Q

With five different isotypes, how do we know which ones to switch? Which isotypes are associated with each signal?

A

T cell help from CD40 and cytokines determines which ones switch.

IFN-gamma: IgG > complement activation and neonate immunity
IL-4: IgE > immunity against helminths
TGF-B: IgA > mucosal immunity

41
Q

What is affinity maturation of B cells during differentiation?

A

B cells with somatically mutated Ig V regions with varying affinities for antigen

B cells with high affinity membrane Ig bind antigen on follicular dendritic cells (FDC) and present antigen to helper T cells

B cells that recognize antigen on FDCs or interact with helper T cells are selected to survive, while those that don’t die.

42
Q

What are the main benefits of affinity maturation?

A

Boosting the number of circulating antibodies/ memory of B cells and the affinity of the antibody for the antigen.

43
Q

What is the B cell response to non-protein antigens?

A

Initiated on Ig receptors of B cells.

Binding of Ag cross links Ig (BCRs) and activates intracellular signaling.

Signaling induces clonal expansion and IgM secretion.

44
Q

When do isotype switching and affinity maturation occur in relation to each other?

A

Simultaneously.

45
Q

What is the function of IgA? IgD? IgE?

A

IgA: mucosal immunity

IgD: Naive B cell antigen receptor

IgE: mast cell activation

46
Q

What is the function of IgG and IgM?

A

IgG: opsinization, complement activation, antibody-dependent cell mediated toxicity, neonatal immunity, and feedback inhibition of B cells.

IgM: Naive B cell antigen receptor, complement activation.

47
Q

What is affinity maturation? What stimulates this?

A

Process by which the affinity of antibodies for protein antigen increases with prolonged exposure.

  • Stimulated by Tfh cells and leads to the formation of germinal centers
  • Bcell entering into germinal center results in Ig variable genes undergoing somatic mutations
48
Q

What are the four effector functions of the antibodies produced? What is each mediated by?

A
  1. Neutralization via IgG and IgA
  2. Opsinization via IgG
  3. Antibody dependent cellular cytotoxicity (ADCC) via IgG and IgE
  4. Complement via IgG and IgM
49
Q

What is neutralization?

A

Antibody blocks penetration of microbe through the epithelial barrier.

Antibody blocks binding of microbe and infection of cells.

Antibody blocks binding of toxin to cellular receptor.

50
Q

What is opsonization? What type of microbe is this used against?

A

Microbe gets covered in IgG.
Opsonized microbe binds to phagocyte Fc receptors (FCYRI), which signals activate phagocyte.
Phagocytosis and killing of microbe occur (usually in the spleen)

Mechanism to encapsulated bacteria.

51
Q

What are the two major functions of opsinization?

A
  1. Phagocytosis

2. Activate ROS, NO, and lysozyme to kill the pathogen

52
Q

What are the two types of Ab-dependent cellular cytotoxicity (ADCC)? Describe each.

A

NK cell: Fc region on antibody recognized by Fc receptors on NK cells. This leads to antibody dependent killing of infected cells using perforin and granzyme.

Eosinophil: IL-5 secreted binds to IL-5 receptors. Fc bound to FCERI on the eosinophils leading to degranulation to digest the helminth.

53
Q

What is the function of the complement cascade? What are the three complement pathways?

A

Complements other immune responses, each cleavage product possesses biological activity.

Alternative pathway
Classical pathway
Lectin Pathway

54
Q

What are the steps in the alternative complement pathway?

A
  1. C3 in serum cleaves itself to C3b and C3a
  2. If bacteria present - C3b stabilized on membrane
  3. C3b cleaves B to Bb and binds it to become C3 convertase
  4. C3 convertase can then convert more C3 into C3b and a through + feedback
  5. Accumulation of Bb and C3b with C5 forms C5 convertase - which cleaves C5 into C5a and C5b.
55
Q

What are the steps in the classical complement pathway?

A
  1. IgM and some IgG subclasses bind microbial surface antigens
  2. C1 cross-links 2 Fc regions and enzyme is active.
  3. C1 cleaves C4 and C2 into C4b and C2a which bind to microbe to form C3 convertase
  4. C3 convertase cleaves C3 into its parts and then C5 convertase forms to cleave C5.
56
Q

What is the Lectin complement pathway?

A

A mannose-binding lectin cleaves C4 and C2 to make a C3 convertase and then a C5 convertase is made to cleave a C5 into its parts.

57
Q

How do the complement pathways converge?

A

They all produce C5b and C5a via C5 convertase.

C5a causes inflammation.

C5b activates C6, C7, and C7 to form a membrane attack complex (MAC) which causes cell lysis.

58
Q

How do you prevent complement from attacking your own tissue?

A

DAF: displaces Bb from C3b

Factor 1: MCP acts as a cofactor for factor-1 mediated proteolytic cleavage of C3b to an inactive form

59
Q

What are three soluble inhibitors that regulate complement? What is the function of each?

A

C1 INH: inhibits C1 serine protease activity

Factor 1: Proteolytically cleaves C3b and C4b

Factor H: causes dissociation of alternative pathway C3 convertase subunits and is a cofactor for factor I medicated cleavage of C3b.

60
Q

What is the function of IgA? How much of out total antibody production is IgA?

A

Highest levels in mucosal lymphoid tissues and specialized for transport across mucosal epithelium.
-60-70% of total daily antibody production aof healthy adult

61
Q

What is IgA’s role in the mucosal epithalia and gut lumen?

A

It binds to poly-Ig on the basolateral surface of the epithelial cell to be transported towards the external environment (gut lumen).

IgA can then neutralize gut pathogens to prevent them from entering tissues.

62
Q

What is the purpose of a vaccination? What is an adjuvant?

A

The process of stimulating protective adaptive immunity to specific antigen by exposure to non-pathogenic forms.

Adjuvant: substance mixed with antigen to increase its immunogenicity.

63
Q

What is the only adjuvant used in vaccines in the united states? How does it work?

A

Aluminum hydroxide gel (alum) - which activates the innate immune system by making CD86

Induces antibody responses independent of TLR signaling and directly activates DCs to secrete IL-1

64
Q

What is opsonization? What is opsonin?

A

The process of coating particles for phagocytosis.

Opsonin are the molecules that coat particles to enhance phagocytosis.

65
Q

How do neonates acquire IgG from their mothers breast milk through the placenta, but how does it get across the baby’s epithelia?

A

Ingested IgG is transported across epithelia by FcRn receptors.

IAHI Block 1 (19 decks)

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