Immunoproliferative disorders

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Immunoproliferative disorders
ICD-10 C88
ICD-9 203
MeSH D007160

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Synonyms and keywords: Immunoproliferative disease, immunoproliferation, immunoproliferative neoplasm


Immunoproliferative disorders are disorders of the immune system that are characterized by the abnormal proliferation of the primary cells of the immune system, which includes B cells, T cells and Natural Killer (NK) cells, or by the excessive production of immunoglobulins (also known as antibodies). These disorders are subdivided into three main classes, which are lymphoproliferative disorders, hypergammaglobulinemia, and paraproteinemia [5].


1. Lymphoproliferative diseases

Lymphoproliferative disorders are a set of disorders characterized by the abnormal proliferation of lymphocytes into a monoclonal lymphocytosis. The two major types of lymphocyes are B cells and T cells, which are derived from pleuripotent hematopoetic stem cells in the bone marrow. Individuals who have some sort of immunodysfuction are susceptible to developing a lymphoproliferative disorder because when any of the numerous control points of the immune system become dysfunctional, immunodeficiency or deregulation of lymphocytes is more likely to occur. There are several inherited gene mutations that have been identified to cause lymphoproliferative disorders, however there are also acquired and Iatrogenic causes [14]

X-linked Lymphoproliferative disorder: There is a mutation on the X chromosome that has been found to be associated with a T and NK cell lymphoproliferative disorder. The mutation is on the long arm of the chromosome, at position 25, which is denoted as Xq25. At this position, there is a deletion in the SH2D1A gene, which codes for an SH2 domain on a signal transducing protein called SLAM-associated protein (SAP).

The term SH2 domain stands for src-homology 2 domain, which is a three-dimensional domain structure of about 100 amino acid residues. These domains are present in many signaling proteins because they permit specific, non-covalent bonding to proteins that contain phosphotyrosines. The amino acid residues adjacent to the phosphotyrosine on the target protein are what determine the unique binding specificity [1]

The SAP protein is important in the signaling events that activate T and NK cells because it functions as an intracellular adapter that transduces T and NK cell activation. Normally, the SAP protein is expressed in the cytoplasm of T and NK cells, where it binds to the cytoplasmic domain of the surface receptor called Signaling Lymphocyte Activation Molecule (SLAM). This binding initiates a signal transduction pathway, which results in the modulation of IFN-γ. A deletion in the SH2D1A gene leads to a non-functional SH2 domain on the SAP protein, which means it is unable to bind to the SLAM molecule, leading to a lack of modulation of IFN-γ, causing uncontrolled cell proliferation. Strangely, in boys with X-linked lymphoproliferative disorder there is an overwhelming T-cell mediated response to the Epstein-Barr Virus (EBV), which often leads to death from bone marrow failure, irreversible hepatitis, and malignant lymphoma. However, the connection between EBV and X-linked lymphoproliferative disorder is yet to be determined [14]

Autosomal Lymphoproliferative Disorder: Some children with autoimmune lymphoproliferative disorders are heterozygous for a mutation in the gene that codes for the Fas receptor. Which is located on the long arm of chromosome 10 at position 24.1, denoted 10q24.1 [2]. This gene is member 6 of the TNF-receptor superfamily (TNFSF6). The Fas receptor contains a death domain and has been shown to play a central role in the physiological regulation of programmed cell death. Normally, stimulation of recently activated T cells by antigen leads to coexpression of Fas and Fas receptor on the T cell surface. The engagement of Fas by Fas receptor results in apoptosis of the cell and is important for eliminating T cells that are repeatedly stimulated by antigens [1]. As a result of the mutation in the Fas receptor gene, there is no recognition of Fas by Fas receptor, leading to a primitive population of T cells that proliferates in an uncontrolled manner [14].

