Immunoglobulin γ3-heavy-chain deposition disease: report of a case and relationship with hypocomplementemia

Soma, Jun; Satô, Kôzô; Sakuma, Tsutomu; Saito, Hiroko; Sato, Hiroshi; Sato, Toshinobu; Abbas, Aïcha; Aucouturier, Pièrre

doi:10.1053/j.ajkd.2003.09.024

Cited by 41 publications

(34 citation statements)

References 23 publications

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“…In most cases of HCDD, especially when a ␥1 or ␥3 chain is involved, complement components including C1 could be demonstrated in a granular or pseudolinear pattern. Complement deposits often were associated with decrease of serum complement (7,8,22,45).…”

Section: Immunofluorescencementioning

confidence: 99%

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Immunoglobulin Light (Heavy)-Chain Deposition Disease

Ronco¹,

Plaisier²,

Mougenot³

et al. 2006

Clinical Journal of the American Society of Nephrology

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110

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Light-, light-and heavy-, and heavy-chain deposition diseases belong to a family of diseases that include light-chain (AL)-amyloid, nonamyloid fibrillary and immunotactoid glomerulonephritis, and cryoglobulinemic glomerulonephritis, in which monoclonal Ig or their subunits become deposited in kidney. In clinical and pathologic terms, light-, light-and heavy-, and heavy-chain deposition diseases essentially are similar and are characterized by prominent renal involvement with severe renal failure; extrarenal manifestations; diabetes-like nodular glomerulosclerosis; marked thickening of tubular basement membranes; and monotypic deposits of light chain, mostly , and/or heavy chain that feature a nonorganized granular, electron-dense appearance by electron microscopy. The most common cause is myeloma. Recent progress has been made in the understanding of the molecular pathomechanisms of Ig-chain deposition and extracellular matrix accumulation, which opens up new therapeutic avenues in addition to eradication of the Ig-secreting plasma cell clone. Because these diseases represent a model of glomerular and interstitial fibrosis that is induced by a single molecule species, a better understanding of their pathomechanisms may help to unravel the pathophysiology of kidney fibrosis and renal disease progression.

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Section: Immunofluorescencementioning

confidence: 99%

“…Deposition of certain HC subclasses, especially IgG3, frequently features classical pathway activation and hypocomplementemia (22).…”

Section: Renal Manifestationsmentioning

confidence: 99%

Immunoglobulin Light (Heavy)-Chain Deposition Disease

Ronco¹,

Plaisier²,

Mougenot³

et al. 2006

Clinical Journal of the American Society of Nephrology

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110

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“…17,18 In HCDD, the most striking molecular characteristic of the pathogenic HC is the deletion of the first constant (CH1) domain, invariably found by immunofluorescence studies of kidney biopsies and molecular studies of bone marrow. 8,9,11,19 In the absence of LC association, deletion of the CH1 domain appears to be a prerequisite for the secretion of an isolated HC, precluding its retention in the endoplasmic reticulum (ER) by the interaction with the GRP78/Bip chaperone. [20][21][22] The V domain also plays a critical role in the pathogenesis of HCDD.…”

Section: Introductionmentioning

confidence: 99%

A mouse model recapitulating human monoclonal heavy chain deposition disease evidences the relevance of proteasome inhibitor therapy

