Week 2- Myeloma and other plasma disorders

Question 1

What are the roles of b cells?

Answer 1

Antigen presentation

Antibody production.

Question 2

What are immunoglobulins?

Answer 2

Antibodies produced by B cells and plasma cells. They are proteins made up of five heavy and 2 light chains. Each antibody recognises a specific antigen.

Question 3

Describe the basic structure of immunoglobulins?

Answer 3

The heavy chain makes up the backbone and the light chains are smaller and stuck onto the back. The end of the ‘Y’ shape has the antigen binding sites.

Question 4

What shape is IgM?

Answer 4

Pentamer- with 5 antigen binding sites.

Question 5

What shape is IgA?

Answer 5

Dimer- with two antigen binding sites.

Question 6

What shape is IgG, IgE and IgD?

Answer 6

They are all monomers with one antigen binding site.

Question 7

Describe the development of B cells? In their immature state what are they made up of?

Answer 7

They are initially produced in the bone marrow.

In their immature state they are just made up of Ig. This is made from the V-D-J region. They then exit the bone marrow to reach their target (and change the Ig to an IgE, or IgG etc).

Question 8

Once B cells leave the bone marrow, what class do they have on them?

Answer 8

Initially they are IgM. However they can undergo class switches and switch to IgG, IgE or IgA.

Question 9

NOTE- as part of the maturation process, the B cells at some point have to visit the lymph nodes. What occurs here?

What happens after they leave the lymph nodes?

Answer 9

They are then exposed to antigens. The ones that bind to the antigen survive and the ones that bind the antigen badly will undergo apoptosis.

They will then either return to the bone marrow as plasma cells or circulate as memory cells.

Question 10

What is a plasma cell?

Answer 10

These are essentially antibody producing factories. They produce a lot of protein and therefore have plentiful RNA, and therefore their cytoplasm is blue. They have a pale perinuclear area- which is the golgi apparatus.

Question 11

In healthy individuals, do they have a polyclonal or monoclonal antibody reportoire? How does this differ in malignancy?

Answer 11

In health you should have polyclonal antibodies. In malignancy you tend to have monoclonal antibodies and are therefore susceptible to infection etc etc.

Question 12

In what situations do you get a polyclonal increase in antibody production?

Answer 12

Reactive changes e.g. infection, autoimmune, malignancy (reaction of the host to the malignant clone), liver disease.

Question 13

In what situations do you get a monoclonal rise in antibodies?

Answer 13

All derived from clonal expansion of a single B cell (therefore you only get that one B cells antibody produced).

Question 14

What is the other term for a monoclonal immunoglobulin (antibody)?

Answer 14

A paraprotein.

Question 15

What are paraproteins a marker of?

Answer 15

Underlying clonal B cell disorder.

Question 16

What investigations allow you to detect immunoglobulins?

Answer 16

Serum electrophoresis. The seperated serum proteins appear as distinct bands or zones. The gamma area is where the immunoglobulins are present.

Question 17

What do you use serum immunofixation for?

Answer 17

It is used to classify the abnormal protein bands in the gamma area.

Question 18

What are Bence Jones proteins?

Answer 18

They are light chains found on urine electrophoresis.

Question 19

Why are Bence Jones proteins clinically relevant?

Answer 19

When immunoglobulins are generated, more light chains than heavy chains are produced, therefore excess light chain production is normally about 0.5g/day. However if this increases they can be found in the urine as Bence Jones proteins.

Question 20

What type of free light chains are there? How do they differ on serum electrophoresis?

Answer 20

Kappa and lamda.

Kappa ones are found on their own whereas lamda ones are generally found as a dimer.

Question 21

If you get a polyclonal increase in light chains, what may this be due too?

Answer 21

Infection

(There are other causes but I’m not sure what).

Question 22

If you get a monoclonal increase in light chains, what can this be due too?

Answer 22

Monoclonal means there is only an increase in the one type of light chain e.g. kappa or lamda.

This could be due to disease processes such as muiltiple myeloma.

Question 23

What are some causes of paraproteinaemia?

Answer 23

Myeloma

Amyloidosis

Lymphoma

Asymptomatic myeloma

Solitary or extramedullary plasmacytoma

Chronic lymphocytic leukaemia

Waldenstroms macroglobulinaemia

Question 24

What is myeloma?

Answer 24

A plasma cell malignancy.

Question 25

How does myeloma affect the body?

