Monoclonal and Polyclonal Gammopathies

Author: WADJORE DAMA Francis
Date: 20/07/2007



Disturbance in synthesis of immunoglobulins; proteins having antibody activity increase greatly in the blood.

A) Polyclonal gammopathies

heteregeneous increase in immunoglobulins involving more than one cell line, maybe cause by any of variety of infiammatory, infectuous or neoplastic disorder.
The most common conditions in the differential diagnosis of polyclonal gammopathy are listed in Table 1

B) Monoclonal Gammopathies

The monoclonal gammopathies, also called paraproteinemias or dysproteinemias, are a group of disorders characterized by the proliferation of one or more clones of differentiated B lymphocytes that each produce an immunologically homogeneous immunoglobulin commonly referred to as a paraprotein or monoclonal (M) protein. The circulating M-protein may consist of an intact immunoglobulin, the light chain only, or (rarely) the heavy chain only. The heavy chain is from one of the five immunoglobulin classes G, A, M, D or E, while the light chain is either kappa or lambda in type.The monoclonal gammopathies encompass a number of diseases including.

a) Multiple myeloma 60% Malignancy of IgG-secreting plasm cell

Multiple myeloma (also known as myeloma or plasma cell myeloma) is a progressive hematologic (blood) disease. It is a cancer of the plasma cell, an important part of the immune system that produces immunoglobulins (antibodies) to help fight infection and disease. Multiple myeloma is characterized by excessive numbers of abnormal plasma cells in the bone marrow and overproduction of intact monoclonal immunoglobulin (IgG, IgA, IgD, or IgE) or Bence-Jones protein (free monoclonal κ and λ light chains). Hypercalcemia, anemia, renal damage, increased susceptibility to bacterial infection, and impaired production of normal immunoglobulin are common clinical manifestations of multiple myeloma. It is often also characterized by diffuse osteoporosis, usually in the pelvis, spine, ribs, and skull.

b)"Waldenströms macroglobulinemia(WM)":10% hypersecreton of IgM

Discovered In 1944, by Jan Gosta Waldenstrom (1906-1996), a Swedish physician
The Waldenstrom's macroglobulinemia is a rare, chronic cancer that is classified as a plasma cell neoplasm. It affects plasma cells, which develop from white blood cells called B-lymphocytes, or B cells.
B cells form in the lymph nodes and the bone marrow, the soft, spongy tissue inside bones. They are an important part of the body's immune (defense) system. Some B cells become plasma cells, which make, store, and release antibodies. Antibodies help the body fight viruses, bacteria, and other foreign substances.
Abnormal plasma cells multiply out of control. They invade the bone marrow, lymph nodes, and spleen and produce excessive amounts of an antibody called IgM. Excess IgM in the blood causes hyperviscosity (thickening) of the blood.
Waldenstrom's macroglobulinemia usually occurs in people over age 65, but can occur in younger people. A review of cancer registries in the United States found that the disease is more common among men than women and among whites than blacks.
Some patients do not experience symptoms. Others may have enlarged lymph nodes or spleen, and may experience fatigue, headaches, weight loss, a tendency to bleed easily, visual problems, confusion, dizziness, and loss of co-ordination. These symptoms are often due to the thickening of the blood. In extreme cases, the increased concentration of IgM in the blood can lead to heart failure.
symptoms,prognosis and treatments in WM.doc


d) Monoclonal gammopathy of undetermined significance 10%
INTRODUCTION: Monoclonal gammopathy of undetermined significance is an asymptomatic disorder associated with serum monoclonal immunoglobulin spike. Its incidence is about 1% in patients of 50 years of age, and rapidly increases in elderly patients. CURRENT KNOWLEDGE AND KEY POINTS: Within the 20 years following diagnosis, about 25% of patients will evolve towards either multiple myeloma (for patients with IgG or IgA) or malignant lymphoproliferative disorder (for patients with IgM). Definition, circumstances associated with a transient monoclonal spike, and currently available parameters used for differential diagnosis with either multiple myeloma or malignant lymphoproliferative disorder are successively discussed. One part of the most usual biological parameters is of prognostic value, and is reviewed in more detail. Recent data concerning immunophenotype, cytogenetics and molecular biology of plasma cells reinforce the link between the asymptomatic condition and multiple myeloma. In monoclonal gammopathy of undetermined significance, some plasma cells resemble normal or reactive plasma cells, whereas others mimic those found in multiple myeloma. FUTURE PROSPECTS AND PROJECTS: The most recent biological data are also discussed in order to evaluate whether some would help to discriminate those patients who will remain asymptomatic lifelong from those who will evolve towards multiple myeloma.

