scholarly journals Sialic Acid-Siglec Axis as Molecular Checkpoints Targeting of Immune System: Smart Players in Pathology and Conventional Therapy

2020 ◽  
Vol 21 (12) ◽  
pp. 4361
Author(s):  
Przemyslaw Wielgat ◽  
Karol Rogowski ◽  
Katarzyna Niemirowicz-Laskowska ◽  
Halina Car
Keyword(s):  
Immune System ◽  
Sialic Acid ◽  
Cancer Therapy ◽  
Conventional Therapy ◽  
Regulatory Mechanism ◽  
Molecular Mimicry ◽  
Cross Reactivity ◽  
Immune Checkpoints ◽  
Molecular Targeting ◽  
Malignant Cells

The sialic acid-based molecular mimicry in pathogens and malignant cells is a regulatory mechanism that leads to cross-reactivity with host antigens resulting in suppression and tolerance in the immune system. The interplay between sialoglycans and immunoregulatory Siglec receptors promotes foreign antigens hiding and immunosurveillance impairment. Therefore, molecular targeting of immune checkpoints, including sialic acid-Siglec axis, is a promising new field of inflammatory disorders and cancer therapy. However, the conventional drugs used in regular management can interfere with glycome machinery and exert a divergent effect on immune controlling systems. Here, we focus on the known effects of standard therapies on the sialoglycan-Siglec checkpoint and their importance in diagnosis, prediction, and clinical outcomes.

New Trends in Anti-Cancer Therapy: Combining Conventional Chemotherapeutics with Novel Immunomodulators

2018 ◽  
Vol 25 (36) ◽  
pp. 4758-4784 ◽  
Author(s):  
Amy L. Wilson ◽  
Magdalena Plebanski ◽  
Andrew N. Stephens
Keyword(s):  
Clinical Trials ◽  
Cell Death ◽  
Immune System ◽  
Cancer Therapy ◽  
Immune Cell ◽  
Cytotoxic T Lymphocyte ◽  
Tumour Microenvironment ◽  
Immune Checkpoints ◽  
Tumour Regression ◽  
Cell Trafficking

Cancer is one of the leading causes of death worldwide, and current research has focused on the discovery of novel approaches to effectively treat this disease. Recently, a considerable number of clinical trials have demonstrated the success of immunomodulatory therapies for the treatment of cancer. Monoclonal antibodies can target components of the immune system to either i) agonise co-stimulatory molecules, such as CD137, OX40 and CD40; or ii) inhibit immune checkpoints, such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death-1 (PD-1) and its corresponding ligand PD-L1. Although tumour regression is the outcome for some patients following immunotherapy, many patients still do not respond. Furthermore, chemotherapy has been the standard of care for most cancers, but the immunomodulatory capacity of these drugs has only recently been uncovered. The ability of chemotherapy to modulate the immune system through a variety of mechanisms, including immunogenic cell death (ICD), increased antigen presentation and depletion of regulatory immune cells, highlights the potential for synergism between conventional chemotherapy and novel immunotherapy. In addition, recent pre-clinical trials indicate dipeptidyl peptidase (DPP) enzyme inhibition, an enzyme that can regulate immune cell trafficking to the tumour microenvironment, as a novel cancer therapy. The present review focuses on the current immunological approaches for the treatment of cancer, and summarizes clinical trials in the field of immunotherapy as a single treatment and in combination with chemotherapy.

scholarly journals GAKG-RGEKG an Epitope That Provokes Immune Cross-Reactivity betweenPrevotellasp. and Human Collagen: Evidence of Molecular Mimicry in Chronic Periodontitis

2016 ◽  
Vol 2016 ◽  
pp. 1-5 ◽  
Author(s):  
Gustavo Alberto Obando-Pereda
Keyword(s):  
Immune System ◽  
Periodontal Disease ◽  
Molecular Mimicry ◽  
Hypothetical Protein ◽  
Cross Reactivity ◽  
World Population ◽  
Human Economy ◽  
Human Proteins ◽  
Human Collagen ◽  
Antigen Presenting

