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BIOM30002 > Lecture 1 - B Lymphocyte Biology and Disease (1) > Flashcards

Lecture 1 - B Lymphocyte Biology and Disease (1) Flashcards

1
Q

What produces antibodies?

A

Plasma B cells/terminally differentiated B cells

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2
Q

What is the structure of an antibody?

A
  • They have 4 chains = 2 heavy and 2 light chains
    o Light and Heavy chains paired by disulphide bond in each dimer
    o Heavy and heavy chain paired by disulphide bonds in each tetramer
  • Each chain has 2 regions: variable and constant
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3
Q

What are antibodies and their function?

A

Globular proteins found in serum, interstitial fluids, mucosal secretions

Function: bind specific epitopes to neutralise foreign pathogens, identifies and neutralises foreign pathogens

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4
Q

What is the variable region?

A
  • Variable regions have antigen-binding functions. The tip of the variable region are the hypervariable regions, which are extremely variable (allows for the millions of antibodies with different antigen binding sites to arise)
  • Variable regions have 2 heavy chain and 2 light chain regions (mirror images)
  • This is where VDJ (H chain) and VJ (L chain occurs) recombination
  • Somatic hypermutation occurs here
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5
Q

What is the constant region?

A

Antibody’s isotype is defined by constant region of heavy chain. Each class differs in sequence + number of domains, hinge region and valency. Each class has a distinct distribution in the body and effector functions

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6
Q

How are antibodies made?

A

B cells are precursors to antibody secreting cells (ASC – plasma cells)
1. Recognise antigen via immunoglobulin on the surface
a. Surface membrane immunoglobulin (SmIG) = B cell receptor (BCR)
2. Break down antigen (Ag) and re-present to T cells as peptides on surface MHC class II
3. T cells then provide activation signals or ‘help’ (CD40L, ICOS, cytokines)
4. Differentiate into an antibody secreting cell (also memory B cells)

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7
Q

What are the immunoglobulin isotypes?

A

IgG, IgD, IgA, IgE and IgM

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8
Q

Describe IgA

A

Molecular forms: Monomer or tetramer
Found in bodily secretions
Protects external openings
Transferrable to offspring via colostrum and breast milk

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9
Q

Describe IgD

A

Molecular form = Monomer
Found on B cell surface
Unknown exact function could be antigen detection

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10
Q

Describe IgE

A

Molecular form = Monomer
Attaches to basophils and mast cells
Involved in allergic response and defend infection by large parasite

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11
Q

Describe IgG

A

Molecular form = Monomer
Found in blood and extracellular fluids
Long term antibody involved in protection of the body
Can be transferred to offspring via placenta

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12
Q

Describe IgM

A

Molecular form = Pentamer
Found in the blood and extracellular fluid
Appears earlier in the infection and offer valuable defence during critical stage of the infection

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13
Q

How do antibodies become fit for the purpose?

A
  • Antigen recognition
  • Antibody responses
  • Isolating and engineering ready-made optimal mAbs
  • Optimising monoclonal antibodies for efficacy
  • Use of monoclonal antibodies for therapy
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14
Q

What forms the antigen binding site of antibodies ?

A

CDRs

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15
Q

Where do lymphocytes arise from?

A
  • All lymphocytes descend from a common lymphoid progenitor (CLP)
    o Natural kill (NK) cells develop in foetal liver
    o T cells develop in thymus
    o B cells develop in bone marrow
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16
Q

Describe the amino acid regions of the variable region

A

There are 7 amino acid regions
* 4 framework regions (makes the scaffold)
* 3 hypervariable CDR

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17
Q

What are the functions of B cells?

A
  • Antibody production
  • Cytokine production
  • Lymphoid tissue organogenesis
  • Tumour immunity
  • Wound healing
  • Transplant rejection
  • Dendritic cell regulation (responsible for antigen-specific responses)
  • Th1/Th2 cytokine balance
  • Co-stimulation
  • Antigen presentation
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18
Q

What recognises the antigen?

A

Surface bound immunoglobulin/B cell antigen receptor. Once recognised the Ig will change form so that it can be released from the cell in a soluble form to move through the bloodstream.

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19
Q

What is the major role of the immune system in B cell development?

A

Immune system must create a repertoire of receptors capable of recognising a large array of antigens while at the same time eliminating self-reactive B cells

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20
Q

Where does B cell development occur?

A

Bone marrow

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21
Q

What are the general steps of B cell development?

