Monoclonal Immunoglobulin Light Chains Research Articles

Cardiac amyloidosis: where are we today?

Systemic amyloidosis is generally considered to be rare, but the heart is frequently involved and is a major determinant of prognosis. New diagnostic imaging methods have recently been developed with the capacity to enhance the accuracy of diagnosis, which will be ever more important with the variety of new treatments on the near horizon. Most cases of cardiac amyloidosis are of either monoclonal immunoglobulin light chain (AL) type, which can occur at any age from young adulthood onwards, or transthyretin (ATTR) type, which can be acquired in elderly individuals or inherited at a younger age. Cardiac involvement is the most serious manifestation of AL amyloidosis, and serum cardiac biomarkers have proved to be of great value in staging disease severity and response to an ever increasing array of chemotherapy agents. Cardiac involvement is the dominant manifestation of nonhereditary ATTR amyloidosis, also known as senile cardiac amyloidosis, the prevalence of which is not known but is probably much greater than currently recognized. A genetic variant in the gene for transthyretin (TTR), which is present in 3-4% of African Americans and probably a similar proportion of black individuals of African descent generally, appears to be associated with increased susceptibility to developing cardiac ATTR amyloidosis in older age. Several novel therapies are in the advanced stages of development for ATTR amyloidosis including TTR protein stabilizers and RNA inhibitors that greatly diminish TTR production. Here, we will review recent developments in the diagnosis and management of cardiac amyloidosis.

Does AL Amyloidosis Have Unique Gene Expression Profile? Meta-Analysis Results

BackgroundImmunoglobulin light chain amyloidosis (AL amyloidosis) is a plasma cell dyscrasia characterized by deposition of amyloid fibrils in various organs and tissues, derived from monoclonal immunoglobulin light chains (LC), leading to organ dysfunction. Until now there is no systematic study of genomic expression of patients with AL amyloidosis compared to other monoclonal gammopathies.Aim of this study was to reveal genomic expression differences between AL amyloidosis patients versus healthy donors (ND), monoclonal gammopathy of undetermined significance (MGUS), smouldering myeloma (SMM) and multiple myeloma (MM) patients.MethodsGene expression profiling data from GEO database (GSE6477, GSE24128) comprised of ND (n=15), MGUS (n=21), SMM (n=24), MM (n=69) and AL (n=16) patients were used. To ensure the comparability between arrays and eliminate the batch effect, quantile normalization was performed. To identify the AL patients´ gene expression profile which significantly differs in comparison with ND, MGUS, SMM or MM patients, we applied SAM algorithm for 6588 selected genes that fulfilled the condition having standard deviation above the median. Genes with fold change ≥1.5 or ≤0.5 and false discovery rate >0.001 were considered as significant. Prediction analysis of microarrays (PAM) using nearest shrunken centroids and cross validation assay was carried out to identify the smallest subsets of genes that were able to accurately predict classes.ResultsComparison of AL patients vs. ND revealed 229 changed genes, AL vs. MGUS 126 genes, AL vs. SMM 338 genes and AL vs. MM 110 genes, respectively. Out of them, the most significantly changed 100 genes from each comparison were further analysed. Some of the genes occurred repeatedly, thus only 256 of genes from all comparisons were unique. Using PAM algorithm we found the genes that have the best predictive power for differentiation AL patients from ND, MGUS, SMM and from MM patients was as followed: RPS6, RPS14, RPS17, RPLA18A, TMEM66, EIF3L, CCDC72, GLTSCR2, NDUFS6, DUSP1, IGLJ3, IGHM, IGKV1-5IGKC///IGKV1-5///IGKV1D-8 and IGHA1///IGHA2///IGHD///IGHG1///IGHG3///IGHG4///IGHM/// IGHV3-23///IGHV4-31///IGHV4-59. Gene expression changes are presented on Figure 1.ConclusionBased on offered meta-analysis, 16 genes representing mostly ribosomal proteins and immunoglobulin regions allow us to detect specific aberrant clone responsible for pre-amyloid production and can serve as candidates for further detailed study.Work was supported by grants IGA NT 12130, NT 14575 and NT 13190. [Display omitted] DisclosuresHajek:Merck: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Honoraria.

