AL-amyloidosis and light-chain deposition disease light chains induce divergent phenotypic transformations of human mesangial cells

Abstract

Human mesangial cells (HMCs) are injured by either excessive amounts or abnormal light chains (LCs), or a combination of both in patients with plasma cell dyscrasias. Consequently, these HMCs undergo phenotypic transformations. HMCs were incubated with eight different light-chains (LCs) for 96 h. These cells, in addition to 51 patient samples from patients with AL-amyloidosis (AL-Am), light-chain deposition disease (LCDD), myeloma cast nephropathy (MCN) and controls were analyzed by immunohistochemistry for CD68, musclespecific actin (MSA), smooth muscle actin (SMA), CD14, and Ham56 protein expressions. All samples were also studied using electron microscopy. Greater staining (four-and three-fold) expressions of CD68 and Ham56, respectively, were observed in the HMCs incubated with AL-Am-LCs compared to those with LCDD-LCs and control. SMA expression levels were five-fold higher in LCDD-LC-treated cells compared to the other categories of LC-treated and control cells. Similar results were obtained in the renal specimens, however, CD68 levels were 12-fold higher in the AL-Am cases compared to the LCDD cases, respectively. Conversely, MSA and SMA levels were three fold higher in the LCDD cases than in the AL-Am ones. No CD14 expression was noted in any of the samples and CD-34 staining of HMCs treated with the various LCs only showed rare positive cells. The renal glomerulus is a complex structure, consisting of a number of cell types performing specialized functions, which all culminate in the filtration of plasma and the production of urine. The glomerular mesangial cell is one of the major cell types and accounts for 30-40% of the total population of the glomerulus. 1 These cells, being of mesenchyme origin, are derived from smooth muscle cell precursors and, although being able at times to perform phagocytic functions, are not from the mononuclear phagocytic (monocytic) system. Ultrastructural and morphological evidence show the glomerular mesangial cells to be similar to smooth muscle cells and express many of their associated proteins.Ultrastructurally, the mesangial cell appears to be remarkably irregular in shape with numerous processes of varying lengths projecting into the surrounding extracellular matrix (ECM) and connecting with the glomerular basement membrane (GBM). The cell generally has an indented nucleus and a small amount of cytoplasmic organelles such as mitochondria, lysosomes, ribosomes, endoplasmic reticulum and stacked Golgi cysternae. 2 Numerous bundles of small intracellular filaments with spindle densities or dense bodies and associated attachment plaques are present in the normal mesangial

Urinary Albumin Excretion Patterns of Patients with Cast Nephropathy and Other Monoclonal Gammopathy–Related Kidney Diseases

“…In animal studies, the type of kidney disease is dictated by the monoclonal protein and not the tumor (6). This is also supported by in vitro data that showed that different light chains (AL versus LCDD) activate different cellular pathways via the same receptor on mesangial cells (7).…”

Cardiac nonamyloidotic immunoglobulin deposition disease

“…In vitro studies in the kidneys by Herrera et al show that processing of the Ig by the mesangial cell and subsequent cellular signaling pathways play an important role in the distinction of the deposits. 15,16 AL amyloidosis can manifest as diastolic dysfunction, conduction abnormalities or congestive cardiac failure. Our series show that incidence of CIDD is almost as frequent as AL amyloidosis in patients with plasma cell dyscrasias (31 vs 39%).…”

Multiple Myeloma

“…Amyloid fibrils are associated with other proteins, including amyloid P, glycosaminoglycans, proteoglycans, fibronectin, and apolipoprotein E (114 -116). In the kidney, the mesangial cells or mesangial macrophages play a central role in amyloidogenesis by endocytosing the precursor proteins into lysosomes, where amyloid fibril formation takes place (84,117). However, not all light chains are amyloidogenic (111,118 -120), and the association between multiple myeloma and amyloid suggests that specific abnormal light-chain sequences underlie fibrillogenesis.…”