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Topic Review
Mitogen-Activated Protein Kinases
Influenza A viral (IAV) infections are common, yet persistent as one of the major contributors towards respiratory viral diseases. With the complete eradication of IAVs seemingly impossible, IAV infections are of major public health concern globally as evident by the need for constant surveillance and vaccine renewals. This entry focuses on the innate immune response against influenza infections and in particular, the roles of mitogen-activated protein kinases (MAPKs) in this response. We first detailed the conventional methods of pathogen recognition of influenza viruses by pathogen recognition receptors (PRRs), leading to the activation of pathways involved in the anti-viral response. Predominantly, we have highlighted the roles that MAPKs (ERK, p38 and JNK) play in the activation of Type I Interferons (IFNs) and pro-inflammatory cytokines to resolve IAV infections. Taking a step further, we also looked at how highly pathogenic influenza A viruses (HPIAVs), as well as aberrant and dysfunctional signalling of the MAPK pathways may lead to a hyperactive immune response that is unwarranted, leading to the progression into acute lung injuries and acute respiratory distress syndrome (ARDS) from a simple infection. Taken together, we hope that this entry may shed some light on the important roles that MAPKs play in the innate immune response towards IAV infections, and to provide important considerations when tackling this global challenge.
  • 1.2K
  • 26 Oct 2020
Topic Review
PD-1 and Its Ligands in Allergy
Programmed cell death 1 (PD-1) and its ligands PD-L1 and PD-L2 are receptors that act in co-stimulatory and coinhibitory immune responses. Signaling the PD-1/PD-L1 or PD-L2 pathway is essential to regulate the inflammatory responses to infections, autoimmunity, and allergies, and it has been extensively studied in cancer.
  • 1.2K
  • 13 Jun 2022
Topic Review
Complement System in Alzheimer’s Disease
Alzheimer’s disease is a type of dementia characterized by problems with short-term memory, cognition, and difficulties with activities of daily living. It is a progressive, neurodegenerative disorder. The complement system is an ancient part of the innate immune system and comprises of more than thirty serum and membrane-bound proteins. This system has three different activating pathways and culminates into the formation of a membrane attack complex that ultimately causes target cell lysis (usually pathogens) The complement system is involved in several important functions in the central nervous system (CNS) that include neurogenesis, synaptic pruning, apoptosis, and neuronal plasticity.
  • 1.2K
  • 30 Dec 2021
Topic Review
Modulating T Cell Responses by Targeting CD3
The CD3-T cell receptor (TCR) is the canonical receptor complex on T cells. It provides the “first signal” that initiates T cell activation and determines the specificity of the immune response. The TCR confers the binding specificity whilst the CD3 subunits facilitate signal transduction necessary for T cell activation. While the mechanisms through which antigen sensing and signal transduction occur in the CD3–TCR complex are still under debate, revelations regarding the intricate 3D structure of the CD3–TCR complex might open the possibility of modulating its activity by designing targeted drugs and tools, including aptamers.
  • 1.2K
  • 15 Mar 2023
Topic Review
Training vs. Tolerance of the Innate Immune System
Trained immunity represents a functional state of the innate immune cells and tissue-resident stem cells adjusting their response to subsequent insults, characterized particularly by a prolonged activation after a resting period, orchestrated mainly by epigenetic reprogramming and the metabolic rewiring of cells. It describes a property of innate immune system to mount memory-like responses against past microbial and non-microbial challenges. In contrast, the refractory state of endotoxin tolerance as opposing reaction of trained immunity has been extensively elaborated and defined as an immunosuppressive state of myeloid cells portrayed by a significant reduction in the inflammatory capacity. Both opposing adaptive reactions of the innate immune system are of fundamental interest since they may represent a double-edged sword counteracting each other, protecting or driving the pathogenesis of a variety of inflammatory diseases. 