A
  • Each B cell starts life without an antigen receptor (made during development)
  • Genes encoding the B-cell receptor are combined and expressed on the cell surface and it is this process from which diversity is generated
    o Diversity in Ig is an intrinsic property of making B cells
  • Progress through B cell development is mediated by successful Ig gene rearrangement
  • Immature B cells are only able to leave bone marrow if they express functional BCR on the surface
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22
Q

What are the main steps of Ig gene rearrangement and B cell maturation?

A
  1. IgH rearrangement
  2. IgL rearrangement
  3. BCR checkpoint
23
Q

What occurs during IgH rearrangement?

A

Pre-pro B cell turns into Pro-B cell

Pre-pro B:
DJ H chain recombination
Expresses CD19
Increase expression of EBF-1 (early B-cell factor 1) –> binds Ig gene promoting accesibility for D-JH locus preparing for 1st step in Ig gene recombination

Pro-B:
Start of VDJ H chain recombination
If successful, progresses to Pre-B cell

24
Q

What occurs during IgL rearrangement?

A

Pre-B cell (large) turns into Pre-B cell (small)

Pre-B cell (large):
Complete VDJ H chain recombination
Clonal expansion
VJ L chain recombination (either kappa or lambda)
Surrogate light chains (kappa and lambda)

Pre-B cell (small)
Successful rearrangement at one allele of H and one of L rallows surface expression of Ig heavy chain and surrogate light chains complex = pre-B cell receptor

25
Q

What occurs during the BCR checkpoint?

A

Immature B cell formed
IgH + (kapp/lambda) light chains form BCR
Btk required
Final checkpoint = exists bone marrow and migrates to periphery (spleen)
Has a functional IgM but no other Ig expression
Expresses B220, CD25, IL-7R, CD19
Negative selection

26
Q

What are the fates of an immature B cell if it is autoreactive?

A

Clonal deletion via BCR-mediated apoptosis
Reactivation of RAG to initate process of light chain receptor editing
Survive and escape the bone marrow but become anergic
B cell loss prior to leaving the BM = central tolerance

27
Q

What happens to a B-cell that is not recognised by an antigen?

A

B-cells are quiescent unless stimulated to respond, so the B-cell will do nothing and eventually die to be replaced by a new cell if not recognised by an antigen.

28
Q

What are the features of mature B cells?

A

Expresses a single species of Ig on its surface
BCR is surface bound Ig
Mature resting B cells express HLA-DR, CD19, CD20, CD40 but NO LONGER express CD10, CD34, RAG1, RAG2 or Tdt
Exits BM, travels to secondary lymphoid organs, then expresses both IgM and IgD
Generates clones of plasma cells that each secretes antigen receptor as soluble Ig - recirculates between blood and lymphoid organs

29
Q

What are the features of plasma cells?

A

Specialist cells that secrete antibody (Ig)
Terminally differentiated cells of B cell lineage
Each PC secretes one type of Ig
Those that arise from follicular B cells are found mainly in the bone marrow and are long-lived
Those that arise from non-follicular B cells are short lived

30
Q

What occurs during B cell activation? What are the types of B cell activated?

A
  • Exposure to antigen or various polyclonal mitogens activates resting B cells and stimulates their proliferation
  • Two major types:
    o T cell dependent (TD)
    o T cell independent (TI)
  • TD: involves protein antigens and CD4+ helper T cells
    o Multivalent antigen binds and crosslinks membrane Ig receptors
    o Activated T cell binds B cell though antigen receptor and via CD40L (T)/ CD40(B) interaction
  • TI: involves multivalent or highly polymerised antigens, does not require T cell help
31
Q

What are the shared features of B and T cell development?

A
  • Antigen receptors are not germline encoded, but are assembled (somatically) by combination and rearrangement of V(D)J minigene segments
  • Both B and T cells undergo antigen receptor (VDJ) rearrangement
  • Checkpoint: both undergo negative selection to remove cells that bind with high self affinity
32
Q

What are the functions of VDJ Ig gene rearrangement?

A
  • Permits random generation of antigen receptors for B and T cells
    o B cells  bone marrow  (heavy and light chain recombination) = BCR
    o T cells  thymus  (aB and yS chain recombination) = TCR
  • Generates receptor diversity
  • Allows for generation of a unique TCR/BCR allowing each cell to have a unique specificity
  • Population of cells are able to recognise a larger variety of antigens (increasing Ag repertoire)
33
Q

How are Immunoglobulin genes encoded?

