Amyloid Light-chain Amyloidosis Research Articles

Predicting Structural Consequences of Antibody Light Chain N-Glycosylation in AL Amyloidosis

Background/Objectives: Antibody light chains form amyloid fibrils that lead to progressive tissue damage in amyloid light chain (AL) amyloidosis. The properties of each patient’s unique light chain appear to determine its propensity to form amyloid. One factor is N-glycosylation, which is more frequent in amyloid-associated light chains than in light chains from the normal immune repertoire. However, the mechanisms underlying this association are unknown. Here, we investigate the frequency and position within the light chain sequence of the N-glycosylation sequence motif, or sequon. Methods: Monoclonal light chains from AL amyloidosis and multiple myeloma were identified from the AL-Base repository. Polyclonal light chains were obtained from the Observed Antibody Space resource. We compared the fraction of light chains from each group harboring an N-glycosylation sequon, and the positions of these sequons within the sequences. Results: Sequons are enriched among AL-associated light chains derived from a subset of precursor germline genes. Sequons are observed at multiple positions, which differ between the two types of light chains, κ and λ, but are similar between light chains from AL amyloidosis and multiple myeloma. Positions of sequons map to residues with surface-exposed sidechains that are compatible with the folded structures of light chains. Within the known structures of λ AL amyloid fibrils, many residues where sequons are observed are buried, inconsistent with N-glycosylation. Conclusions: There is no clear structural rationale for why N-glycosylation of κ light chains is associated with AL amyloidosis. A better understanding of the roles of N-glycosylation in AL amyloidosis is required before it can be used as a marker for disease risk.

Antibody Aggregation: A Problem Within the Biopharmaceutical Industry and Its Role in AL Amyloidosis Disease.

Due to the large size and rapid growth of the global therapeutic antibody market, there is major interest in understanding the aggregation of protein products as it can compromise efficacy, concentration, and safety. Various production and storage conditions have been identified as capable of inducing aggregation of polyclonal and monoclonal antibody (mAb) therapies such as low pH, freezing, light exposure, lyophilisation and increased ionic strength. The addition of stabilising excipients to these therapeutics helps to combat the formation of aggregates with future aggregation inhibition mechanisms involving the introduction of point mutations and glycoengineering within aggregation prone regions (APRs). Antibody aggregation also plays an integral role in the pathogenesis of a condition known as amyloid light chain (AL) amyloidosis which is characterised by the production of improperly folded and amyloidogenic immunoglobulin light chains (LCs). Current diagnostic tools rely heavily on histological staining with their future moving towards amyloid component identification and proteomic analysis. For many years, treatment options designed for multiple myeloma (MM) have been applied to AL amyloidosis patients by depleting plasma cell numbers. More recently, treatment strategies more specific to this condition have been developed with many designed to recognize amyloid fibrils and trigger their degradation without causing systemic plasma cell cytotoxicity. Amyloid fibrils in AL disease and aggregates in antibody therapeutics are both formed through the oligomerisation of misfolded / modified proteins attempting to reach a thermodynamically stable, free energy minimum that is lower than the respective monomers themselves. Although the final morphologies are different, by understanding the principles underlying such aggregation, we expect to find common insights that may contribute to the development of new and effective methods of antibody aggregation and/or amyloidosis management. We envision that this area of research will continue to be very relevant in both industry and clinical settings.

Systemic Amyloid Light Chain Amyloidosis With Repeated Syncope Due to Severe Orthostatic Hypotension Caused by Autonomic Neuropathy: A Case Report

Systemic Amyloid Light Chain Amyloidosis With Repeated Syncope Due to Severe Orthostatic Hypotension Caused by Autonomic Neuropathy: A Case Report

Single-center analysis of cardiac amyloidosis using 99mTc-HMDP imaging for diagnosis and evaluation after tafamidis treatment.

