Immunoglobulin light chain (AL)-amyloidosis was one of the first types of amyloidosis discovered and still little is known about its pathogenic mechanisms. One major obstacle is the very heterogeneous condition; in fact, every patient could be considered to have their own disease since symptoms and outcome vary enormously. The reason for this is not known but intrinsic factors of the immunoglobulin light chain (LC) and the fact that every LC is unique seem to be important. Post-translational modifications such as glycosylation and proteolysis are most certainly involved. By using western blotting, we studied in detail the proteolytic pattern in six patients with AL-amyloidosis of kappa type with the aid of three peptide antisera against two domains in the constant segment and one conserved domain in framework 3 of the variable region. Materials from one to five organs were analysed. The result clearly demonstrates that the fragmentation pattern was similar in amyloid of different organs in one patient but differed greatly between patients. Full-length, N-, and C-terminal fragments were detected with the three antisera. The results strongly support the hypothesis that proteolytic cleavage occurs after fibril formation.

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BackgroundAmyloid is insoluble aggregated proteins deposited in the extra cellular space. About 25 different proteins are known to form amyloid in vivo and are associated with severe diseases such as Alzheimeŕs disease, prion diseases and type-2 diabetes. Light chain (AL) -amyloidosis is unique among amyloid diseases in that the fibril protein, a monoclonal immunoglobulin light chain, varies between individuals and that no two AL-proteins with identical primary structures have been described to date. The variability in tissue distribution of amyloid deposits is considerably larger in systemic AL-amyloidosis than in any other form of amyloidosis. The reason for this variation is believed to be based on the differences in properties of the amyloidogenic immunoglobulin light chain. However, there is presently no known relationship between the structure of an AL-protein and tissue distribution.Methodology/Principal FindingsWe compared the pattern of amyloid deposition in four individuals with amyloid protein derived from variable light chain gene O18-O8, the source of a high proportion of amyloidogenic light chains, and in whom all or most of the fibril protein had been determined by amino acid sequencing. In spite of great similarities between the structures of the proteins, there was a pronounced variability in deposition pattern. We also compared the tissue distribution in these four individuals with that of four other patients with AL-amyloid derived from the L2-L16 gene. Although the interindividual variations were pronounced, liver and kidney involvement was much more evident in the latter four.Conclusions/SignificanceWe conclude that although the use of a specific gene influences the tissue distribution of amyloid, each light chain exhibits one or more determinants of organ-specificity, which originate from somatic mutations and post-translational modifications. Eventual identification of such determinants could lead to improved treatment of patients with AL amyloidosis.

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Donor lymphocyte infusions in amyloid light chain amyloidosis: induction of a "graft-versus-plasma cell-dyscrasia effect"Systemic amyloid light chain (AL) amyloidosis is a rare protein folding disorder with poor prognosis due to multiple organ impairment (mainly heart and kidney). Underlying disease is a monoclonal gammopathy in most patients, only a small portion has symptomatic multiple myeloma. Treatment results in AL amyloidosis have improved in recent years. Apart from high-dose chemotherapy with melphalan supported by autologous stem cells (HDM) 1 and melphalan-dexamethasone combination therapy 2 new drugs active in multiple myeloma (MM) have become available.3-5 The main goal of treatment is to improve or at least preserve the function of the affected organs by elimination or control of the monoclonal plasma cell disorder.1 Long-term survival (>10 years) in about 20% of patients with complete remission (CR) after HDM could be shown recently. However, more than 50% of the patients do not achieve CR or relapse after initial therapy. Treatment of these patients has not been well investigated. It was recently shown that allogeneic stem cell transplantation (allo-SCT) could be an option for eligible patients leading to sustained CR.7 However, allo-SCT is a clinical challenge in this fragile patient group. Donor lymphocyte infusion (DLI) might be an approach to further increase CR rate after allo-SCT using reduced-intensity conditioning (RIC) as shown in MM.8 However, there are no data about application of DLI in this rare and fatal disorder.Two patients with systemic AL amyloidosis were treated with allo-SCT in both centers until 2007. We administered DLI in both patients because they did not reach CR after allo-SCT.

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