Clinical Presentation and Treatment Responses in IgM AL Amyloidosis, a Series of 106 Patients

Objective: AL amyloidosis is a multiorgan disease due to deposition of misfolded monoclonal immunoglobulin light chains. AL amyloidosis with IgM paraproteinemia is a rare variant of this disease; accounting for approximately 6% of AL amyloidosis cases. The clonal cell of origin may be a plasma cell or lymphoplasmacytic cell, and treatments targeting each have been employed. This study describes clinical and laboratory features of IgM AL amyloidosis patients and their response to different therapeutic regimens.Methods: 106 patients with IgM-related AL amyloidosis were evaluated at the BUMC Amyloidosis Center during 1996-2012. Treatment and response information was available on 46 treated after 2003, during the era of new agents for plasma cell diseases. In this cohort, there were 5 treatment groups: high-dose melphalan/stem cell transplant (HDM/SCT); bortezomib-based regimens; standard doses of the alkylating agents melphalan or cyclophosphamide; immunomodulatory agents (IMiDs); and rituximab-based regimens. Treatment regimens were assigned by bone marrow pathology and patient-specific factors.Results: For the 106 patients, the median age at diagnosis was 67 years (range: 38-89 years) with 52 (56%) males. The kidney was the most commonly involved organ (51%) followed by heart (41%) and GI tract (23%). Median IgM was 590 g/dL (range: 29-9130). The clonal population had lambda light chain restriction in 69% of patients. For the 46 patients treated after 2003, overall response rates and rates of very good partial or complete responses were were 100% and 80% respectively, with HDM/SCT; 82% and 30% with bortezomib-containing regimens; 80% and 25% with regimens that included rituximab; 75% and 0% with regimens in which an IMiD was included; and 63% and 20% with other alkylator regimens. There was no association between treatment response and organ involvement, sex, or age. DisclosuresSloan:Millenium: Consultancy.

Mesangial cells as amyloid factory: a unique contribution of animal models.

AL amyloidosis is a severe complication of plasma-cell disorders, secondary to monoclonal immunoglobulin light chain (LC) deposition in the kidney and other organs. Though the physicochemical properties of amyloid-forming monoclonal LCs have been demonstrated to be involved in their propensity to aggregate, it remains unclear where, when, and finally why amyloid fibrils are formed in vivo. Teng et al. shed light on this long-standing issue thanks to a new animal model.

Understanding biology to tackle the disease: Multiple myeloma from bench to bedside, and back.

Multiple myeloma (MM) is a cancer of antibody-producing plasma cells. The pathognomonic laboratory finding is a monoclonal immunoglobulin or free light chain in the serum and/or urine in association with bone marrow infiltration by malignant plasma cells. MM develops from a premalignant condition, monoclonal gammopathy of undetermined significance (MGUS), often via an intermediate stage termed smoldering multiple myeloma (SMM), which differs from active myeloma by the absence of disease-related end-organ damage. Unlike MGUS and SMM, active MM requires therapy. Over the past 6 decades, major advancements in the care of MM patients have occurred, in particular, the introduction of novel agents (ie, proteasome inhibitors, immunomodulatory agents) and the implementation of hematopoietic stem cell transplantation in suitable candidates. The effectiveness and good tolerability of novel agents allowed for their combined use in induction, consolidation, and maintenance therapy, resulting in deeper and more sustained clinical response and extended progression-free and overall survival. Previously a rapidly lethal cancer with few therapeutic options, MM is the hematologic cancer with the most novel US Food and Drug Administration-approved drugs in the past 15 years. These advances have resulted in more frequent long-term remissions, transforming MM into a chronic illness for many patients.

