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(Journal of Leukocyte Biology. 2004;76:528-536.)
© 2004 by Society for Leukocyte Biology

Immunologic basis for the rare occurrence of true nonsecretory plasma cell dyscrasias

Catherine Decourt, Horia Radu Galea, Christophe Sirac and Michel Cogné1

CNRS UMR 6101, Laboratory of Immunology, Faculté de Médecine et Hôpital Universitaire Dupuytren, Limoges, France

1 Correspondence: CNRS UMR 6101, Laboratoire d’Immunologie, 2, rue du Dr. Marcland, 87025 Limoges, France. E-mail: cogne{at}unilim.fr


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ABSTRACT
 
Lymphocytes and plasma cells are major actors of the adaptive immune response and can rightly be considered as human health keepers. However, recombination and mutation events occurring at high rate in the B cell lineage also expose these cells to gene alterations, potentially resulting in uncontrolled and life-threatening cell proliferation. Although in cultured cell lines, such gene alterations frequently generate nonsecretory variants, most immunoproliferative B cell disorders feature in vivo immunoglobulin (Ig) secretion. In this paper, we review the molecular mechanisms involved in various instances of the rare, nonsecretory myelomas, in light of current notions about the molecular control of Ig production, assembly, and secretion in normal B cells. We finally document the attractive hypothesis that B cell clones, which retain nonsecretable, intracellular Igs, may be ideal, in vivo targets for efficient anti-idiotypic immune responses, and clones featuring an abundant secretion may by contrast easily induce T cell anergy and escape the anti-tumoral immune surveillance.

Key Words: immunoproliferative • B cells • immunoglobulin secretion • myeloma


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IMMUNOGLOBULIN (Ig) PRODUCTION THROUGH THE BROAD SPECTRUM OF IMMUNOPROLIFERATIVE B CELL DISORDERS
 
Immunoproliferative disorders include multiple diseases, ranging from the oligoclonal or monoclonal benign forms (monoclonal gammopathies of undetermined significance) to the most malignant proliferations. In the B cell lineage, these disorders are usually classified according to the predominant maturation stage of the proliferating cells. Actually, blockade at a given maturation stage is a common feature of lymphoid malignancies. Although acute leukemias and many cases of lymphomas are related to the pre-B or pro-B lymphocyte stage, myeloma cells, on the contrary, feature proliferation of terminally differentiated plasma cells migrating to the bone marrow. Proliferation of differentiated cells mostly occurs in adults or in the elderly, and an increased frequency is in some professionals [1 2 3 ]. The proliferating plasma cells most often secrete large amounts of monoclonal Igs, which can easily be detected by electrophoresis as peaks in the patient’s serum and/or urines and subsequently, be typed by methods such as immunofixation. Three situations are encountered with regard to Ig secretion [4 5 6 ]. In the first one, a complete monoclonal Ig molecule is found as a peak in the serum as a result of a stoechiometric production of heavy chains (HC) and light chains (LC). In the second case, the complete Ig molecule is found in the serum together with a free Ig LC [7 ], which in addition, is itself most often excreted in the urines as a Bence Jones protein. This situation with an unbalanced production of Ig chains and an excess of free LC is over-represented among myeloma cases. Secretion of free monoclonal LC results in a high prevalence of specific complications related to the precipitation or deposition of LC in different tissues including heart, lungs, liver, and most of all, kidneys. Lastly, in up to 10% of myeloma cases, the only detectable secreted monoclonal component corresponds to a free LC, present in serum and in urines, and Ig HC production is lost. It is striking that loss of LC production is much less frequent, and synthesis of free HC was only reported in the three very rare conditions known as nonsecretory myeloma, HC diseases (HCD), and HC deposition diseases (HCDD) [8 , 9 ]. Although free, full-size HC would be retained intracellularly, free, secreted HC with a variable (V) region deletion [often combined with an internal constant (C) region deletion] feature HCD and secreted HC with an internal deletion restricted to the C region feature HCDD. In the latter situation, the short HC account for tissue deposits similar to those reported for some precipitating, free LC, likely as a result of peculiar, tridimensional structures of the V domains promoting self-aggregation and/or deposition in the tissues [10 11 12 13 14 15 16 ].

