CLS 404 Immunology Protein Abnormalities Paraprotein Diseases CLS 404 Immunology Protein Abnormalities

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

Dysproteinemia Any serum protein abnormality

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+ The constant region is at the carboxyl end of the molecule. The structure at this end of the Ig is the same for each molecule of that heavy class. The variable region is at the amino end of the molecule. The structure at this end varies to accommodate the specificity of the antibody. 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 B Cell Malignant Plasma Cell Y Y Y Y Normal Plasma Cell Y Y Y Y Y Y Y Y Y The malignant plasma cell will replicate more quickly, and produce more antibody than the normal plasma cell. Y Y Y Y Y Y Y Y Y Y Y Y Y

Multiple Myeloma Kahler’s disease

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

Monoclonal Gammopathy of Undetermined Significance MGUS Monoclonal Gammopathy of Undetermined Significance

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

Symptoms None

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

Waldenström's Macroglobulinemia Lymphoplasmacytic Lymphoma

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

Prognosis Survival usually better than with multiple myeloma - approximately 5 years

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)

Alpha Heavy Chain Disease Mediterranean Lymphoma

Characteristics Affects young adults More common in those of Mediterranean or Middle Eastern decent

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

Symptoms Diarrhea Malabsorption Weight loss

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

Treatment Antibiotics Anti-lymphoma therapy Corticosteroids

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 Usually occurs in the elderly More common in men

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.

Prognosis Poor in many cases – death in 1-2 years

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

Please view the next presentation “Diagnosis of Paraprotein Diseases” The End Please view the next presentation “Diagnosis of Paraprotein Diseases”