Heavy chain disease

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Heavy chain disease
Specialty Immunology, hematology

Heavy chain disease is a form of paraproteinemia and plasma cell dyscrasia that involves the proliferation of cells producing immunoglobulin heavy chains. [1]

Contents

This disease is characterized by an excessive production of heavy chains that are short and truncated. These heavy chain disease proteins have various deletions, mainly in their amino-terminal part, which causes the heavy chains to lose the ability to form disulfide bonds with the light chains. The defect in the immunoglobulins presumably arises during somatic hypermutation. [2] Deletion of the N-terminal part of the heavy chain disease protein leads to aggregation and signaling of the B cell receptor, [3] presumably due to the loss of the anti-aggregating properties of the light chain. [4]

Classification

There are four forms:

IgA/αHCD

The most common type of heavy chain disease is the IgA type, known as αHCD. The most common type of αHCD is the gastrointestinal form (known as immunoproliferative small intestine disease or IPSID), but it has also been reported in the respiratory tract, and other areas of the body. [10]

IgG/γHCD

Franklin's disease (gamma heavy chain disease) It is a very rare B-cell lymphoplasma cell proliferative disorder which may be associated with autoimmune diseases and infection is a common characteristic of the disease. [6] It is characterized by lymphadenopathy, fever, anemia, malaise, hepatosplenomegaly, and weakness. The most distinctive symptom is palatal edema, caused by nodal involvement of Waldeyer's ring. Diagnosis is made by the demonstration of an anomalous serum M component that reacts with anti-IgG but not anti-light chain reagents. Bone marrow examination is usually nondiagnostic. Patients usually have a rapid downhill course and die of infection if left untreated or misdiagnosed.

Patients with Franklin disease usually have a history of progressive weakness, fatigue, intermittent fever, night sweats and weight loss and may present with lymphadenopathy (62%), splenomegaly (52%) or hepatomegaly (37%). The fever is considered secondary to impaired cellular and humoral immunity, and thus recurrent infections are the common clinical presentation in Franklin disease. Weng et al. described the first case of Penicillium sp. infection in a patient with Franklin disease and emphasized the importance of proper preparation for biopsy, complete hematologic investigation, culture preparation and early antifungal coverage to improve the outcome. [6] [10]

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.

IgM/μHCD

The IgM type of heavy chain disease, μHCD, is often misdiagnosed as chronic lymphoid leukemia (CLL) because the two diseases are often associated with each other and show similar symptoms. [11]

Related Research Articles

<span class="mw-page-title-main">Antibody</span> Protein(s) forming a major part of an organisms immune system

An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the pathogen, called an antigen. Each tip of the "Y" of an antibody contains a paratope that is specific for one particular epitope on an antigen, allowing these two structures to bind together with precision. Using this binding mechanism, an antibody can tag a microbe or an infected cell for attack by other parts of the immune system, or can neutralize it directly.

<span class="mw-page-title-main">Immunoglobulin M</span> One of several isotypes of antibody

Immunoglobulin M (IgM) is one of several isotypes of antibody that are produced by vertebrates. IgM is the largest antibody, and it is the first antibody to appear in the response to initial exposure to an antigen. In humans and other mammals that have been studied, plasmablasts residing in the spleen are the main source of specific IgM production.

<span class="mw-page-title-main">Cryoglobulinemia</span> Medical condition

Cryoglobulinemia is a medical condition in which the blood contains large amounts of pathological cold sensitive antibodies called cryoglobulins – proteins that become insoluble at reduced temperatures. This should be contrasted with cold agglutinins, which cause agglutination of red blood cells.

<span class="mw-page-title-main">X-linked agammaglobulinemia</span> Medical condition

X-linked agammaglobulinemia (XLA) is a rare genetic disorder discovered in 1952 that affects the body's ability to fight infection. As the form of agammaglobulinemia that is X-linked, it is much more common in males. In people with XLA, the white blood cell formation process does not generate mature B cells, which manifests as a complete or near-complete lack of proteins called gamma globulins, including antibodies, in their bloodstream. B cells are part of the immune system and normally manufacture antibodies, which defend the body from infections by sustaining a humoral immunity response. Patients with untreated XLA are prone to develop serious and even fatal infections. A mutation occurs at the Bruton's tyrosine kinase (Btk) gene that leads to a severe block in B cell development and a reduced immunoglobulin production in the serum. Btk is particularly responsible for mediating B cell development and maturation through a signaling effect on the B cell receptor BCR. Patients typically present in early childhood with recurrent infections, in particular with extracellular, encapsulated bacteria. XLA is deemed to have a relatively low incidence of disease, with an occurrence rate of approximately 1 in 200,000 live births and a frequency of about 1 in 100,000 male newborns. It has no ethnic predisposition. XLA is treated by infusion of human antibody. Treatment with pooled gamma globulin cannot restore a functional population of B cells, but it is sufficient to reduce the severity and number of infections due to the passive immunity granted by the exogenous antibodies.

