scholarly journals Involvement of Alarmins in the Pathogenesis and Progression of Multiple Myeloma

2021 ◽  
Vol 22 (16) ◽  
pp. 9039
Author(s):  
Giuseppe Murdaca ◽  
Alessandro Allegra ◽  
Francesca Paladin ◽  
Fabrizio Calapai ◽  
Caterina Musolino ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Immune System ◽  
Plasma Cells ◽  
Bone Erosion ◽  
High Mobility ◽  
Host Immune System ◽  
Scientific Publications ◽  
Study Selection ◽  
Asymptomatic Stage ◽  
Shock Proteins

Objective: Multiple Myeloma (MM) is a haematological disease resulting from the neoplastic transformation of plasma cells. The uncontrolled growth of plasma cells in the bone marrow and the delivery of several cytokines causes bone erosion that often does not regress, even in the event of disease remission. MM is characterised by a multi-step evolutionary path, which starts with an early asymptomatic stage defined as monoclonal gammopathy of undetermined significance (MGUS) evolving to overt disease. Data Sources and Study Selection: We have selected scientific publications on the specific topics “alarmis, MGUS, and MM”, drawing from PubMed. The keywords we used were alarmines, MGUS, MM, and immune system. Results: The analysis confirms the pivotal role of molecules such as high-mobility group box-1, heat shock proteins, and S100 proteins in the induction of neoangiogenesis, which represents a milestone in the negative evolution of MM as well as other haematological and non-haematological tumours. Conclusions: Modulation of the host immune system and the inhibition of neoangiogenesis may represent the therapeutic target for the treatment of MM that is capable of promoting better survival and reducing the risk of RRMM.

CD40 Ligand Stimulation of Multiple Myeloma Cells Results in Upregulation of Surface Expressed Heat Shock Proteins and Increased Antigenicity.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3351-3351
Author(s):  
Charles A. Gullo ◽  
William Hwang ◽  
Melvin Au ◽  
Edward A. Greenfield ◽  
Kenneth C. Anderson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Immune System ◽  
Heat Shock ◽  
Cell Membrane ◽  
Heat Shock Proteins ◽  
Flow Cytometric Analysis ◽  
Cd40 Ligand ◽  
Flow Cytometric ◽  
Shock Proteins ◽  
Stimulation Of

Abstract Effective immune-based therapies against the plasma cell malignancy, multiple myeloma (MM), are currently lacking. Identification of novel antigens (Ag) on the surface of MM cells to use as cellular targets for the destruction of cancer cells by the body’s immune system has been of great interest. We and others have demonstrated that CD40 stimulation of MM cells results in marked upregulation of membrane bound proteins such as Ku86. Using CD40 triggered MM cells as immunogens and hybridoma technology; we generated a monoclonal antibody (mAb), 6D11, that recognizes a CD40 induced cell membrane Ag on MM cells. This Ag is detectable on the surface of MM cells using indirect immunofluorescence flow cytometric analysis. Moreover, in Western immunoblotting assays, 6D11 mAb reacts with a 94 kDa protein, which is strongly associated with a 78 kDa protein. Using high performance liquid chromatography and protein microsequencing, we confirm that these proteins are the heat shock proteins (HSP), glucose-regulated peptide 94 (GRP94) and GRP78, respectively. These data were confirmed using co-immunprecipitation experiments. Furthermore, we demonstrate through indirect immunofluorescence flow cytometric analysis and quantitative real time reverse transcription polymerase chain reaction (RQ-PCR) that CD40 ligand (CD40L) stimulation of MM cells results in rapid upregulation of both GRP94 and GRP78. Since HSPs have been shown to play a role in both Ag presentation, as well as the intracellular transport of cellular Ags, it is tempting to speculate that cell membrane expression of tumor-specific peptides could also be induced via CD40 triggering. Accordingly, CD40 induced cell membrane HSP expression resulted in increased antigenicity as determined by increased co-stimulatory molecule expression on Ag presenting cells (APC) and by increased immunoreactivity in mixed lymphocyte reactions (MLR). This suggests that CD40 induced HSP expression may indeed result in increased recognition of MM cancer by the immune system. Our study therefore supports the development of CD40-based targeted cell therapies against MM.