Other Inherited Causes: Boys with X-linked immunodeficiency syndrome are at a higher risk of mortality associated with EBV infections, and are predisposed to develop a lymphoproliferative disorder or lymphoma. Children with common variable immune deficiency (CVID) are also at a higher risk of developing a lymphoproliferative disorder. Some disorders that predispose a person to lymphoproliferative disorders are severe combined immuno deficiency (SCID), Chédiak-Higashi syndrome, Wiskott-Aldrich syndrome (an X-linked recessive disorder) and Ataxia telangiectasia. Interestingly, even though Ataxia telangiectasia is an autosomal recessive disorder, people who are heterozygotes for this still have an increased risk of developing a lymphoproliferative disorder [14].

Acquired Causes: Viral infection is a very common cause of lymphoproliferative disorders. The most common is congenial HIV infection because it is highly associated with acquired immunodeficiency, which often leads to lymphoproliferative disorders [14].

Iratogenic causes: There are many lymphoproliferative disorders that are associated with organ transplantation and immunosuppressant therapies. In most reported cases, these cause B cell lymphoproliferative disorders, however some T cell variations have been described [14]. The T cell variations are usually caused by the prolonged use of T cell suppressant drugs, such as sirolimus, tacrolimus or cyclosporine A [14].

2. Hypergammaglobulinemia

Hypergammaglobulinemia is a condition that is characterized by the increased levels of a certain immunoglobulin in the blood serum [5]. The name of the disorder refers to the position of the excess of proteins after serum protein electrophoresis (found in the gammaglobulin region). Most hypergammaglobulinemias are caused by an excess of immunoglobulin M (IgM), because this is the default immunoglobulin type prior to class switching. Some types or hypergammaglobulinemia are actually caused by a deficiency in the other major types of immunoglobulins, which are IgA, IgE and IgG. There are 5 types of hypergammaglobulinemias associated with hyper IgM [9].

Type 1- X-linked Immunodeficency with Hyper IgM: X-linked immunodeficiency with hyper–immunoglobulin M, which is also called type 1 hyper IgM, is a rare form of primary immunodeficiency disease caused by a mutation in the Tumor Necrosis Factor Super Family member 5 (TNFSF5) gene, which codes for CD40 ligand. This gene is located on the long arm of the X chromosome at position 26, denoted Xq26 [10]. Normally, CD40 ligand is expressed on activated T cells, and is necessary to induce immunoglobulin class switching from IgM to the other immunoglobulin types. It does this by binding to its ligand, CD40, which is found expressed on the surface of B cells [1]. The mutation in the TNFSF5 gene causes there to be no recognition of CD40 by CD40 ligand, and thus the T cells do not induce Ig class switching in B cells, so there are markedly reduced levels of IgG, IgA, and IgE, but have normal or elevated levels of IgM. CD40 ligand is also required in the functional maturation of T lymphocytes and macrophages, so patients with this disorder have a variable defect in T-lymphocyte and macrophage effector function, as well as hyper IgM [1].

Type 2: Immunodeficiency with hyper IgM type 2 is caused by a mutation in the Activation-Induced Cysteine Deaminase (AICDA) gene, which is located on the short arm of chromosome 12. The protein that is encoded by this gene is called Activation-Induced Cysteine Deaminase (AICDA) and functions as an RNA-editing deaminase that induces somatic hypermutation, class switch recombination, and immunoglobulin gene conversion in B cells [8]. When a person is homozygous for the mutation in the AICDA gene, the protein fails to function, and thus somatic hypermutation, class switch recombination, and immunoglobulin gene conversion cannot occur, which creates an excess of IgM [9].

Type 3: Immunodeficiency with hyper IgM type 3 is caused by a mutation in the gene that codes for CD40. As mentioned above, CD40 is expressed on the surface of B cells, and its binding to CD40 ligand on activated T cells induces Ig class switching [1]. When the mutation is present, there is no signal for B cells to undergo class switching, so there is an excess of IgM and little to no other immunoglobulin types produced [9].