Amylose AL

AL amyloidosis belongs to the group of conformational diseases. It is the most common type of amyloidosis with an estimated 500 new cases per year in France. It is due to a small and usually indolent plasma cell clone which synthesizes an unstable, misfolded monoclonal immunoglobulin light chain that is prone to aggregate and form amyloid fibrils. Non-invasive biopsy such as abdominal fat aspiration or minor salivary gland biopsy should be performed to confirm the diagnosis and if negative, involved tissues have to be examined. Clinical presentation is very diverse, as AL amyloidosis can affect almost any organ or tissue in the body, other than the brain. The kidney is the most frequent organ involved, whereas heart disease characterized by restrictive cardiomyopathy is the most severe. Early diagnosis, before advanced cardiomyopathy, is essential for improving outcome. The association of alkylating agent and high-dose dexamethasone is effective in almost two-thirds of patients. Combinations of proteasome inhibitors, dexamethasone, and alkylating agents achieve high response rates. Close monitoring of clonal and organ response is mandatory to guide therapy changes and duration. New treatments designed to eliminate amyloid deposits are under development.

44-Year-Old Man With Exertional Dyspnea, Weight Loss, and Palpitations

44-Year-Old Man With Exertional Dyspnea, Weight Loss, and Palpitations

Increased serum free light chains precede the presentation of immunoglobulin light chain amyloidosis.

Patients with immunoglobulin light chain amyloidosis (AL amyloidosis) generally present with advanced organ dysfunction and have a high risk of early death. We sought to characterize monoclonal immunoglobulin (M-Ig) light chains before clinical presentation of AL amyloidosis. We obtained prediagnostic sera from 20 cases with AL amyloidosis and 20 healthy controls matched for age, sex, race, and age of serum sample from the Department of Defense Serum Repository. Serum protein electrophoresis with immunofixation and serum free light chain (FLC) analysis were performed on all samples. An M-Ig was detected in 100% of cases and 0% of controls (P < .001). The M-Ig was present in 100%, 80%, and 42% of cases at less than 4 years, 4 to 11 years, and more than 11 years before diagnosis, respectively. The median FLC differential (FLC-diff) was higher in cases compared with controls at all time periods, less than 4 years (174.8 v 0.3 mg/L; P < .001), 4 to 11 years (65.1 v 2.2 mg/L; P < .001), and more than 11 years (4.5 v 0.4 mg/L; P = .03) before diagnosis. The FLC-diff was greater than 23 mg/L in 85% of cases and 0% of controls (P < .001). The FLC-diff level increased more than 10% per year in 84% of cases compared with 16% of controls (P < .001). Increase of FLCs, including within the accepted normal range, precedes the development of AL amyloidosis for many years.

Evaluation of Monoclonal and Oligoclonal Gammopathies in a Pediatric Population in a Major Urban Center

A growing body of literature has documented monoclonal proteins in children. Little is known about their associated diagnoses. We retrospectively evaluated all patients (aged 0-21 years) with abnormal findings on serum immunofixation electrophoresis (SIFE) from 2005 to 2011. We also documented the monoclonal immunoglobulin classes and light chain types involved and then correlated these data with the clinical diagnoses. A total of 695 SIFE tests were performed on this patient population. Of these, 95 SIFE tests (14%) identified a gammopathy (from 83 different patients), and of these, 74 (11%) demonstrated only a monoclonal gammopathy (from 63 different patients). The most common associated diagnosis in the study interval was ataxia-telangiectasia (22%). No patient in the study population was diagnosed with multiple myeloma or Waldenström macroglobulinemia. The significance and presence of a monoclonal or oligoclonal gammopathy in pediatric and young adult populations is distinct from that seen in adults.