This study aimed to evaluate the diagnostic performance of 99mTc-hydroxymethylene diphosphonate (99mTc-HMDP) imaging for cardiac amyloidosis and to demonstrate changes in cardiac uptake of 99mTc-HMDP after tafamidis treatment. Seventy-five patients with suspected cardiac amyloidosis who underwent 99mTc-HMDP imaging were included. We compared visual Perugini grades and semiquantitative heart-to-contralateral (H/CL) area ratios, myocardial maximum standardized uptake value (SUVmax), and peak of SUV (SUVpeak) between cardiac transthyretin amyloidosis (ATTR) and amyloid light-chain amyloidosis (AL). Comparison of interobserver reproducibility between H/CL ratios and myocardial SUVmax/SUVpeak was performed. H/CL ratio of 99mTc-HMDP and myocardial SUVmax/SUVpeak were compared before and after tafamidis administration for cardiac wild-type ATTR. Among 75 patients, 20 patients (26.7%) were visually positive based on Perugini grade. Fifteen and three patients were pathologically identified as cardiac ATTR and AL, respectively. ATTR group (n = 15) had significantly higher H/CL ratios of 99mTc-HMDP than AL group (n = 3) (P = 0.003). ATTR group (n = 15) had significantly higher myocardial SUVmax/SUVpeak of 99mTc-HMDP than AL group (n = 2) (P = 0.015). Myocardial SUVmax/SUVpeak had better interobserver reproducibility than H/CL ratios. After tafamidis treatment for cardiac wild-type ATTR, the decrease in myocardial SUVpeak was significant but not in H/CL ratios and myocardial SUVmax. H/CL ratio and SUVmax/SUVpeak in 99mTc-HMDP imaging were useful for diagnosing cardiac ATTR. Myocardial SUVpeak may be useful for monitoring changes in cardiac uptake after tafamidis treatment for cardiac ATTR.

Digital whole-slide imaging of changes in amyloid after peripheral blood stem cell transplantation in patients with amyloid light-chain amyloidosis.

Peripheral blood stem cell transplantation (PBSCT) has made amyloid light-chain (AL) amyloidosis treatable. After PBSCT, hematological complete remission (HCR) can be achieved, leading to improved renal prognosis. The purpose of this study was to evaluate whether whole slide imaging of biopsy samples shows a post-treatment reduction in amyloid deposits in patients with AL amyloidosis. Patients were divided into three groups: Group A (n = 8), not eligible for PBSCT and treated with other therapies; Group B (n = 11), treated with PBSCT and achieved HCR; and Group C (n = 5), treated with PBSCT but did not achieve HCR. Clinical findings and amyloid deposition in glomeruli, interstitium, and blood vessels were compared before and after treatment using digital whole-slide imaging. Proteinuria and hypoalbuminemia improved more in Group B than in the other groups, and in Group B, amyloid deposition improved more in the glomeruli than in the interstitium and blood vessels. The long-term renal and survival prognosis was better in Group B than in the other groups. PBSCT can be expected to improve long-term clinical and renal histological prognosis in patients with AL amyloidosis who achieve HCR. Amyloid disappearance from renal tissue may take a long time even after clinical HCR.

Gene Expression Sets and Renal Profiling from the Renal AL Amyloid Involvement and NEOD00 (RAIN) Trial

There is an unmet need to understand the mechanisms by which amyloid deposition drives alterations in the kidney. We leveraged renal biopsies from amyloid light-chain (AL) amyloidosis participants of the Renal AL Amyloid Involvement and NEOD00 (RAIN) trial (NCT03168906) to perform transcriptional profiling and to employ a novel histologic scoring tool. Our objective was to utilize a transcriptome-driven approach to identify AL molecular signatures that may be prognostic. Clinical data were correlated to histologic and molecular findings. A composite scarring injury and amyloid score (AS) were assigned to each biopsy. Glomerular and tubulointerstitial (TI) compartments were microdissected and sequenced separately. Expression data were compared to healthy living donors and focal segmental glomerulosclerosis (FSGS) profiles. Differentially expressed genes were determined. Cluster analysis revealed 2 distinct patient clusters (G1 and G2) based on gene expression. The AS was higher in the TI compartment (6.5 vs. 4.5; P= 0.0290) of G2. Glomeruli showed activation of fibrotic pathways and increased canonical signaling of LPS/IL-1. TNF activation was noted in TI. Enriched ingenuity canonical pathways included "coagulation system," "GADD45 signaling," and "Wnt/Ca+ pathway," among others. For AL versus living donors, ingenuity pathway analysis identified enrichment in PI3K/Akt signaling. Gene regulators of cellular proliferation were enriched in the amyloid group. Despite the small sample size, we identified 2 distinct groups of patients with AL based on molecular signatures. Detailed studies of a larger cohort encompassing omics technologies at a single cell resolution will further help to identify the response of individual kidney cell types to amyloid deposits, potentially leading to the development of novel therapeutic targets.