Periodontal disease afflicts 20% of world population. This process usually occurs in the form of being lethargic and chronic, and consequently this disease is known as chronic process. All chronic diseases constantly cause activation of the immune system, and therefore the presentation of microbial peptides which are presented to lymphocytes by professional antigen presenting cells can present microbial peptides very similar to important structures of human economy causing autoimmune diseases, process known as molecular mimicry. Thus, the aim of this study was to verify the presence of molecular mimicry phenomenon between periodontopathogens and human proteins. Blasting microbes of Socransky periodontal complexes against human collagen were performed and then the proteins with similarities were modelled and were screened in the MHI binding virtual methods. The epitopes selected were produced and plasma of chronic periodontal volunteers was obtained and a dot immunobinding assay was performed. Hypothetical protein ofPrevotellasp. and human collagen epitopes with high similarities were positive for dot immunobinding assay. With this result it can be suggested that the mimicry phenomena can occur on periodontal disease.

scholarly journals The Role of Immune Checkpoints after Cellular Therapy

2020 ◽  
Vol 21 (10) ◽  
pp. 3650 ◽  
Author(s):  
Friederike Schmitz ◽  
Dominik Wolf ◽  
Tobias A.W. Holderried
Keyword(s):  
Immune System ◽  
T Cell ◽  
Cellular Therapy ◽  
Immune Checkpoints ◽  
Malignant Cells ◽  
Malignant Diseases ◽  
Cell Therapies ◽  
Car T Cell ◽  
Anti Cancer ◽  
Car T

Cellular therapies utilize the powerful force of the human immune system to target malignant cells. Allogeneic hematopoietic stem cell transplantation (allo-HCT) is the most established cellular therapy, but chimeric antigen receptor (CAR) T cell therapies have gained attention in recent years. While in allo-HCT an entirely novel allogeneic immune system facilitates a so-called Graft-versus-tumor, respectively, Graft-versus-leukemia (GvT/GvL) effect against high-risk hematologic malignancies, in CAR T cell therapies genetically modified autologous T cells specifically attack target molecules on malignant cells. These therapies have achieved high success rates, offering potential cures in otherwise detrimental diseases. However, relapse after cellular therapy remains a serious clinical obstacle. Checkpoint Inhibition (CI), which was recently designated as breakthrough in cancer treatment and consequently awarded with the Nobel prize in 2018, is a different way to increase anti-tumor immunity. Here, inhibitory immune checkpoints are blocked on immune cells in order to restore the immunological force against malignant diseases. Disease relapse after CAR T cell therapy or allo-HCT has been linked to up-regulation of immune checkpoints that render cancer cells resistant to the cell-mediated anti-cancer immune effects. Thus, enhancing immune cell function after cellular therapies using CI is an important treatment option that might re-activate the anti-cancer effect upon cell therapy. In this review, we will summarize current data on this topic with the focus on immune checkpoints after cellular therapy for malignant diseases and balance efficacy versus potential side effects.

Antibody specificity and promiscuity

2019 ◽  
Vol 476 (3) ◽  
pp. 433-447 ◽  
Author(s):  
Deepti Jain ◽  
Dinakar M. Salunke
Keyword(s):  
Immune System ◽  
Molecular Mimicry ◽  
A Priori ◽  
Rapid Evolution ◽  
Cross Reactivity ◽  
Immune Defense ◽  
Autoimmune Response ◽  
Antigenic Determinants ◽  
Antibody Specificity ◽  
Foreign Antigen

Abstract The immune system is capable of making antibodies against anything that is foreign, yet it does not react against components of self. In that sense, a fundamental requirement of the body's immune defense is specificity. Remarkably, this ability to specifically attack foreign antigens is directed even against antigens that have not been encountered a priori by the immune system. The specificity of an antibody for the foreign antigen evolves through an iterative process of somatic mutations followed by selection. There is, however, accumulating evidence that the antibodies are often functionally promiscuous or multi-specific which can lead to their binding to more than one antigen. An important cause of antibody cross-reactivity is molecular mimicry. Molecular mimicry has been implicated in the generation of autoimmune response. When foreign antigen shares similarity with the component of self, the antibodies generated could result in an autoimmune response. The focus of this review is to capture the contrast between specificity and promiscuity and the structural mechanisms employed by the antibodies to accomplish promiscuity, at the molecular level. The conundrum between the specificity of the immune system for foreign antigens on the one hand and the multi-reactivity of the antibody on the other has been addressed. Antibody specificity in the context of the rapid evolution of the antigenic determinants and molecular mimicry displayed by antigens are also discussed.

