Light Chain Deposition Disease

Because the renal plasma flow represents 20% of the total plasma flow and the glomerulus is the renal filtering unit continuously exposed to plasma proteins, the glomerulus is a prominent target for deposition of abnormal proteins or proteins with a peculiar affinity for constituents of the capillary wall. Among these proteins, monoclonal Ig or their heavy-chain (HC) or light-chain (LC) subunits are responsible for a wide spectrum of glomerular diseases that can be classified into two categories by electron microscopy (Table 1). The first category is those with organized deposits and includes diseases with fibril formation, mainly amyloidosis, and diseases with microtubule formation, including cryoglobulinemic kidney and immunotactoid glomerulonephritis. Only amyloid deposits stain for Congo red, a tinctorial property related to the β-pleated sheet organization of amyloid fibrils common to all forms of amyloid. The second category of diseases is characterized by nonorganized electron-dense granular deposits. They are localized in basement membranes in most tissues, especially the kidney, and define a disease now called monoclonal Ig deposition disease (MIDD) (1,2), a term that by convention excludes Ig-derived amyloidosis. MIDD differs from amyloidosis by the lack of affinity for Congo red. The distinction between amyloid light-chain (AL) amyloidosis and MIDD also is justified by the different pathophysiology of amyloid that implicates one-dimensional elongation of a pseudocrystalline structure and MIDD that involves nonorganized amorphous precipitation of Ig chains (see Pathogenesis section).Table 1: Glomerular diseases with monoclonal immunoglobulin depositionHistory It was known from the late 1950s that nonamyloidotic forms of glomerular disease resembling diabetic glomerulosclerosis could occur in multiple myeloma (3,4). The presence of monoclonal LC in these lesions was recognized in 1973 by Antonovych et al. (5) and confirmed by Randall et al. (6), who published in 1976 the first description of LC deposition disease (LCDD). Although the deposits in AL amyloidosis contain monoclonal LC or LC fragments, the term light-chain deposition disease is used only for the disease that features nonamyloid electron-dense granular deposits as described by Randall et al. (6). Monoclonal HC were found together with LC in the tissue deposits from certain patients (6,7), and the term light- and heavy-chain deposition disease (LHCDD) (1) was proposed. More recently, deposits containing monoclonal HC in the absence of detectable LC were observed in patients who were affected by otherwise typical Randall's disease (heavy-chain deposition disease [HCDD]) (8), and the first series of four patients was reported in 1999 (9). Pathogenesis At variance with amyloidosis, lesions in MIDD are related clearly to accumulation of extracellular matrices (ECM). The Ig chains that are responsible for this effect display peculiar structural properties and proneness to precipitate in certain extracellular areas where they most likely stimulate ECM production. Ig Chain Structure Ig are made up of two pairs of subunits: two HC and two LC, each of which includes a variable domain implicated in antigen recognition, and a constant region that itself includes one or several domains and that activates a variety of effector systems. Binding to antigen and activating effector cells or complement (i.e., antibody function) is made possible by the association of two HC and two LC. LC may be of κ or λ type, with one constant and one variable domain (termed CL and VL). HC may be of nine isotypes (μ, γ1, γ2, γ3, γ4, α1, α2, δ, and ε) that define Ig classes and subclasses: IgM, IgG (including IgG1 to IgG4), IgA (including IgA1 and IgA2), IgD, and IgE. HC include from the -NH2 to the -COOH terminus one variable domain (VH) from a common repertoire for all isotypes and three (for IgG, IgA, and IgD) or four (for IgM and IgE) constant domains, termed CH1 to CH4 (see Figure 1).Figure 1.: Domain structure of an IgG. The light- (LC) and heavy-chain domains are shown in gray and white, respectively. VL, light-chain (LC) variable domain; CL, LC constant domain; VH, heavy-chain (HC) variable domain; CH, HC constant domain.Normal Ig display a striking structural heterogeneity that is borne essentially by the variable domains and is related to the diversity of the antigenic determinants that they are supposed to recognize. These regions of the Ig chains are encoded by numerous gene segments, the rearrangement of which occurs during B-cell differentiation and is mandatory for Ig production. Comparison of VH and VL sequences allowed definition of variability subgroups on the basis of their homologies: HC express six VH subgroups, κ chains express four Vκ subgroups, and λ chains express six Vλ subgroups. The variability of VH and VL is even higher in three small peptidic portions called complementarity determining regions (CDR1, CDR2, and CDR3) that form three loops at one end of the domain that constitutes the antibody binding site. At variance with normal polyclonal Ig, monoclonal Ig are secreted by a single clone of differentiated B cells that expands excessively, either in a tumoral context (myeloma, Waldenström's disease, etc.) or without patent hematologic malignancy (monoclonal gammopathy of undetermined significance). A monoclonal Ig may be secreted as free LC (or rarely, HC) that displays structural anomalies causing tissue deposition. Abnormal Structures of LC Variable Domains In LCDD, isotype restriction is significant; κ chains occur in approximately 80% of cases. This contrasts with the