e)Rare cause: systemic amyloid light-chain (AL) amyloidosis, solitary plasmacytoma, heavy chain disease

Characteristics features of monoclonal gammopathies in Table 0

C) Hypogammaglobinemia (no peak or shallow peak in gamma range)

a)Due to inherited immune deficiency:

a1)X-linked IgA deficiency: common 1/750birth
a2) Agammaglobulinemia:rare

b) acquired causes: malignancies, immunosuppressive drugs, HIV, measles, malnutrition.

It is extremely important to differentiate monoclonal from polyclonal gammopathies. Monoclonal gammopathies are associated with a clonal process that is malignant or potentially malignant. In contrast, polyclonal gammopathies may be caused by any reactive or inflammatory process, and they usually are associated with nonmalignant conditions.


Protein eletroforesis
Protein electrophoresis should be undertaken whenever multiple myeloma, Waldenström's macroglobulinemia, or MGUS is suspected.

Immunotyping is used to identify the clonality (type) of M-proteins observed on electrophoresis and to probe further for the presence of monoclonal proteins when suspicion persists despite a normal protein electrophoretogram. In addition, screening for systemic AL amyloidosis requires the use of serum and urine immunotyping since the quantity of M proteins in the vast majority of cases is too small to be detected by electrophoresis.

Quantitation of immunoglobulin
Quantitation of IgG, IgA and IgM, is routinely carried out by nephelometric and turbidimetric procedures that measure the light scattered by the macromolecular lattices formed from the reaction of immunoglobulin heavy chains with polyvalent class-specific heavy chain antisera. These procedures are currently fully automated which makes them convenient to use both in serial monitoring of disease progression in monoclonal gammopathy and in monitoring for hyperviscosity syndrome. In addition, quantitation is clinically useful in detecting and monitoring the polyclonal hypogammaglobulinemia that results from functional impairment of the normal immunoglobulin producing cells of the bone marrow by excessive expansion of the malignant clone(s).

Serum viscosity
Determination of serum viscosity is clinically indicated in any patient with a monoclonal gammopathy and symptoms of oronasal bleeding, blurred vision, dilatation of retinal veins, flame-shaped retinal hemorrhages, unexplained congestive heart failure, or neurologic symptoms such as headaches, vertigo, nystagmus, deafness, tinnitus, ataxia, diplopia, paresthesias, disorientation, stupor, or somnolence.

Cryoglobulins are immunoglobulins and complement components that precipitate upon refrigeration of serum. The major clinical manifestations of mixed cryoglobulinemia include palpable purpura, arthralgias, lymphadenopathy, hepatosplenomegaly, peripheral neuropathy, and hypocomplementemia (with the fall in C4 levels often being most prominent). For patients for whom cryoglobulinemia is a significant clinical problem, plasma exchange and newer therapies such as Rituximab can be considered. After phlebotomy, blood must be maintained at 37oC during delivery to the laboratory and prior to clotting and centrifugation in order to avoid premature loss of the cryoglobulins among the separated cells. The serum is then placed in a refrigerator or ice bath and examined at 24 hours for the presence of cryoprecipitate. If no precipitate is observed, the specimen is kept at 4oC for an additional six days, at which time it is examined once again for precipitate. Any precipitate is washed at 4oC, re-dissolved in warmed buffer and subjected to immunoelectrophoresis with monospecific antisera to determine the type of immunoglobulin in the precipitate.


