Myeloma & Plasma Cell Dyscrasias Flashcards by Nicolas Persson

What are functions of B cells?

Antibody production
Acting as antigen presenting cells

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What are B cells derived from?

Pluripotent HSCs in marrow

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What are immunoglobulins?

Antibodies produced by B cells and plasma cells

Each Immunoglobulin recognises a specific antigen; can be expressed on B cell surface (as the B cell receptor) or released into the blood stream as antibodies by plasma cells

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What are immunoglobulins made of?

Made up of 2 heavy (μ, α, δ, γ, or ε) and 2 light chains (κ or λ)

The heavy chain type determines the class of antibody produced e.g. gamma heavy chains found in IgG antibodies, mu heavy chains found in IgM antibodies

All antibodies will contain either kappa or lambda light chains e.g. IgGK, IgAL

Together the type of heavy and light chains are called the isotype of the antibody

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What chain type determines class of antibody produced?

Heavy chain

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What immunoglobulins are monomers?

IgD, IgE, IgG

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What immunoglobulin is a dimer?

IgA

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What immunoglobulin is a pentamer?

IgM

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Describe B cell development

Initial production and development takes place in the bone marrow

Under control / influence of microenvironment

Ig variable element generated from V-D-J region recombination early in development

Self-reactive cells removed

Immature B cells with immunoglobulin (Ig) on their surface exit bone marrow ready to meet their target

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What does VDJC stand for in VDJ recombination?

Light chains have only V and J segments so less diversity

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What enzymes do the actual cleavage and recombination in VDJ recombination?

RAG 1 and RAG2

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How does VDJ recombination of heavy chain gene segments work?

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Where do B cells go in the periphery?

Travel to follicle germinal centre of the lymph node where they encounter antigen

Identify the antigen and improve the fit by somatic hypermutation or are deleted

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What is somatic hypermutation?

B cells expressing BCR with high affinity for antigen survive and proliferate

Those with poor affinity undergo apoptosis

Somatic so only affects VDJ segments, does not affect germline DNA, so not passed on

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What is class switching?

This is how we are able to produce a near infinite variety of highly specific B cell receptors and hence antibodies

Similar process occurs for T cells

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Draw out normal B lymphocyte maturation

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What is the plasma cell?

A factory cell that pumps out antibodies

Eccentric clock face nucleus on H+E; open chromatin (synthesising mRNA); plentiful blue cytoplasm (laden with protein); pale perinuclear area (Golgi apparatus)

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Describe what can cause a polyclonal increase in immunoglobulins

Produced by many different plasma cell clones
Reactive to:
- Infection
- Autoimmune
- Malignancy: reaction of the host to the malignant clone
- Liver disease

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Describe monoclonal rise in immunoglobulins

All derived from clonal expansion of a single B cell

Identical antibody structure and specificity (identical size and charge)

Monoclonal immunoglobulin = paraprotein

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What is a paraprotein?

Monoclonal immunoglobulin

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What is a paraprotein a marker of?

Underlying clonal B cell or plasma cell disorder

How do we detect immunoglobulins?

Serum electrophoresis

What is serum immunofixation?

To classify abnormal protein bands

What is Bence Jones protein?

An unusual protein precipitate found on warming urine which redissolved when heated

100 years later BJP identifies as immunoglobulin light chains

Detected by urine electrophoresis and immunofixation

Describe why excess free light chains can appear in urine

When immunoglobulins are synthesised in plasma cells, more light chains than heavy chains are produced and free light chains are secreted into plasma along with intact immunoglobulin In a normal person, approximately half a gram of free light chains are produced per day. Kappa free light chain is usually present as monomers while lambda is predominantly dimeric If there is a polyclonal increase in the number of plasma cells (possibly due to infection) or a monoclonal increase, due to multiple myeloma, then the amount of free light chains in the plasma will increase

What are causes of paraproteinaemia?

How does myeloma happen?

What is monoclonal gammopathy of undetermined significance (MGUS)?

Usually a small amount of paraprotein Bone marrow plasma cells <10% No evidence of myeloma end organ damage (normal calcium, normal renal function, normal haemoglobin, no lytic lesions, no increase in infections; very common)

How does myeloma affect the body?

How is myeloma classified?

What is the pathophysiology of lytic bone disease?

What are symptoms of hypercalcemia?

Stones Bones Abdominal groans Psychiatric moans Thirst, dehydration Renal impairment

What drugs can be used for hypercalcemia?

Bisphosphonates such as pamidronate act by inhibiting osteoclasts

Why does myeloma cause renal failure?

30% of patients have renal impairment at diagnosis Tubular cell damage by excess light chains Light chain deposition tubules; cast nephropathy

What is cast nephropathy?

Damage may be reversible with prompt treatment Hydration, stop nephrotoxic drugs Switch off light chain production with steroids / chemo

How do we treat myeloma and how do we monitor response?

What is autologous haemopoeitic stem cell transplant?

A way of delivering high dose chemotherapy relatively safely

How do you control symptoms in myeloma?

Opiate analgesia (avoid NSAIDs) Local radiotherapy - good for pain relief or spinal cord compression Bisphosphonates - corrects hypercalcemia and bone pain Vertebroplasty - inject sterile cement into fractured bone to stabilise

What is amyloidosis?

Group of disorders characterised by faulty misfolded proteins which clump together to form insoluble aggregates in tissue (amyloid)

What is AL amyloidosis?

Rare disorder- due to small plasma cell clone like in MGUS Mutation in light chain > altered structure Misfolded light chains precipitate in tissues as an insoluble beta pleated sheet that forms long fibrils Amyloid accumulation in tissues causes organ damage, slowly progressive

How do you treat AL amyloidosis?

Chemo to switch off abnormal light chain supply Poor prognosis if cardiac amyloid

Describe organ damage in AL amyloid

Describe how to diagnose amyloidosis

Organ biopsy confirming AL amyloid deposition - Congo red stain - Rectal or fat biopsy may be done if high clinical suspicion (less invasive) Evidence of deposition in other organs - SAP scan - Echo / cardiac MRI - Nephrotic range proteinuria

What is seen on Congo red staining in AL Amyloidosis?

What is a SAP scan?

What is Waldenström's Macroglobulinemia (IgM paraprotein)?

IgM antibody is what shape?

Pentameric

What are clinical features of Waldenstrom's?

What is treatment for Waldenstrom's?

Chemotherapy Plasmapheresis (removes paraprotein from circulation)

How do we treat hyperviscosity?

Remove patient plasma rich in IgM paraprotein Replace with donor plasma Viscosity reduced