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Exam 3 > 03/15a B & T Cell Life > Flashcards

03/15a B & T Cell Life Flashcards

1
Q

What are the three general stages of B cell development? Where do they occur?

A

1) Generation of naïve mature B cells - bone marrow
2) Initial activation of B cells - B cell follicles and B-T zone
3) Continued activation of B cells - germinal centers

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2
Q

What are the three genetic elements of the Ig heavy chain?

A

V (variable)
D (diversity)
J (joining)

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3
Q

What are the two genetic elements of the Ig light chain?

A

V (variable)

J (joining)

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4
Q

What protein mediates the recombination of VDJ sites?

A

RAG

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5
Q

What is N-region addition?

A

The random insertion of nucleotides to the DJ or VD junctions of the heavy chain by terminal deoxynucleotide transferase
Affects the sequence of CDR3
Another way to generate genetic diversity and increase variability in antigen-binding regions

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6
Q

What is the function of the pre-BCR?

A

“Tests” the newly-rearranged heavy chain (combined with a dummy light chain) to ensure that there are no frameshift mutations
Determines if the heavy chain rearrangement was successful –> proceed to light chain rearrangement

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7
Q

What is the function of Bruton’s tyrosine kinase?

A

Plays a critical role in B cell signaling and maturation

Btk gene is located on the X chromosome, and is frequently mutated

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8
Q

What is the result of Btk mutation?

A

X-linked Agammaglobulinemia (males only)

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9
Q

What is X-linked Agammaglobulinemia?

A

A common congenital immunodeficiency disorder
Characterized by loss of pre-BCR and B cell maturation signaling
Results in reduced or absent B cells and low levels of serum antibodies

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10
Q

What is allelic exclusion? Why is this significant to B cell maturation?

A

The expression of only a single allele (maternal OR paternal) on each B cell
This results in the expression of identical heavy and light chain variable domains

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11
Q

How does a B cell express both IgM and IgD?

A

Transcription of both the IgM and IgD constant regions, followed by alternative splicing of mRNA

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12
Q

What is a mature naïve B cell?

A

A B cell that has undergone VDJ recombination with generation of junctional diversity and allelic exclusion
Also known as a follicular B cell
Antigen-specificity of each cell is SET

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13
Q

What is a follicular B cell?

A

A mature naïve B cell

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14
Q

How are B1 and marginal zone B cells activated? What is their reaction?

A

By binding to intact antigen (usually polysaccharides), which cross-links many BCRs
Antigen processing by APCs and T cell help are NOT required
Short-lived, produce mainly IgM

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15
Q

How are follicular B cells activated? What is their reaction?

A

By binding to intact antigen, usually proteins (which tend to be poorly-stimulating)
Antigen-processing by APCs is NOT required
Require T cell help

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16
Q

What other systems or receptors of B cells contribute to and enhance B cell activation against pathogens?

A

PRRs - recognize PAMPs

Complement receptors - recognize components of complement bound to pathogens

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17
Q

How do B cells recruit the help of T cells? Describe the general process

A

BCRs bind to an intact protein antigen
Part of the antigen is internalized, processed, and displayed via MHC II
MHC II-peptide complex interacts with and activates T cells

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18
Q

How do T cells provide help to B cells?

A

Make CD40L and cytokines
B cells are activated by CD40 engagement and cytokine interaction
B cell proliferate and differentiate into short-lived plasma cells that make low-affinity antibody

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19
Q

What is the germinal center reaction?

A

Interaction of short-lived plasma cells, follicular helper T cells, and follicular dendritic cells that occurs in the germinal centers of lymphoid tissue

20
Q

What are the results of a germinal center reaction?

A

Massive proliferation of B cells
Class switching of B cells
Affinity maturation
Generation of long-lived plasma cells (make high-affinity antibody) and memory B cells

21
Q

What is class-switching?

A

Another type of B cell genomic rearrangement that results in a new antibody isotype (constant region)
Does not require RAG

22
Q

What enzyme mediates class-switching?

A

Activation-Induced Deaminase (AID)

23
Q

What signals regulate the generation of different antibody isotypes?

A

Cytokines!

Examples - IL-4 stimulates production of IgE, IFN-gamma stimulates production of IgG subclasses

24
Q

What is the result of a deficiency of CD40L?

A

Tfh cell cannot help B cells, which thus lose the ability to perform class-switching
Leads to decreased levels of IgG and IgA and elevated levels of IgM
Causes Hyper IgM Syndrome (X-linked)

25
Q

What is affinity maturation? How does it occur?

