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+

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

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

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

The End

Please view the next presentation

“Diagnosis of Paraprotein Diseases”