Apart from the Ig-secreting myelomas described above, 1–5% of all myeloma cases [17 ] do not show any monoclonal Ig production, for which they were named "nonsecretory myelomas." Altogether, nonsecretory plasma cell dyscrasias were rarely reported in the literature and will be the focus of this review.


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NONSECRETORY MYELOMA: A RARE ENTITY STILL GETTING RARER
 
Nonsecretory myeloma features the classical bone marrow infiltration by monoclonal plasma cells and its pathological consequences (bone pain, skeletal lesions), without any emergence of monoclonal Ig or Bence Jones protein in patient’s serum and/or urines. Because of the lack of circulating monoclonal protein, the identification of the disease is more difficult than for secretory myelomas and relies on skeletal, radiological studies and bone marrow biopsies. As a result of this difficulty, the frequency of nonsecretory myeloma might be underestimated. Among the few reported cases, the original observations of two different aspects of plasma cells lacking Ig secretion led to define two kinds of nonsecretory myelomas as "nonproducers" or "true nonsecretors" [18 ]. The former corresponded to cells lacking Ig synthesis, and in the latter situation, cells completed synthesis of Ig chains and were unable to excrete them, albeit at low levels, preventing their detection by conventional methods. Consequently, nonsecretory myelomas were further classified using immunofluorescence and/or electron microscopy, such as to check for the lack of production or the lack of secretion of the monoclonal Ig [19 20 21 ]. In fact, most cases of nonsecretory myeloma might be related to a third type, which should be referred to as "false nonsecretors": In several reported cases with demonstrated intracellular Ig chains, the lack of a serum monoclonal component contrasted with pathological evidences that the Ig chains were exported outside of the plasma cells. Several mechanisms may account for such a false nonsecretion. In one case, "buddings" of the cell membranes contained cytoplasmic and endoplasmic reticulum (ER) materials and were postulated to excrete Ig within vesicles that therefore could not be detected in serum as soluble proteins [21 ]. In several other cases, although monoclonal Ig were absent from serum and urines, kidney nonamyloid (Randall-type) deposits or myeloma casts clearly pointed to the accumulation of a monoclonal Ig at a distance from the proliferating cells, and in one case, studies at the molecular level confirmed that myeloma cells were producing the very same glycosylated monoclonal V{kappa}IV LC, which was identified within kidney deposits [20 , 22 ]. Altogether, it seems that in most nonsecretory cases, plasma cells effectively synthesize and secrete Ig, which are then rapidly cleared from the serum as a result of proteolysis or their deposition in tissues, making them undetectable in body fluids by conventional, immunochemistry techniques [19 20 21 22 ]. In a recent study, the use of a sensitive, immunochemical method allowed detection of an excess of serum-free LC production in more than two-thirds of the so-called nonsecretory myeloma cases [23 ].


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MECHANISMS FOR THE LOSS OF Ig PRODUCTION OR SECRETION IN MONOCLONAL PLASMA CELLS
 
Finally, true nonsecretors or nonproducers appear as the most rare conditions among nonsecretory plasma cell dyscrasias. Although nonproducers have not been documented at all with regard to their mechanisms, molecular studies were only performed in two cases of true nonsecretors, both related to a loss of LC production [8 , 9 ]. A case of nonsecretory HCD was correlated with genomic deletion of the polyadenylation site, which normally allows production of secreted type {alpha} chains. As a result, only membrane form-truncated {alpha} HC were produced by the monoclonal plasma cells in the absence of any LC [8 ]. Similarly, a case of nonsecretory myeloma was also found associated with the loss of LC and together with the production of a truncated {gamma}1 HC, which lacked the V domain, was retained intracellularly and subsequently degraded within 12 h. LC loss was a result of mutations in the expressed {kappa}-chain gene, and an insertion at the variable/diversity/joining (VDJ) junction resulted in skipping an enlarged VDJ exon and production of a truncated {gamma}1 HC [9 ].