increased λ to κ ratio seen in amyloidosis. Data on N-terminal sequences of the LC from six consecutive patients with LCDD suggested an overrepresentation of the rare VκIV variability subgroup (10). This subgroup features a longer CDR1 loop that contains some hydrophobic residues. The role of LC variable region (VL) in LC deposition is suggested by the fact that amino acid changes in VL were sufficient to promote tissue deposition in mice that expressed a human LCDD VκIV chain (11). The primary structures of a few additional LCDD precursors were analyzed at the cDNA (12,13) and protein levels (14). As in AL amyloidosis, no common structural motif emerged from these studies. The most remarkable observations were unusual hydrophobic residues at positions where they either could be exposed to the solvent or strongly modify the conformation, especially in the CDR (13,14). In particular, molecular modeling experiments performed on VκI and VκIV LC underline the presence of leucine, isoleucine, or tyrosine at positions 27 and/or 31 in all known cases of LCDD. Other nonpolar groups may be exposed on CDR regions, which suggests that hydrophobic interactions are important either in the amorphous precipitation of LC or in the mechanisms that lead to overproduction of ECM components (15). Of note, in contrast to LCDD LC, those involved in AL amyloidosis often present particular acidic residues in CDR and might form fibrils through electrostatic interactions. When pathogenic LC could not be detected in the serum and urine, which occurred in 15 to 30% of patients, they seemed to be N-glycosylated in all tested cases (10,16). In vitro biosynthetic labeling experiments on short-term cultures showed that LC that were absent in the urine actually were secreted by the bone marrow plasma cells (1,17,18). Thus, together with the presence of hydrophobic residues, glycosylation might increase the LC propensity to precipitate in tissues and displace the equilibrium from soluble toward deposited amorphous forms. Truncated HC Twenty-two cases of HCDD have been reported (19 and reviewed in reference 20). In all patients, a monotypic HC without LC was detected in the deposits. A deletion of the CH1 domain was found in the deposited or circulating HC in the 10 patients with γ HCDD where it was searched for. It also was suggested in a patient with α HCDD (21). Deletions of the CH1, hinge, and CH2 domains were found in one case (8). The loss of the CH1 domain suggests that secretion of the free, abnormal HC is required for tissue deposition. Normal HC associate posttranslationally with Ig binding protein (BIP) in the endoplasmic reticulum. The LC later assemble with HC, and the complex is transferred to the Golgi apparatus for further processing and secretion. Because the binding site of BIP is located in the CH1 domain, when a mutant HC lacks the CH1 domain, it fails to associate with BIP and thus may be secreted as a free subunit in the circulation. However, CH1 deletion seems necessary but not sufficient for deposition, and it is likely that the VH also contributes to tissue deposition, ultrastructural aspects of the deposits, and ECM accumulation. Indeed, in HC disease, a lymphoproliferative disorder with free HC secretion without corresponding tissue deposition, the variable regions are found to be deleted partially or entirely, together with the CH1 domain. In HCDD, the variable regions are present without major structural alteration, although in the two cases in which they were sequenced (8,22), they contained unusual amino acid substitutions that might change the physicochemical properties (e.g., charge, hydrophobicity). In addition, the structure of an HCDD HC (8) was strikingly similar to that reported in a case of amyloid HC amyloidosis (23), from which it differed essentially at the V domain level. It is worth noting that in most cases of HCDD, the circulating HC is associated with a λ-type LC. This bias may reflect a preferential association of the VH with λ VL domains. Deposition Does Not Mean Pathogenicity The finding by Solomon et al. (24) of unexpectedly frequent (14 of 40) deposition of human monoclonal LC along basement membranes in a mouse experimental model raises the question of the relationship between tissue precipitation and pathogenic effects. Human LC that were found deposited along basement membranes in mice were predominantly of the λ type (9 of 14), contrasting with the striking predominance of κ chains in MIDD (24). In addition, LC deposition similar in aspect to LCDD by immunofluorescence but with no or only scanty granular electron-dense deposits in the tubular basement membrane may occur in the absence of glomerular lesions and tubular basement membrane thickening (19,25). One patient (Aucouturier P, Droz D, personal data) had an important LC secretion and typical basement membrane deposits by immunofluorescence in the kidney, without histologic alteration, and with normal renal functions 2 yr after kidney biopsy. Thus, the propensity of a given LC to form deposits does not necessarily mean that it is pathogenic, and immunofluorescence staining should not be considered a sufficient criterion for pathologic diagnosis of MIDD. As shown by characteristic pathologic changes and experimental evidence, MIDD lesions are associated with local fibrosis. LC-Induced Mesangial Fibrosis Results of an in vitro study (26) suggest that pathogenic Ig chains may stimulate mesangial cells to secrete ECM components through growth factors, in particular transforming growth factor-β (TGF-β). LC-induced overproduction of collagen IV, laminin, fibronectin, and tenascin was shown to be