scholarly journals The Nobel Prize in Physiology or Medicine 2018 was awarded to Cancer Therapy by Inhibition of Negative Immune Regulation

2019 ◽  
Vol 2 (3) ◽  
Author(s):  
Fukumi Furukawa
Keyword(s):  
Cell Death ◽  
Immune System ◽  
Cancer Therapy ◽  
Cancer Patients ◽  
Nobel Prize ◽  
Immune Regulation ◽  
Cytotoxic T Lymphocyte ◽  
Immune Checkpoints ◽  
Karolinska Institute ◽  
Fight Against Cancer

   On October 1, The Nobel Prize in Physiology or Medicine 2018 was awarded jointly to Dr. James P. Allison and Dr. Tasuku Honjo "for their discovery of cancer therapy by inhibition of negative immune regulation.The Nobel Assembly at Karolinska Institute released the comments that Dr. Allison and Dr. Honjo showed how different strategies for inhibiting the brakes on the immune system could be used in the treatment of cancer [1-5]. The seminal discoveries by the two laureates constitute a landmark in our fight against cancer. https://www.nobelprize.org/prizes/medicine/2018/prize-announcement/I sincerely wish to congratulate two recipients, co-workers and many patients cooperated in clinical trials. In this journal, we have published several reviews and papers on immunity checkpoints so far. The reason is that the mission of this journal is in scientific awareness and dissemination of new immunotherapy.I herein introduce briefly my previous report with some modification [6]. Immune checkpoints inhibitors (ICIs) have opened promising avenues in the treatment of cancer. Various blocking antibodies targeting programmed cell death -1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are approved for human use. They significantly improved disease outcome in a number of cancer patients by boosting anti-tumor immune responses. As Seidel, Otsuka and Kabashima described in their review article [7], mortality among advanced stage patients and the frequency of treatment-related adverse events remain high with current treatment. And, it is also noteworthy that unexpected immune related adverse effects (irAEs) appear, even when it becomes better to be administered to many cancer patients [8]. Unfortunately, the mechanisms of endocrine irAEs by ICIs, remain unclear, and optimal prevention, prediction, and treatment of the irAEs are still uncertain. However, appropriate uses and index setting related to prognosis are being studied in many fields such as dermatology [9] and other organs [6,7].While solving such problems, we have to understand that the mechanisms of immunogenic cell death are now moving from concepts to the clinic. We will explain the mechanism behind ICD and how it will perhaps breathe a new life into chemotherapy use in cancer, not front and center but as a helpful hand to immunotherapy [10].For a long time many scientists or doctors attempted to engage the immune system in the fight against cancer. Many clinicians stared at cancer patients who were to be dying by their side, mourning their inability. However, cancer therapy by inhibition of negative immune regulation checkpoint therapy has fundamentally changed the way we view how cancer can be managed and many patients will receive much better care and cure. 

scholarly journals Exploring the Impact of Ketodeoxynonulosonic Acid in Host-Pathogen Interactions Using Uptake and Surface Display by Nontypeable Haemophilus influenzae

mBio ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sudeshna Saha ◽  
Alison Coady ◽  
Aniruddha Sasmal ◽  
Kunio Kawanishi ◽  
Biswa Choudhury ◽  
...  
Keyword(s):  
Immune System ◽  
Sialic Acid ◽  
Haemophilus Influenzae ◽  
Pathogenic Bacteria ◽  
Molecular Mimicry ◽  
Surface Display ◽  
Sialic Acids ◽  
Complement C3 ◽  
Nontypeable Haemophilus Influenzae ◽  
The Impact

