Monoclonal cell replicates and makes more dysfunctional cells

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Last updated: December 18, 2019

            Monoclonal Gammopathy of Undetermined Significance was aterm introduced over three decades ago. Monoclonal gammopathies reflect conditions in which abnormal amounts ofimmunoglobulins are produced by a clone that developed from a single pro-B germcell and may be part of a disease process or benign (Attaelmannan &Levinson, 2000).  The cause of MGUS isstill unknown.  MGUS was beforeconsidered a benign monoclonal gammopathy but it was then recognized that thedisorder can evolve into a malignant monoclonal gammopathy.  Monoclonal gammopathy is also known asparaproteinemia which is an excessive amount of protein in the blood.              To understand monoclonal gammopathy we must firstunderstand about bone marrow because that is where MGUS originates.  The abnormal proteins found in the blood withmonoclonal gammopathy grow from a small number of plasma cells.

  MGUS is also called pre- myeloma as it isbelieved to be a precursor to this form of cancer.  During a protein electrophoresis there willbe an M-spike where the gamma antibodies are located, and this is wheregammopathy cones from. With MGUS monoclonal expansion takes place.  This means that the cell replicates and makesmore dysfunctional cells and those cells make more dysfunctional cells and soforth.

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  It is of unknown significancebecause it is unknown at which rate the cells will multiply and what percent ofpeople affected will develop Myeloma.Paraproteinsmay be categorized into light chains only, heavy chains only or wholeimmunoglobulins.  The types of lightchains are kappa and lambda and the heavy chains are alpha(IgA) which preventscolonization by pathogens, gamma (IgG) which provides the majority ofantibody-based immunity against invading pathogens, mu(IgM) which eliminatespathogens 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 havenot been exposed to antigens and epsilon (IgE) which binds to allergens andtriggers histamine release from mast cells and basophils (“Antibody”,n.d.). Heavychains or whole immunoglobulins tend to remain within the blood vessels while lightchains frequently escape and are excreted by the kidneys into urine where theytake the name Bence Jones proteins.

 These Bence Jones proteins are produced by neoplastic plasma cells.  The light chains were detected in the past byheating a urine sample which caused the protein to precipitate.  Today electrophoresis of concentrated urineis used.              Heavy chain disease is a form of monoclonal gammopathythat involves the proliferation of cells producing immunoglobulin heavy chains(“Heavy Chain Disease”, n.d.).  Heavychain disease proteins have many deletions in the amino-terminal part.  This makes it difficult for heavy chains toform disulfide bonds with the light chains.

 This deletion leads to aggregation and signaling of the B-cell receptorswhich is probably due to the loss of the anti-aggregating properties of thelight chain (“Heavy chain disease”, n.d.). Immunoglobulins consist of fourpolypeptide chains which include two heavy chains (H chains) and two lightchains (L chains).  Heavy and lightchains are fastened together by disulfide bonds and covalent forces.  The disulfide bonds differ in number at thehinge which is known as the inter H chain region.  This is how you can tell the antibodies onefrom another and determines if it is IgA, IgG, IgM, IgD, and IgE.

  Each whole antibody consists of a constantCOOH terminal end called the Fc region and variable NH2 terminal end called Fab.Fc stands for (Fragment, crystallizable) region and is important in making surethat 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 sitesthat can bind two antigens (in general identical) and, therefore, recognizespecific foreign objects.  The variableend of each antibody controls antigen combining sites, whereas the Fc regioncontains common determinates (Attaelmannan & Levinson, 2000).

              Monoclonal antibodies are made by identical immune cellsthat are clones of a unique parent cell.  Monoclonal antibodies can have monovalent affinity which means that thecan bind to the same epitope.  The IgMand IgD are located on the B-cell surface and are recognition receptors.  These two are also the immunoglobulins formedearly in the normal response to an immunogen. When the B-cell is activated class switching from the IgM and IgD heavychains to the IgG, IgE, and IgA occurs. B-cells then mature and home to the bone marrow.  Monoclonal gammopathies occur when a singleabnormal cell line predominates.  Theabnormal cells may produce an intact immunoglobulin, free light chains withoutheavy chains and rarely heavy chains (Attaelmannan & Levinson, 2000).

              The phenotypic profile of myelomatous plasma cells isCD38+, CD56+ and 19-.  In the person withmonoclonal gammopathy of undetermined significance there are two populations ofplasma cells.  One is normal andpolyclonal CD38+, CD56+, CD19+ and the other is clonal and has an abnormalimmune phenotype CD38+, CD56+, CD19-.  Ahigh monoclonal protein concentration, a high percentage of plasma cells in thebone marrow, an IgA monoclonal protein and an abnormal free light-chain ratioare predictors of an increased risk of progression to Multiple Myeloma andother malignant plasma cell disorders (Blade, 2006.  Many patients with monoclonal gammopathy remainstable for years however many progress to B-cell Lymphoma, Chronic LymphocyticLeukemia, Waldenstrom’s Macoglobulinemia, primary Amyloidosis and MultipleMyeloma.             Out of all the complications monoclonal gammopathy seemsto mostly develop into Multiple Myeloma. With MGUS the M protein level is less than 3 g/dL, the clonal plasmacells in the bone marrow is less than 10% and there is no myeloma definingevent.

  The middle stage to MultipleMyeloma is Smoldering Multiple Myeloma which is asymptomatic.  It is a step closer to Multiple Myeloma asthing begin to progress such as the M protein is now 3g/dL serum or above orequal to 500mg/24 hour in the urine and bone marrow plasma cells above or equalto 10-60%, but at this point the patient still remains asymptomatic.  When monoclonal gammopathy progresses toMultiple Myeloma there I underlying cell proliferate disorder, 1 or moremyeloma defining events, 1 or more CRAB features present which include; calciumelevation, renal impairment, anemia and bone pain, lesions or fractures, clonalplasma cells in bone marrow greater or equal to 60%, serum free light chainration above or equal to 100 and more than one MRI focal lesion.              As described before monoclonal gammopathy bad cells arecloned and the replication continues to occur at an accelerated rate but notenough to impede cell function of the other cells in the bone marrow.  With multiple myeloma occurs the bad cellsare replicated at even faster rate and it crowds the bone marrow making itdifficult 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 toomany 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 thatdissolve your bone.              There are many tests that need to be performed to keep aneye on the monoclonal gammopathy for any sudden changes.  This testing is necessary to determine whichM-protein is causing the immediate problem and can usually be done yearly.  The necessary blood test includes a CBC, aserum creatinine and a serum calcium. These tests are necessary to count the blood cells in your blood, tocheck for a decline in kidney function and to check the amount of calcium inyour blood.  The doctor may ask you tocollect a 24-hour urine to see if any abnormal proteins are being releasedthrough your urine and again to check for any kidney damage.

  Sometime a CT scan, MRI of PET scan may beperformed to see any abnormalities in the bone related to MGUS.  A bone marrow test may also be performed to determinethe percentage of plasma cells present.                Although monoclonal gammopathy of undeterminedsignificance is said to have no symptoms it can cause some medicalproblems.  Peripheral neuropathy iscaused by the MGUS IgM.  The use ofsupplements may be necessary to protect nerve tissue.  People with MGUs are also more at risk forosteoporosis and for increased fractures of the hip and back than the normalpopulation.

  Due to the decreasedproduction of normal immunoglobulins, patients with MGUS are more than twice aslikely 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 infectiousdiseases.         

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