More frequently in myeloma cases with bona fide Ig secretion, the loss of Ig secretion by only a small proportion of proliferating cells leads to the generation of true, nonsecretory plasma cells known as Mott cells. These cells synthesize complete Ig molecules but are totally unable to secrete them or to degrade them, although being still able to divide normally [24 ]. As a consequence, Ig containing inclusion bodies accumulate in the cell. Such inclusions are usually surrounded by membranes in dilated portions of the ER and are called Russell bodies. Plasma cells containing inclusion bodies and called Mott cells (Fig. 1A ) were first described with a slightly different aspect, as their inclusions were made up of electron-dense material poorly or not delineated by a membrane [25 ]. Since this initial description, many pathologists stopped making any distinction between both aspects, as they clearly relate to a similar intracellular aggregation of nonsecreted Ig. Since the description of the ER-associated degradation (ERAD) pathway (discussed later in this review), which allows the exportation of misfolded proteins from the ER to the proteasome in the cytosol for their subsequent degradation, it also appears likely that Ig accumulating into the ER could well be transported to the cytoplasm before their aggregation into inclusion bodies. In addition to plasma cell dyscrasias, Mott cells originating from the CD5+ autoreactive B cell population are frequently encountered in the course of autoimmune diseases and in the autoimmune mouse strain motheaten [26 , 27 ], without any clear proof yet that both phenomenons have common mechanisms. Although the formation of the inclusion bodies is not totally explained, a study performed on thymectomized autoimmune mice suggested that Mott cells were thymodependent plasmacytoid cells resulting from chronic B cell activation accompanied by impaired Ig secretion [26 ]. This activation would lead to exagerated Ig hypermutation and to the appearance of unsecretable, misfolded, or aggregated Ig molecules [28 ].



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  		Figure 1. Some morphological aspects of intracellularly retained Igs. (A) Mott cells in the course of myeloma. Staining of a bone marrow biopsy with hematoxylin, eosin, and saffron (original magnification, x250). Arrows indicate proteic inclusions (Russell bodies). (B) Intracellular {kappa}-chain crystallization in the course of smoldering myeloma associated with Fanconi syndrome. A bone marrow biopsy was observed by electron microscopy, showing intracellular Ig LC crystals (indicated by arrows) within a plasma cell (original magnification, x8000). (C) Intracellularly precipitating IgG3 crystals. Optic microscopy of 8A4-cultured cells producing a crystallizing IgG3 (original magnification, x400). Arrows indicate the crystals present in the cytoplasm.

Many different mechanisms could arrest the production of at least one Ig chain, including occurrence of terminators within hypermutating variable genes, secondary V(D)J rearrangements associated with out-of-frame or aberrant junctions, or abnormal class-switch recombination events accompanied with truncations of the HC exons. Such molecular mechanisms have been widely documented in HCD patients [8 , 29 ] and are also responsible for the frequent in vitro occurrence of nonsecretory variants from plasmacytoma or hybridoma cell lines [30 31 32 33 ]. However, it remains to be understood why these processes show a strong in vivo bias toward the loss of HC rather than LC. Arrest of HC production with sustained LC secretion indeed occurs in a number of myeloma cases, and loss of LC production (potentially blocking secretion of a remaining, full-size HC and resulting in a true, nonsecretory phenotype) has never been demonstrated in the absence of HC abnormalities. This led to the hypothesis that nonsecreted, full-size HC may be toxic for plasma cells [34 35 36 37 ]. As this bias is mostly observed for B cell variants occurring in vivo, one could also hypothesize that the rare occurrence of nonsecretion may be related to a selective in vivo disadvantage for cells that lose Ig secretion. Indeed, in vitro and in vivo, strong apoptotic responses may result from the ER accumulation of unfolded proteins, as it would be the case for unassembled HC. Finally, it is clear in B cell malignancies that the IgH locus is frequently disrupted as a result of the translocation of various oncogenes, and it was recently shown that many LC myeloma cases show a translocation of one IgH allele and a nonfunctional VDJ rearrangement on the other one [38 ].