Type 4: Immunodeficiency with hyper IgM type 4 is poorly characterized. All that is known is that there is an excess of IgM in the blood, with normal levels of the other immunoglobulins. The exact cause is yet to be determined [9].

Type 5: Immunodeficiency with hyper IgM type 5 is caused by a mutation in the Uracil DNA Glycosylase (UNG) gene, which, like AICDA, is located on chromosome 12. This codes for Uracil DNA Glycosylase, which is responsible for excising previous uracil bases that are due to cytosine deamination, or previous uracil misincorporation from double-stranded previous DNA substrates. This enzyme is also responsible for helping with gene conversion during somatic recombination in B cells. The mutation in the gene causes an enzyme that does not function properly, thus gene conversion does not proceed and class switching cannot occur [9].

3. Paraproteinemia

The final class of immunoproliferative disorders is paraproteinemia. These disorders are characterized by the presence of any abnormal protein that is involved in the immune system, which are most often immunoglobulins and are associated with the clonal proliferation of lymphocytes [5].

When a paraproteinemia is present in the blood, there will be a narrow band, or spike, in the serum protein electrophoresis because there will be an excess of production of one protein [6].

There are two large classes of blood proteins: albumin and globulin. They are generally equal in proportion, but albumin is much smaller than globulin, and slightly negatively charged, which leads to an accumulation at the end of the electrophoretic gel. The globulins separate out into three regions on the electrophoretic gel, which are the α band, the β band, and the γ band. The α band can be separated into two components: α1 and α2. The α1 region consists mostly of α1-antitrypsin and α1-acid glycoprotein. The α2 region is mostly haptoglobin, α2-macroglobulin, α2-antiplasmin and ceruloplasmin. The β band consists of transferring, low-density lipoproteins, and complement system proteins [7]. The γ band is where the immunoglobulins appear, which is why they are also known as gammaglobulins [1]. The majority of paraproteins appear in this band [7].

Some examples of paraproteinemias are Heavy Chain disease, Cryoglobulinemia, Waldenström macroglobulinemia, and at least one disorder associated with each immunoglobulin type. Some of these are discussed below.

Heavy Chain Disease: Heavy chain disease is one of the more interesting paraptoteinemias. This disease is characterized by an excessive production of immunoglobulin heavy chains that are short and truncated. The amino acid sequence on the amino terminal is completely normal, but there is a deletion in the protein structure that extends from the middle of the variable region, through the first domain of the constant region, and ending just before the position of the first disulfide bond between the two heavy chains. This deletion causes the heavy chains to lose the ability to form disulfide bonds with the light chains. The defect in the immunoglobulins arises during the faulty coupling of the variable and constant regions during somatic recombination. The most common type of heavy chain disease is the IgA type, known as αHCD. This is because the most common immunoglobulin in the body is IgA. The most common type of αHCD is the digestive form, however it has also been reported in the respiratory tract, and other areas of the body [13]. IgM and IgG heavy chain diseases, which are known as μHCD and γHCD respectively, are fairly common and are present in various tissues [13].

The γHCD can be divided into three categories based on the various clinical and pathological features. These categories are disseminated lymphoproliferative disease, localized proliferative disease and no apparent proliferative disease. Disseminated lymphoproliferative disease is found in 57-66% of patients diagnosed with γHCD. Lymphadenopathy and constitutional symptoms are the usual features [3].

Localized proliferative disease is found in approximately 25% of γHCD patients. This is characterized by a localization of the mutated heavy chains in extramedullary tissue, or solely in the bone marrow [13]. No apparent proliferative disease is seen in 9-17% of patients with γHCD, and there is almost always an underlying autoimmune disorder in these patients [3].

The IgM type of heavy chain disease, μHCD, is often misdiagnosed as chronic lymphoid leukemia (CLL) due to the fact that the two diseases are often associated with each other and show similar symptoms [3].