Expression of heat shock proteins 27 and 72 correlates with specific commensal microbes in different regions of porcine gastrointestinal tract

2014 ◽  
Vol 306 (12) ◽  
pp. G1033-G1041 ◽  
Author(s):  
Hao-Yu Liu ◽  
Johan Dicksved ◽  
Torbjörn Lundh ◽  
Jan Erik Lindberg
Keyword(s):  
Immune System ◽  
Heat Shock ◽  
Heat Shock Proteins ◽  
Bacterial Species ◽  
Host Immune System ◽  
Gi Tract ◽  
Microbe Interactions ◽  
Cell Type Specific ◽  
Host Microbe Interactions ◽  
Shock Proteins

The gastrointestinal (GI) tract of mammals is inhabited by trillions of microorganisms, resulting in exceedingly complex networking. The interaction between distinct bacterial species and the host immune system is essential in maintaining homeostasis in the gut ecosystem. For instance, the gut commensal microbiota dictates intestinal mucosa maturation and its abundant immune components, such as cytoprotective heat shock proteins (HSP). Here we examined physiological expression of HSP in the normal porcine GI tract and found it to be gut region- and cell type-specific in response to dietary components, microbes, and microbial metabolites to which the mucosa surface is exposed. Correlations between HSP72 expression and ileal Lactobacillus spp. and colonic clostridia species, and between HSP27 expression and uronic acid ingestion, were important interplays identified here. Thus this study provides novel insights into host-microbe interactions shaping the immune system that are modifiable by dietary regime.

scholarly journals Immunological Dysregulation in Multiple Myeloma Microenvironment

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Alessandra Romano ◽  
Concetta Conticello ◽  
Maide Cavalli ◽  
Calogero Vetro ◽  
Alessia La Fauci ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stromal Cells ◽  
Plasma Cells ◽  
Clinical Manifestations ◽  
Suppressor Cells ◽  
Matrix Proteins ◽  
Host Immune System ◽  
Hematologic Disease

Multiple Myeloma (MM) is a systemic hematologic disease due to uncontrolled proliferation of monoclonal plasma cells (PC) in bone marrow (BM). Emerging in other solid and liquid cancers, the host immune system and the microenvironment have a pivotal role for PC growth, proliferation, survival, migration, and resistance to drugs and are responsible for some clinical manifestations of MM. In MM, microenvironment is represented by the cellular component of a normal bone marrow together with extracellular matrix proteins, adhesion molecules, cytokines, and growth factors produced by both stromal cells and PC themselves. All these components are able to protect PC from cytotoxic effect of chemo- and radiotherapy. This review is focused on the role of immunome to sustain MM progression, the emerging role of myeloid derived suppressor cells, and their potential clinical implications as novel therapeutic target.

scholarly journals miR-335-laden B Cell-Derived Extracellular Vesicles Promote SOX4-Dependent Apoptosis in Human Multiple Myeloma Cells

2021 ◽  
Vol 11 (12) ◽  
pp. 1240
Author(s):  
Elisabetta Lombardi ◽  
Gonzalo Almanza ◽  
Kinga Kowal ◽  
Marco Valvasori ◽  
Francesco Agostini ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Transcription Factor ◽  
Extracellular Vesicles ◽  
Plasma Cells ◽  
Cell Model ◽  
Hypoxia Inducible Factor ◽  
Tumor Development ◽  
High Mobility ◽  
Incurable Cancer ◽  
Human Multiple Myeloma

Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells in the bone marrow. Despite novel therapies, MM still remains an incurable cancer and new strategies are needed. Increased expression of the transcription factor Sex-determining region Y-related high-mobility-group box transcription factor 4 (SOX4) has been correlated with tumor development and progression through a variety of distinct processes, including inhibition of apoptosis, increased cell invasion and metastasis, and induction and maintenance of cancer-initiating cells. The role of SOX4 in MM is largely unknown. Since SOX4 is a known target of miR-335, we used miR-335 to assess whether SOX4 modulation could promote apoptosis in MM cells. Using an MM cell model we show that miR-335 acts both on SOX4-related genes (AKT, PI3K) and hypoxia-inducible factor 1-alpha (Hif1-α). In addition, we show miR-335-laden extracellular vesicles induced in B cells (iEVs) are also effective in targeting SOX4, causing apoptosis. Collectively, we propose that miR-335-laden iEVs could be developed as a novel form of gene therapy in MM.

scholarly journals Understanding GroEL and DnaK Stress Response Proteins as Antigens for Bacterial Diseases

Vaccines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 773
Author(s):  
Kezia R. Fourie ◽  
Heather L. Wilson
Keyword(s):  
Immune System ◽  
Stress Response ◽  
Cell Surface ◽  
Virulence Factors ◽  
Cellular Localization ◽  
Vaccine Development ◽  
Host Immune System ◽  
A Cell ◽  
Stress Response Proteins ◽  
Shock Proteins