<span class="mw-page-title-main">Immunoglobulin heavy chain</span> Large polypeptide subunit of an antibody

The immunoglobulin heavy chain (IgH) is the large polypeptide subunit of an antibody (immunoglobulin). In human genome, the IgH gene loci are on chromosome 14.

Common variable immunodeficiency (CVID) is an immune disorder characterized by recurrent infections and low antibody levels, specifically in immunoglobulin (Ig) types IgG, IgM and IgA. Symptoms generally include high susceptibility to foreign invaders, chronic lung disease, and inflammation and infection of the gastrointestinal tract. CVID affects males and females equally. The condition can be found in children or teens but is generally not diagnosed or recognized until adulthood. The average age of diagnosis is between 20 and 50. However, symptoms vary greatly between people. "Variable" refers to the heterogeneous clinical manifestations of this disorder, which include recurrent bacterial infections, increased risk for autoimmune disease and lymphoma, as well as gastrointestinal disease. CVID is a lifelong disease.

<span class="mw-page-title-main">Monoclonal gammopathy</span> Medical condition

Monoclonal gammopathy, also known as paraproteinemia, is the presence of excessive amounts of myeloma protein or monoclonal gamma globulin in the blood. It is usually due to an underlying immunoproliferative disorder or hematologic neoplasms, especially multiple myeloma. It is sometimes considered equivalent to plasma cell dyscrasia. The most common form of the disease is monoclonal gammopathy of undetermined significance.

<span class="mw-page-title-main">Immunoglobulin class switching</span> Biological mechanism

Immunoglobulin class switching, also known as isotype switching, isotypic commutation or class-switch recombination (CSR), is a biological mechanism that changes a B cell's production of immunoglobulin from one type to another, such as from the isotype IgM to the isotype IgG. During this process, the constant-region portion of the antibody heavy chain is changed, but the variable region of the heavy chain stays the same. Since the variable region does not change, class switching does not affect antigen specificity. Instead, the antibody retains affinity for the same antigens, but can interact with different effector molecules.

<span class="mw-page-title-main">Isotype (immunology)</span>

In immunology, antibodies are classified into several types called isotypes or classes. The variable (V) regions near the tip of the antibody can differ from molecule to molecule in countless ways, allowing it to specifically target an antigen . In contrast, the constant (C) regions only occur in a few variants, which define the antibody's class. Antibodies of different classes activate distinct effector mechanisms in response to an antigen . They appear at different stages of an immune response, differ in structural features, and in their location around the body.

Angioimmunoblastic T-cell lymphoma is a mature T-cell lymphoma of blood or lymph vessel immunoblasts characterized by a polymorphous lymph node infiltrate showing a marked increase in follicular dendritic cells (FDCs) and high endothelial venules (HEVs) and systemic involvement.

Immunoglobulin heavy locus, also known as IGH, is a region on human chromosome 14 that contains a gene for the heavy chains of human antibodies.

<span class="mw-page-title-main">IGHG2</span> Gene in the species Homo sapiens

Ig gamma-2 chain C region is a protein that in humans is encoded by the IGHG2 gene.

Ig heavy chain V-III region VH26 is a protein that in humans is encoded by the IGHV@ gene.

<span class="mw-page-title-main">IGHG3</span> Gene in the species Homo sapiens

Ig gamma-3 chain C region is a protein that in humans is encoded by the IGHG3 gene.

X-linked lymphoproliferative disease is a lymphoproliferative disorder, usually caused by SH2DIA gene mutations in males. XLP-positive individuals experience immune system deficiencies that render them unable to effectively respond to the Epstein-Barr virus (EBV), a common virus in humans that typically induces mild symptoms or infectious mononucleosis (IM) in patients. There are two currently known variations of the disorder, known as XLP1 and XLP2. XLP1 is estimated to occur in approximately one in every million males, while XLP2 is rarer, estimated to occur in one of every five million males. Due to therapies such as chemotherapy and stem cell transplants, the survival rate of XLP1 has increased dramatically since its discovery in the 1970s.

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<span class="mw-page-title-main">Humoral immune deficiency</span> Medical condition

Humoral immune deficiencies are conditions which cause impairment of humoral immunity, which can lead to immunodeficiency. It can be mediated by insufficient number or function of B cells, the plasma cells they differentiate into, or the antibody secreted by the plasma cells. The most common such immunodeficiency is inherited selective IgA deficiency, occurring between 1 in 100 and 1 in 1000 persons, depending on population. They are associated with increased vulnerability to infection, but can be difficult to detect in the absence of infection.