Mesenchymal Stem Cells in Mesangial Repair in a Model of Immunoglobulin Light Chain-Mediated Mesangial Injury

Mesangial injury produced by glomerulopathic monoclonal immunoglobulin light chains leads to two diametrically opposed results: matrix loss from mesangiolysis / replacement of mesangial matrix with amyloid (AL-amyloidosis) and increased matrix (light chain deposition disease), depending on the physicochemically abnormal light chains involved. In both situations; however, there is loss of mesangial cells resulting from apoptosis induced by the glomerulopathic light chains. This unique experimental model of mesangial injury resulting in divergent manifestations allows examining the role of mesenchymal stem cells in mesangial glomerular repair in the two typical prototypes of alterations that occur in the mesangium when injured by a variety of injurious agents. In vitro and ex vivo platforms are used to translate information from the in-vitro to the in-vivo arenas. Both platforms highlight the same sequence of events that take place: mesenchymal stem cells identify the site of damage, clear the damaged mesangium by eliminating debris from apoptotic cellular elements and deposited “foreign” (not belonging in the normal mesangium) material and eventually differentiate into mature mesangial cells laying down new matrix. Each of the platforms employed exhibited certain advantages and limitations in visualizing and understanding the processes that occur. When the information generated was combined, a clear view of mechanisms involved and how mesenchymal stem cells participated in mesangial repair emerged.

Thermal Stability Threshold for Amyloid Formation in Light Chain Amyloidosis

Light chain (AL) amyloidosis is a devastating disease characterized by amyloid deposits formed by immunoglobulin light chains. Current available treatments involve conventional chemotherapy and autologous stem cell transplant. We have recently concluded a phase III trial comparing these two treatments. AL amyloidosis patients who achieve hematological complete response (CR) do not necessarily achieve organ response regardless of the treatment they received. In order to investigate the possible correlation between amyloid formation kinetics and organ response, we selected AL amyloidosis patients from the trial with kidney involvement and CR after treatment. Six patients were selected and their monoclonal immunoglobulin light chains were characterized. The proteins showed differences in their stability and their kinetics of amyloid formation. A correlation was detected at pH 7.4, showing that less stable proteins are more likely to form amyloid fibrils. AL-T03 is too unstable to form amyloid fibrils at pH 7.4. This protein was found in the only patient in the study that had organ response, suggesting that partially folded species are required for amyloid formation to occur in AL amyloidosis.

The Significance Of Abnormal Plasma Cell Clone In Bone Marrow Of Primary Systemic Light Chain Amyloidosis Patients

