Figure - available from: Frontiers in Immunology
This content is subject to copyright.
Cytokine levels in the serum of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) patients. Forty cytokines and 2 cytokine receptors were quantified using the Biorad Luminex technology in the serum of 34 MGUS and 30 MM patients. The 6 cytokines found to be differently expressed in MGUS vs MM patients were: IL-11, HGF, SDF-1α, RANTES, TFG-β1, TFG-β2, and TGF-β3. Horizontal bars indicate median values ± ranges. Statistical analysis was performed using Student t-test. *p < 0.05 and **p < 0.01.
Source publication
Multiple myeloma (MM) and its pre-cancerous stage monoclonal gammopathy of undetermined significance (MGUS) allow to study immune responses and the chronology of inflammation in the context of blood malignancies. Both diseases are characterized by the production of a monoclonal immunoglobulin (mc Ig) which for subsets of MGUS and MM patients target...
Citations
... It is known that infectious pathogens are associated with diverse B-cell malignancies, either through direct cell infection leading to transformation or via antigen (Ag)-induced stimulation causing indirect cell transformation, or a combination of both mechanisms. Chronic cancer-associated in ammation is established in hematological malignancies, especially in myeloma [33] and chronic myeloproliferative neoplasms (MPNs) [34,35]. In the case of monoclonal gammopathy of undetermined signi cance (MGUS), where the paraprotein level is < 30 g/L and the monoclonal immunoglobulin may constitute 20-70% of total immunoglobulin, the production of polyclonal IgG is sustained [36]. ...
Background
The progression of monoclonal gammopathies is affected by a range of factors, including the microenvironment surrounding plasma cells. It is recognized that TGF-β1 plays a distinct role in stimulating IgA production. Hence, this study aims to investigate whether individuals with serum IgA monoclonal immunoglobulins (paraproteins) exhibit elevated total TGF-β1 levels compared to those with IgG or IgM paraproteins.
Method
To achieve this goal, individuals with a positive laboratory findings of monoclonal gammopathy, were segregated according to the paraprotein class, as well as according to the type of the light chain. Total TGF-β1 levels were assessed in blood serum samples containing IgG (n = 50), IgM (n = 31), and IgA (n = 46) paraproteins.
Results
Elevated level of TGF-β1 was confirmed in sera with IgA paraproteins (median 25.8 ng/ml; interquartile range IQR: 19.0-33.7) compared to those having IgG (median: 18.2 ng/ml; IQR: 14.3–22.1; P < 0.001) or IgM paraproteins (21.5 ng/ml; IQR: 15.0-27.4; P = 0.043). Also, higher TGF-β1 level was detected in sera with IgMλ then those with IgMκ paraproteins (P = 0.043).
Conclusions
This research affirms the role of TGF-β1 in the pathophysiology of IgA monoclonal gammopathies and potential switch towards IgA isotype, known for less favorable prognosis.
... Obviously this first step is required in MGUS but also in MM, even though the quantity of polyclonal Igs is often reduced in MM patients. A patient's monoclonal IgG or IgA can be separated from non-clonal Igs using electric charge by running a SPE on an agarose gel, and after staining of one lane of the gel, by cutting carefully the band corresponding to the patient's monoclonal IgG or IgA, then eluting the monoclonal Ig from the gel into phosphate buffer saline (PBS) (17,18,25,32). The purity of the monoclonal IgG or IgA preparation can be verified using isoelectric focusing (IEF) followed by blotting and immune revelation (17,18,25,32). ...
... A patient's monoclonal IgG or IgA can be separated from non-clonal Igs using electric charge by running a SPE on an agarose gel, and after staining of one lane of the gel, by cutting carefully the band corresponding to the patient's monoclonal IgG or IgA, then eluting the monoclonal Ig from the gel into phosphate buffer saline (PBS) (17,18,25,32). The purity of the monoclonal IgG or IgA preparation can be verified using isoelectric focusing (IEF) followed by blotting and immune revelation (17,18,25,32). Due to the much larger molecular mass of the monomers that constitute pentameric IgMs (185-190 kDa), compared to dimeric IgGs (150 kDa) and IgAs (160 kDa), this approach does not work as well for monoclonal IgMs. ...
... gondii), Borrelia burgdorferi (B. burgdorferi)] (17,18,25,32,33). Infectious lysates, proteins, peptides and antigens are spotted in triplicate on glass slides with 16 pads of nitrocellulose (33). ...
