Gamma heavy chain disease and rheumatoid arthritis

Dickson, John R.; Harth, Manfred; Bell, David A.; Komar, Ronald; Chodirker, William B.

doi:10.1016/0049-0172(89)90045-0

Cited by 10 publications

(5 citation statements)

References 15 publications

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“…A few papers report about the occurrence of amyloidosis in the course of κ-heavy chain disease [45,46], but it was not proven in these cases that the amyloid derives from Η-chains. We recently had the opportunity to study the amyloid fibrils of a patient with primary amyloidosis.…”

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confidence: 99%

Amyloid formation from Immunoglobulin chains

Eulitz¹

1992

Biological Chemistry Hoppe-Seyler

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Amyloid 1 was first discovered during the examination of tissue by Rudolf Virchow in 1854.Because it could be stained in a similar manner as starch with iodine in Lugol's solution it was named "amyloid" by Virchow [1]. The deposition of this substance occurs extracellularly in small blood vessels and various organs. Examination under the light microscope reveals a homogeneous eosinophilic substance with hyaline appearance. Nowadays the diagnosis of amyloidosis still depends mainly on the examination of bioptic material from involved organs. Main criteria are the staining of amyloid with Congo red [2] and a characteristic green birefringence in polarized light.The formation of amyloid is associated with many different disorders and impairs the normal organ function when the deposits are severe. There have been controversial discussions about the nature of this substance for more than one hundred years. The observation by electron microscopy that the deposited material is composed of fibrils was a first step toward the unraveling of the mysteries of this disease [3]. A further major breakthrough happened when it became possible to extract amyloid fibrils from the tissue [4]. It was proven by serological and chemical methods that proteins are the main constituents of extracted amyloid fibrils and not, as supposed for a long time, starchlike polysaccharides. Particularly amino acid sequence analysis was applied successfully to identify the individual proteins which participate in the formation of amyloid deposits. These studies revealed that amyloidosis is not a single entity but is connected to a still growing range of various disorders and diseases. The current state of research in this field has been summarized by an international nomenclature committee at the Vlth International Symposium on Amyloidosis [5], which was held in Oslo in 1990.Because several excellent reviews on amyloidosis have been published [6-10], this paper concentrates only on amyloid formation from immunoglobulin chains. Magnus-Levy (in 1931 [11]) and Apitz (in 1940 [12]) were the first authors to report on correlations between multiple myeloma 1 Abbreviations: Protein A = amyloid associated protein; apoSAA = serum precursor of protein AA; AL-type = amyloid derived from immunoglobulin light chains; VHjjj = V-regions of immunoglobulin heavy (H) chains, subgroup III; CH = constant regions of H-chains

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confidence: 99%

Amyloid formation from Immunoglobulin chains

Eulitz¹

1992

Biological Chemistry Hoppe-Seyler

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“…Although amyloidosis has been reported to occur in patients with other forms of monoclonal malignant or seemingly benign B-cell proliferative disorders-e.g., y-heavy-chain disease (4,5), the presence of immunoglobulin heavy polypeptide chains in amyloid deposits has heretofore, to our knowledge, not been established. We now document that the amyloid deposits in a patient with widespread systemic amyloidosis associated with monoclonal serum and urinary immunoglobulins (including a -heavy-chain protein) consisted of an aberrant related heavy chain.…”

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confidence: 99%

Immunoglobulin heavy-chain-associated amyloidosis.

Eulitz

Weiss

Solomon

1990

Proc. Natl. Acad. Sci. U.S.A.

117

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Immunoglobulin-or multiple myelomaassociated amyloidosis has been distinguished by the tissue deposition of Congophilic, -fibrillar protein consisting of light chains or light-chain fragments (AL amyloidosis). We now report the isolation and characterization of another form of immunoglobulin-associated amyloid obtained from a patient who had extensive systemic amyloidosis and in whom the amyloid deposits consisted not of light chains but rather of an unusual form of heavy chain. This component, isolated from splenic amyloid extracts, represented an internally deleted IgG1 heavy chain as evidenced by immunochemical, electrophoretic, and amino acid sequence analyses. A comparable immunoglobulin-related monodonal protein, consisting only of IgG heavy chains, was present in the patient's urine. Based on serologic reactivity with a battery of anti-immunoglobulin antisera, these two immunoglobulin-related components were antigenically identical; however', when compared to normal IgG, both were deficient in Fc-associated -chain determinants. The structural abnormality of the amyloid -chain protein was further evidenced by SDS/PAGE and immunoblotting analyses: An unusually low molecular mass of s22 kDa was found for this material vs. the expected value of -55 kDa for a normal y heavy chain. Despite the lack of certain Fc determinants, the amyloid and urinary heavy-chain proteins expressed the IgG1 subclass allotype marker Glm(a) located on the third constant region (CH3) domain of the internally deleted IgG1 heavy chains. That the amyloid' protein contained an intact CH3 domain was established through amino acid sequence analyses of cyanogen bromide fragments and peptides generated by a lysine-specific protease. These studies also revealed that the vchain amyloid protein contained the complete heavy-chain variable (VH) domain [including the diversity (DH) and joining (JH) segments] that was contiguous with the CH3 domain. The low molecular mass of the protein resulted from'the total absence of the first (CH1), hinge, and second (CH2) heavy-chain constant regions. Such extensive CH deletions and the presence of a complete VH distinguish this amyloid-associated heavy chain from all other heretofore characterized vheavy-chain disease proteins. This heavy-chainrelated form of immunoglobulin-associated amyloidosis is tentatively designated AH amyloidosis.

