Paraprotein Diseases

1. Paraprotein Diseases CLS 404 Immunology Protein Abnormalities

2. 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

3. Objectives • For each disease listed on the previous slide, discuss: • Patient population affected • Etiology (when known) • Symptoms • Prognosis • Treatment

4. Dysproteinemia • Any serum protein abnormality

5. 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

6. 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 Review of B lymphocyte cell line

7. Normal Lymphocytes (left) &Plasma Cell (right) in Peripheral Blood Note: Plasma cells are not normally seen in peripheral blood

8. 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-

9. 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-

10. 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.

11. Monoclonal Gammopathy B Cell Malignant Plasma Cell Y Y Y Y Normal Plasma Cell Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y

12. Multiple Myeloma Kahler’s disease

13. 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

14. 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.

15. Characteristics • Early in disease, plasma cells with normal appearance and function Plasma Cell in bone marrow

16. 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)

17. 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

18. 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%

19. 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.

20. 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

21. 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

22. 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

23. MGUS Monoclonal Gammopathy of Undetermined Significance

24. 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

25. Symptoms • None

26. Prognosis • Good – patient often remains stable for years • May progress to multiple myeloma, Waldenström's macroglobulinemia, or amyloidosis in some patients

27. 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

28. Waldenström's Macroglobulinemia Lymphoplasmacytic Lymphoma

29. Characteristics • Patients typically older than seen in multiple myeloma • Occurs more frequently in males • Occurs more frequently in Caucasians • Develops slowly

30. 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

31. Etiology • Malignant change effects a cell that lies between the mature B cell and the plasma cell (plasmacytoid lymphocytes) Plasmacytoid lymphocytes

32. 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

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

34. 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)

35. Alpha Heavy Chain Disease Mediterranean Lymphoma

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

37. 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

38. Symptoms • Diarrhea • Malabsorption • Weight loss

39. 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

40. Treatment • Antibiotics • Anti-lymphoma therapy • Corticosteroids

41. 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

42. Amyloidosis Accumulation of amyloid (a waxy, stringy protein) in patients with persistent infection or plasma cell disorders

43. Characteristics • Usually occurs in the elderly • More common in men

44. 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

45. 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.

46. Prognosis • Poor in many cases – death in 1-2 years

47. 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

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