In LCDD, the primary structure of the light chain likely has some importance in its ability to deposit in the body. Several proteins from patients with LCDD have been sequenced, and some conclusions can be drawn from analysis of the primary structure. The kappa light chains are more likely to be of the V-region subtype, of which Vκ[kappa]_IV seems to be overrepresented, though κ[kappa]_I–IV has been described [31–33]. There is no consistent structural motif or specific residue that has been shown to be responsible for the pathogenicity of these proteins; however, certain features have emerged. First, the amino acid substitutions appear to derive from somatic mutations, as opposed to germline mutations. Second, though the substitutions can occur throughout the protein, they are most common in the complementarity-containing region [31]. Third, the mutations described in both kappa and light chains are more likely to introduce hydrophobic residues, suggesting a disturbance in protein–protein interaction, destabilization of the protein, and subsequent deposition in tissues [31, 34, 35]. The predisposition to aggregation can be demonstrated in a murine model of LCDD, in which transfected mice with vectors containing kappa light chain sequence from a human subject with LCDD of the Vκ[kappa]_IV subtype showed light-chain deposition in the kidney [36]. Lastly, posttranslational modification has also been implicated in creating pathologic light chains, as the isolate of one kappa light chain from a patient with LCDD had a mutation that resulted a new N-glycosylation site [37].

The mesangial cell is also an important factor in the pathogenesis of this disease. In a series of in vitro studies by Herrera et al., it has been demonstrated that mesangial cells are integral in the deposition of excess extracellular matrix (ECM) proteins that characterize the pathologic lesion of nodular glomerulosclerosis [38–40]. In one of the initial studies, cultured mesangial cells were incubated with light chains from patients with either amyloidosis, MCN, or LCDD [38]. The authors were able to show that mesangial cells cultured with amyloid light chains initially had an increase in ECM proteins, then a reduction to below control levels with a concurrent increase in collagenase activity. In contrast, mesangial cells cultured with LCDD light chains showed proliferation of mesangial cells followed by excess ECM formation, a reduction in collagenase activity, and mesangial nodules consistent with nodular glomerulosclerosis.

One important ECM protein that was present in these nodules was tenascin. Tenascin is a component of the mesangial ECM that is present in low levels in normal mesangium, but is present in much higher amounts in pathologic conditions of the kidney [41]. In addition, transforming growth factor β[beta] (TGF-β[beta]) is a known inducer of tenascin production and has been shown by the same authors to be present in the glomeruli of patients with LCDD [17]. Tenascin is degraded by the matrix metalloproteinase (MMP) 7. In the same in vitro model described above, the culture media from mesangial cells incubated with LCDD light chains showed a marked reduction in MMP-7 levels in comparison to those incubated with amyloid light chains [42] as well as an increase in TGF-β[beta] and platelet-derived growth factor β[beta] [40]. Interestingly, later studies have shown that MMP-7 is produced by mesangial cells, but the cells are for some reason unable to secrete it [40]. These experiments suggest that there is some intrinsic feature of the light chain itself that promotes or inhibits ECM production, alters regulation of ECM breakdown by MMPs and collagenase, and thereby produces different pathologic entities. One lingering question is how the same light chain is able to produce different types of deposits in the same individual or even in the same organ as described above (see Pathology).

HCDD was first described as a distinct entity in 1992 by Tubbs et al. [43], where the proposed name was pseudo-γ[gamma] heavy-chain deposition disease. As mentioned above, the heavy chain in HCDD is more likely to be of the γ[gamma] class [8, 9], with some rarer cases of the α[alpha] subtype [16] and only one case of the μ[mu] subtype [44]. In most reported cases of γ[gamma]-HCDD, there is a deletion of the first constant (CH1) domain [18, 45–47], resulting in a truncated protein. One theory as to the mechanism of disease is that as these proteins lack the CHI portion, they cannot bind to the heavy-chain-binding protein (BiP) in the endoplasmic reticulum [48] and therefore are secreted into circulation rather than being degraded [49]. There may also be some amino acid substitutions in the complementarity-determining regions (CDRs) and framework regions that can change the property of the heavy chain, making it more likely to deposit in tissues [18, 50].

Further insight into the pathogenesis of HCDD can be gained by further subtyping the heavy chain. There have been reports of γ[gamma]1–4 subtypes [18, 43, 45, 49]. All of the γ[gamma]3 subtypes and the majority of the γ[gamma]1 subtypes reported have had low serum complements and deposition of C1q and C3 on immunofluorescence [49]. However, those with γ[gamma]4-HCDD and the one case of γ[gamma]2-HCDD did not have low serum complement or deposition of C3 and C1q. This is consistent with what is known about the classical pathway of the complement system, where IgG3 binds C1q most avidly, followed by IgG1 and IgG2 [51]. IgG4 fixes complement very poorly and is unable to activate the classical pathway. In a review of all the cases reported of γ[gamma]-HCDD, 11/19 patients had hypocomplementemia, as opposed to the five reported cases of α[alpha]-HCDD, where no patients had hypocomplementemia [16]. Interestingly, in all cases of α[alpha]-HCDD, crescents were observed on light microscopy. As crescents are rare in MIDD, this feature highlights the subtle but real pathogenic differences between all the subtypes of MIDD based on the characteristics of the deposited immunoglobulin. More research into the properties of the various immunoglobulins in MIDD may help explain the varied pathologic and clinical features of these different subtypes.