B cell differentiation defects Flashcards by Robert Mitchell

What TFs are important for commitment to the C cell lineage and expressed in pro B cells?

EBF, E2A and PAX5
induce proliferation and expression of genes for BCR and its signalling.
E.g. RAG1/2

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What are the BCR recombination steps that occur in pro and pre-pro to pre B cell stages?

Pro B cell: Initial D-J BCR recombination

Pre pro and Pre B cell: V-DJ recombination,

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What is presented on cell surface at the pre B cell stage?

What signals does it give?

The rearrnaged heavy chain along with a surrogate lamda 5 and VpreB light chain.

Tonic signalling through this complex gives positive survival and proliferation signals.

also initiates allelic exclusion of the other BCR locus.

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When does V-J rearrangement occur?

At the small pre B cell stage.

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What does immature B cell have that small pre B cell doesn’t?
What selection process then occurs?

Cell surface expression of the IgM/IgD.
Negative selection occurs.
autoreactive B cells are clonally deleted or undergo receptor editing/anergy.

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Where do immature B cells go?

Migrate out of BM into spleen to become transitional cells.

Further selection and BAFF signalling before they differentiate into mature B cells.

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What other molecules involved in BCR complex and co-stimulation upon Ag binding?

Iga/B also called CD79a/b.
CR2 (will bind opsonised C3d)
CD19 and CD81.

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waht are the classical 4 functions of humoral response?

neutralisation.
Opsonisation for phagocytosis
Opsonisation for ADCC
complement activation (cell lysis and inflammation)

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What other stage in life are humoural responses important in?

neonatal immunity

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What are Ab independent functions of B cells regarding T cells and adaptive immunity?

Co stimulation for T cells, and antigen presentation to T cells.

cytokine secretion and important for Lymphoid tissues organogenesis. (e.g. LN, spleen and peyers patches).

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What stages of B cell life can IEI affecting B cell differentiation affect?

anywhere from HSC to memory B cell formation.

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B cell defects can be intrinsic and extrinsic to B cells.

Whats ane example of an extrinsic defect leading to B cell differentiation defect?

Lack of T cell help, e.g. CD40L deficiency. (or anything affecting T cells)

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Two examples of deficiencies that cause wider defects than just B cells.

RAG1/2 and DNA repair defects affects T and B cells (T- B- NK+ SCID).

AK2 (reticular dysgenesis) defect of haematopoietic cells. impairs ability of HSC to differentiate along myeloid and lymphoid lineage. (T- NK- B- SCID).

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What are classical infections of pyogenic encapsulated bacteria in B cell differentiation defects?

S. pneumoniae and H. influenzae.

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Where are typical bacterial infections found in Ab deficiencies? COmplicattions?

recurrent infections of respiratory tact- sinusitis, otitis media, chest infections and GI tract.

Chronic infection can cause bronchiectasis and chronic sinusitis.

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What kind of viral infections and protozoal infections are they susceptible to?

Enteroviruses and Giardia.

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What unusual bacteria caused septic arthritis?

mycoplasma and ureaplasma

What kind of autoimmune conditions associated with B cell immune dyregulation?

autoimmune thrombo cytopenia and neutropenia.

Lymphoproliferation.

3 general classes of antibody deficiencies?

B cells are absent- agammaglobunemia.

combined variable immunodeficiency (CVID)- IgG reduced + IgM/and/or IgA low. B cells are present.

Hyper IgM syndromes, due to CSR or SHM/ GC formation defects. B cell numbers are normal.

What might give you a high number of B cells?

GOF constitutive NF-KB signalling.

What kind of mutations can affect B cell differentiation in the BM?

These will have low numbers of B cells- agammaglobunemia

Could be due to RAG1/2- BCR formation.
Or could also be due to signalling components

What kind of conditions affect B cells in peripheral lymphoid organs?

CVID phenotype normally (B cells present but IgG defecient)
Or hyper IgM.

Caused by genes affecting class switching/ SHM.
Or B cell survival or response to antigens

What are features of agammagolbunemia and what is most common reason?

less than 1% B cells.
Pan agammaglobunemia.

XLA (due to mutation in BTK, causes arrest of development past pre B cells differentiation)

When does XLA normally present itslef?

Late onset?

NOrmally within 3-6 months, or up to 3 years.
After maternal Ig has waned.

Can be later onset if due to a hypmorphic mutation.

What other feature might be present in XLA (think alternative functions of B cells)

Pacuity of lympoid tissues (underdevelopment of spleen.)

What tests might you do to confirm XLA?

B cell counts in blood (using CD19 and CD20) Intracellular expression of BTK in monocytes. (two populations would be seen for mother). Functional assays if expression present- sequencing. Bone marrow differentiation. (don't progress from TdT+ CD19+ to CD19+ TdT-).

What would you see as markers of pre B cell arrest?

Stuck as CD19+ TdT+, don't progress and become TdT-.

What are some autosomal causes of agammaglobunemia?

Mutations in TFs important for early development e.g. TCF3). Mutations in components of the pre BCR (CD19, CD79, lamda5/VpreB) Or in signalling components downstream of pre BCR (e.g. BLNK or GOF PIK3CD)

When might you suspect autosomal causes of agammaglobulinemia?

if female, male with BTK discounted, or consanguinity.

What are some indications of differences betwen agamma. and CVID?

CVID has later onset. More hetergenous, some may have evidence of cellular defect- susceptibility to viruses. More complex non-infectious complications. Many have polygenic causes.

Examples of complex CVID associations.

autoimmunity, GI disease and malignancy.

What 3 things are more likely to be found with mongenic CVID?

younger onset, consanguinity and familial presentations.

What mutations might cause monogenic CVID?

e.g. genetic defects affecting BAFFR or TWEAK.

What kind defects can affect CSR and SHM?

Those afffecting T and B cell interactions (CD40L-CD40) B cell intrinsic defects (AID and UNG) Chromatin remodelling and DNA repair defects.

What is an X linked hyper IgM condition? | Why is there susceptibility to opportunistic infections?

CD40L deficiency. May affect T cell activity (and how it interacts with innate cells), so leads to opportunistic infections e.g. pneumocystis jirovecci and also cyrptosporidium.

What can a complication of cryptosporidium infectosn be?

can affect bile ducts and lead to schelrosing cholangitis.

Is CD40 deficiency X linked?

no it would be AR.

What is CD154?

CD40L on T cells.

Two autosome hyper IgM for each involved in CSR/SHM and in affecting DNA?

AID (AD or AR) and UNG (AR) involved in CSR/SHM INO80 (AR) involved in chromatin remodelling durig SCR. MSH5 (AR) DNA mismatch repair enzyme- susceptibility to cancer.

What are four causes of specific Ab deficiencies?

selective IgA (asymptomatic- rarely symptomatic) IgG subclass deficeity (asymptomatic) kappa chain deficiency (all lamda and asymptomatic) specific (functional deficiency) Reduced ability to generate Abs mostly to specific polysaccharides (symptomatic)

Treatments for B cell differentaion defects?

for agamma, CVID and hyper IgM- replacement Ig therapy. May be complimented with prophylactic antibiotics. Antibiotics normally for specific Ab deficiencies or for mild cases. If complex cases, then immunosuppression and cancer therapy may be needed.