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CELLULAR REGULATION OF Ig SECRETION IN PHYSIOLOGY
 
Correct folding of entire Igs
Igs are the main effectors of the humoral immune response. They are produced by B lymphocytes and exist as membrane-bound receptors or secreted effector molecules. Each Ig molecule is composed of two HC and two LC. Crystallographic data and in vitro folding experiments have shown that both chains consist in a series of domains that fold independently of each other [39 , 40 ], each forming a compact structure composed of two twisted ß sheets stabilized by a disulfide bond [41 ]. During B cell maturation, HC are most often synthesized before LC genes are rearranged and expressed. In pre-B cells, the HC may form homodimers and be transported to the cell membrane in association with surrogate LC, which are only expressed at the pre-B cell stage [42 ]. Afterwards, full-length HC will only be exported by mature B cells within assembled H2L2 molecules, and absence of surrogate LC and LC would lead to HC retention in the ER [43 , 44 ].

The requirements for secretion of a protein are the proper folding of the polypeptide chain(s) and the correct assembly of subunits in the case of multimeric proteins. Polypeptides that fail to fold or assemble correctly are retained within the ER by molecular chaperones and are finally degraded. ERAD consists in retrotranslocation of peptides from the ER lumen to the cytosol via the Sec61 protein channel for degradation by the proteasome [45 46 47 ]. The intracellular stage at which secretion is blocked is transport from the ER. This situation is well known in the case of Mott plasma cells defective in Ig secretion. Their intracellular inclusions merely consist in distended ER cisternae filled with Ig as a result of the Ig secretion blockade [48 ]. Nevertheless, the presence of inclusion bodies does not alter transport of other secretory or membrane molecules nor affect the cell division [28 ], thus suggesting that the accumulation of Ig is neutral to them. Valetti and co-workers [28 ] proposed that the inclusion bodies represent a general response of cells to the accumulation of abundant, nondegradable proteins, which fail to exit from the ER. The specifics of why these particular proteins could not leave the ER, and other unfolded Ig are exported to the proteasome could result from their three-dimensional structure. For unassembled molecules, the exposed thiols constitute major intracellular retention elements [49 ]. Thiol-mediated retention would involve the formation of reversible disulfide bonds with the protein matrix of the ER. The presence of an acidic residue next to the critical cysteine would allow the masking of the thiol and thus the transport of the protein to another cell compartment, whereas the absence of such a residue would favor disulfide bonding and ER retention [49 ]. This could explain why in certain Mott cells, Ig secretion was partially rescued by fusion with a {kappa} LC-secreting hybridoma [50 ], thereby allowing another type of Ig assembly and likely masking the exposed thiols.

Igs under chaperone supervision
Different steps of ER quality control have been characterized and shown to involve molecular chaperones. The best-characterized chaperone protein is the Ig CH-binding protein (BiP), which is ubiquitously expressed [43 , 44 ]. It associates transiently with numerous secretory proteins and more stably with misfolded polypeptides [45 ]. BiP was first identified based on its capacity to bind the Ig HC [43 ] and shown to be an ER member of the hsp70 class of stress proteins. BiP was also shown to interact with the LC [51 ]. In vitro studies showed that BiP preferentially binds peptides containing the heptameric motif HyXHyXHyXHy, where Hy is a hydrophobic residue, and X is any amino acid [52 ]. It is thought that these hydrophobic residues would be buried upon protein folding, thus providing a mechanism for the transient interaction of nascent proteins with BiP. Thus, it is not only the presence of BiP-binding sites but their specific folding and its kinetics that determine whether a protein will undergo transient or prolonged association with BiP [53 ].

BiP-binding sites were identified in the V and C domains of the HC and LC [53 ]. Normally, during the assembly of an Ig molecule, BiP associates transiently with HC and LC to catalyze their folding and their subsequent assembly. Efficient assembly of complete Ig allows their secretion or membrane expression. Conversely, BiP mediates ERAD of unassembled polypeptides. Kinetics of degradation corresponds to the kinetics of BiP/Ig-chain complex dissociation [54 ]. BiP is not degraded with its ligand but delivers its ligand to the degradation machinery [55 ]. Activity of BiP is adenosine 5'-triphosphate (ATP)-dependent [56 ].