Subsets of patients diagnosed with a monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM) or multiple myeloma (MM), present with a monoclonal immunoglobulin (Ig) specific for an infectious pathogen, including hepatitis C and B viruses (HCV, HBV), Helicobacter pylori and several Herpesviruses. Such cases are likely initiated by infection, since in the context of HCV- or HBV-infected patients, antiviral therapy can lead to the disappearance of antigenic stimulation, control of clonal plasma cells, and reduced or suppressed monoclonal Ig production. Complete remission has been obtained with anti-HCV therapy in refractory MM with a HCV-specific monoclonal Ig, and antiviral treatments significantly improved the probability of survival of MM patients infected with HCV or HBV prior to the diagnosis of MM. Monoclonal Igs may also target glucolipids, particularly glucosylsphingosine (GlcSph), and GlcSph-reducing therapy can lead to complete remission in SMM and MM patients presenting with a GlcSph-specific monoclonal Ig. The present review describes the importance of determining the target of the monoclonal Ig of MGUS, SMM and MM patients, and discusses the efficacy of target-reducing treatments in the management of MGUS, SMM and MM cases who present with a monoclonal Ig reactive against a treatable infectious pathogen or GlcSph.
... The END and generalized bone loss that are observed in MGUS/MGSS reflect an abnormal accentuation of this physiological process. The release of inflammatory cytokines observed in MGUS/MGSS beyond what is observed in normal individuals could explain such excesses of senescence [39]. Thus, excessive aging through endosteal niche degeneration and sterile bone inflammaging creates a permissive BME that favors MGUS/MGSS. ...
... Ig-gene mutations remain active in sporadic MGUS, suggesting that MGUS remains dependent on a specific antigen, which is frequently (but not always) an auto-antigen present inside the bone marrow. Finally, MGUS is suggested to emerge from an inflammatory environment in a manner similar to Ig/auto-antibodies in auto-immune diseases [39]. Thus, permanent MGUS cases are probably due to the permanent stimulation by an Ag in the whole organism, especially the bone marrow. ...
Multiple Myeloma (MM) and its preexisting stage, termed Monoclonal Gammopathy of Undetermined Significance (MGUS), have long been considered mainly as genomic diseases. However, the bone changes observed in both conditions have led to a reassessment of the role of the bone microenvironment, mainly the endosteal niche in their genesis. Here, we consider the disruption of the endosteal niche in the bone marrow, that is, the shift of the endosteal niche from an osteoblastic to an osteoclastic profile produced by bone senescence and inflammaging, as the key element. Thus, this disrupted endosteal niche is proposed to represent the permissive microenvironment necessary not only for the emergence of MM from MGUS but also for the emergence and maintenance of MGUS. Moreover, the excess of osteoclasts would favor the presentation of antigens (Ag) into the endosteal niche because osteoclasts are Ag-presenting cells. As such, they could significantly stimulate the presentation of some specific Ag and the clonal expansion of the stimulated cells as well as favor the expansion of such selected clones because osteoclasts are immunosuppressive. We also discuss this scenario in the Gaucher disease, in which the high incidence of MGUS and MM makes it a good model both at the bone level and the immunological level. Finally, we envisage that this endosteal niche disruption would increase the stochasticity (epigenetic and genetic instability) in the selected clones, according to our Tissue Disruption-induced cell Stochasticity (TiDiS) theory.
... For each patient, agarose gel electrophoresis and purification of the monoclonal Ig from other Igs present in serum samples were performed as published previously [17][18][19][20]27 and detailed in the Supplementary Appendix. ...
... . Thus three different assays were used to determine the target of monoclonal Igs of HBV+ patients, after purification of each monoclonal Ig : i) a GlcSph immunoblot assay, to determine whether a monoclonal Ig recognizes GlcSph; ii) the multiplex infectious antigen microarray (MIAA) assay, to determine whether purified monoclonal Igs recognize one infectious pathogen among different pathogens; and iii) dot blot assays designed to confirm that HBV or other pathogens, proteins or Ag, were recognized by the purified monoclonal Igs[17][18][19][20]27,28 . All assays are detailed in the Supplementary Appendix. ...