In this study we analyzed the immunophenotype characteristics of the plasma cells and evaluated the significance of the abnormal plasma cell clone in bone marrow in primary systemic light chain amyloidosis (AL) patients. Fresh bone marrow samples were collected from 74 cases of plasma cell disease (PCD), including 51 cases of AL, 21 cases of multiple myeloma (MM), 2 cases of Waldenström's macroglobulinemia (WM). All patients diagnosed according to WHO 2008 diagnostic criteria. The diagnosis of AL was confirmed by the presence of monoclonal immunoglobulin or free light chain in blood or urine, and/or amyloidosis in fat tissues or biopsies by Congo red staining. Ten healthy donors were also collected as controls. Their clinical characteristics and immunophenotype of bone marrow cells were compared and analyzed. The immunophenotype were analyzed with a panel of antibodies including CD45, CD38, CD138, CD117, CD56, CD19, CD20, Igκ, Igλ, CD7, CD22, CD3, CD34 and CD27 by flow cytometry (FCM). The results were for statistical processing.The prominent feature of AL patients was multi-organ and multi-system involvement. Kidney was the major organ involvement (82.4%), followed by cardiovascular system (58.8%); MM mainly had the clinical manifestations of bone lesions (85.7%) and renal involvement (47.6%). The serum immunoglobulin of AL mainly manifested as λ light chain (74.5%), while the majority of MM manifested as κ (61.9%). In the 51 patients of AL, the ratio of plasma cellsin bone marrow was mean 3.87% (0.17∼9.34%) by FCM, and 4.47% (0∼14.5%) by morphological examination. In MM, the ratio of plasma cells was mean 13.17% (1.30∼48.91%) by FCM and 33.55% (3.0∼81.5%) by morphological examination. The plasma cells proportion between AL and MM had significant difference (P< 0.05). The κ or λ light chain restriction can be used for the detection of abnormal plasma cell clones in AL patients. The κ/λ ratio>4.0 or <0.5 can be used as the criteria to identify light chain restriction in plasma cells in AL patients. The 31/51 cases of AL could detected abnormal plasma cell clone that used κ/λ light chain restriction and were mainly expressed λ light chain (24/31, 77.4%). The 21 cases of MM had light chain restriction, mainly expressed κ light chain (13/21, 61.9%) (P<0.05). In CD45/SSC scattergram, the position of abnormal plasma cells of AL patients varied in a wider range. According to the features of CD38+/CD138+ as the basic markers for plasma cells, abnormal plasma cells were CD45 negative or weak positive in AL patients, similar to the CD45 level distribution in malignant plasma cells in MM. In WM, the proliferated cells were plasmacytoid lymphocytes with CD45 weakly or strong positive. FCM can identify abnormal plasma cell clone in bone marrow of AL patients. In 51cases of AL, 78.4% of bone marrow plasma cells were CD56+, 68.6% were CD117+, and 88.2% were CD19-. In 21 of MM, 66.7% were CD56+, 38.1% were CD117+, and 90.4% were CD19-. These results manifested significant difference compared with those of normal plasma cells (P< 0.05). In 2 cases of WM, these plasmacytoid lymphocytes were CD19+ and CD56-, CD117-.The ratios of CD56+, CD117+, CD19-, and CD45-/dim in bone marrow plasma cells were significantly higher in AL patients than in WM patients and healthy individuals (P<0.05), but were similar to those in MM patients (P>0.05). The main difference between AL and MM was the larger size of plasma cell group in MM (P＜0.05).In summary, according to light chain restricted expression and abnormal immunephenotype by FCM analysis we can determine abnormal plasma cell clone in bone marrow of AL patients and the abnormal plasma cells clone can be used as an important diagnostic marker of AL. Disclosures:No relevant conflicts of interest to declare.

Clinical Presentation and Treatment Responses In IgM-Related AL Amyloidosis

AL amyloidosis is a multiorgan disease due to deposition of misfolded monoclonal immunoglobulin light chains. AL amyloidosis associated with IgM paraproteinemia is a rare variant of this disease, constituting approximately 6% of AL amyloidosis cases in the literature. The clonal cell of origin may be a plasma cell or a lymphoplasmacytic cell, and treatments targeting each of these populations have been employed. This study defines the clinical and laboratory characteristics of IgM-related AL amyloidosis patients as well as their response to different therapeutic regimens.We identified 94 patients with IgM-related AL amyloidosis evaluated at the BUMC Amyloidosis Center from 2003 through 2012 for which data was available on 50 who completed treatment. The median age at diagnosis was 65 years (range: 42-79 years) with 31 (62 %) males. The most commonly involved organ was the kidney (59%) followed by heart (37%) and GI tract (22%). The mean IgM was 1049 g/dL (range: 29-9130). The clonal population had lambda light chain restriction in 34 (68%) of patients. Patients were categorized into 5 treatment groups: high-dose melphalan/stem cell transplant (HDM/SCT), bortezomib-based, non-transplant alkylating agents based (melphalan or cyclophosphamide), immunomodulatory agents (IMiDs), and rituximab-based. This grouping was not mutually exclusive. The highest hematologic response rate was observed with HDM/SCT (10/10: 100%), followed by non-transplant alkylating agents (16/22: 73%), bortezomib (7/10: 70%) rituximab (9/13: 69%) then by IMiDs (2/4: 50%). We did not observe an association between positive response to treatment and organ involvement, sex or age at diagnosis.In conclusion, IgM-related ALamyloidosis is an unusual variant of AL amyloidosis. Multiple active therapies with different mechanisms of action exist; treatment should be tailored based upon clinicopathologic and patient-specific factors. Disclosures:Sloan:Millenium: Consultancy.

