paraprotein diseases cls 404 immunology protein abnormalities
Post on 19-Dec-2015
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Objectives
Describe the immunologic characteristics of the following paraprotein diseases:
Multiple Myeloma Monoclonal Gammopathy of Undetermined
Significance (MGUS) Waldenström’s Macroglobulinemia Alpha Heavy Chain Disease Amyloidosis
Objectives
For each disease listed on the previous slide, discuss:
Patient population affected Etiology (when known) Symptoms Prognosis Treatment
Paraprotein Diseases
Caused by malignant changes to plasma cells or the B lymphocyte cell line.
Exhibit either: Excessive amounts of normal immunoglobulin
proteins (Igs) Accumulation of Igs in an abnormal location Structurally abnormal Igs
Review of B lymphocyte cell line Where do B cells mature?
What is the first immunoglobulin produced by B cells?
Where are mature, activated B cells found?
The mature B cell differentiates into which 2 cells?
Bone marrow
IgM with surrogate light chain produced by the pre B cell, complete IgM in the immature B cell
Germinal centers of secondary lymphoid organs such as the spleen
Plasma cells that secrete immunoglobulins (antibodies) & memory B cells
Normal Lymphocytes (left) &Plasma Cell (right) in Peripheral Blood
Note: Plasma cells are not normally seen
in peripheral blood
Review of the basic structure of immunoglobulins
Which of these are the heavy chains?
Name the 5 classes of heavy chain. Gamma, mu, alpha, delta
and epsilon Which of these are the light
chains? Name the 2 classes of light
chain. Kappa and lambda
NH3+
COO-
Review of the basic structure of immunoglobulins
Where is the constant region of the molecule?
Where is the variable region? Which region defines the
specificity of the antibody? Variable
Which region is responsible for the physical properties of the antibody, such as ability to activate complement and binding to macrophages? Constant
NH3+
COO-
Monoclonal Gammopathy
Accumulation of a single protein that arises from proliferation of a single plasma cell clone.
Since each B cell can respond to only one antigenic epitope, a plasma cell derived from that B cell produces antibody that is reactive against that unique epitope (monoclonal antibody).
Malignant changes to that plasma cell result in uncontrolled production of its specific antibody.
The specificity of the monoclonal antibody (M protein) varies between patients, but each affected patient has only one M protein specificity.
Monoclonal Gammopathy
Y
B Cell
Normal
Plasma Cell
Malignant Plasma Cell
YY Y
Y
Y
Y YY
Y
Y
Y
Y
Y
YY
Y
YYY
Y
Y
Y
Y
Y Y
Characteristics
Malignancy of mature plasma cells The most common plasma cell dyscrasia Affects adults between the ages of 40 – 70
Blacks are affected twice as often as whites Men are affected twice as often as women Appears to be an association with certain
occupations and environmental hazards, such as chemicals, radiation, asbestos, etc
Characteristics
Clusters of malignant plasma cells throughout the bone marrow Lytic bone lesions
Bone marrow filled with malignant plasma cells.
Notice the cells of abnormal size and cells with more than one nucleus.
Characteristics
Early in disease, plasma cells with normal appearance and function
Plasma Cell in bone marrow
Characteristics
As disease progresses, appearance and function of plasma cells are both abnormal
Note the cell with two nuclei (at black arrow) and immature cells with prominent nucleoli (at red arrows)
Characteristics
Monoclonal protein present in serum, but decreased levels of other immunoglobulins Monoclonal immunoglobulin is IgG in 50% of cases;
IgA in 25% and IgM in 15-20% of cases. IgD and IgE myeloma is rare.
Structure of the monoclonal immunoglobulin is normal
Excess production of kappa or lambda light chains that are not joined to a heavy chain Bence Jones proteins Found in urine – not seen in serum Structurally normal
Etiology
Multiple chromosomal translocations and genetic deletions affecting the B lymphocyte line lead to the generation of malignant plasma cell clones.
Abnormal clones have adhesion molecules which cause the plasma cells to bond to bone marrow stromal cells.