Subsets of multiple myeloma (MM) and monoclonal gammopathies of undetermined significance (MGUS) present with a monoclonal immunoglobulin specific for hepatitis C virus (HCV), thus are presumably HCV-driven, and antiviral treatment can lead to the disappearance of antigen stimulation and improved control of clonal plasma cells. Here we studied the role of hepatitis B virus (HBV) in the pathogenesis of MGUS and MM in 45 HBV-infected patients with monoclonal gammopathy. We analysed the specificity of recognition of the monoclonal immunoglobulin of these patients, and validated the efficacy of antiviral treatment (AVT). For 18/45 (40%) HBV-infected patients, the target of the monoclonal immunoglobulin was identified: the most frequent target was HBV (n=11), followed by other infectious pathogens (n=6), and glucosylsphingosine (n=1). Two patients whose monoclonal immunoglobulin targeted HBV (HBx and HBcAg), implying that their gammopathy was HBV-driven, received AVT and the gammopathy did not progress. AVT efficacy was then investigated in a large cohort of HBV-infected MM patients (n=1367), who received anti-HBV treatments, or not, and compared to a cohort of HCV-infected MM patients (n=1220). AVT significantly improved patient probability of overall survival (p=0.016 for the HBV-positive cohort, p=0.005 for the HCV-positive cohort). Altogether, MGUS and MM disease can be HBV- or HCV-driven in infected patients, and the study demonstrates the importance of antiviral treatment in such patients.
... Although the precise role that accumulating senescent BM-MSCs play in MGUS-to-MM progression is currently unknown, emerging evidence suggests an association between BM-MSC senescence and MM disease progression. Analysis of serum cytokine profiles of MGUS patients has revealed that MGUS is associated with a shift towards a pro-inflammatory phenotype compared with healthy individuals [167]. In particular, it has been shown that serum protein levels of canonical SASP factor IL-6 is elevated in MGUS and SMM patients compared with healthy individuals [141,168,169]. ...
Acute myeloid leukaemia (AML), chronic lymphocytic leukaemia (CLL), and multiple myeloma (MM) are age-related haematological malignancies with defined precursor states termed myelodysplastic syndrome (MDS), monoclonal B-cell lymphocytosis (MBL), and monoclonal gammopathy of undetermined significance (MGUS), respectively. While the progression from asymptomatic precursor states to malignancy is widely considered to be mediated by the accumulation of genetic mutations in neoplastic haematopoietic cell clones, recent studies suggest that intrinsic genetic changes, alone, may be insufficient to drive the progression to overt malignancy. Notably, studies suggest that extrinsic, microenvironmental changes in the bone marrow (BM) may also promote the transition from these precursor states to active disease. There is now enhanced focus on extrinsic, age-related changes in the BM microenvironment that accompany the development of AML, CLL, and MM. One of the most prominent changes associated with ageing is the accumulation of senescent mesenchymal stromal cells within tissues and organs. In comparison with proliferating cells, senescent cells display an altered profile of secreted factors (secretome), termed the senescence-associated-secretory phenotype (SASP), comprising proteases, inflammatory cytokines, and growth factors that may render the local microenvironment favourable for cancer growth. It is well established that BM mesenchymal stromal cells (BM-MSCs) are key regulators of haematopoietic stem cell maintenance and fate determination. Moreover, there is emerging evidence that BM-MSC senescence may contribute to age-related haematopoietic decline and cancer development. This review explores the association between BM-MSC senescence and the development of haematological malignancies, and the functional role of senescent BM-MSCs in the development of these cancers.
... In normal physiological conditions, inflammatory response system keeps various chemokines and cytokines such as pro-inflammatory factors and anti-inflammatory factors in balance. Previous studies of inflammatory responses primarily focused in the field of injury, infection, autoimmune diseases, hematological disorders and malignancies [8][9][10][11] . There was growing evidence that inflammatory responses also played significant roles in solid malignancies. ...
There was growing evidence that inflammatory responses played significant roles in malignancies. However, the impact of pro-inflammatory-to-anti-inflammatory factor ratio in tumor tissues has not been investigated in gastric cancer (GC) yet. We collected patient data from The Cancer Genome Atlas (TCGA) database. A total of 270 stomach adenocarcinoma (STAD) patients without distant metastasis were included in the study. After screening 12 candidate pro-inflammatory-to-anti-inflammatory pairs, only the IL-6/IL-10 mRNA expression ratio in tumor tissues had a significant effect on overall survival (OS) of STAD patients (P = 0.014). X-tile analysis showed that the greatest survival differences were obtained when the cutoff value of IL-6/IL-10 mRNA expression ratio was set at 1.3 and 5.5. With the low-ratio group (IL-6/IL-10 mRNA expression ratio: < 1.3) as reference, OS time for both the medium-ratio group (IL-6/IL-10 mRNA expression ratio: 1.3–5.5) and the high-ratio group (IL-6/IL-10 mRNA expression ratio: > 5.5) was significantly shorter (P < 0.05). Multivariate Cox regression analyses indicated that IL-6/IL-10 mRNA expression ratio was an independent prognostic factor for OS and disease-specific survival (DSS). These findings provided a novel and powerful tool for a more rational management of GC patients.