  • 1.2K
  • 10 Mar 2023
Topic Review
Cryptococcus
Cryptococcosis is a disease caused by the pathogenic fungi Cryptococcus neoformans and Cryptococcus gattii, both environmental fungi that cause severe pneumonia and may even lead to cryptococcal meningoencephalitis. Although C. neoformans affects more fragile individuals, such as immunocompromised hosts through opportunistic infections, C. gattii causes a serious indiscriminate primary infection in immunocompetent individuals. Typically seen in tropical and subtropical environments, C. gattii has increased its endemic area, largely due to climatic factors that favor contagion in warmer climates. It is important to point out that not only C. gattii, but the Cryptococcus species complex produces a polysaccharidic capsule with immunomodulatory properties, enabling the pathogenic species of Cryptococccus to subvert the host immune response during the establishment of cryptococcosis, facilitating its dissemination in the infected organism. C. gattii causes a more severe and difficult-to-treat infection, with few antifungals eliciting an effective response during chronic treatment. 
  • 1.2K
  • 26 Jul 2022
Topic Review
Fungal Beta-Glucans
The importance of a well-functioning and balanced immune system has become more apparent in recent decades. Various elements have however not yet been uncovered as shown, for example, in the uncertainty on immune system responses to COVID-19. Fungal beta-glucans are bioactive molecules with immunomodulating properties.
  • 1.2K
  • 01 Jun 2021
Topic Review
Delta133p53 Isoforms of Human TP53
The TP53 gene is a critical tumor suppressor and key determinant of cell fate which regulates numerous cellular functions including DNA repair, cell cycle arrest, cellular senescence, apoptosis, autophagy and metabolism. The delta133p53 isoforms are critical regulators of these biological processes in human physiology and diseases such as cancer.  
  • 1.2K
  • 28 Sep 2021
Topic Review
Still’s Disease and Kawasaki Disease
Still’s disease and Kawasaki disease (KD) today belong to the group of cytokine storm syndromes, a pathophysiological set related to excessive activation of the innate immune response. 
  • 1.2K
  • 30 Jul 2021
Topic Review
TNF’s Pathway in CD
Crohn’s disease (CD) is a chronic disorder characterized by full thickness patchy inflammation of the gastrointestinal tract. The pathogenesis is multifactorial and involves defective innate immune responses, microbiome alterations, and dysregulated activation of the acquired component of mucosal immunity. One of the molecular mediators that is involved at different levels in the initiation and progression of intestinal inflammation characteristic of CD is tumor necrosis factor (TNF).
  • 1.2K
  • 15 Oct 2021
Topic Review
Interleukin-18
Interleukin (IL)-18 was originally discovered as a factor that enhanced IFN-γ production from anti-CD3-stimulated Th1 cells, especially in the presence of IL-12. Upon stimulation with Ag plus IL-12, naïve T cells develop into IL-18 receptor (IL-18R) expressing Th1 cells, which increase IFN-γ production in response to IL-18 stimulation. 
  • 1.2K
  • 21 Jan 2022
Topic Review
Immune Checkpoint Inhibitors in Melanoma
Despite of melanoma immunogenicity, this tumor develops immune escape mechanisms that stimulate a fast melanoma progression. Such mechanisms include impaired antigen presentation by tumor cells, accumulation of dysfunctional effector T cells and generation of the immunosuppressive TME represented by MDSC, TAN, CAF, TAM, and Treg. Therefore, numerous approaches were developed to reinvigorate the anti-tumor immune response. Recently approved immunotherapies with ICI (anti-PD-1, anti-PD-L1 and anti-CTLA-4 antibodies) have revolutionized the treatment of melanoma. This treatment significantly increased the survival of melanoma patients and provided a durable control of the disease [26,27,28]. However, the response rates to ICI are still restricted. Thus, further efforts should be undertaken to maximize the efficacy of ICI treatment. This aim could be achieved by improving the selection of patients who might benefit from the ICI therapy, by applying early radiological findings and by measuring predictive markers from tumor and liquid biopsies. Furthermore, the combination of different ICI (such as ipilimumab and nivolumab), their combination with targeting of the immunosuppressive TME or with other anti-cancer therapies could significantly improve the efficacy of tumor immunotherapy. Furthermore, targeting of other immune checkpoints (such as LAG-3, TIM-3, TIGIT) and its combination with approved ICI are currently under investigation.