The most visible aspect of myeloma disease is its effect on bones throughout the body. In the majority of patients with multiple myeloma, soft spots develop where the bone structure has been damaged. These can extend from the inner bone marrow to the outside surface of the bone. Soft spots appear as "holes" on a standard bone x-ray and are referred to as osteolytic lesions (see figure). These lesions weaken the bone, causing pain and increasing the risk of fractures.

Figure legend
Myeloma cells in the bone marrow cause osteolytic lesions, which appear as "holes" on an x-ray. Weakened bones increase the likelihood of fracture.

Although it affects the bone, myeloma is considered a hematologic cancer (or blood cancer), because it develops in the blood's B cells. Treatment of myeloma differs from that of bone cancers (known as sarcomas of the bone).

Causes of Bone Destruction in Myeloma
Bone destruction by osteolytic lesions is caused by two separate events. Rapid growth of myeloma cells inhibits normal bone-forming cells, damaging bone. In addition, production of substances that activate the cells that resorb bone called osteoclasts is increased. Osteoclasts normally break down old or worn out bone and work with bone-forming cells to repair bone. Increased activity of osteoclasts, however, causes bone loss with concomitant loss of bone repair and growth from the suppression of bone formation.

Normal Bone Cell Activity
Normally, osteoclasts function with bone-forming cells called osteoblasts to rebuild areas of bone that are wearing out (fatigued). This process is called bone remodeling and healthy bone is continually being remodeled.

During the normal process of bone remodeling, the following steps occur:
Osteoclasts are attracted to the area of fatigued bone.
Osteoclasts remove the fatigued bone by breaking it down, creating a cavity in the bone.
Osteoblasts are attracted to the cavity in the bone.
Osteoblasts fill in the cavity with a matrix or framework.
Eventually, new bone forms.

Bone Cell Activity in Myeloma
Normally, the activity of the osteoclasts and osteoblasts is well balanced–the osteoclasts clear out the fatigued bone and the osteoblasts begin the rebuilding of new bone. In patients with multiple myeloma, bone resorption by the osteoclasts is increased and exceeds bone reformation. Calcium lost from the bones appears in increasing amounts in the patient's serum and urine. This increase in bone resorption may result in pain, bone fractures, spinal cord compression, and hypercalcemia.

In myeloma there is an increase in osteoclast activity that is caused by factors called osteoclastic activating factors or OAFs. These osteoclastic activating factors are known to be released by tumor cells and include a variety of soluble factors known as cytokines. Some of these cytokines are shown in the figure I

The Bone Marrow Microenvironment and it's Role in Bone Resorption
The bone marrow microenvironment is the area within the bone (the marrow) where stem cells develop into blood cells and the cells of the immune system. In multiple myeloma, the bone marrow microenvironment is the area where the malignant plasma cells develop and grow. An important and promising area of myeloma research is the investigation of ways to make the bone marrow microenvironment less hospitable to myeloma cells.

The bone marrow microenvironment plays an important role in the increased bone resorption that occurs in myeloma. The following steps outline what happens:
Within the bone marrow microenvironment, tumor cells adhere to the bone marrow stromal cells (BMSCs), which are the structural cells of the bone marrow.

Adherence of the multiple myeloma cells to stromal cells increases the stromal cell production of the growth factor interleukin 6, which appears to be necessary for the continued growth and survival of the myeloma cells.

Adherence of the myeloma cells to stromal cells also allows the myeloma tumor cells to produce other osteoclast-activating factors including interleukin 1-beta (IL-1β) and tumor necrosis factor-alpha.

These osteoclast-stimulating factors prompt the bone marrow stromal cells and the osteoblasts to produce yet another growth factor called RANKL.

TNF induces the development and growth of osteoclast cells and thus increases osteoclast activity that results in the bone disease of myeloma.

This increase in osteoclastic activity also results in the release of certain cytokines such as IL-6, which contribute to tumor cell growth and survival.
A clearer understanding of these mechanisms may make it possible to develop more effective treatments to interrupt, slow down, or halt the series of steps that lead to bone disease and contribute to tumor cell growth and survival in myeloma.

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