... 15,16 Paraprotein deposition is also involved in the pathogenesis of MGUS. 17 In this study, we estimated the prevalence and incidence of atherosclerotic disease (acute myocardial infarction, peripheral artery disease, ischemic stroke), structural heart disease (heart failure, conduction disease), pulmonary hypertension (cor pulmonale), valvular disease (aortic stenosis, aortic regurgitation, mitral stenosis, mitral regurgitation), aortopathy (aortic dissection, aneurysm), pericarditis, and arrhythmias (atrial fibrillation) in patients with MGUS versus age-and sex-matched control patients. ...
Background
Monoclonal gammopathy of undetermined significance (MGUS) is associated with renal dysfunction, inflammation, and increased cardiovascular mortality, but the cardiovascular risks are not fully understood.
Objectives
The authors explored the association of MGUS with a spectrum of cardiovascular diseases using the Danish nationwide databases.
Methods
Between 1995 and 2018, patients 18 years and older with MGUS were age- and sex-matched (1:10) with control patients and followed prospectively until December 31, 2018, for the occurrence of cardiovascular diseases. Patients diagnosed with multiple myeloma, lymphoma, or amyloidosis were excluded. Multivariable adjusted hazard ratios (HRs) for cardiovascular outcomes were estimated using Cox proportional hazard regression.
Results
Patients with MGUS (n = 8,189; mean age 69.8 ± 11.7 years; 51.2% male) had higher prevalence of cardiovascular risk factors at baseline, including hypertension (48.0% vs 38.5%) and type 2 diabetes (13.0% vs 9.3%), compared with control patients. Outcomes included an increased risk of heart failure (HR: 1.55; 95% CI: 1.41-1.69), acute myocardial infarction (HR: 1.22; 95% CI: 1.06-1.40), ischemic stroke (HR: 1.16; 95% CI: 1.03-1.30), atrial fibrillation (HR: 1.32; 95% CI: 1.23-1.42), aortic aneurysm (HR: 1.55; 95% CI: 1.28-1.89), aortic stenosis (HR: 1.60; 95% CI: 1.41-1.82), aortic regurgitation (HR: 1.67; 95% CI: 1.34-2.07), heart block (HR: 1.32; 95% CI: 1.08-1.61), peripheral artery disease (HR: 1.69; 95% CI: 1.47-1.95), cor pulmonale (HR: 2.06; 95% CI: 1.55-2.73), and venous thromboembolism (HR: 1.43; 95% CI: 1.24-1.65). A sensitivity analysis including only patients without certain comorbidities (type 2 diabetes, hypertension, acute myocardial infarction, and chronic kidney disease) yielded similar results.
Conclusions
MGUS is associated with a broad spectrum of cardiovascular diseases, with greater relative risks observed for diseases previously associated with infiltrative and inflammatory disorders. Further studies are warranted to explore the underlying mechanisms.
... A high incidence of malignant tumors is observed in CKD due to the chronic increase in cytokines and growth factors caused by hyperazotemia, low renal clearance of proinflammatory cytokines, and oxidative stress [8]. Furthermore, high levels of sialic acid are present in the monoclonal immunoglobulins of MGUS and MM [9], and this was observed in the analysis of 2817 CKD patients in a hospital in Turkey, with the report of malignancy on 6.7% of patients (188) and 2.6% of MM [10]. ...
Background:
Autoimmune/inflammatory syndrome induced by adjuvants is a disease associated with an unregulated hyperactivity of the immune system and may also be associated with a high frequency of hematologic malignancies. Report. This is a case of a female with ASIA-MO syndrome secondary to infiltration of mineral oil for aesthetic purposes and presented with multiple episodes of urolithiasis resulting in renal impairment of her left kidney confirmed by scintigraphy and ending in unilateral nephrectomy. Retrospective renal piece analysis confirmed tubulointerstitial infiltration with light chains and plasma cells. Paraffin fixation prevented subsequent immunofluorescence analysis for better follow-up of the patient.