Answer 25

The clonal plasma cells have direct tumour affects and also the effects of the paraprotein.

Question 26

How does myeloma affect the body (in terms of direct tumour cell affects)?

Answer 26

Bone lesions Increased calcium Bone pain Replace normal bone leading to marrow failure.

Question 27

How does myeloma affect the body (in terms of paraprotein mediated affects)?

Answer 27

Renal failure Immune suppression Hyperviscocity Amyloid

Question 28

NOTE- in myeloma there is an increase in osteoclast activity, and suppresion of osteoblast activity therefore you can get pathological fractures and bone lesions. You can get multiple, punched out lytic lesions in the skull and wedge fractures in the spine etc.

Question 29

What are the symptoms of hypercalcaemia?

Answer 29

STONES-renal colic and hypercalcaemic stones BONES-increased osteolysis and fractures GROANS- abdominal groans- anorexia, NandV. Psychic MOANS- depression, confusion, hallucinations and coma

Question 30

Why do you get hypercalcaemia in muiltiple myeloma?

Answer 30

Breakdown of bone leads to increased calcium levels.

Question 31

How can myeloma affect the kidneys?

Answer 31

30% of patients have renal impairment at diagnosis You can get: Tubular cell damage from the light chains Light chain deposition- cast nephropathy Sepsis Hypercalcaemia and dehydration Drugs- NSAIDs Amyloid Hyperuricaemia

Question 32

NOTE- light chains are filtered by the glomeruli and enter the renal nephron. They are toxic to renal cells and can cause acute tubular necrosis. They can also stick together if the concentration is high enough and cause a plug in the nephron- this can cause acute kidney failure.

Question 33

What is cast nephropathy?

Answer 33

The casts (clumps of light chains) are excreted in the urine. Needs to be treated promptly with steroids, the hypercalcaemia needs to be treated and so does the dehydration.

Question 34

What is the treatment for myeloma?

Answer 34

Use high dose steroids as these are toxic to plasma cells. E.g. dexamethasone or prednisolone. Aklylating agents e.g. cyclophosphamide Novel agents e.g. thalidomide Can use high dose chemo or autologous stem cell transplant in fit patients.

Question 35

How can you monitor response to treatment in myeloma?

Answer 35

Monitor paraprotein levels.

Question 36

What additional treatment (symptomatic) can you give myeloma patients?

Answer 36

Opiate analgesia (avoid NSAIDs as poor renal function) Local radiotherapy- good for pain releif or spinal cord compression Bisphosphonates- corrects hypercalcaemia and bone pain Vertebroplasty- injection of sterile cement into bone to stabilise fractures.

Question 37

What is monoclonal gammopathy of uncertain significance?

Answer 37

Paraprotein of less than 30g/l Bone marrow plasma cells \<10% No evidence of myeloma end organ damage- normal calcium, normal renal function, normal Hb, no lytic lesions, no increase in infections.

Question 38

What is AL amyloidosis?

Answer 38

Its a rare disorder of plasma cell clones. The light chains produced by the plasma cells have just the right structure to stick together and form beta pleated sheets. Instead of being a small soluble protein they become a large sheet of proteins capable of tissue damage.

Question 39

What does accumalation of amyloids in tissues cause?

Answer 39

End organ damage that slowly progresses. It is a multisystem disease. In the kidney- causes nephrotic syndrome In the heart- causes cardiomyopathy In the liver- organomegaly and deranged LFTs Autonomic and peripheral neuropathy Malabsorption in the GI tract.

Question 40

How do you diagnose Al amyloidosis?

Answer 40

Biopsy with staining. Stains congo red. Rectal or fat biopsy may be done if high clinical suspicion. Apple green birefringence under polarised light.

Question 41

What is Waldonstroms macroglobulinaemia?

Answer 41

Clonal disorder of cells intermediate between lymphocyte and plasma cells. Have a characteristic IgM paraprotein.

Question 42

What effects can Waldonstroms macroglobulinaemia cause?

Answer 42

Tumour effects- lymphadenopathy, splenomegaly, marrow failure Paraprotein effects- hyperviscocity, neuropathy

Question 43

What are the clinical features of Waldonstroms macroglobulinaemia?

Answer 43

Hyperviscocity syndrome- fatigue, visual disturbance, confusion, coma, bleeding, cardiac failure B symptoms- night sweats, weight loss Treatment- chemotherapy, plasmapheresis.