Monoclonal Gammopathy of Undetermined Significance was a
term introduced over three decades ago.
Monoclonal gammopathies reflect conditions in which abnormal amounts of
immunoglobulins are produced by a clone that developed from a single pro-B germ
cell and may be part of a disease process or benign (Attaelmannan &
Levinson, 2000). The cause of MGUS is
still unknown. MGUS was before
considered a benign monoclonal gammopathy but it was then recognized that the
disorder can evolve into a malignant monoclonal gammopathy. Monoclonal gammopathy is also known as
paraproteinemia which is an excessive amount of protein in the blood.
To understand monoclonal gammopathy we must first
understand about bone marrow because that is where MGUS originates. The abnormal proteins found in the blood with
monoclonal gammopathy grow from a small number of plasma cells. MGUS is also called pre- myeloma as it is
believed to be a precursor to this form of cancer. During a protein electrophoresis there will
be an M-spike where the gamma antibodies are located, and this is where
gammopathy cones from. With MGUS monoclonal expansion takes place. This means that the cell replicates and makes
more dysfunctional cells and those cells make more dysfunctional cells and so
forth. It is of unknown significance
because it is unknown at which rate the cells will multiply and what percent of
people affected will develop Myeloma.
may be categorized into light chains only, heavy chains only or whole
immunoglobulins. The types of light
chains are kappa and lambda and the heavy chains are alpha(IgA) which prevents
colonization by pathogens, gamma (IgG) which provides the majority of
antibody-based immunity against invading pathogens, mu(IgM) which eliminates
pathogens in the early stages of B-cell immunity before there is sufficient IgG,
delta (IgD) which functions mainly as an antigen receptor on B cells that have
not been exposed to antigens and epsilon (IgE) which binds to allergens and
triggers histamine release from mast cells and basophils (“Antibody”,n.d.). Heavy
chains or whole immunoglobulins tend to remain within the blood vessels while light
chains frequently escape and are excreted by the kidneys into urine where they
take the name Bence Jones proteins.
These Bence Jones proteins are produced by neoplastic plasma cells. The light chains were detected in the past by
heating a urine sample which caused the protein to precipitate. Today electrophoresis of concentrated urine
Heavy chain disease is a form of monoclonal gammopathy
that involves the proliferation of cells producing immunoglobulin heavy chains
(“Heavy Chain Disease”, n.d.). Heavy
chain disease proteins have many deletions in the amino-terminal part. This makes it difficult for heavy chains to
form disulfide bonds with the light chains.
This deletion leads to aggregation and signaling of the B-cell receptors
which is probably due to the loss of the anti-aggregating properties of the
light chain (“Heavy chain disease”, n.d.). Immunoglobulins consist of four
polypeptide chains which include two heavy chains (H chains) and two light
chains (L chains). Heavy and light
chains are fastened together by disulfide bonds and covalent forces. The disulfide bonds differ in number at the
hinge which is known as the inter H chain region. This is how you can tell the antibodies one
from another and determines if it is IgA, IgG, IgM, IgD, and IgE. Each whole antibody consists of a constant
COOH terminal end called the Fc region and variable NH2 terminal end called Fab.
Fc stands for (Fragment, crystallizable) region and is important in making sure
that each antibody gives an appropriate immune response for a given antigen. Fab stands for (fragment antigen-binding)
region. It consists of the arms of the Y, for example which contain the sites
that can bind two antigens (in general identical) and, therefore, recognize
specific foreign objects. The variable
end of each antibody controls antigen combining sites, whereas the Fc region
contains common determinates (Attaelmannan & Levinson, 2000).
Monoclonal antibodies are made by identical immune cells
that are clones of a unique parent cell.
Monoclonal antibodies can have monovalent affinity which means that the
can bind to the same epitope. The IgM
and IgD are located on the B-cell surface and are recognition receptors. These two are also the immunoglobulins formed
early in the normal response to an immunogen.