Maxillary pain is the first indication of the presence of multiple myeloma: A case report

Multiple myeloma is a primary malignancy of bone marrow characterized by the clonal proliferation of plasma cells and production of monoclonal immunoglobulin. The disease occurs more frequently in males, with the average age at diagnosis being ∼60 years. The first manifestation of multiple myeloma is varied and depends on the sites and extent of involvement. The predominant clinical symptoms of multiple myeloma are associated with bone pain and renal dysfunction. Neoplastic cells usually produce large amounts of monoclonal immunoglobulin light or heavy chains that can be detected in serum or urine, while plasmacytoma may be identified on marrow biopsy. The present study reported on the case of a 69-year-old male patient presenting with a complaint of a painful lesion in the left maxilla. Physical examination, imaging, laboratory investigations and biopsy were conducted, confirming the diagnosis of multiple myeloma. The results obtained suggest that the dentist should address oral manifestations as first indications of multiple myeloma.

Plasma Cell Myeloma: Literature Review and Case Study

1. Karen Ferreira, MS, MLS (ASCP)CM[⇑][1] 1. Department of Pathology, Hematology, Rhode Island Hospital, Providence, RI 1. Address for Correspondence: Karen Ferreira MS, MLS (ASCP)CM, Department of Pathology, Hematology, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903 401-444-4215, KAFerreira{at}Lifespan.org 1. Explain the pathophysiology of multiple myeloma. 2. Outline the different subsets of presentation. 3. Correlate the immunophenotype with the clinical and genetic aspects of myeloma. 4. List the results of the laboratory tests routinely evaluated in multiple myeloma. Introduction Plasma cell myeloma (multiple myeloma, myelomatosis, medullary plasmacytosis, Kahler's disease) is a B-cell neoplasm resulting from the expansion of a single clone of plasma cells (PC). The PCs synthesize a monoclonal immunoglobulin (paraprotein), a monoclonal immunoglobulin light chain (Bence-Jones protein) or both.1 The Bence-Jones proteins may lead to renal failure and the paraproteins can lead to peripheral blood (PB) hyperviscosity.2 Plasma cell myeloma (PCM) is clinically heterogeneous and may present with no symptoms or as an extremely aggressive disease.3 PCM is usually confined to the bone marrow (BM), with extramedullary involvement seen only in end stage cases.4,5 Epidemiology and Etiologies PCM constitutes 10-15% of all hematologic malignancies and 1% of all malignancies.6,7,8 PCM incidence increases with age with 40% of patients presenting under 60 years and only 2% occurring under the age of 40. The median age at diagnosis is 70. Incidence is greater in men than women (1.4:1), and occurs twice as frequently in African Americans than in Caucasians. The risk of PCM increases by 3.7 fold for individuals with a first degree relative with the disease.9,10 In 2007 approximately 20,000 new cases were diagnosed and 11,000 patients died from the disease.11,12 Clinical Features/Diagnostic Criteria The patients usually present with bone pain and pathologic fractures (due to lytic bone lesions). Anemia (due to bone marrow replacement of clonal PCs), recurrent infections (decreased normal immunoglobulin levels), and renal failure (Bence Jones deposition in kidneys) are common findings. Other clinical findings include hyperviscosity syndrome, hypercalcemia (increased osteoclastic activity), and epidural… ABBREVIATIONS: PCM – plasma cell myeloma, PC – plasma cell, PB – peripheral blood, BM – bone marrow, NCAM - neural cell adhesion mutation, VDC – cyclophosphamide, dexamethazone, bortezimib 1. Explain the pathophysiology of multiple myeloma. 2. Outline the different subsets of presentation. 3. Correlate the immunophenotype with the clinical and genetic aspects of myeloma. 4. List the results of the laboratory tests routinely evaluated in multiple myeloma. [1]: #corresp-1