maximal at 72 h of incubation with mesangial cells (27). Accumulation may be increased by a concomitant inhibition of collagenase IV, which also is mediated by TGF-β. None of these effects was found with amyloid LC (27). One way to prevent the LC-induced fibrosis is to study the detailed mechanism of putative ligand-receptor interactions that may govern the ability of a given LC to stimulate the ECM synthesis. Other possibilities are to prevent the secretion of TGF-β or to interfere with the TGF-β signaling pathway. Renal Pathology Light Microscopy Despite clinical manifestations that feature impairment of glomerular function in most cases, MIDD should not be considered a purely glomerular disease. In fact, tubular lesions may be more conspicuous than the glomerular damage. Tubular lesions are characterized by the deposition of a refractile, eosinophilic, periodic acid-Schiff (PAS)-positive, ribbon-like material along the tubular basement membrane (Figure 2A). The deposits predominate around the distal tubules, the loops of Henle, and, in some instances, the collecting ducts whose epithelium is flattened and atrophied. Typical myeloma casts are only occasionally seen in forms of MIDD (see for association with myeloma In a fibrosis including deposits is associated with tubular Light microscopy of an LC with of tubular basement membranes and fibrosis. periodic acid-Schiff deposits the between in an in A in B lesions are more glomerulosclerosis is the most it is found in to of patients with LCDD. of the mesangial ECM was observed in all cases of HCDD, with in all of Mesangial are of material and often are by mesangial The capillary loops at the of and may may contain a material that is to that present in the of the These lesions diabetic but some are the of the is in a given the are and lesions as and of the are not In cases with prominent and mesangial the glomerular features glomerulonephritis. forms of LCDD an increase in mesangial and in mesangial cells and a thickening of the basement membranes that are and Glomerular lesions may not even be detected by microscopy but ultrastructural These lesions may of glomerular disease or be by LC with a pathogenic diagnosis be without the and all may contain deposits in with their basement membranes (Figure not the staining of but they may be associated with Congo amyloid deposits in approximately of patients Microscopy A in the diagnosis of the forms of MIDD is immunofluorescence of the of monotypic LC and/or HC along tubular basement This criterion is for the diagnosis of MIDD. The tubular deposits stain strongly and predominate along the loops of and the distal tubules, but they also often are detected along the In the of glomerular immunofluorescence displays In patients with deposits of monotypic Ig chains are found along the glomerular basement membranes and, to a in the The staining in is than that observed along the tubular basement This may not be a function of the of deposited several cases in which glomerular immunofluorescence was the presence of of granular glomerular deposits by electron microscopy have been reported of deposited LC thus might change their In patients without (Figure glomerular staining occurs mainly along the basement but it may the in some cases. A staining are found in and of renal from a κ LC without staining is shown along tubular basement and deposits are shown in an wall. Glomerular staining involves and capillary basement membranes as as increased In a patient who with myeloma and renal immunofluorescence of renal with the of antibody showed numerous myeloma casts and staining of most of the tubular basement In the of a κ deposits along Renal from a patient with HC deposition disease. immunofluorescence with antibody staining of mesangial areas and capillary in this no staining along basement membranes of the patients with HCDD, immunofluorescence with polyclonal and monoclonal is typical deposits of or HC may be γ may be of the kidney with monoclonal for the constant domains of the γ HC allowed of a deletion of the CH1 domain in all tested cases. In most cases of HCDD, those with deposits of that does not complement components could be in a granular or The proteins amyloid and that are associated with AL amyloidosis and are not present in LCDD deposits. The of glomerular proteins been in associated with LCDD and are made of normal ECM constituents type IV, laminin, that are in and stain for the small and In a series of patients with renal diseases including AL amyloidosis, and LCDD, TGF-β was detected only in of the patients with LCDD and glomerular lesions In the it was found essentially in diabetic which may suggest that to the glomerular may similar Microscopy The most characteristic ultrastructural feature is the presence of to granular electron-dense deposits along the aspect of the tubular basement In the they predominate in a along the glomerular basement membrane and are located mainly along and in the They also can be found in mesangial and the of small between the fibrils have been reported in a few patients with LCDD or with The association of monoclonal LC deposits, along renal with typical myeloma is more frequent than reported (see Figure B and It was found in of 72 patients with nonamyloid monoclonal LC deposits in a series and in of patients with MIDD in a study and some ribbon-like tubular basement membranes are seen in than of the patients In addition, one of the patients not have deposits by electron The lack of ECM accumulation in most of these patients who present with renal in the of a myeloma may be to for the of fibrosis or to a effect of the LC, As the presence of