Cytokines are released from both the plasma cells and the stromal cells Increases the proliferation of the myeloma cells Inhibits apoptosis of myeloma cells
Increases plasma cell population to over 10% of the marrow constituents Normal is <5%
Etiology
Myeloma cells also release factors that increase the formation of blood vessels. This provides the oxygen and nutrients that
promote tumor growth. Plasma cells invade bone cavities, destroying
the structure.
Symptoms
Bone pain & increase in fractures Anemia and bleeding, as malignant plasma cells
crowd out normal hematopoietic cells in the marrow Increased serum calcium as bone is destroyed Impaired renal function
Bence Jones proteins occlude renal tubules Shortness of breath, confusion, and chest pain due to
increased serum viscosity Caused by the excess protein in the serum
Prognosis
Fair with appropriate treatment Survival approximately 3 years
May develop amyloidosis, damaging vital organs
Death occurs due to: Infection
Lower number of WBCs Lower quantities of normal immunoglobulins
Anemia and bleeding Renal failure
Treatment
Chemotherapy Bone marrow transplant – autologous
transplant used following high dose chemotherapy
Corticosteroids – combined with chemotherapy in patients who are not candidates for bone marrow transplant
Bisphosphonates to treat bone symptoms
Characteristics
Also called benign monoclonal gammopathy Precancerous condition Monoclonal protein present without the
invasive symptoms of multiple myeloma Usually seen in people over age 70
Prognosis
Good – patient often remains stable for years May progress to multiple myeloma,
Waldenström's macroglobulinemia, or amyloidosis in some patients
Treatment
As there are no symptoms, there is no need for treatment
Patient will be monitored for an increase in monoclonal protein level and physical symptoms of more serious paraprotein disease
Characteristics
Patients typically older than seen in multiple myeloma Occurs more frequently in males Occurs more frequently in Caucasians
Develops slowly
Characteristics
IgM paraproteinemia Structure of IgM is usually the typical
pentamer, but may be found as a monomer Malignant cells found in the spleen and
lymphoid nodes, as well as the bone marrow Antibody produced may have specificity to
red blood cell antigens agglutination of RBCs in the extremities, blocking
small blood vessels which leads to tissue damage hemolysis of RBCs, resulting in anemia
Etiology
Malignant change effects a cell that lies between the mature B cell and the plasma cell (plasmacytoid lymphocytes)
Plasmacytoid lymphocytes
Symptoms
Anemia Bleeding due to interference between
platelets & coagulation factors Hyperviscosity impairs blood flow to the
fingers, toes, brain, & eyes Accumulation of IgM molecules results in
kidney damage
Treatment
Chemotherapy Plasma exchange to remove excess
immunoglobulins In some cases, bone marrow transplant In some cases, splenectomy (removes B cells
in germinal centers which in turn reduces antibody production)
Characteristics
Lymphoid tissue in the GI tract becomes infiltrated with lymphocytes and plasma cells
Cells may be normal to extremely bizarre in appearance
Alpha chain may have abnormal structure
Prognosis
Guarded – some patients experience complete remission with appropriate therapy while others die despite intensive therapy
When treatment fails, disease progression is rapid Death within 1 year
Other Heavy Chain Diseases
Gamma Heavy Chain Disease – seen in elderly Symptoms –enlarged liver and spleen, recurrent
infections, and anemia Some patients experience no symptoms Treatment with anti-lymphoma drugs and
corticosteroids Mu Heavy Chain Disease – rare
Symptoms include enlarged spleen, liver and abdominal lymph nodes
Survival and response to treatment varies
Amyloidosis
Accumulation of amyloid (a waxy, stringy protein) in patients with persistent infection or plasma cell disorders
Characteristics
Protein comprised of immunoglobulin fragments Variable region All or part of the constant domain
Protein deposits in a variety of tissues Other forms of amyloidosis exist that do not
have an immune basis
Symptoms
Tissue damage from amyloid deposits and inflammation. Numbness, tingling and pain in extremities Major organ failure
Difficulty maintaining blood pressure due to decreased vascular elasticity as amyloid protein deposits build up along blood vessel walls.
Treatment
No specific treatment Treat underlying infection or plasma cell
disorder to limit disease progression Damage done from protein deposits cannot
be reversed Limited use of organ transplants to “stall” the
disease Eventually new organ is damaged by
accumulating amyloid protein