Bacteria do not simply express a constitutive panel of proteins but they instead undergo dynamic changes in their protein repertoire in response to changes in nutritional status and when exposed to different environments. These differentially expressed proteins may be suitable to use for vaccine antigens if they are virulence factors. Immediately upon entry into the host organism, bacteria are exposed to a different environment, which includes changes in temperature, osmotic pressure, pH, etc. Even when an organism has already penetrated the blood or lymphatics and it then enters another organ or a cell, it can respond to these new conditions by increasing the expression of virulence factors to aid in bacterial adherence, invasion, or immune evasion. Stress response proteins such as heat shock proteins and chaperones are some of the proteins that undergo changes in levels of expression and/or changes in cellular localization from the cytosol to the cell surface or the secretome, making them potential immunogens for vaccine development. Herein we highlight literature showing that intracellular chaperone proteins GroEL and DnaK, which were originally identified as playing a role in protein folding, are relocated to the cell surface or are secreted during invasion and therefore may be recognized by the host immune system as antigens. In addition, we highlight literature showcasing the immunomodulation effects these proteins can have on the immune system, also making them potential adjuvants or immunotherapeutics.

scholarly journals A case of multiple myeloma presenting as scalp swelling with intracranial extension

2013 ◽  
Vol 04 (04) ◽  
pp. 445-448 ◽  
Author(s):  
Satya Bhusan Senapati ◽  
Sudhansu Sekhar Mishra ◽  
Manmath Kumar Dhir ◽  
Srikanta Das ◽  
Kalpalata Tripathy
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cells ◽  
Bone Erosion ◽  
Malignant Lesion ◽  
Malignant Neoplasm ◽  
Intracranial Extension ◽  
Histopathological Study ◽  
Skull Bone ◽  
Characteristic Features

ABSTRACTMultiple myeloma is a malignant neoplasm of bone marrow affecting plasma cells. It is usually detected in skull bone with characteristic features of multiple punched-out lesions. Its presentation as a solitary scalp swelling with underlying skull bone erosion and intracranial extension is very rare. A 35-year-old female presented to us with complains of rapidly growing left-side scalp swelling with right-side paresis and simple partial seizure of right upper limb. Local examination, X-ray skull, CT scan, and MRI of brain were suggestive of a malignant lesion. Near total excision of lesion was done. Histopathological study was suggestive of plasmacytoma of skull. Bone marrow study further confirmed it as a case of multiple myeloma. Cases presenting with solitary osteolytic skull lesions, possibility of plasmacytoma, or multiple myeloma should be kept in mind.

scholarly journals African trypanosomes expressing multiple VSGs are rapidly eliminated by the host immune system

2019 ◽  
Vol 116 (41) ◽  
pp. 20725-20735 ◽  
Author(s):  
Francisco Aresta-Branco ◽  
Margarida Sanches-Vaz ◽  
Fabio Bento ◽  
João A. Rodrigues ◽  
Luisa M. Figueiredo
Keyword(s):  
Immune System ◽  
Antibody Response ◽  
Disease Severity ◽  
High Mobility ◽  
Surface Glycoprotein ◽  
Monoallelic Expression ◽  
Host Immune System ◽  
Simultaneous Exposure ◽  
Knock Out ◽  
African Trypanosomes

Trypanosoma brucei parasites successfully evade the host immune system by periodically switching the dense coat of variant surface glycoprotein (VSG) at the cell surface. Each parasite expresses VSGs in a monoallelic fashion that is tightly regulated. The consequences of exposing multiple VSGs during an infection, in terms of antibody response and disease severity, remain unknown. In this study, we overexpressed a high-mobility group box protein, TDP1, which was sufficient to open the chromatin of silent VSG expression sites, to disrupt VSG monoallelic expression, and to generate viable and healthy parasites with a mixed VSG coat. Mice infected with these parasites mounted a multi-VSG antibody response, which rapidly reduced parasitemia. Consequently, we observed prolonged survival in which nearly 90% of the mice survived a 30-d period of infection with undetectable parasitemia. Immunodeficient RAG2 knock-out mice were unable to control infection with TDP1-overexpressing parasites, showing that the adaptive immune response is critical to reducing disease severity. This study shows that simultaneous exposure of multiple VSGs is highly detrimental to the parasite, even at the very early stages of infection, suggesting that drugs that disrupt VSG monoallelic expression could be used to treat trypanosomiasis.