When the B-cell is activated class switching from the IgM and IgD heavy
chains to the IgG, IgE, and IgA occurs.
B-cells then mature and home to the bone marrow. Monoclonal gammopathies occur when a single
abnormal cell line predominates. The
abnormal cells may produce an intact immunoglobulin, free light chains without
heavy chains and rarely heavy chains (Attaelmannan & Levinson, 2000).
The phenotypic profile of myelomatous plasma cells is
CD38+, CD56+ and 19-. In the person with
monoclonal gammopathy of undetermined significance there are two populations of
plasma cells. One is normal and
polyclonal CD38+, CD56+, CD19+ and the other is clonal and has an abnormal
immune phenotype CD38+, CD56+, CD19-. A
high monoclonal protein concentration, a high percentage of plasma cells in the
bone marrow, an IgA monoclonal protein and an abnormal free light-chain ratio
are predictors of an increased risk of progression to Multiple Myeloma and
other malignant plasma cell disorders (Blade, 2006. Many patients with monoclonal gammopathy remain
stable for years however many progress to B-cell Lymphoma, Chronic Lymphocytic
Leukemia, Waldenstrom’s Macoglobulinemia, primary Amyloidosis and Multiple
Out of all the complications monoclonal gammopathy seems
to mostly develop into Multiple Myeloma.
With MGUS the M protein level is less than 3 g/dL, the clonal plasma
cells in the bone marrow is less than 10% and there is no myeloma defining
event. The middle stage to Multiple
Myeloma is Smoldering Multiple Myeloma which is asymptomatic. It is a step closer to Multiple Myeloma as
thing begin to progress such as the M protein is now 3g/dL serum or above or
equal to 500mg/24 hour in the urine and bone marrow plasma cells above or equal
to 10-60%, but at this point the patient still remains asymptomatic. When monoclonal gammopathy progresses to
Multiple Myeloma there I underlying cell proliferate disorder, 1 or more
myeloma defining events, 1 or more CRAB features present which include; calcium
elevation, renal impairment, anemia and bone pain, lesions or fractures, clonal
plasma cells in bone marrow greater or equal to 60%, serum free light chain
ration above or equal to 100 and more than one MRI focal lesion.
As described before monoclonal gammopathy bad cells are
cloned and the replication continues to occur at an accelerated rate but not
enough to impede cell function of the other cells in the bone marrow. With multiple myeloma occurs the bad cells
are replicated at even faster rate and it crowds the bone marrow making it
difficult for all other cell functioning to occur. When this action happens,
the antibodies made to fight infection cannot be made. In multiple myeloma the body releases too
many proteins into your bones and blood.
This causes a build up in your body and the result is organ damage. Next the plasma cells release chemicals that
dissolve your bone.
There are many tests that need to be performed to keep an
eye on the monoclonal gammopathy for any sudden changes. This testing is necessary to determine which
M-protein is causing the immediate problem and can usually be done yearly. The necessary blood test includes a CBC, a
serum creatinine and a serum calcium.
These tests are necessary to count the blood cells in your blood, to
check for a decline in kidney function and to check the amount of calcium in
your blood. The doctor may ask you to
collect a 24-hour urine to see if any abnormal proteins are being released
through your urine and again to check for any kidney damage. Sometime a CT scan, MRI of PET scan may be
performed to see any abnormalities in the bone related to MGUS. A bone marrow test may also be performed to determine
the percentage of plasma cells present.
Although monoclonal gammopathy of undetermined
significance is said to have no symptoms it can cause some medical
problems. Peripheral neuropathy is
caused by the MGUS IgM. The use of
supplements may be necessary to protect nerve tissue. People with MGUs are also more at risk for
osteoporosis and for increased fractures of the hip and back than the normal
population. Due to the decreased
production of normal immunoglobulins, patients with MGUS are more than twice as
likely to get viral and bacterial infections. These patients should practice good hand hygiene,
get a yearly flu shot and stay clear of friends and family members with infectious