Immunoproliferative disorders 28/02/23 Flashcards
What can hypergammaglobinlinaemias?
They can be monoclonal or polyclonal.
What are gammapathies?
A disorder characterised by abnormality of gamma globulins (antibodies).
Can monoclonal gammopathies be benign or malignant?
They can be benign or malignant and results from a single clone of plasma cells producing high levels of a single class and type of antibody, referred to as monoclonal protein, M protein or Paraprotein.
What are examples of monoclonal gammopathies?
Multiple myeloma, Waldenstrom primary macroglobulinemia, light chain disease, heavy chain disease, and monoclonal gammopathy of undetermined significance.
What are polyclonal gammopathies?
Polyclonal gammopathy is a secondary disease, with increased levels of 2 or more antibodies, produced by several clones of plasma cells.
What is lambda?
A free light chain which is a dimer/large polymer.
What is Kappa?
A free light chain which is a monomer.
How are excess light chains removed from the body?
The excess light chains enter the kidneys and because of their low molecular weight they pass through the glomerulus and into the proximal tubule where they are reabsorbed and degraded into smaller peptides which are then recycled.
How much light chain is secreted normally?
Normally 1-10 mg of light chains daily reach distal tubule and into urine.
How much light chain is secreted in monoclonal gammopathies?
In monoclonal gammopathies the capacity of the proximal tubule can be overwhelmed, so much higher levels of light chains is seen in the urine.
What is a monoclonal gammopathy?
Monoclonal gammopathy is defined as a disease characterised by monoclonal immunoglobulin in the serum and/or urine.
What causes the total plasma immunoglobulin levels?
Total plasma immunoglobulin results from millions of plasma clones, polyclonal antibody response.
What are plasma cells regulated by and why does it go wrong?
Plasma cell production regulated by homeostasis. Chromosome abnormalities allow plasma cells to overcome growth restraints. Growth of abnormal plasma clone which secretes its antibody (monoclonal antibody, paraprotein or M protein).
What causes the B cells to become malignant and become malignant plasma cells?
In a B-cell tumour every cell has an identical immunoglobulin gene rearrangement. This proves they have originated from the same cell. B cell tumours from different patients have different rearrangements and this reflects the diversity of rearrangements found in normal B cells of healthy people. Tumours retain the characteristics of the cell type from which they arose, particularly when the tumour is relatively differentiated (and thus slow growing). Human tumours corresponding to all stages of B cell development have been found. Among the characteristics retained by the tumours is their location in the lymphoid tissues, tumours derived from mature naïve B cells are found in lymph node follicles, forming follicular centre cell lymphoma, whereas plasma cell tumours (called myelomas) are found in the bone marrow. B cell tumours have been useful to learn about the immune system (because can get large quantities of the cells). The first sequences of heavy and light chains were obtained from people with multiple myeloma.
What is MGUS?
MGUS is the commonest subtype of monoclonal gammopathy. Patient does not have symptoms due to the monoclonal gammopathy, so they are picked up doing investigations for another condition.
-Monoclonal band is less than 30g/L.
-Less than 10% plasma cells in the bone marrow.
-The incidence of MGUS increases with age, affecting 1% in >50s, and increasing to 10% in >80s.
-It has a Higher incidence in African-Caribbean patients.
.Most patients die with MGUS rather than because of it, however, 1% transform into the malignant form of MG, known as multiple myeloma.
-Patients with MGUS should be monitored annually to identify patients who have progressed and then be treated.
What is multiple myeloma?
Multiple myeloma demonstrates the following characteristics:
-Cancer of the bone marrow
-Malignant monoclonal proliferation of bone marrow marrow plasma cells, and accumulation of plasma cells in the bone marrow
-Lytic bone lesions
-Monoclonal immunoglobulin in serum and/or urine
-Typically present with bone pain, anaemia, infections, renal failure, and sometimes hyper viscosity syndrome
What are the typical laboratory tests and results for MM patients?
Laboratory features:
-Electrophoresis of serum or urine shows a monoclonal protein in 90% of patients
-Increased serum calcium, low haemoglobin, raised mean cell volume (MCV) and increased erythrocyte sedimentation rate
What is the incidence of MM?