A

Increased affinity of an antibody for a given antigen
Occurs through somatic mutations in the DNA
Requires AID
As more antibodies are produced, antigen is eliminated
Antigen stimulation and T cell interaction provide survival signals to B cells - this selects only for B cell clones that make high-affinity antibody

26
Q

What is the result of a deficiency in AID?

A

Hyper IgM Syndrome - no class-switching, decreased IgG and IgA, elevated IgM

27
Q

How do booster immunzations provide increased immunity?

A

Through affinity maturation - multiple challenges by an antigen stimulate more germinal center reactions and thus improved antibody affinity

28
Q

What are the two possible fates of germinal center B cells?

A

Plasma cells

Memory B cells

29
Q

What are plasma cells?

A

Very long-lived, morphologically distinct, terminally differentiated B cells that make abundant antibodies

30
Q

What are memory B cells? What are their functions and abilities?

A

Long-lived B cells that can survive without antigen stimulation
Circulate OR remain in lymphoid organs
Mount rapid responses to subsequent antigen exposures
Can undergo subsequent germinal center reactions, and can thus also undergo subsequent class-switching and affinity maturation

31
Q

What five T cell life events occur in the thymus?

A

1) Proliferation of T cell precursors (double-negative cells)
2) Generation of TCR diversity by gene rearrangement (double-positive cells)
3) Positive and negative selection of cells that recognize self MHC + peptide (single-positive cells)
4) Negative selection to eliminate cells that react to self antigen
5) Release of mature single-positive T cell into circulation

32
Q

What are the important cells of the thymic cortex?

A

Cortical epithelial cells

Cortical macrophages

33
Q

What are the functions of thymic cortical epithelial cells?

A

Express MHC I and II + ubiquitous self peptides
Express IL-7 (T cell growth factor)
Function in positive selection and initial negative selection of T cells

34
Q

What is the function of thymic cortical macrophages?

A

Eliminate dying thymocytes that didn’t pass initial selection

35
Q

What are the important cells of the thymic medulla?

A

Medullary epithelial cells

Medullary dendritic cells and macrophages

36
Q

What are the functions of the thymic medullary epithelial cells?

A

Express MHC I and II

Function in negative selection of thymocytes

37
Q

What are the functions of the thymic medullary dendritic cells and macrophages?

A

Express MHC I and II + tissue-specific self peptides
Function in negative selection of thymocytes
Eliminate dying thymocytes

38
Q

How does TCR recombination compare to BCR recombination?

A

Similar to VDJ recombation - coordinated by RAG proteins
TCRs do NOT undergo class-switching, somatic mutation, or affinity maturation - there is no change in structure after the initial recombination

39
Q

What is the result of a deficiency in RAG?

A

Severe Combined Immunodeficiency Syndrome (SCIDS)
No VDJ recombination
No generation of BCRs or TCRs, and thus no B cells or T cells

40
Q

What determines positive selection of thymocytes?

A

Not binding to self MHC - if receptors cannot bind to self MHC, cells die by neglect (lack of signaling)

41
Q

What determines the initial negative selection of thymocytes?

A

Binding too strongly to self MHC - receptors that bind too well are potentially auto-reactive, so cells die of apoptosis

42
Q

What determines the final negative selection of thymocytes?

A 
Autoimmune regulator (AIRE), a transcription factor present in thymic medullary cells which drives expression of tissue-specific proteins
Single-positive thymocytes which react to these proteins are negatively selected and killed by apoptosis
43
Q

What is the result of a deficiency in AIRE?

A

Autoimmune Polyendocrine Syndrome type 1 - spontaneous autoimmunity against a variety of endocrine organs
A very rare disorder

44
Q

When does T cell production peak? What does this mean for the anatomy of the thymus?

A

Peaks at pre-puberty and declines significantly with age, which results in thymic involution - thymic cells are replaced by fat
Low level T cell production continues with age

45
Q

What is the significance of T cell selection with regard to bone marrow transplantation?

A

Thymocytes educated by recipient cortical epithelial cells must be able to interact with donor APCs
Recipient thymic epithelial cells and donor stem cells MUST share some MHC homology, or else donor APCs will not recognized

46
Q

What is DiGeorge syndrome?

A

Hypoplasia or agenesis of the thymus, most frequently caused by a chromosomal deletion
Results in deficient T cell maturation and a lack of T cell immunity

Exam 3 (10 decks)

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