Primary Hepatic Amyloidosis: An Untimely Death

Purpose: Primary hepatic amyloidosis, also termed hepatic AL amyloidosis, is characterized by the deposition of amyloid fibril-forming monoclonal immunoglobulin light chains within the liver. This disease often starts with mild signs, such as hepatomegaly and elevated alkaline phosphatase. Over time, this progresses to liver dysfunction, ascites, portal hypertension, liver failure, and death. A 63-year-old African-American female presented to the hospital with a one-month history of abdominal distension and jaundice. Her physical findings included ascites and massive hepatomegaly, and labs showed an elevated alkaline phosphatase (ALP) 1989 U/L, total bilirubin 4.8 mg/dL, aspartate aminotransferase (AST) 92 U/L, alanine aminotransferase (ALT) 43 U/L, platelet (PLT) 750 K/uL, prothrombin time (PT) 24.5 seconds, INR 2.2, total protein 5.5 g/dL, albumin 2.6 g/dL, blood urea nitrogen (BUN) 11 mg/dL and creatinine (Cr) 0.4 mg/dL. A CT scan of the abdomen revealed hepatomegaly with an echogenic lesion in the right hepatic lobe, splenomegaly, and ascites. A liver biopsy was done, showing Congo red stain with apple-green birefringence consistent with amyloidosis. Her bone marrow biopsy showed amyloidosis with aberrant kappa-restricted plasma cell population. She was diagnosed with hepatic AL amyloidosis, and she was started on bortezomib and dexamethasone. However, one month later, she had an elevated ALP 3274 U/L, total bilirubin 26.7 mg/dL, AST 101 U/L, ALT 57 U/L, PLT 357 K/uL, PT 35.8 seconds, INR 3.5, and Cr 3.5 mg/dL. She had a renal ultrasound that showed an increased echogenicity of both kidneys. Given her poor performance status, she did not receive dialysis or further chemotherapy. She was sent home with hospice, and passed away less than one month later. Prognosis is poor in patients with hepatic amyloidosis, with a mean survival of 10-14 months from diagnosis. This disease usually presents with mild clinical findings; however, once liver failure develops, the survival rate declines rapidly. Although this disease has a poor prognosis, early diagnosis can lead to more effective therapy.

A Strategy for Synthesis of Pathogenic Human Immunoglobulin Free Light Chains in E. coli

Monoclonal immunoglobulin light chains are normally synthesized in excess compared to the heavy chain partners and can be detected in serum and urine (“free” LC). Occasionally free LC are per se cause of organ toxicity, as in free LC-related disorders. In AL amyloidosis, the most common of these conditions, free LC with peculiar biophysical properties related to their primary structure damage target organs and organize in amyloid fibrils. Unlimited availability of well-characterized free LC is instrumental to investigate the toxic effect of these proteins and to study their interactions with targets. We present a straightforward strategy to obtain recombinant monoclonal free LC by using a bacterial system. These proteins, expressed as inclusion bodies, were subjected to solubilization and refolding procedures to recover them in native form. To minimize differences from the circulating natural LC, full-length recombinant LC were expressed, i.e. complete of variable and constant regions, with the original amino acid sequence along the entire protein, and with no purification tags. The strategy was exploited to generate free LC from three AL amyloidosis patients. After purification, recombinant proteins were biochemically characterized and compared to the natural Bence Jones protein isolated from one of the patients. Results showed that the recombinant free LC were properly folded and formed homodimers in solution, similar to the natural Bence Jones protein used for comparison. Furthermore, as proof of pathogenicity, recombinant proteins formed amyloid fibrils in vitro. We believe that the present strategy represents a valuable tool to speed research in free LC-related disorders.