Give incidence overall it is a relatively common malignancy in the elderly, affecting 3 per 100,000, but is very rare in those less than 40 years. MM thought to possibly result from excess production of IL-6. Rapidly progressive if untreated, patients usually die within a year. With standard chemo, life expectancy following diagnosis was 3 years, although survival is now increasing due to more aggressive treatments. Median age for the disease is 65-70 years old.
What are the types of paraprotein secreted?
The type of protein produced by the clone of abnormal plasma protein cells varies.
Most produce a whole immunoglobulin molecule comprising heavy and light chain molecules.
-IgG 60%
-IgA 20%
-IgD 1%
-IgE very rare
-IgM is even rarer
About 10% of myeloma patients have a clone producing one of the light chains only.
in less than 1 % of myelomas the cells are so abnormal they cannot secrete the Ig (but can be seen in the cytoplasm). This is known an non-secretory myeloma. On bone marrow examination there are large numbers of plasma cells, greater than 10% of nucleated bone marrow cells and their cells are packed with one immunoglobulin isotype. More rarely, the cells cannot produce Ig/Ig fragments, this is known as non-producing myeloma.
What is the Bence Jones protein?
The monoclonal light chain may be synthesised in excess and as it has a low molecular weight it is excreted by the kidney. This is known as Bence-Jones protein.
This monoclonal antibody is shown by doing serum protein electrophoresis, followed by densitometry and is evident as a tall peak.
What do patients suspected of having MM require?
All patients with suspected multiple myeloma require a 24-hour urinalysis by protein electrophoresis to determine the presence of Bence Jones proteinuria and kappa or lambda light chains. In patients with renal involvement, Fanconi syndrome may be the presenting manifestation. This syndrome is characterized by aminoaciduria, hyponatremia, hypoglycaemia associated with glucosuria, low anion gap and hyperchloremic metabolic acidosis. If multiple myeloma is strongly suspected and electrophoresis is “normal,” serum immunofixation may be more sensitive in identifying a small M protein. Only rarely is there no monoclonal proliferation (i.e., non-secretory multiple myeloma), which occurs in 1 percent of patients.
MM summary?
-All secretory myelomas produce excess free light chains
-If renal function is good it can rapidly deal with large quantities of monoclonal light chains
-Free light chains may be produced in quantities that overwhelm the tubules and appear in the urine as proteinuria
-Proteinuria is defined as the presence of protein in the urine. Proteins filtered through the glomeruli should be actively reabsorbed in the tubules and so proteinuria should normally be absent or minimal
-The Light chains are monoclonal and on urine electrophoresis form discrete bands and immunofixation determines whether κ or λ
-The monoclonal light chains are known as Bence Jones and they found in the urine of patients with renal failure
-As the myeloma progresses, the renal tubules suffer increasing damage resulting in deteriorating, and this and may be the presenting symptom
What is immune paresis?
Light chain myeloma often have immune paresis. Immune paresis is suppression of normal immunoglobulin production by a malignant plasma clone. Low immunoglobulin levels may be the only sign of a small serum free light chain or an IgD monoclone (reason for doing immunofixation on samples with low immunoglobulin even if no abnormal electrophoretic band seen in serum electrophoresis).
What happens to the bones during MM?
Bone damage is due to the breakdown of the homeostatic control of bone remodelling by osteoclasts and osteoblasts. Osteoclasts dissolve bone and in the myeloma patient their activity is upregulated where the myeloma cells are found, as there is an imbalance in the regulatory system. Plasma cells often proliferate in bone forming areas which are replaced by a circular clone of plasma cells. This results in bone lesions (lytic lesions/osteolytic lesions) that on x-ray look like holes punched out of bone.
Multiple myeloma is not confined to a specific bone or location within a bone (often found in skull but can affect any part of the skeleton). It tends to involve the entire skeleton. When only one lesion is found it is called a plasmacytoma. Most doctors believe that plasmacytoma is simply an early, isolated form of multiple myeloma. Plasma cells release IL-6 which acts as Osteoclast activating factor, which may be responsible for the lytic lesions and the associated generalised osteoporosis.