scholarly journals Cancer immunoediting and immune dysregulation in multiple myeloma

Blood ◽  
2020 ◽  
Vol 136 (24) ◽  
pp. 2731-2740 ◽  
Author(s):  
Kyohei Nakamura ◽  
Mark J. Smyth ◽  
Ludovic Martinet
Keyword(s):  
Multiple Myeloma ◽  
Immune System ◽  
Immune Cells ◽  
Plasma Cells ◽  
Cancer Immunoediting ◽  
Bm Niche ◽  
Clinical Responses ◽  
Smoldering Myeloma ◽  
Immunosuppressive Cells ◽  
Made In

Abstract Avoiding immune destruction is a hallmark of cancer. Over the past few years, significant advances have been made in understanding immune dysfunction and immunosuppression in multiple myeloma (MM), and various immunotherapeutic approaches have delivered improved clinical responses. However, it is still challenging to completely eliminate malignant plasma cells (PCs) and achieve complete cure. The interplay between the immune system and malignant PCs is implicated throughout all stages of PC dyscrasias, including asymptomatic states called monoclonal gammopathy of undetermined significance and smoldering myeloma. Although the immune system effectively eliminates malignant PCs, or at least induces functional dormancy at early stages, malignant PCs eventually evade immune elimination, leading to progression to active MM, in which dysfunctional effector lymphocytes, tumor-educated immunosuppressive cells, and soluble mediators coordinately act as a barrier for antimyeloma immunity. An in-depth understanding of this dynamic process, called cancer immunoediting, will provide important insights into the immunopathology of PC dyscrasias and MM immunotherapy. Moreover, a growing body of evidence suggests that, together with nonhematopoietic stromal cells, bone marrow (BM) immune cells with unique functions support the survival of normal and malignant PCs in the BM niche, highlighting the diverse roles of immune cells beyond antimyeloma immunity. Together, the immune system critically acts as a rheostat that fine-tunes the balance between dormancy and disease progression in PC dyscrasias.

scholarly journals IL-21 signaling promotes early dissemination of KSHV infection in B lymphocytes

2021 ◽  
Author(s):  
Nedaa Alomari ◽  
Farizeh Aalasm ◽  
Romina Nabiee ◽  
Jesus Ramirez Castano ◽  
Jennifer Totonchy
Keyword(s):  
T Cells ◽  
Immune System ◽  
B Cells ◽  
Plasma Cells ◽  
Cultured Cells ◽  
Host Immune System ◽  
Kshv Infection ◽  
Human Host ◽  
Early Stages ◽  
Immunological Mechanisms

AbstractKaposi’s sarcoma-associated herpesvirus (KSHV) extensively manipulates the host immune system and the cytokine milieu, and cytokines are known to influence the progression of KSHV-associated diseases. However, the precise role of cytokines in the early stages of KSHV infection remains undefined. Here, using our unique model of KSHV infection in tonsil lymphocytes, we investigate the influence of host cytokines on the establishment of KSHV infection in B cells. Our data demonstrate that KSHV manipulates the host cytokine microenvironment during early infection and susceptibility generally associated with downregulation of multiple cytokines. However, we show that IL-21 signaling promotes KSHV infection by promoting both plasma cell numbers and increasing KSHV infection in plasma cells. Our data reveal that IL-21 producing T cells, particularly Th17/Tc17 and central memory CD8+ T cells may represent immunological factors that modulate host-level susceptibility to KSHV infection. These results suggest that IL-21 plays a significant role in the early stages of KSHV infection in the human immune system and may represent a novel mechanism to be further explored in the context of preventing KSHV transmission.Author SummaryVery little is known about how KSHV is transmitted and how it initially establishes infection in a new human host and this lack of information limits our ability to prevent KSHV-associated cancers by limiting its person-to-person transmission. Saliva is thought to be the primary route of person-to-person transmission for KSHV, making the tonsil a likely first site for KSHV replication in a new human host. In particular, the tonsil is likely to be the first place KSHV is able to enter B cells, which are thought to be a major site of persistent infection. Our previous work identified plasma cells as a highly targeted cell type in early KSHV infection in cultured cells from human tonsil. In this study, we show that the human cytokine IL-21 promotes both overall KSHV infection and the establishment of infection in plasma cells. We also investigate the immunological mechanisms underlying this effect. Our results demonstrate that IL-21 and IL-21-producing cells are a novel factor that influences the initial establishment of KSHV infection in humans.

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