Davis and co-workers [57 ] identified four potential BiP-binding peptides in LEN and SMA VL sequences. Two of these peptides bind BiP with affinities similar to those of the entire VL proteins and are located in conserved ß strands that are buried in the hydrophobic core of the folded V domain. Binding of BiP to one or both of these peptide sequences maintains the two halves of the ß sandwich in an open conformation, with reduced C23 and C88 residues [57 ].

In the case of HC, BiP interacts transiently with multiple HC domains, but only its interaction with the CH1 domain seems to be persistent and responsible for ER retention. Lee and co-workers [51 ], using a simplified HC (VH-CH1), suggested that in the absence of LC expression, the CH1 domain neither folds nor forms its intradomain disulfide bond and therefore remains a substrate for BiP. Thus, it seems that in vivo, LC are required to achieve the folding of the CH1 domain and the subsequent release of BiP. Alternatively, in vitro addition of ATP to BiP-HC complexes causes the release of the chaperone and allows the folding of the CH1 domain in the absence of LC. The authors suggest that LC are not directly responsible for the folding of the CH1 domain but act by releasing BiP from its HC substrate, therefore allowing it to fold and to assemble into H2L2 molecules that will then be able to leave the ER and be secreted.

Specific interactions of BiP with the CH1 domain are probably mostly a feature of {gamma} and {alpha} HC, and by the contrary, deletions of only the V domain but not CH1 have been shown to allow the secretion of free, truncated µ chains that were not trapped by BiP in a number of instances [29 , 58 59 60 61 62 ]. HC lacking the V and/or CH1 domain do not associate with BiP and can be secreted as free chains [63 ]. Conversely, HC lacking the CH2 or CH3 domain still associate with BiP [63 ]. Stable interactions between HC and BiP are involved in retention of free, full-length HC, which are thus degraded in proteasomes [64 ].

Mutants lacking HC may secrete free LC [65 ], contrasting with free HC, which are not secreted but are retained in the ER and degraded [42 , 66 ]. Most free LC bind BiP transiently through their V domain and can be secreted as monomers or homodimers. Only some nonsecreted LC bind BiP in a stable manner as partially oxidized molecules [67 ]. In the absence of HC, such LC are retained and degraded within the cell. One explanation for such a secretion blockade is that at least for some LC, dimerization would be a prerequisite for complete folding and secretion [67 ]. However, as many free LC are able to be secreted without any previous dimerization, the lack of LC secretion rather relates in other cases to the presence of a peculiar retention motif in the LC structure, signaling its irreversible binding to BiP [68 69 70 ]. Although well documented for in vitro-generated variants, such a situation with loss of HC and intracellularly retained LC has not been reported during in vivo B cell proliferations.

A single amino acid can block the whole secretion process
In LC, the CL domain (with its canonical invariant structure) can assume by itself the mature-fold state [54 ]. Conversely and as a result of the variability of their sequences, some VL and VH domains may be unable to fold by themselves and need close VH/VL interactions to form the antigen-binding site and achieve the mature fold. In that way, several specific sequences of VL domains were shown to prevent secretion of free LC by altering the folding of the domain, resulting in stable BiP/LC complexes. In this manner, VL domains determine the physical stability of a BiP/LC complex or of the nonassembled LC [54 ]. Many mutant LC, carrying substitutions in the VL domain, bind BiP more avidly than their wild-type counterparts [55 , 68 , 69 ]. Conversely, truncated {kappa} chains, consisting of a signal sequence directly attached to the C domain, are translocated across the ER membrane but are not transported further [71 ].