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“…To the best of our knowledge, 15 γ-HCD patients with RA as an underlying disease have been reported. 3,[6][7][8]10,11,[13][14][15][16][17][18][19][20] Two γ-HCD patients were treated using MTX and corticosteroid 10 or MTX alone 11 for RA before the onset of LPD, and were later found to have γ-HCD; therefore, γ-HCD in these 2 patients is considered to be iatrogenic immunodeficiency-associated LPD, because this LPD subtype is tentatively defined as that arising in patients with autoimmune diseases with a history of treatment with immunosuppressive agents such as MTX, 9 although the causative mechanism of MTX for the development of LPD has not been elucidated. One more γ-HCD patient had been treated using MTX for seronegative RA; however, the patient did not have constitutive symptoms, lymph node swelling, hepatosplenomegaly, tumoral lesions, or bone marrow abnormality at the time of γ-HCD diagnosis.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, γ-HCD in this patient lacked the clinical features of LPD and the diagnosis of iatrogenic immunodeficiency-associated LPD was unlikely. In the remaining 12 γ-HCD patients with RA, MTX or immunosuppressants were not used for RA treatment, 3,[6][7][8][13][14][15][16][17][18][19] although the treatment agent was not described for one patient. 7 Therefore, the present case may be the third reported case of γ-HCD as iatrogenic immunodeficiency-associated LPD.…”

Section: Discussionmentioning

confidence: 99%

Gamma heavy chain disease (γ-HCD) as iatrogenic immunodeficiency- associated lymphoproliferative disorder: Possible emergent subtype of rheumatoid arthritis-associated γ-HCD

Tsunemine¹,

Zushi²,

Sasaki³

et al. 2019

J Clin Exp Hematopathol

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Gamma heavy chain disease (γ-HCD) is a B-cell neoplasm that produces a truncated immunoglobulin γ-heavy chain lacking the light chain-binding sites, subsequently forming an incomplete immunoglobulin molecule without a corresponding light chain. 1-5 γ-HCD is rare and to date, approximately 150 cases have been reported. 5 The clinical features of γ-HCD are heterogeneous, resembling marginal zone lymphoma, plasmacytoma, lymphoplasmacytic lymphoma (LPL), and chronic lymphocytic leukemia, and most patients with this disorder have generalized disease. 5,6 Some γ-HCD patients (25-30%) also have autoimmune diseases, commonly rheumatoid arthritis (RA). 3,6-8 The therapeutic modality for RA, however, has greatly changed in recent years, including treatments with different biologicals and methotrexate (MTX), in addition to corticosteroid and non-steroidal anti-inflammatory drugs. As a consequence, iatrogenic immunodeficiency-associated lymphoproliferative disorder (LPD), most commonly MTX-associated LPD, has emerged as a complication in recent years. 9 Iatrogenic immunodeficiency-associated LPD exhibits a wide spectrum of clinical features, including diffuse large B-cell lymphoma, follicular lymphoma, MALT lymphoma, lymphoplasmacytic lymphoma (LPL), and peripheral T-cell lymphoma. 9 Along with the changes in the therapeutic modality for RA, γ-HCD as iatrogenic immunodeficiency-associated LPD should be taken into consideration. We encountered a γ-HCD patient who had been treated with MTX, and infliximab and adalimumab for RA and Crohn's disease, respectively.

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Gamma heavy chain disease and rheumatoid arthritis

Cited by 10 publications

References 15 publications

Amyloid formation from Immunoglobulin chains

Amyloid formation from Immunoglobulin chains

Immunoglobulin heavy-chain-associated amyloidosis.

Gamma heavy chain disease (γ-HCD) as iatrogenic immunodeficiency- associated lymphoproliferative disorder: Possible emergent subtype of rheumatoid arthritis-associated γ-HCD

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