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Flashcards in Lymphoma and myeloma Deck (36)
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Is B-cell differentiation Ag dependent or independent?



Where does B-cell differentiation take place?

Bone marrow


What is the antigen-dependent stage of b-cell differentiation?

Mature naïve B-cells develop into proliferating blast cells after encounter with antigen and can either apoptose, differentiate into a short-lived plasma cell or enter the germinal centre (GC)


What is direct activation of naive B cells?

By antigens - cells will either apoptose, differentiate into short-lived plasma cells producing IgM - no memory or migrate into a germinal centre.


What is a germinal centre?

Formed from 3-10 naïve B-cells and eventually contains 10,000-15,000 B-cells.


Where do somatic hypermutation and class switching take place?

Germinal centre


What is the process by which naive B-cell blasts become either plasma or memory B cells?

1. proliferation
2. immunoglobulin somatic hypermutation
3. class switch
4. selection and differentiation


What happens during proliferation?

Following antigen stimulation, B-cells differentiate into centroblasts which accumulate in the dark zone of the GC; these are highly proliferative with a cell cycle that is completed within 6-12 hours. Within centroblasts, the anti-apoptopic genes eg: BCL-2 are downregulated and proapoptopic molecules eg: CD95 therefore only cells which generate highly specific receptors to the antigen in the GC will survive.


What happens to centroblasts to increase intraclonal diversity?

Somatic hypermutation of the Ig V-region.


What do centroblasts mature to?

Non-proliferating centrocytes


Where are centrocytes found?

In the light zone of the GC


What occurs in centrocytes?

Class switching - alters the Ig constant regions to IgG, IgA or IgE


What happens if a centrocytes Ig gene mutation results in a low affinity Ab for the given Ag?

Undergoes apoptosis


What happens if the Ig gene mutation results in increased affinity?

They can bind the antigen which up to now has been trapped by complelment receptors on follicular dendritic cells.


What do the centrocytes do with antigen once they have bound it?

Process the antigen, present it to T-cells which express CD40 ligand; this binds to the B-cell CD40 and rescues it from apoptosis.


What is required for B-cell differentiation post-GC?

Inactivation of BCL6


What is one of the inactivation mechanisms of BCL6? (i.e. the one mentioned in the lecture)

The CD40-CD40ligand interaction stimulates centrocyte expression of IRF4 which represses BCL6


What is protein electrophoresis?

- The laboratory technique whereby serum is placed in a gel and exposed to an electric current
- Five major fractions are normally identified: Serum albumin, Alpha-1 globulins, Alpha-2 globulins, Beta blogulins, Gamma globulins


What is immunofixation?

- Enables the detection and identification of monoclonal immunoglobulins
- Performed when “M-spike” seen on electrophoresis
- Serum or urine is placed on a gel and electric current is applied to separate the proteins
- Anti-immunoglobulin antisera is added to each migration lane
- If the immunoglobulin is present, a complex precipitated


What is myeloma?

An incurable malignant disorder of clonal plasma cells


What is the epidemiology of myeloma?

- Annual incidence of 60-70 per million in the UK
- Median age at presentation = 70 years
- Higher incidence in Afro-Caribbean ethnic groups compared with Caucasians


What is myeloma preceded by?

Monoclonal gammopathy of undetermined significance


What are the diagnostic criteria for myeloma?

Clonal BM plasma cells >10% or biopsy-proven bony or extramedullary plasmacytoma AND any one or more of: CRAB features or MDEs


What are CRAB features?

C = Calcium (elevated)
R = Renal failure
A = Anemia
B = Bone lesions.


What are MDEs?

Myeloma defining events.


What are the three myeloma defining events?

- > 60% clonal plasma cells on BM biopsy
- SFLC ratio >100mg/L provided the absolute level of the involved LC is >100mg/L
- >1 focal lesion on MRI measuring >5mm


What is the effect of myeloma on the kidney?

- 20-25% of patients have renal insufficiency at diagnosis - 50% have renal insufficiency at some point during their disease course
- 50% will have persistent renal impairment despite therapy
- 2-12% will require RRT


How is AKI with suspected myeloma managed?

- Medical emergency
- Blood film
- Electrophoresis
- Immunofixation
- Bone marrow biopsy with flow cytometry
- Dialysis


What is the risk of pogression from MGUS to myeloma?

1% per year


What is AL amyloidosis?

Amyloid light chain (AL) amyloidosis - Light chain fragments misfold and self-aggregate to form beta-pleated fibrils


What are the features of AL amyloidosis?

- Nephrotic-range proteinuria: Mainly albumin. Small monoclonal light chain component
- Cardiac and liver involvement in 30%
- Peripheral neuropathy in 10%
- ESRF in 40%


What is follicular lymphoma?

- Neoplastic disorder of lymphoid tissue
- Type of non-Hodgkin lymphoma characterised by slowly enlarging lymph nodes
- Accounts for approximately 15% of all non-Hodgkin lymphoma diagnoses
- Incidence rises with age
- M=F


What is the acquired chromosomal abnormality in the majority of cases of follicular lymphoma?

Translocation - t(14:18)


What is the consequence of the t(14:18) translocation?

Brings the BCL2 proto-oncogene under the influence of the immunoglobulin heavy-chain gene, leading to over-expression of the BCL2 protein.


What is the survival rate of follicular lymphoma?

Median survival 8-10 years
Five-year overall survival 72-77%


What is the follicular international prognostic index (FLIPI)?

- age >60 years
- Ann Arbor stage III or IV
- LDH above the limit of normal at diagnosis
- Hb

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