Cardiac Amyloidosis: A Comprehensive Review of Pathophysiology, Diagnostic Approach, Applications of Artificial Intelligence, and Management Strategies.

Cardiac amyloidosis (CA) is a serious and often fatal condition caused by the accumulation of amyloid fibrils in the heart, leading to progressive heart failure. It involves the misfolding of normally soluble proteins into insoluble amyloid fibrils, with transthyretin and light-chain amyloidosis being the most common forms affecting the heart. Advances in diagnostics, especially cardiac magnetic resonance imaging and non-invasive techniques, have improved early detection and disease management. Artificial intelligence has emerged as a diagnostic tool for cardiac amyloidosis, improving accuracy and enabling earlier intervention through advanced imaging analysis and pattern recognition. Management strategies include volume control, specific pharmacotherapies like tafamidis, and addressing arrhythmias and advanced heart failure. However, further research is needed for novel therapeutic approaches, the long-term effectiveness of emerging treatments, and the optimization of artificial intelligence applications in clinical practice for better patient outcomes.The article aims to provide an overview of CA, outlining its pathophysiology, diagnostic advancements, the role of artificial intelligence, management strategies, and the need for further research.

Prognostic Value of Serum Galectin-3 for Survival in Patients with Cardiac Light-Chain Amyloidosis.

Amyloid light-chain (AL) amyloidosis is a multisystem disorder, with cardiac amyloid infiltration being a prevalent manifestation. This study aimed to explore the prognostic value of galectin-3 (Gal-3), a soluble marker associated with fibrosis, inflammation, heart failure, and kidney injury, in patients with cardiac AL amyloidosis. A total of 60 patients who were diagnosed with cardiac AL amyloidosis from January 2015 to May 2018 were enrolled. The prognostic value of Gal-3 was assessed. Receiver operating characteristic (ROC) curves were used to evaluate the predictive accuracy of Gal-3. A Gal-3 cut-off value was identified to predict survival rates. The ROC curves demonstrated a moderate predictive accuracy of Gal-3 for 0.5- and 5-year survival, with area under the curve (AUC) values of 0.722 and 0.788, respectively. A Gal-3 cut-off value of 15.154 ng/mL was found to predict survival. Kaplan-Meier survival analysis revealed a significant difference in mean overall survival between patients with Gal-3 levels below and above the established cut-off (69.2 months versus 42.1 months, respectively; p = 0.036). Multivariate analysis confirmed that Gal-3 > 15.154 ng/mL remained an independent predictor of survival (HR 2.451, 95% CI 1.017-5.910, p = 0.046). This study suggests that Gal-3 holds independent prognostic value for survival in patients with cardiac AL amyloidosis. Gal-3 could potentially enhance the prognostic capabilities of the current soluble markers, thereby improving the management of cardiac AL amyloidosis. However, further validation in larger prospective studies is warranted.

Recent insights into haematology and peripheral nerve disease.

The association between clonal haematological disorders and peripheral nerve disease is recognized. Paraproteinaemic phenomena are the most common mechanism, but direct neural lymphomatous infiltration is seen and can be challenging to diagnose. Traditional and novel anticancer therapies have neuropathic side effects. Novel studies using sensitive techniques are refining the incidence of peripheral neuropathy in patients with a monoclonal gammopathy, and the pathogenesis of IgM Peripheral neuropathy (PN) and POEMS syndrome. Recent series give insight into the characteristics and diagnostic challenges of patients with neurolymphomatosis and amyloid light chain amyloidosis. There is an increasing repertoire of effective anticancer drugs in haematological oncology, but chemotherapy-related neuropathy remains a common side effect. This review of the current literature focuses on recent updates and developments for the paraproteinaemic neuropathies, and the evaluation, diagnosis and treatment of peripheral nerve disease due to high-grade and low-grade lymphomas and lymphoproliferative disorders.