Several mutations in the VL domain were shown to block secretion. The GR15 (Gly15->Arg) replacement in the variable domain of a {lambda}II chain is sufficient to block its secretion by the MOPC-315 myeloma cell line [72 ]. A point mutation, FS62 (Phe 62->Ser), in a {lambda}I chain resulted in a mutant chain, which was retained in the ER in association with BiP [72 ]. Another example of nonsecreted LC is provided by the mutation YH87 (Tyr 87->His) in the myeloma cell line MOPC-21 {kappa} chain. Its association with the BiP chaperone prevented secretion. Beside such complete blockades, partial secretion defects were also reported as a result of unusual LC conformations: for example, the F10 mouse hybridoma cell line displays free {kappa}-chain secretion and ER inclusion bodies containing large {kappa} LC-composed fibrils [73 ].

Recent studies in our laboratory also stressed out the importance of the VL amino acid sequence in the LC secretion rate by transfectomas expressing human myeloma Ig LC [74 , 75 ]. The SP2/0 cell line, lacking endogenous Ig, was transfected with vectors allowing a strong expression of Ig chains in B cells [76 ]. These vectors contained the cDNAs encoding the Bence Jones proteins from two patients or their variants (with single amino acid substitutions). Despite a grossly similar level of {kappa} mRNA production, some of these clones occasionally displayed strikingly low {kappa} LC-secretion rates. In some instances, a point mutation in the V{kappa} sequence accounted by itself for intracellular retention. For example, the {kappa} LC ISE [12 ] secretion rate increased by more than 30 folds (from 75 ng/mL to 2400 ng/mL) upon introduction of the AG64 mutation (Ala 64->Gly). On the contrary, the CHEB {kappa} LC [11 ] was secreted at 35 µg/mL, and its AS30 mutant (Ala 30->Ser) was secreted nearly 15 times less (2.2 µg/mL) [75 ]. These results highlight the strong influence of the LC amino acid sequence, and a single mutation leads to a partial blockade of secretion.

How Ig can escape from intracellular retention
Another aspect of the ER retention concerns the contribution of C-terminal Cys residues in this process. LC possess five Cys residues: four of them are implicated in the formation of disulfide bonds in the variable and constant regions, and the fifth one establishes the intermolecular bond with the HC. The C-terminal Cys represents a retention element for some unassembled LC whose secretion was only possible in the presence of reducing agents or upon assembly with HC [49 , 77 ]. In the ER lumen, {lambda} chains may covalently associate with various matrix proteins through the Cys 214 residue [49 ]. This thiol-dependent ER retention of {lambda} chains is a reversible process. Secreted LC do not possess unpaired Cys residues, as the two internal bonds have already formed, and the C-terminal Cys is masked or covalently linked to another LC or to a HC [65 ]. Conversely, nonsecreted, free LC do not form dimers and thus would need to be associated to HC before secretion. In the absence of HC, some LC occur as partially oxidized, BiP-bound molecules until they are degraded [67 ]. For example, the mutated YH87 {kappa} chain (from myeloma cell line MOPC-21) was not secreted alone but upon addition of a {gamma} HC [78 ]. In that case, molecular modeling of the {kappa} chain and of the entire IgG molecule showed that His 87 is buried in the hydrophobic interface between VL and VH [78 ]. In the same manner, addition of a µ HC to the above-mentioned, nonsecreted FS62 {lambda}I LC allowed the assembly of an entire IgM molecule, which was secreted [67 ]. It is stricking, however, that an additional substitution (AV60) in the LC sequence, although unable to signal LC retention by itself, resulted in conjunction with the FS62 substitution into an intracellular retention that could no longer be released by a µ HC [69 ]. Thus, depending on a global structure of the LC variable domain, HC addition would not always be possible or sufficient to allow the Ig secretion [69 ].

In some other cases, the addition of a HC can also increase the secretion of LC, which alone are poorly secreted by plasma cells. For example, in the SP2/0 ARN plasmacytoma cell clone, we determined the secretion rate of the ARN {kappa}I LC at only 1.6 µg/mL rate [10 ]. Transfection of that clone with a vector encoding a µ HC allowed assembly of a complete IgM{kappa}, and the amount of {kappa}I LC detectable in the cell supernatant underwent a fivefold increase and reached 7.4 µg/mL (Table 1 ). Although the {kappa} chain alone likely underwent prolonged interactions with ER chaperones and a slowed trafficking, association with a µ HC displaced chaperone/LC complexes and improved secretion of the LC within complete IgM molecules.