ABSTRACT Surface expression of the common vertebrate sialic acid (Sia) N-acetylneuraminic acid (Neu5Ac) by commensal and pathogenic microbes appears structurally to represent “molecular mimicry” of host sialoglycans, facilitating multiple mechanisms of host immune evasion. In contrast, ketodeoxynonulosonic acid (Kdn) is a more ancestral Sia also present in prokaryotic glycoconjugates that are structurally quite distinct from vertebrate sialoglycans. We detected human antibodies against Kdn-terminated glycans, and sialoglycan microarray studies found these anti-Kdn antibodies to be directed against Kdn-sialoglycans structurally similar to those on human cell surface Neu5Ac-sialoglycans. Anti-Kdn-glycan antibodies appear during infancy in a pattern similar to those generated following incorporation of the nonhuman Sia N-glycolylneuraminic acid (Neu5Gc) onto the surface of nontypeable Haemophilus influenzae (NTHi), a human commensal and opportunistic pathogen. NTHi grown in the presence of free Kdn took up and incorporated the Sia into its lipooligosaccharide (LOS). Surface display of the Kdn within NTHi LOS blunted several virulence attributes of the pathogen, including Neu5Ac-mediated resistance to complement and whole blood killing, complement C3 deposition, IgM binding, and engagement of Siglec-9. Upper airway administration of Kdn reduced NTHi infection in human-like Cmah null (Neu5Gc-deficient) mice that express a Neu5Ac-rich sialome. We propose a mechanism for the induction of anti-Kdn antibodies in humans, suggesting that Kdn could be a natural and/or therapeutic “Trojan horse” that impairs colonization and virulence phenotypes of free Neu5Ac-assimilating human pathogens. IMPORTANCE All cells in vertebrates are coated with a dense array of glycans often capped with sugars called sialic acids. Sialic acids have many functions, including serving as a signal for recognition of “self” cells by the immune system, thereby guiding an appropriate immune response against foreign “nonself” and/or damaged cells. Several pathogenic bacteria have evolved mechanisms to cloak themselves with sialic acids and evade immune responses. Here we explore a type of sialic acid called “Kdn” (ketodeoxynonulosonic acid) that has not received much attention in the past and compare and contrast how it interacts with the immune system. Our results show potential for the use of Kdn as a natural intervention against pathogenic bacteria that take up and coat themselves with external sialic acid from the environment.

Therapeutic Monoclonal Antibodies in Clinical Practice against Cancer

2020 ◽  
Vol 20 (16) ◽  
pp. 1895-1907
Author(s):  
Navgeet Kaur ◽  
Anju Goyal ◽  
Rakesh K. Sindhu
Keyword(s):  
Monoclonal Antibody ◽  
Monoclonal Antibodies ◽  
Clinical Practice ◽  
Therapeutic Agent ◽  
Hematologic Malignancies ◽  
Immune Checkpoints ◽  
Malignant Cells ◽  
Main Target ◽  
Therapeutic Monoclonal Antibodies ◽  
Cancerous Cells

The importance of monoclonal antibodies in oncology has increased drastically following the discovery of Milstein and Kohler. Since the first approval of the monoclonal antibody, i.e. Rituximab in 1997 by the FDA, there was a decline in further applications but this number has significantly increased over the last three decades for various therapeutic applications due to the lesser side effects in comparison to the traditional chemotherapy methods. Presently, numerous monoclonal antibodies have been approved and many are in queue for approval as a strong therapeutic agent for treating hematologic malignancies and solid tumors. The main target checkpoints for the monoclonal antibodies against cancer cells include EGFR, VEGF, CD and tyrosine kinase which are overexpressed in malignant cells. Other immune checkpoints like CTLA-4, PD-1 and PD-1 receptors targeted by the recently developed antibodies increase the capability of the immune system in destroying the cancerous cells. Here, in this review, the mechanism of action, uses and target points of the approved mAbs against cancer have been summarized.

scholarly journals Synthetic mycobacterial diacyl trehaloses reveal differential recognition by human T cell receptors and the C-type lectin Mincle

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Josephine F. Reijneveld ◽  
Mira Holzheimer ◽  
David C. Young ◽  
Kattya Lopez ◽  
Sara Suliman ◽  
...  
Keyword(s):  
T Cells ◽  
Fatty Acid ◽  
Immune System ◽  
T Cell ◽  
Cross Reactivity ◽  
Lipid Binding ◽  
Human Immune System ◽  
Human T Cell ◽  
Human T Cells ◽  
Pure Compounds