A

Immunoglobulin genes are encoded on 3 separate genes on 3 loci

There are 2 light chain loci and 1 heavy chain loci
Heavy chain rearranged first, then only one of the light chains (random but usually K)
Second chance of VJ recombination of other light chain occurs during receptor editing checkpoint (to prevent self-reactivity and can be a mechanism to escape negative selection)

34
Q

How are variable regions formed?

A

By somatic recombination
* 1 light + 1 heavy germline mini gene segments are somatically recombined
* Produces a unique DNA sequence encoding a unique variable region
* V(D)J rearrangement of variable gene regions occurs in pre/pro B cells

35
Q

What are the ways to generate BCR/antigen receptor diversity?

A
  1. Random selection: and rearrangement of minigene segments in Heavy and Light chain genes for joining at each locus
  2. Independent rearrangement: at heavy and light chain loci: and pairing of various combinations
  3. Imprecision of junctions: (N region diversification, random insertion of nucleotides at junction regions, mediated by the enzyme Tdt)
  4. Somatic hypermutation and affinity maturation: single point mutations in hypervariable regions and selection of highest affinity binding receptors
36
Q

What are primary immunodeficiencies?

A

A group of rare diseases characterised by the impaired ability to produce a normal immune response
* Results in recurrent or severe or persistent infections
* NOT caused by other diseases/not the same as secondary or acquired immunodeficiencies

37
Q

What are the classes of PIDs?

A

There are 8 classes of PIDs defined by the IUIS spanning the adaptive and innate immune systems.
1. Antibody deficiencies
2. Combined T and B cell deficiencies
3. Well-defined syndromes with immonodeficiency
4. Diseases of immune dysregulation
5. Congenital defects of phagocyte number or function or both
6. Innate immunity defects
7. Autoinflammatory disease
8. Complement deficiencies

38
Q

What are antibody deficiencies? (PIDs)

A

A PID where there is loss of humoral immunity (but cellular immunity is mostly intact).

In antibody deficiencies, B cells are affected (i.e., B cells may be absent, reduced in number, have developmental defects, or have differentiation defects).

 X-linked agammaglobulinemia (XLA) – due to blocks in B cell development
 Common variable immunodeficiency (CVID) – due to defects in B cell differentiation
 Hyper IgM syndromes (HIGM) – due to defects in B cell activation/differentiation

39
Q

What are combined immunodeficiencies?

A

A PID where there is a combined loss of humoral and cellular immunity. In combined immunodeficiencies, either:
o Only T cells are affected or
o Both T cells and B cells can be affected.
Because CD4+ (helper) T cells regulate B cells, intrinsic T cell defects can also lead to antibody deficiency (i.e. no help, no antibody)
EXAMPLE = SCID

40
Q

Why do some of these deficiencies appear in more than one category?

A

Defects in some molecules principally effect antibody formation, but they have secondary effects in other systems. (CD40 and CD40L deficiencies) : appear in both T and B deficiences, and antibody deficiencies.

41
Q

What is the treatment for severe PIDS?

A

Example of severe PIDS = SCID, X-linked agammaglobulinemia
The whole immune system is replaced as treatment because it would be completely missing in these cases.
o Haematopoietic stem cell transplantation (HSCT)/bone marrow transplantation: person receives haematopoietic stem cells (HSCs) from a healthy donor to replace their immune system. These are the cells that give rise to blood cells (e.g. B cells and T cells).
o Gene therapy: uses autologous HSCs (from the same individual) transplantation to deliver stem cells with added or edited versions of the missing or malfunctioning gene that causes the PID

42
Q

What is the treatment for less severe PIDS?

A

Examples of less severe PIDS = Hyper IgM syndrome, X-linked lymphoproliferative disease – XLP, common variable immunodeficiency – CVID, immunosuppression, graft vs host disease

In these cases people still have some antibody left in their immune system so replacement of the whole immune system is not a good option
o Replace antibodies through Ig replacement therapy (IRT): typically administered intravenously or self-administered sub-cutaneous Ig (SCIg) – a regular and lifelong process
o Precision therapies: therapies that specifically target disrupted pathway/protein in a patient – must known the underlying cause/genetic defect – gene therapy is an option

43
Q

What are in-born errors in pre-BCR signalling?