Right Ventricular Strain Improves the Echocardiographic Diagnosis and Risk Stratification of Transthyretin Cardiac Amyloidosis Among Other Phenotypes of Left Ventricular Hypertrophy

Cardiac amyloidosis is a diffuse disease affecting all cardiac chambers. The value of right ventricular free-wall strain is uncertain as an echocardiographic red flag. We hypothesized that right ventricular free-wall strain is of added value for diagnostic and prognostic purposes in patients with transthyretin cardiac amyloidosis (ATTR-CA). A diagnosis of ATTR-CA required positive Tc-99m pyrophosphate scintigraphy and negative serum clonal dyscrasia. Patients with left ventricular (LV) hypertrophy (LVH; interventricular septal thickness ≥1.2cm) by echocardiography and negative pyrophosphate scintigraphy served as controls after exclusion of amyloid light-chain cardiac amyloidosis. Longitudinal strain was computed with speckle-tracking echocardiography. We studied 108 subjects with ATTR-CA and 106 controls with LVH, retrospectively. Right ventricular free-wall strain was independently associated with the diagnosis of ATTR-CA after adjusting for classical echocardiographic parameters, namely, relative apical sparing (RAS), e', and E/e'. Right ventricular free-wall strain≥-16% was incremental to LV RAS in the overall group and in the subgroup without extreme wall thickness (≤1.4cm; Harrell's C, net reclassification improvement=0.213, P<.001; and net reclassification improvement= 0.463, P=.015, respectively). Major adverse cardiovascular and cerebrovascular events (heart failure hospitalization, stroke, death) occurred in 47 ATTR-CA patients, during follow-up (median, 38; range, 6-60months). Right ventricular free-wall strain≥-16% was associated with 3-fold increased risk of MACCE in ATTR-CA patients independently of age, comorbidities, B-type natriuretic peptide, and tafamidis treatment. Right ventricular free-wall strain was additive to LV ejection fraction for risk stratification (chi square =10.2; P=.017). Right ventricular free-wall strain>-16% has incremental value to LV RAS for the differential diagnosis of ATTR-CA among LVH phenotypes and is associated with poor prognosis.

Systemic AL kappa chain amyloidosis in a captive Bornean orangutan (Pongo pygmaeus)

Systemic amyloid light-chain (AL) amyloidosis is an infrequent disease in which amyloid fibrils derived from the immunoglobulin light chain are deposited in systemic organs, resulting in functional impairment. This disease has been notably uncommon in animals, and nonhuman primates have not been reported to develop it. In this study, we identified the systemic AL kappa chain amyloidosis in a captive Bornean orangutan (Pongo pygmaeus) and analyzed its pathogenesis. Amyloid deposits were found severely in the submucosa of the large intestine, lung, mandibular lymph nodes, and mediastinal lymph nodes, with milder lesions in the liver and kidney. Mass spectrometry-based proteomic analysis revealed an abundant constant domain of the immunoglobulin kappa chain in the amyloid deposits. Immunohistochemistry further confirmed that the amyloid deposits were positive for immunoglobulin kappa chains. In this animal, AL amyloidosis resulted in severe involvement of the gastrointestinal submucosa and lymph nodes, which is consistent with the characteristics of AL amyloidosis in humans, suggesting that AL amyloid may have a similar deposition mechanism across species. This report enhances the pathological understanding of systemic AL amyloidosis in animals by providing a detailed characterization of this disease based on proteomic analysis.

Human IL-6 fosters long-term engraftment of patient-derived disease-driving myeloma cells in immunodeficient mice.

Multiple myeloma is a largely incurable and life-threatening malignancy of antibody-secreting plasma cells. An effective and widely available animal model that recapitulates human myeloma and related plasma cell disorders is lacking. We show that busulfan-conditioned human IL-6-transgenic (hIL-6-transgenic) NSG (NSG+hIL6) mice reliably support the engraftment of malignant and premalignant human plasma cells, including from patients diagnosed with monoclonal gammopathy of undetermined significance, pre- and postrelapse myeloma, plasma cell leukemia, and amyloid light chain amyloidosis. Consistent with human disease, NSG+hIL6 mice engrafted with patient-derived myeloma cells developed serum M spikes, and a majority developed anemia, hypercalcemia, and/or bone lesions. Single-cell RNA sequencing showed nonmalignant and malignant cell engraftment, the latter expressing a wide array of mRNAs associated with myeloma cell survival and proliferation. Myeloma-engrafted mice given CAR T cells targeting plasma cells or bortezomib experienced reduced tumor burden. Our results establish NSG+hIL6 mice as an effective patient-derived xenograft model for study and preclinical drug development of multiple myeloma and related plasma cell disorders.