AbstractThe cell wall of Mycobacterium tuberculosis is composed of diverse glycolipids which potentially interact with the human immune system. To overcome difficulties in obtaining pure compounds from bacterial extracts, we recently synthesized three forms of mycobacterial diacyltrehalose (DAT) that differ in their fatty acid composition, DAT1, DAT2, and DAT3. To study the potential recognition of DATs by human T cells, we treated the lipid-binding antigen presenting molecule CD1b with synthetic DATs and looked for T cells that bound the complex. DAT1- and DAT2-treated CD1b tetramers were recognized by T cells, but DAT3-treated CD1b tetramers were not. A T cell line derived using CD1b-DAT2 tetramers showed that there is no cross-reactivity between DATs in an IFN-γ release assay, suggesting that the chemical structure of the fatty acid at the 3-position determines recognition by T cells. In contrast with the lack of recognition of DAT3 by human T cells, DAT3, but not DAT1 or DAT2, activates Mincle. Thus, we show that the mycobacterial lipid DAT can be both an antigen for T cells and an agonist for the innate Mincle receptor, and that small chemical differences determine recognition by different parts of the immune system.

scholarly journals The structure of SeviL, a GM1b/asialo-GM1 binding R-type lectin from the mussel Mytilisepta virgata

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Kenichi Kamata ◽  
Kenji Mizutani ◽  
Katsuya Takahashi ◽  
Roberta Marchetti ◽  
Alba Silipo ◽  
...  
Keyword(s):  
Immune System ◽  
Sialic Acid ◽  
Ligand Binding ◽  
Steric Hindrance ◽  
Sequence Similarity ◽  
Binding Assays ◽  
Subunit Interface ◽  
Nmr Techniques ◽  
And Control ◽  
Asialo Gm1

AbstractSeviL is a recently isolated lectin found to bind to the linear saccharides of the ganglioside GM1b (Neu5Ac$$\alpha$$ α (2-3)Gal$$\beta$$ β (1-3)GalNAc$$\beta$$ β (1-4)Gal$$\beta$$ β (1-4)Glc) and its precursor, asialo-GM1 (Gal$$\beta$$ β (1-3)GalNAc$$\beta$$ β (1-4)Gal$$\beta$$ β (1-4)Glc). The crystal structures of recombinant SeviL have been determined in the presence and absence of ligand. The protein belongs to the $$\beta$$ β -trefoil family, but shows only weak sequence similarity to known structures. SeviL forms a dimer in solution, with one binding site per subunit, close to the subunit interface. Molecular details of glycan recognition by SeviL in solution were analysed by ligand- and protein-based NMR techniques as well as ligand binding assays. SeviL shows no interaction with GM1 due to steric hindrance with the sialic acid branch that is absent from GM1b. This unusual specificity makes SeviL of great interest for the detection and control of certain cancer cells, and cells of the immune system, that display asialo-GM1.

scholarly journals Thromboses and Hemostasis Disorders Associated with Coronavirus Disease 2019: The Possible Causal Role of Cross-Reactivity and Immunological Imprinting

2021 ◽  
Author(s):  
Darja Kanduc
Keyword(s):  
Immune System ◽  
Severe Acute Respiratory Syndrome ◽  
Natural Infection ◽  
Vascular Diseases ◽  
Cross Reactivity ◽  
Active Immunization ◽  
Thromboembolic Complications ◽  
Human Proteins ◽  
Almost All

AbstractBy examining the issue of the thromboses and hemostasis disorders associated with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) through the lens of cross-reactivity, it was found that 60 pentapeptides are shared by SARS-CoV-2 spike glycoprotein (gp) and human proteins that— when altered, mutated, deficient or, however, improperly functioning— cause vascular diseases, thromboembolic complications, venous thrombosis, thrombocytopenia, coagulopathies, and bleeding, inter alia. The peptide commonality has a relevant immunological potential as almost all of the shared sequences are present in experimentally validated SARS-CoV-2 spike gp-derived epitopes, thus supporting the possibility of cross-reactions between the viral gp and the thromboses-related human proteins. Moreover, many of the shared peptide sequences are also present in pathogens to which individuals have previously been exposed following natural infection or vaccinal routes, and of which the immune system has stored imprint. Such an immunological memory might rapidly trigger anamnestic secondary cross-reactive responses of extreme affinity and avidity, in this way explaining the thromboembolic adverse events that can associate with SARS-CoV-2 infection or active immunization.

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