Cryoglobulinemia: Cryoglobulinemia is a type of paraproteinemia characterized by the presence in serum of immunoglobulins that precipitate at low temperatures (around 0ºC). There are three different types of cryoglobulins that have been observed to form in the blood. Type I is composed of isolated monoclonal immunoglobulins, while types II and III are immunocomplexes formed by monoclonal or polyclonal IgM respectively. Types II and III have rheumatoid factor (RF) activity and bind to polyclonal immunoglobulins. These two types are referred to as mixed cryoglobulinemia (MC). When the temperature is raised, the precipitated cryoglobulins will dissolve back into the serum [11].

Type I cryoglobulins make up 10-15% of the total cases. These are composed of a single monoclonal immunoglobulin paraprotein (usually IgM). Sometimes, these are represented by light chains only and can be extracted from the urine, or they will accumulate in blood serum in the event of renal failure [11].

Type II cryoglobulins account for 50-60% of reported cases. They usually have a polyclonal component, usually IgG, and a monoclonal component, usually IgM, which has a RF function. The IgM can recognize intact IgG or either the Fab region or Fc region of IgG fragments. This is why most type II cryoglobulins are IgM-IgG complexes [11].

Type III cryoglobulins account for 25-30% of the reported cases. These have very similar function to the type II cryoglobulins, however they are composed for polyclonal IgM and IgG molecules [11].

In 2006 it was discovered that there are unusual cryoglobulins that show a microheterogeneous composition, with an immunochemical structure that cannot be fit into any of the classifications. A classification of a type II-III variant has been proposed due to the fact that they are composed of oligoclonal IgMs with traces of polyclonal immunoglobulins [12]


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4. Géoui, T, Buisson, M, Tarboutiech, N, Pascal-Burmeister, W. New Insights on the role of the γ-Herpesvirus Uracil-DNA Glycosylase leucine loop revealed by the structure of the Epstein-Barr virus enzyme in a complex with an inhibitor protein. J Mol Biol 366 (1): 117-131

5. Health Communication Network. Immunoproliferative disorders- Topic Tree. Accessed March 2007.

6. Ma, E.S.K and Lee, E.T.K. A case of IgM paraproteinemia in which serum free light chain values were within reference intervals. Clinical Chem 53: 362-363.

7. Martínez-Gómez, M.A, Carril-Avilés, M.M, Sagrado, S, Villanueva-Camañas, R.M, Medina-Hernández, M.J. Characterization of antihistamine- human serum protein interactions by capillary electrophoresis. J Chromatography A 1147 (2): 261-269.

8. Noguchi, E, Skibasaki, M, Inudo, M, Kamioka, M, Yokouchi, Y, Yamakawa-Kobayashi, K, Hamaguchi, H, Matsui, A, Arinami, T. Association between a new polymorphism in the activation-induced cytidine deaminase gene and atopic asthma and the regulation of total serum IgE levels. J Allergy and Clinical Immuno 108: 382-386.

9. Online Mendelian Inheritance in Man. Immunodeficiency with hyper IgM. Accessed March 2007.

10. Park, L.C. X-linked Immunodeficiency with hyper IgM. Emedicine. February 20, 2007. Accessed March 2007.

11. Tedeschi, A., Barate, C., Minola, E., Morra, E. Cryoglobulinemia. Blood Reviews. Available online February 7, 2007.

12. Tissot, J.D, Schifferli, J.A, Hochstrasser, D.F. Two-dimensional polyacrylamide gel electrophoresis analysis of cryoglobulins and identification of an IgM-associated peptide. J Immunol Meth 173: 63–75.

13. Wahner-Roedler, D.L, Kyle, R.A. Heavy Chain Diseases. Best Practise & Research Clinical Haematology 18 (4): 729-746.

14. Winter, S.S. Lymphoproliferative disorders. Emedicine. December 20, 2006. Accessed March 2007.

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