Une cause rare de maladie kystique pulmonaire : maladie à dépôts de chaînes légères d’immunoglobuline

Light chain deposition disease is a rare clinical entity characterized by deposition of monoclonal immunoglobulin light chains in organs. The kidneys are almost always affected, while the lung manifestations that have been reported, including nodular or diffuse disease, especially cystic lesions, are unusual.We report the case of a 60-year-old man with a diffuse infiltrative lung disease characterized by numerous apical cysts. The diagnosis of light chain deposition cystic lung disease was obtained by surgical lung biopsy. Light chain deposits in the salivary glands were the only extrapulmonary manifestation. Despite 12 chemotherapy cycles, the patient's lung function and radiological appearances worsened.This is the fourth case describing a cystic lung disease due to light chain deposition in the literature. It highlights the need for comprehensive investigations so as not to miss this rare cause of cystic lung disease, which appears to be related to a primary pulmonary lymphoproliferative disorder. The only treatment that appears to be effective is lung transplantation.

Membranoproliferative glomerulonephritis associated with IgA-λ monoclonal gammopathy

Dear Editor, From September 2008 to April 2013, 4 patients were found to have amonoclonal IgA-λ component by serum immunofixation electrophoresis among 29 membranoproliferative glomerulonephritis (MPGN) patients, pathologically confirmed via renal biopsy during the same period in our facility (Table 1). All patients were male, and the median age was 53.0(45–65) years. The severity of proteinuria and renal insufficiency varied among patients. The extent of plasma cell dyscrasia was categorized as monoclonal gammopathy of undetermined significance (MGUS) in three patients and POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) in the other. The diagnosis of MPGN was made via light microscopic observations, and interestingly, no IgA or λ light chain deposit was detected by immunofluorescence surveys. Electron microscopy revealed thickening of basement membrane (inner layer in particular), cellular interposition, diffuse effacement of the foot processes of podocytes, and scattered deposits in subendothelial and mesangial regions (Fig. 1). Patient 1 was treated with prednisone and cyclophosphamide, and proteinuria decreased from 1.86 to 0.34 g/24 h at 3year follow-up. Patient 2 was treated with dexamethasone and thalidomide, but proteinuria increased from 0.24 to 0.81 g/24 h after 1 year. Patients 3 and 4 did not get any specific treatment. The serum creatinine level was stable in all patients during follow-up (0.72– 1.22 mg/dl). The spectrum of renal involvement secondary to plasma cell diseases have been drastically expanded recently. Aside from previously acknowledged entities, including myeloma cast nephropathy, AL amyloidosis, monoclonal immunoglobulin deposition disease, and light chain proximal tubulopathy, the territory of primary glomerulonephritis has also been shattered [1, 2]. Proliferative glomerulonephritis secondary to monoclonal IgG, IgA, or immunoglobulin light chain deposits has been well-described since 2004 [3–5]. The most recent candidate for this heterogeneous group was proposed by Sethi et al. in 2010. In a single-center study, they identified 28 monoclonal/biclonal Igs among total 126 MPGN patients, in which 68 cases were hepatitis negative and evaluated for gammopathy [6]. IgM-κ and IgG-κ were most commonly encountered, and more than half of the patients were categorized as MGUS. Under these circumstances, a recent perspective article in Blood proposed the terminology “monoclonal gammopathy of renal significance (MGRS)” [2]. Here, we presented the first report of MPGN associated with IgA-λ monoclonal gammopathy. Along with the other two patients with IgM-κ and IgG-κ paraproteins, the overall occurrence of monoclonal gammopathy among MPGN B. Wu :W. Wang : F. Li (*) : S. Zou :Y. Cheng Department of Hematology, Zhongshan Hospital Fudan University, 180 Fenglin Road, Shanghai 200032, China e-mail: li.feng@zs-hospital.sh.cn

Retinal pigment epithelial detachments and tears, and progressive retinal degeneration in light chain deposition disease

Background/purposeLight-chain deposition disease (LCDD) is a rare condition characterised by deposition of monoclonal immunoglobulin light chains (LCs) in tissues, resulting in varying degrees of organ dysfunction. This study reports the...