Clinical and imaging characteristics of patients with cardiac amyloidosis- a single center observational study

Amyloidosis is a disease characterized by the deposition of protein fibrils. Cardiac involvement is a significant factor in determining prognosis. This study aimed to examine the clinical profile, outcomes, and long-term mortality rates in patients with transthyretin (ATTR) and amyloid light-chain (AL) amyloidosis. The retrospective cohort study included 94 patients with amyloidosis (69 with AL and 25 with ATTR amyloidosis) diagnosed between 2010 and 2022. The study involved multimodality imaging (ECG, echocardiography and cardiac magnetic resonance (CMR) data and survival analyses. Patients with ATTR amyloidosis were older and had a higher proportion of males compared to those with AL amyloidosis. Cardiac involvement was more prevalent in the ATTR group, including atrial fibrillation (AF), while pleural and pericardial effusion were more frequent in the AL group. Biomarkers such as NT-proBNP and troponin T were significantly elevated in both groups and were associated with all-cause mortality only in univariate analyses. CMR data, especially typical late gadolinium enhancement (LGE) was not associated with increased mortality, while pleural effusion and left atrial dilatation on echocardiography were identified as powerful predictors of mortality. In conclusion, both AL and ATTR amyloidosis exhibited poor outcomes. Cardiac involvement, particularly dilated left atrium and pleural effusion on echocardiography were associated with an increased risk of mortality, while typical LGE on CMR was not.

Expert Center for cardiac amyloidosis: reality and perspectives

Aim. To evaluate the features of diagnosis of amyloid cardiomyopathy (ACMP), differential diagnosis of different types of amyloidosis and its clinical manifestations. Materials and methods. Were analyzed 150 cases of patients who consulted at the Expert Center for Amyloidosis with suspicion of the presence of ACMP. 63 patients were diagnosed with ACMP: 25 (39.7%) – women, 38 (60.3%) – men, with an average age of 64.1±1.5. 36 (57.1%) patients had AL-amyloidosis (immunoglobulin amyloid light-chain amyloidosis), 25 (39.7%) – ATTR-amyloidosis (transthyretin amyloidosis), 2 (3.2%) – AA-amyloidosis with heart failure (reactive systemic amyloidosis caused by hypersecretion of á-globulin). The analysis of clinical manifestations depending on the type of amyloidosis, data of laboratory and instrumental methods of diagnosis is carried out. Results. In most cases, 53 (84.1%) patients, amyloidosis manifested as signs of heart failure. Among cardiac manifestations, shortness of breath (95.2%), general weakness (93.7%), lower limb edema (76.2%) were the most common. To confirm the diagnosis, despite the high accuracy of the speckle-tracking echocardiography and magnetic resonance imaging of the heart with gadolinium, in rare cases a biopsy is required (e.g. there is a combination of clinical signs of several types of amyloidosis). Biopsy of the affected organ was performed in 31 (49.2%) patients. The strategy for further pathogenetic treatment depends on the determination of the type of amyloidosis. Free light chains of immunoglobulins were detected in 57.1% of cases, which allowed diagnosis of AL-amyloidosis. In 17 (38.6%) patients myocardial scintigraphy with 99mTc-pyrophosphate showed signs of ATTR-amyloidosis, which with a negative result of immunochemical studies allows non-invasive diagnosis of it. Conclusion. ACMP is a disease with an extremely adverse prognosis. Raising the awareness of specialists about ACMP is an important goal. With timely diagnosis, pathogenetic therapy can be started early, which will improve the quality of life and prognosis of patients with ACMP.

