1. CLS 404 Immunology Protein Abnormalities
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. 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

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+
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-

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
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

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. Monoclonal Gammopathy of Undetermined Significance
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. Please view the next presentation “Diagnosis of Paraprotein Diseases”
The End
Please view the next presentation
“Diagnosis of Paraprotein Diseases”