Conclusion:
The presence of positive immunofixation kappa chains explained the sudden deterioration of renal function with monoclonal gammopathy of renal significance which concluded in an association between diseases, such as multiple light chain myeloma, as a final diagnosis.
... Alternatively, a prominent reduction in regulatory T cells could predispose people to an exaggerated immune response and cytokine storm which are major features of the COVID-19-related hyperinflammation syndrome [94]. A state of systemic chronic low-grade inflammation is a feature of both obesity and various hematologic malignant states, such as MDS, acute leukemias, MM and NHL [95][96][97][98]. This feature can promote or be inherent in "inflammaging", which refers to a state of immune cell senescence and dysregulation [99], predisposing to adverse COVID-19-related outcomes [99,100]. ...
Simple Summary
Obesity is epidemiologically and likely, causally related to various hematological cancers, while both conditions may predispose to severe SARS-CoV-2 infection. The COVID-19 pandemic brought about a variety of obstacles with respect to numerous aspects in the management of hematological malignancies. In the present overview, the evidence linking obesity with the development of hematological cancers and their role as risk factors for severe COVID-19 is critically appraised. Furthermore, the various challenges which emerged during the the pandemic are reviewed, regarding not only the treatment of the underlying hematological malignancies themselves, but also the prevention and therapeutic management of SARS-CoV-2 infection in this patient group. Lastly, we discuss further unresolved issues which need to be addressed in order to optimize the management of patients with hematologic cancers in the course of ongoing COVID-19 pandemic.
Abstract
The COVID-19 pandemic brought about an unprecedented societal and healthcare system crisis, considerably affecting healthcare workers and patients, particularly those with chronic diseases. Patients with hematologic malignancies faced a variety of challenges, pertinent to the nature of an underlying hematologic disorder itself as well as its therapy as a risk factor for severe SARS-CoV-2 infection, suboptimal vaccine efficacy and the need for uninterrupted medical observation and continued therapy. Obesity constitutes another factor which was acknowledged since the early days of the pandemic that predisposed people to severe COVID-19, and shares a likely causal link with the pathogenesis of a broad spectrum of hematologic cancers. We review here the epidemiologic and pathogenetic features that obesity and hematologic malignancies share, as well as potential mutual pathophysiological links predisposing people to a more severe SARS-CoV-2 course. Additionally, we attempt to present the existing evidence on the multi-faceted crucial challenges that had to be overcome in this diverse patient group and discuss further unresolved questions and future challenges for the management of hematologic malignancies in the era of COVID-19.
... Antigen-mediated stimulation led to an increase in the amount of monoclonal Ig and plasma cells in a murine model, confirming the role of chronic antigenic stimulation in the pathogenesis of MM. Independently, we recently reported that one-quarter of all MM cases might be initiated by infectious pathogens, including EBV and HCV (17,18). In this line, a recent meta-analysis demonstrated a higher risk (2.67-fold) of developing MM in HCV-infected patients than in controls (11). ...
... Agarose gel electrophoresis and purification of patients' monoclonal Ig from other Igs present in serum samples was performed as described (17,18,22,23) ( Figure S1 in the Supplementary Appendix). Protein concentrations were determined on a Nanodrop ND-1000 spectrophotometer. ...
Multiple myeloma (MM) remains an incurable plasma cell malignancy. While its origin is enigmatic, an association with infectious pathogens including hepatitis C virus (HCV) has been suggested. Here we report nine patients with monoclonal gammopathy of undetermined significance (MGUS) or MM with previous HCV infection, six of whom received antiviral treatment. We studied the evolution of the gammopathy disease, according to anti-HCV treatment and antigen specificity of purified monoclonal immunoglobulin, determined using the INNO-LIA™ HCV Score assay, dot-blot assays, and a multiplex infectious antigen microarray. The monoclonal immunoglobulin from 6/9 patients reacted against HCV. Four of these patients received antiviral treatment and had a better evolution than untreated patients. Following antiviral treatment, one patient with MM in third relapse achieved complete remission with minimal residual disease negativity. For two patients who did not receive antiviral treatment, disease progressed. For the two patients whose monoclonal immunoglobulin did not react against HCV, antiviral treatment was not effective for MGUS or MM disease. Our results suggest a causal relationship between HCV infection and MGUS and MM progression. When HCV was eliminated, chronic antigen-stimulation disappeared, allowing control of clonal plasma cells. This opens new possibilities of treatment for MGUS and myeloma.