Duodenal amyloidosis: a clinical case

BACKGROUND: Amyloidosis is a chronic systemic disease that, in some cases, affects the organs of the gastrointestinal tract.&#x0D; CLINICAL CASE DESCRIPTION: A 62-year-old patient complained of painless enlargement of the lymph nodes in the supraclavicular region on the left side according to the puncture biopsy of the lymph node — reactive lymphoid hyperplasia. During the examination, duodenal amyloidosis was accidentally detected. The results of additional studies to determine the type of amyloid were nonspecific. The patient refused to continue the examination.&#x0D; CONCLUSION: This clinical case of duodenal amyloidosis is unusual and clearly demonstrates the difficulties of diagnosis, including the absence of a clinic and the nonspecificity of the endoscopic and radiological picture during the examination. In addition, the absence of an established chronic disease characteristic of amyloid A amyloidosis and the results of laboratory and instrumental research methods, excluding amyloid light chain amyloidosis and transthyretin amyloidosis, emphasise the main role of clinicians in diagnosing the underlying disease.

Impact of Premedication De-Escalation on Incidence of Infusion-Related Reactions With Daratumumab.

Daratumumab is an anti-CD38 monoclonal antibody used to treat multiple myeloma and light chain amyloidosis. Because daratumumab may cause reactions after intravenous or subcutaneous (SC) administration, the manufacturer labeling recommends administration of premedications before every dose. Given incidence of infusion reactions appears to be rare after cycle 1, in April 2022, the Mayo Clinic implemented a practice change in which premedications were omitted from all daratumumab order sets after completion of cycle 1. This study investigated the safety of this practice. A retrospective chart review at the Mayo Clinic reviewed eligible patients with multiple myeloma or amyloid light-chain (AL) amyloidosis who received their first dose of daratumumab within the 4 months preceding the date of implementation (preimplementation group) or no more than 4 months after (postimplementation group) the date of implementation on April 13, 2022. Data were collected only from the first eight once per week doses of daratumumab. The primary outcome was the incidence of infusion-related reactions. Data analyzed used descriptive statistics. Nearly all patients (95.9%) received daratumumab by SC route of administration. Of the 97 patients in the preimplementation group, >90% received premedications throughout cycles 1 and 2, and five patients (5.2%) experienced infusion reactions. Of 72 patients in the postimplementation group, <20% received premedications during cycle 2 and three patients (4.2%) experienced infusion reactions. All infusion reactions occurred within the first daratumumab cycle, indicating elimination of cycle 2 premedications did not cause any infusion reactions. No patient experienced more than one infusion reaction. Omission of premedications after cycle 1 of daratumumab did not increase the incidence of infusion. Premedications may safely be omitted after cycle 1 of daratumumab when administered by the SC route.

Assessment of Tp-Te interval in patients with cardiac AL amyloidosis.

Prolonged Tp-Te interval is strongly associated with fatal ventricular arrhythmias and mortality. This association has been demonstrated in various diseases. However, the current literature does not give any information on Tp-Te interval in cardiac amyloid light-chain (AL) amyloidosis. We retrospectively screened 116 cardiac AL amyloidosis patients and 35 patients were included in the study. Demographic, laboratory, 12-lead electrocardiographic (QTc, Tp-Te V1-V6) and transthoracic echocardiographic data of the patients were analysed and compared with 35 healthy controls. QTc and Tp-Te V2-V5 were significantly prolonged in the cardiac AL amyloidosis group (p < 0.05). Also, there was a positive and statistically significant correlation between the parameters of QTc and Tp-Te V3-V6, and also between the parameters of interventricular septum thickness at enddiastole and Tp-Te V2-V5. We present the first strong evidence of prolonged Tp-Te intervals in patients with cardiac AL amyloidosis. There may also be a relationship between prolonged Tp-Te interval and the development of arrhythmia in this patient group, as in some other groups. There is a need for prospective studies examining the relationship of prolonged Tp-Te interval with arrhythmias and its prognostic significance in cardiac AL amyloidosis.

Immune checkpoint expression patterns on T cell subsets in light-chain amyloidosis: VISTA, PD-1, and TIGIT as potential therapeutic targets.