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  		Table 1. Correlation between Intracellular Retention and Reduced Frequency of Tumor Growth in Mice

Altogether, Ig secretion appears as tightly linked to multiple factors, ranging from the amino acid sequences of both chains to their stoechiometric association and to their proper folding. Several molecular chaperones are devoted to the legitimity control of the secreted molecules. Recent experiments showed that the chaperones themselves are up-regulated upon the cellular differentiation from B lymphocyte to plasma cell. This phenomenon is regulated by the transcription factor Xbp-1, as part of an unfolded protein response (UPR) pathway, which is believed to detect and compensate for excessive protein accumulation into the ER [79 80 81 ]. The molecular targets for this UPR are several transcription factors and chaperones such as BiP and GRP94, which are at this point overexpressed [79 , 82 ]. These molecular changes are necessary to copious Ig synthesis and secretion and thus allow B cells to escape UPR-induced apoptosis while differentiating into plasma cells [83 , 84 ]. For a given B cell clone, this situation is even complicated by the fact that these molecular changes are concomitant to clonal proliferation. As an example, long-term hybridoma cultures exhibit frequent loss of productivity over time as a result of the expansion of nonproducing subpopulations of cells, leading to the progressive conversion of a producer to a nonproducer. A lack of HC production in some subpopulations was also reported while LC were still produced [85 ]. Hybridomas that produce levels of LC similar or less than HC levels preferentially lose the HC secretion, which could suggest a possible regulatory mechanism and the preferential loss of Ig chains that cannot assemble and be secreted [85 ]. Various factors have been evoked as possibly responsible for the outgrowth of such variants, ranging from culture conditions (cell-freezing and thawing procedures, low serum concentration) [86 , 87 ] to genetic alterations (chromosome loss in hybrid cells or random mutations) [35 , 86 ]. Actually, Ig VL- and VH-encoding genes may be submitted to frequent mutation events in B cells undergoing the somatic hypermutation program linked to the in vivo affinity maturation of antibodies [88 , 89 ]. This can also occur in vitro in cultured B cells [90 ]. By analogy to the loss of HC production in hybridomas that do not produce enough LC [85 ], we reported the spontaneous in vitro outgrowth of variants with V region mutations that restored high-level secretion in a case where hybridoma cells produced an intracellularly precipitating Ig [91 ]. The 8A4 hybridoma cells, producing a murine IgG3{kappa} cryoglobulin (2.3 µg/mL; Fig. 1C ), spontaneously mutated in vitro by deleting three codons from the V{kappa} region, leading to the expansion of a clone secreting seven times more IgG3{kappa} (15.9 µg/mL) and not any more showing intracellular Ig precipitation. Once again, this case clearly demonstrates the importance of the VL and/or VH amino acid sequences in the cellular control of the Ig secretion.


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INCIDENCE OF Ig SECRETION ON THE TUMOR GROWTH
 