Somatic hypermutation is a cellular mechanism by which the immune system adapts to the new foreign elements that confront it, as seen during class switching. A major component of the process of affinity maturation, SHM diversifies B cell receptors used to recognize foreign elements (antigens) and allows the immune system to adapt its response to new threats during the lifetime of an organism. Somatic hypermutation involves a programmed process of mutation affecting the variable regions of immunoglobulin genes. Unlike germline mutation, SHM affects only an organism's individual immune cells, and the mutations are not transmitted to the organism's offspring. Because this mechanism is merely selective and not precisely targeted, somatic hypermutation has been strongly implicated in the development of B-cell lymphomas and many other cancers.

Epstein–Barr virus–associated lymphoproliferative diseases are a group of disorders in which one or more types of lymphoid cells, i.e. B cells, T cells, NK cells, and histiocytic-dendritic cells, are infected with the Epstein–Barr virus (EBV). This causes the infected cells to divide excessively, and is associated with the development of various non-cancerous, pre-cancerous, and cancerous lymphoproliferative disorders (LPDs). These LPDs include the well-known disorder occurring during the initial infection with the EBV, infectious mononucleosis, and the large number of subsequent disorders that may occur thereafter. The virus is usually involved in the development and/or progression of these LPDs although in some cases it may be an "innocent" bystander, i.e. present in, but not contributing to, the disease.

References

  1. ↑ "Heavy Chain Diseases: Plasma Cell Disorders: Merck Manual Home Edition" . Retrieved 2008-02-29.
  2. ↑ Goossens T, Klein U, Küppers R (1998). "Frequent occurrence of deletions and duplications during somatic hypermutation: Implications for oncogene translocations and heavy chain disease". PNAS. 95 (5): 2463–8. Bibcode:1998PNAS...95.2463G. doi: 10.1073/pnas.95.5.2463 . PMC   19376 . PMID   9482908.
  3. ↑ Corcos D, Dunda O, Butor C, Cesbron JY, Lorès P, Bucchini D, Jami J (1995). "Pre-B-cell development in the absence of lambda 5 in transgenic mice expressing a heavy-chain disease protein". Curr. Biol. 5 (10): 1140–8. doi: 10.1016/S0960-9822(95)00230-2 . PMID   8548286. S2CID   18737035.
  4. ↑ Corcos D, Osborn MJ, Matheson LS, Santos F, Zou X, Smith JA, Morgan G, Hutchings A, Hamon M, Oxley D, Brüggemann M (2010). "Immunoglobulin aggregation leading to Russell body formation is prevented by the antibody light chain". Blood. 115 (2): 282–8. doi: 10.1182/blood-2009-07-234864 . PMID   19822901.
  5. ↑ Fakhfakh F, Dellagi K, Ayadi H, Bouguerra A, Fourati R, Ben Ayed F, Brouet JC, Tsapis A (1992). "Alpha heavy chain disease alpha mRNA contain nucleotide sequences of unknown origins". Eur. J. Immunol. 22 (11): 3037–40. doi:10.1002/eji.1830221141. PMID   1425927. S2CID   85132431.
  6. 1 2 3 Weng CH, Wang RC, Hsieh TY, Tsai CA, Lin TH (July 2012). "Penicillium pneumonia in a patient with newly diagnosed Franklin disease". Am J Med Sci. 344 (1): 69–71. doi:10.1097/MAJ.0b013e31824a8927. PMID   22543591.
  7. ↑ Wahner-Roedler DL, Witzig TE, Loehrer LL, Kyle RA (2003). "Gamma-heavy chain disease: review of 23 cases". Medicine (Baltimore). 82 (4): 236–50. doi: 10.1097/01.md.0000085058.63483.7f . PMID   12861101. S2CID   5320931.
  8. ↑ Wahner-Roedler DL, Kyle RA (1992). "Mu-heavy chain disease: presentation as a benign monoclonal gammopathy". Am. J. Hematol. 40 (1): 56–60. doi:10.1002/ajh.2830400112. PMID   1566748. S2CID   37749139.
  9. ↑ Vilpo JA, Irjala K, Viljanen MK, Klemi P, Kouvonen I, Rönnemaa T (1980). "Delta-Heavy chain disease: A study of a case". Clin Immunol Immunopathol. 17 (4): 584–94. doi:10.1016/0090-1229(80)90154-3. PMID   6777103.
  10. 1 2 3 Wahner-Roedler DL, Kyle RA (2005). "Heavy chain diseases". Best Pract Res Clin Haematol. 18 (4): 729–46. doi:10.1016/j.beha.2005.01.029. PMID   16026747.
  11. 1 2 3 Fermand JP, Brouet JC, Danon F, Seligmann M (1989). "Gamma heavy chain "disease": heterogeneity of the clinicopathologic features. Report of 16 cases and review of the literature". Medicine (Baltimore). 68 (6): 321–35. doi: 10.1097/00005792-198911000-00001 . PMID   2509855. S2CID   29644848.
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