Amyloid light chain (AL) amyloidosis is a rare plasma cell dyscrasia with dismal prognosis. This study aims to investigate the T-cell immune checkpoint expression patterns in systemic AL amyloidosis and its relationship with clinicobiological traits. We examined the frequencies of V-domain immunoglobulin suppressor of T cell activation+ (VISTA+), programmed cell death 1+ (PD-1+), T cell immunoglobulin and mucin-domain-containing-3+ (Tim-3+), T cell immunoreceptor with Ig and ITIM domains+ (TIGIT+) T cells in peripheral blood (PB) and bone marrow (BM) from 19 patients with newly diagnosed AL amyloidosis. Patients with AL amyloidosis had significantly higher percentages of VISTA+ and PD-1+ T cells in PB than healthy individuals (HIs), with no statistical differences in BM. The percentages of some double-positive T cells in PB were also considerably higher in AL amyloidosis than those in HIs. Additionally, the patients with renal involvement had more PD-1+ and TIGIT+ T cells than the patients without, and PD-1+CD3+%, PD-1+CD4+%, PD-1+Treg% were positively correlated with 24-hour proteinuria levels. Furthermore, the AL amyloidosis patients had higher counts of PD-1+ Treg in PB than multiple myeloma (MM) patients, while the MM patients had higher counts of TIGIT+ T cells than AL amyloidosis patients. Collectively, this is the first report of elevated proportions of VISTA+ and PD-1+ T cells in PB of AL amyloidosis patients, indicating an immunosuppressive milieu, and the increased PD-1+ and TIGIT+ T cells were associated with renal damage. VISTA, PD-1, and TIGIT may be potential targets for reversing T-cell exhaustion in AL amyloidosis.

Amyloid Protein in AL-Amyloidosis. Natural History and Potential for Regression

Amyloid light chain amyloidosis is the most commonly seen form of systemic amyloidosis and is characterized by the accumulation of circulating monoclonal immunoglobulin light chain precursors arising from an abnormal clone of plasma cells. These light chain precursors demonstrate a propensity for misfolding, aggregation and deposition as highly stable fibrillar cross-linked beta sheets in various tissues and organs in a manner characteristic of other forms of systemic amyloidosis. There have been great advances in the treatment of the underlying plasma cell dyscrasia with improved long-term survival but the persistence of extracellular amyloid deposits in the tissues of vital organs, particularly the heart and kidney remains a significant cause of morbidity and mortality even in those patients in whom a hematological complete response has been achieved. This review focuses on the importance of early diagnosis and treatment on limiting the extent of amyloid protein accumulation and organ dysfunction and the current state of knowledge on the potential for resorption and clearance of these amyloid deposits in patients with amyloid light chain amyloidosis. The status of current novel anti-fibrillar agents is reviewed and future strategies for effectively intervening to improve organ function and survival these individuals is discussed.

Monoclonal Gammopathies of Undetermined Significance and Abnormal Serum Protein Rates Prevelance in Blood Donors: For Improved Transfusion Safety

ABSTRACT Background and Objectives: Protein abnormalities include monoclonal gammopathies of undetermined significance (MGUS) and malignant lymphoplasmacytic tumors such as multiple myeloma (MM), Waldenström macroglobulinemia, and amyloid light-chain amyloidosis. MGUS prevalence increases with age, especially in individuals over 50. MGUS progresses to various lymphoplasmacytic diseases, including smoldering MM and MM. Almost all blood donors (BDs) are asymptomatic but some of them could present protein abnormalities. Our objective was to assess the prevalence and impact of protein abnormalities and monoclonal gammopathies (MGs) on transfusion safety among BDs in Morocco. Methods: Two hundred eighty-one serum samples were collected from BDs aged over 40 years old. Total serum protein measurement and protein electrophoresis were performed using the Architect ci8200 and Capillarys-2-Piercing automated systems, respectively. Immunofixation was conducted using hydrates. Results: Protein levels ranged between 59 and 87 g/L (average = 71.69 ± 4.96 g/L). Our results showed 195 (69.39%) normal profiles, 6 (2.13%) MGs, 14 (4.98%) heterogeneous restriction of γ-globulins, and 66 other abnormalities (23.48%) regarding the levels of albumin and proteins from alpha and beta fractions. Conclusion: Our preliminary results appeal to blood transfusion professionals regarding ethical considerations and transfusion safety. BDs with abnormal protein levels should benefit systematically from diagnostic tests and therapies.