A
  • Pre-BCR is required to signal rearrangement success in the developing B cell
  • Mutations that block this success signal, block B cells development -> i.e. no B cells = no antibody (agammaglobulinemia)
  • Can be defects in rearrangement or signalling proteins
    o Iga/b are scaffolding proteins – autosomal recessive mutation
    o BLNK is an adapter protein – autosomal recessive mutation
    o Syk and Btk are kinases
  • Known as agammaglobulinemia
44
Q

What occurs when there are mutations in the BTK gene?

A

X-linked agammaglobulinemia (XLA) occurs due to Bruton’s tyrosine kinase (BTK) mutations
Mutations examples =
* Mutations occur along the entire gene with no single mutation occurring
* Inactivating mutations
* Some result in residual Btk expression and signalling (milder disease, later onset)
* Some result in complete loss of function (severe, early-onset)
* Mutation maintained in population by de novo events (spontaneous, not carried by parents)
* BTK encoded on X-chromosome, thus only affects XY chromosome pairs

45
Q

What are the clinical features of XLA?

A

Complete absence/very little serum Ig (all isotypes)
Complete absence circulating B cells (may be some B cells if milder mutation), XLA babies still have T-cells
Recurrent infections: primarily Strep. Pneumonia, Haemophilus influenza B
Recurrent otitis in children and sinusitis in adults

46
Q

How is XLA diganosed?

A

Average age of diagnosis is 3 years old
Known family history of XLA means sooner diagnosis

Clinical presentation and/or family history
* Serum Ig levels are measured (baby needs to be > 1 year to rule of the chance of maternal antibodies affecting measurement)
* Count CD19+ B cells (Pre-B cells)
* BTK sequencing

Gene-based diagnoses
* Prenatal = chorionic villus sampling, CVS, amniocentesis
* BTK Sanger sequencing for infants
* Gene panel
* KRECs newborn screening identifies infants, at birth (TRECs normal)

47
Q

What are the risks associated with diagnostic delay of XLA?

A

Chronic pulmonary disease, growth delays, early mortality, susceptibility to S.pneumoniae, H.influenza, Staphylococcus spp. At greater risk of pneumonias and bacterial infections as well

48
Q

What is the role of maternal antibodies?

A
  • Maternal antibodies offer protection in the first months
  • As the maternal Ig wanes, child develops recurrent and/or severe infections, e.g.:
    o Lung (pneumonia, bronchitis)
    o Ear (otitis)
    o Eye (conjunctivitis)
    o Sinus (sinusitis)
  • Severe-life threatening bacterial infections
  • Usually well protected against viruses (exception is fatal adenoviral encephalitis)
48
Q

What is the role of maternal antibodies?

A
  • Maternal antibodies offer protection in the first months
  • As the maternal Ig wanes, child develops recurrent and/or severe infections, e.g.:
    o Lung (pneumonia, bronchitis)
    o Ear (otitis)
    o Eye (conjunctivitis)
    o Sinus (sinusitis)
  • Severe-life threatening bacterial infections
  • Usually well protected against viruses (exception is fatal adenoviral encephalitis)
49
Q

What are the two types of Ig replacement therapies (IRT) for XLA?

A
  1. IRT administered via intravenous immunoglobulin - IVIg
  2. IRT administered via subcutaneous immunoglobulin - SCIg
50
Q

What is the process of administering IVIg?

A

Purified IgG from pooled human sera (many donors) via alcohol fractionation
Dose is 400-600 mg/kg every month in clinic. Takes 2-4 hours per infusion
Contains all IgG subclasses (and trace amounts of IgM and IgA)
Ideal to maintain IgG at 5-10 g/L at lowest trough (normal is 12 g/L)
Broad-spectrum of antibody specificity

51
Q

What is the process of administering SCIg?

A

Self-administered weekly in abdomen, thigh and forearms, via small pump
Dose is lower than intravenous adminsteration, dose is 100-500 mg/kg
Freedom for travel, work, avoid absences, independence for young people
Avoids peaks/troughs of IVIG
Fewer infections in between treatment

52
Q

What are possible reasons for a failure to respond to an infection?

A
  • No B cells (agammaglobulinemia/XLA without B cells)
  • No CD4+ ‘helper’ T cells (Severe Combined Immunodeficiency, SCID)
  • No B or T lymphocytes (Severe combined immunodeficiency, SCID)
  • B & T cells present but:
    o No signal from CD4+ cell to the B Cell
    o Failure of the B cell to respond to T-cell signals
    o Failure of the B cell to respond to antigen binding

BIOM30002 (14 decks)

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