Plasma Cell Disorders Flashcards
Describe a typical appearing plasma cell.
eccentric nucleus with blue cytoplasm and perinuclear bare spot (hoff body); nuclear chromatin may have “clock face chromatin”
Describe the differentiation of B cell that occurs in the bone marrow and the lymph node.
VDJ recombination occurs within the bone marrow
Mature cells after meeting their antigen can undergo hypermutation within the germinal center
Ig class switching can occur with the help of T cell
Plasma cells produce antibodies that are useful in 3 main ways to fight infection.
neutralization through adherence to bacteria
opsonization to promote phagocytosis
activation of complement which causes lysis and enhances opsonization
Where can plasma cell be found?
after exiting the germinal center, plasma cells migrate to the medullary cords or leave via the efferent lymphatics and migrate to the bone marrow (via cytokines)
Describe what is the purpose of the variable regions of the heavy and light chains and which determines the isotope?
variable regions of H and L chains form the antigen binding site, the heavy chain determines the isotope of the chain
Note the salient structural features of IgG, IgA, IgM, and IgE.
IgG: most common, forms monomers (gamma HC)
IgA: forms dimers, mucosal surfaces (alpha HC)
IgM: large pentameric molecules, very glycosolated and activate complement well (mu HC)
IgE: involved in allergenic reaction (epsilon HC)
Note the common locations of IgG, IgA, IgM, and IgE.
IgG: crosses placenta, interstitial space
IgM: primarily intravascular space
IgA secreted in gut, lungs and breast milk
IgE: associated with mast cell and below epiethelial surfaces
Describe how a SPEP or UPEP results may signify production of monoclonal antibodies.
antibodies are contained in the gamma globulin region on an electrophoresis, polyclonal populations will lead to a broad hump in the gamma globulin region, monoclonal antibody production will lead to “church steeple” spike instead (there is no way to know protein isotope from SPEP)
*note elevated or broader than normal humps can signify hyper gammaglobenemia
How can UPEP results in combination with SPEP results be diagnostic?
SPEP may only show hypogammaglobinemia, some myelomas only secrete light chain and the way to detect light chain is through its secretion in urine
if a cancer produces exclusively light chain, there may be a decrease of intact immunoglobin in the plasma
What is the purpose of immunofixation?
determining the isotype of gamma globulin present (does not quantify immunoglobulin)
serum is run on gel in several lanes and then each lane fixed with antisera, after washing the gel is stained for a specific class of immunoglobulin
What is MGUS?
(4% of population has) monoclonal gammaopathy without clinical or histologic evidence of neoplasia (low volume monoclonal growth, most are asymptomatic)
10-25% of patients with MGUS go on to develop myeloma, risk of progression of MGUS is est. at 1%/ year
Define multiple myeloma.
plasma cell neoplasia that originate from a post-germinal center (long-lived) plasma cell
What populations have higher risk for multiple myeloma
incidence is rising and is higher in the aged, in men, 2x higher in AfAm, those who have a family history, a radiation exposure, farming exposure or agent orange exposure
Describe the molecular causes of plasma cell myeloma.
associated with primary translocations involving the immunoglobulin chain IgH (heavy chain) or either light chain locus; all MM have numeric or chromosomal structural abnormalities
i.e. MMSET< cyclin D3, D1, c-MAF, MAFB
What pathways, when mutated, have shown to be associated with MM?
NFkappaB pathway activation
MAPK pathway
Malignant plasma cells cause bone marrow infiltration, osteolysis and paraprotein production, what are the consequences of these abnormalities?
bone marrow infiltration: bone marrow failure: anemia and infections
osteolysis: pathological fractures and lytic bone lesions, hypercalciema
paraprotein production: kidney damage and amyloid deposition, may interfere with clotting
How does MM contribute to bone lesions?
myeloma cells produce osteoclast activating factor RANKL as well as inhibits signally which inhibits osteoblast differentiation via DKK1
increases osteoclast activity and decreases osteoblast activitivity
Which are the most common monoclonal proteins among MM patients?
IgG 52%
IgA 21%
light chain only 16%
Very few: IgD, IgE
Describe the process and cause of Reuleaux formation.
formation of RBC stacks is due to excess antibodies neutralizing the charge on RBC and allowing them to clump together
Describe the bone marrow biopsy of a patient with MM.
hyper cellular marrow with predominantly plasma cells,
What is cast nephropathy?
excess gamma globulin cannot be absorbed by proximal tubules and it reaches the distal tubules forming casts and areas of blockage (can lead to glomerular unit death)
What is plasmacytoma?
localized tumors of plasma cells (can or don’t have to be associated with bone structure
Discuss possible treatments for MM.
chemotherapy and radiotherapy (new agents thalidomide or bortezomib- proteasome inhibitor)
bisphosphonates to slow bone destruction and treat hyeprcalcemia
pain control and palliative measures, avoid dehydration and nephrotoxic drugs
autologous stem cell transplant (mostly incurable 3-5yr survival)
What is Waldenstrom’s Macroglobulinemia?
a mixture of clonal related lymphoid, lymphoplasmacytoid and plasma cells secreteing monoclonal IgM (causes hyper viscosity) and infiltrate marrow, lymph nodes, and spleen