As a result of the fact that plasma cells differentially secrete Ig or LC according to their sequence and their ability to fold properly, one can speculate that this secretion rate has a direct incidence on the malignant plasma cell proliferation rate in vivo and on the tumor growth. Actually, among residues playing a special role in LC secretion, some are highly conserved, and their mutation likely impairs the correct LC folding. Like any unfolded ER protein exported toward the proteasome and therein degraded into peptides [92 ], the unfolded Ig chain should thus be degraded into peptides and processed through the major histocompatiblity complex (MHC) class I presentation pathway. Some cytokines, such as interferon-{gamma} [93 ], modulate the proteasome composition and activity [94 ]. Once peptides are produced by the proteasome, they translocate via the transporter associated with the antigen processing complex [94 ] back into the ER, where calnexin and tapasin control the MHC class I molecule folding and facilitate peptide loading [95 ]. Thus, antigenic determinants (derived from mutated Ig chains) may be presented at the B cell surface and recognized by cytotoxic T lymphocytes. There is increasing evidence from the pathology that the capacity of malignant plasma cells to present idiotypes (Id) as self-antigens may contribute to tumor surveillance [96 97 98 ]. For example, we recently demonstrated that endogenous LC peptides were presented on LC-producing plasma cells [99 , 100 ]. In these studies, S67 cells producing the human CHEB {kappa}I LC [11 ] were irradiated and used to immunize BALB/c mice. Viable S67 cells were then grafted to immunized or naive control mice, which were surveyed for tumor development. Immunization clearly protected mice from the tumor growth by inducing a T helper cell type 1 (Th1) response directed against the LC determinants [99 , 100 ]. In addition, transfection of the immunizing cells so that they produced granulocyte macrophage-colony stimulating factor and interleukin-12 strongly enhanced the Th1-type response. It is thus clear that a plasma cell line is capable of presenting peptides from an endogenously produced LC in association with MHC class I molecules. In some instances, it also appeared that low secretor clones showing intracellular retention of Ig were less tumorigenic than high secretors, maybe as a result of a more efficient presentation of determinants from intracellularly degraded Ig chains. Two such hybridomas intracellularly retained {kappa} chains in one case (clone ARN) and a complete IgG3{kappa} forming crystals in the ER in the other case. Variants were generated by transfecting a µ HC gene, which restored secretion of a complete IgM in the first case, and by selecting a point mutation, which suppressed crystal formation and allowed efficient IgG3 secretion in the second case. In both instances, suppressing intracellular retention enhanced the frequency of tumor formation when cells were injected into mice (Table 1) . Thus, plasmacytoma cells producing Ig that are retained intracellularly seemed to be less aggressive. On line with this interpretation, untransfected SP2/0 cells synthesizing no Ig chain and thus unable to present any Ig-related peptide, gave rapid and aggressive tumors in nearly all the animals when grafted to mice (Table 1) . By analogy in myeloma, low secretory or nonsecretory cells with intracellular retention of Ig would elicit a more efficient anti-idiotypic Th1-type response than high secretors and would undergo spontaneous remission (accounting for their rare occurrence) or have a better prognosis. It is for example striking that plasma cell dyscrasias associated with Fanconi syndrome, characterized by monoclonal L chains forming intracellular crystals within tumoral cells (and within renal tubular cells), usually displays the clinical presentation of monoclonal gammopathy of undetermined significance (MGUS) or of smoldering myeloma [101 , 102 ]. Furthermore, in a recent experimental animal model, Bogen and co-workers [103 ] showed that a serum monoclonal myeloma protein concentration exceeding 50 µg/ml led to the rapid deletion of the Id-specific T cells, thus allowing the malignant clone to escape an antitumoral-immune response.

From all this, it is tempting to speculate that the low incidence of nonsecretory myeloma among all myeloma cases could be related to diagnostic difficulties and to a less-aggressive evolution or even to a spontaneous involution of the tumor as a result of an efficient T cell anti-idiotypic response. Obviously, smoldering myeloma or cell proliferations resembling MGUS but lacking monoclonal Ig secretion would have major probabilities to escape diagnosis made by conventional techniques. At least for those cases that reach a significant tumoral mass and with an overt proliferative disease, it was noticed that true nonsecretory cases were associated with a lower percentage of plasma cells in the bone marrow and with a median survival of 46 months instead of 21 months for secretors [104 ]. Altogether, the emerging picture is thus that true nonproducers rarely occur, not only as B cells may get survival signals from the production of Igs [105 , 106 ] but also as intracellular retention of monoclonal Ig may target malignant cells for destruction more efficiently by anti-tumoral immunity.


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ACKNOWLEDGEMENTS
 
This work was supported by grants from Association pour la Recherche sur le cancer (Grant #4403), Ligue Nationale contre le Cancer and Conseil Régional du Limousin.

Received February 24, 2004; accepted April 16, 2004.


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