Bonaud

Bender

Touchard

et al. 2015

Blood

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Key Points• We created the first transgenic mouse model recapitulating the early pathologic features of Randall-type heavy chain deposition disease.• Production of a truncated immunoglobulin heavy chain heightens plasma cell sensitivity to bortezomib via a terminal unfolded protein response.Randall-type heavy chain deposition disease (HCDD) is a rare disorder characterized by glomerular and peritubular amorphous deposits of a truncated monoclonal immunoglobulin heavy chain (HC) bearing a deletion of the first constant domain (CH1). We created a transgenic mouse model of HCDD using targeted insertion in the immunoglobulin k locus of a human HC extracted from a HCDD patient. Our strategy allows the efficient expression of the human HC in mouse B and plasma cells, and conditional deletion of the CH1 domain reproduces the major event underlying HCDD. We show that the deletion of the CH1 domain dramatically reduced serum HC levels. Strikingly, even with very low serum level of truncated monoclonal HC, histologic studies revealed typical Randall-type renal lesions that were absent in mice expressing the complete human HC. Bortezomibbased treatment resulted in a strong decrease of renal deposits. We further demonstrated that this efficient response to proteasome inhibitors mostly relies on the presence of the isolated truncated HC that sensitizes plasma cells to bortezomib through an elevated unfolded protein response (UPR). This new transgenic model of HCDD efficiently recapitulates the pathophysiologic features of the disease and demonstrates that the renal damage in HCDD relies on the production of an isolated truncated HC, which, in the absence of a LC partner, displays a high propensity to aggregate even at very low concentration. It also brings new insights into the efficacy of proteasome inhibitor-based therapy in this pathology. (Blood. 2015;126(6):757-765) IntroductionTissue deposition of a monoclonal immunoglobulin fragment frequently complicates plasma cell disorders.1,2 Among the wide spectrum of renal diseases associated with monoclonal gammopathies, Randall-type monoclonal immunoglobulin deposition disease (MIDD) is a multisystemic disorder with prominent renal manifestations including glomerular proteinuria and renal failure. 1,[3][4][5] Kidney lesions in MIDD are characterized by nonamyloid amorphous linear deposits of a monoclonal immunoglobulin fragment along tubular, and in most cases, vascular and glomerular basement membranes (BMs). Nodular glomerulosclerosis and diffuse thickening of tubular BMs are commonly observed. 3,6 The most frequent type of MIDD is related to deposition of monoclonal light chain (LC) (LCDD), mostly of the k isotype, but deposits composed of monoclonal heavy chain (HC) only (HCDD) or of light and heavy chain (LHCDD) have been also described. 3,7 Most reported cases of HCDD were characterized by gHC deposits. 4,5,[8][9][10][11] The mechanisms involved in the deposition of monoclonal Ig fragments in MIDD remain poorly understood. Structural peculiarities of the V domains o...

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“…These deposits have a nonorganized, granular, electron-dense appearance on electron microscopy images [1][2][3]. In cases of HCDD, the deposited gamma heavy chains belong to a single subclass, with gamma 1-4 and alpha heavy chain subtypes having been reported [1,2,[4][5][6][7][8][10][11][12][13][14][15]. The clinical presentations include hypertension, proteinuria, hematuria, and renal insufficiency.…”

Section: Discussionmentioning

confidence: 99%

“…On admission, her height and body weight were 167 cm and 87 kg, respectively; her weight had increased by 13 Renal biopsy obtained 15 glomeruli, none of which had global sclerosis. All the glomeruli showed proliferation with a diffuse increase in mesangial matrix that formed nodular lesions (Fig.…”

Section: Case Reportmentioning

confidence: 99%

Gamma 1-heavy chain deposition disease accompanied by IgG kappa in serum, urine, and bone marrow

et al. 2013

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A 32-year-old Japanese woman presented with hypertension, nephrotic syndrome, microhematuria, and severe hypocomplementemia. Her serum creatinine concentration increased from 1.46 mg/dL (129.0 lmol/L) to 3.46 mg/dL (305.8 lmol/L) over 1 month. Renal biopsy revealed Congo red-negative nodular glomerulosclerosis accompanied by mesangial proliferation. There was extensive staining of immunoglobulin (Ig) G in the glomerular and tubular basement membranes and expanded mesangial regions. Staining was negative for IgA, IgM, and kappa and lambda light chains and positive for the gamma 1 IgG subclass. Staining for constant domains of the gamma heavy chains showed a deletion of the first constant domain (CH1). Electron microscopy revealed electrondense deposits in the glomerular and tubular basement membranes and mesangium. These findings indicated gamma 1-heavy chain deposition disease (HCDD). Serum and urine immunoelectrophoresis revealed an IgG kappa monoclonal band, whereas bone marrow biopsy revealed monoclonal plasmacytosis with positive staining for kappa chains. HCDD associated with kappa light chain is extremely rare. We report the first case of HCDD with IgG kappa detected in the serum, urine, and bone marrow.

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Immunoglobulin γ3-heavy-chain deposition disease: report of a case and relationship with hypocomplementemia

Cited by 41 publications

References 23 publications

Immunoglobulin Light (Heavy)-Chain Deposition Disease

Immunoglobulin Light (Heavy)-Chain Deposition Disease

A mouse model recapitulating human monoclonal heavy chain deposition disease evidences the relevance of proteasome inhibitor therapy

Gamma 1-heavy chain deposition disease accompanied by IgG kappa in serum, urine, and bone marrow

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