LC deposits along the tubular basement membrane is not sufficient to a diagnosis of MIDD. of LCDD The clinical features of MIDD are renal and as in AL amyloidosis. Data from the series as published an unexpectedly wide of affected to with a Mean to be higher in patients with LCDD and myeloma than in those with MIDD to Renal Renal is a constant feature of and of and renal often the clinical In to of the patients, is associated with However, in approximately of it is than and these patients mainly a (Figure 2A). is not with the of at and may occur in the absence of glomerular lesions by is more frequent to than one for a in which is with a few The of is variable but be to The and of renal are features of MIDD. In most cases, renal function which is a for Renal features of the patients with HCDD are similar to those seen in LCDD and (see MIDD is a disease, but LC deposits may be and found only at and are the most common deposits were constant in patients whose was (Figure They are to and basement membranes of without associated or with and multiple of resembling with of function are the most but several patients and and some of of manifestations have been in as as 80% of the reported cases of LCDD, but they be with of of disease. and are and may and a in similar to that seen in amyloid. As in the kidney and the immunofluorescence showed monotypic LC deposits in the and areas of the in all cases also may occur along the and in the as as in the bone and They may be responsible for of the reported and The most common disease in MIDD is which for to of MIDD and of LC deposits associated with myeloma MIDD and AL amyloidosis are found at in and of myeloma patients, AL amyloidosis, often is the disease that to the of myeloma at an In some patients who first with myeloma and with monoclonal Ig without kidney disease, LCDD occurred when the disease after together with Ig structural Because was shown to Ig gene the disease in these patients might from the of a clone by the from MIDD may Waldenström's and in rare cases It often occurs in the absence of a detectable even after In a monoclonal bone marrow plasma can be by immunofluorescence The diagnosis of MIDD be in patient who or or who that and a monoclonal Ig in the serum and/or the The also is seen in AL amyloidosis, but the more often is associated with the λ LC Because including to a monoclonal Ig in 15 to 30% of patients, renal an role in the diagnosis of MIDD and of the associated The diagnosis is made by the of tissue from an affected in most cases the kidney, with the of a of Ig including and LC to stain the deposits. When the for a single HC isotype and does not stain for LC the diagnosis of HCDD should be (see The diagnosis of plasma on bone marrow and bone marrow with and, with and to for a multiple myeloma are present in no more than of the patients with LCDD. of and HCDD A monotypic HC is associated with the monotypic LC in approximately of patients with LCDD. HC and LC precipitate as subunits or as a Ig to be In one found different of kidney deposition of the HC and LC of the HC structure deletion were in and pathologic in patients with are similar to those in LCDD. The first patients with HCDD were reported in (8). Twenty-two cases have been described (19 and reviewed in reference 20). The clinical and pathologic features of HCDD are the as in LCDD, although several can be lesions of are constant in patients with HCDD, only a staining of tubular basement membranes was seen in some patients (Figure deposits are frequent in these patients than in those with LCDD. They have been reported in in in in in around and in of the and reviewed in reference 20). of complement with renal complement deposition are present in most patients with or HCDD In some patients with HCDD, a monoclonal be detected in serum and urine (8). In patients, a monoclonal can be found in but no deletion is found in the HC (9). of the deleted HC that in serum by (Figure This finding suggests that serum also should be performed in patients with LCDD in have to a circulating monoclonal study after of a from the serum of patients A and were with monoclonal of Ig domain as that contained a monoclonal normal with constant domain (including the two and an γ chain of IgG1 with CH1 domain The from the serum of patient A also a free λ LC et with of the and The of MIDD mainly deposits of LC can be or that to from of from to 10 by the of a related disease, AL amyloidosis, is more with a of Although renal is patient can be with and patient and renal The only of renal patient seems to be the serum at the of the presence of multiple myeloma does not to renal or patient in of renal and patient are in patients with with those who present with myeloma As in AL amyloidosis, should be at Ig production. is in patients with MIDD and It is in the absence of malignancy given the of LCDD and the absence of especially in patients without detectable However, it to patients with or a of the hematologic disease. can in of the LC deposits been in some patients after with bone marrow or of mesangial lesions and LC deposits also was reported after These observations are of they that glomerular lesions are and they for in patients with been performed in a few patients with MIDD and renal of the disease is should be performed kidney In MIDD is a rare disease that is characterized by renal as a of the deposition of a monotypic LC and/or HC of Glomerular lesions are similar to diabetic that MIDD may as a model for the of this of the MIDD is the only glomerular disease in which the is As in AL amyloidosis, are required to define the to clinical and of renal for This was by a from the