  • 1.2K
  • 30 Oct 2020
Topic Review
Saliva-Assisted Transmission
Saliva-assisted transmission (SAT) is defined as the property of tick saliva to enhance the transmission and establishment of tick-borne pathogens. Tick saliva contains multiple biomolecules that act to repress host immune responses, hemostasis, inflammation, and itchiness. These molecules can be exploited by tick-borne pathogens by increasing their expression or directly binding. The focus of this entry is in defining the mechanism that tick-borne pathogens use to subvert tick salivary secretions in their advantage.
  • 1.2K
  • 03 Mar 2021
Topic Review
Adoptive Immunotherapy beyond CAR T-Cells
The aging of the world population leads to a constant increase of cancer-related morbidity and mortality. Treatment of late-stage tumors has become a significant burden on the healthcare system globally. Adoptive cell immunotherapy is supposed to prolong life with cancer and ideally cure cancer after a single infusion of the cell product. Arguably, the most impressive clinical therapy in this field is based on chimeric antigen receptor (CAR) T-cells capable of curing up to 25–50% of previously incurable patients with B-cell malignancies. Diverse cell therapies are already efficiently used in clinics for cancer treatment (such as tumor infiltrating lymphocytes, transgenic αβ T-cells) and several novel promising cell therapies are in development (such as CAR M-cells, transgenic γδ T-cells, CAR NK-cells). Here, we summarize the recent literature data with the focus on T-cell receptor-based therapies and overview the most advanced systems for manufacturing of clinical grade cell products. 
  • 1.2K
  • 22 Dec 2021
Topic Review
Rheumatic Manifestations for ICIs
Immune checkpoint inhibitors (ICI) are monoclonal antibodies that activate the immune system aiming at enhancing antitumor immunity.  Their clinical efficacy is well documented but the side effects associated with their use are still under investigation.  These drugs cause several immune related adverse events (ir-AE) some of which stand within the field of Rheumatology.  Herein, we performed a literature review in an effort to evaluate all publicly available clinical data regarding rheumatic manifestations associated with ICI.  The most common musculoskeletal ir-AEs are inflammatory arthritis, polymyalgia rheumatica and myositis.  Non musculoskeletal rheumatic manifestations are less frequent with the most prominent being sicca, vasculitides and sarcoidosis.  Cases of systemic lupus erythematosus or scleroderma are extremely rare.  The majority of musculoskeletal ir-AE are of mild/moderate severity and can be managed with steroids with no need for ICI discontinuation.  In severe cases, more intense immunosuppressive therapy and permanent ICI discontinuation may be employed.  Oncologists should periodically screen patients receiving ICI for new onset inflammatory musculoskeletal complaints and seek a rheumatology consultation in cases of persisting symptoms.
  • 1.2K
  • 28 Oct 2020
Topic Review
The Viral Agents of BRDC
Bovine respiratory disease complex (BRDC) is a multifactorial disease of cattle which presents as bacterial and viral pneumonia. The causative agents of BRDC work in synergy to suppress the host immune response and increase the colonisation of the lower respiratory tracts by pathogenic bacteria. Environmental stress and/or viral infection predispose cattle to secondary bacterial infections via suppression of key innate and adaptive immune mechanisms. This allows bacteria to descend the respiratory tract unchallenged. BRDC is the costliest disease among feedlot cattle, and whilst vaccines exist for individual pathogens, there is still a lack of evidence for the efficacy of these vaccines and uncertainty surrounding the optimum timing of delivery. 
  • 1.2K
  • 14 Apr 2021
Topic Review
Autophagy
Hepatitis C virus induces autophagy and temporally regulates the autophagic flux to support its replication. It uses autophagic membranes as a platform for its RNA replication, autophagic vacuoles to support its morphogenesis and autophagy to suppress host innate immune responses.  
  • 1.2K
  • 02 Feb 2021
Topic Review
Ezrin, VASO-Active Intestinal Peptide and COVID-19
SARS-CoV-2 infection inhibits interferon expression, while hyper-activating innate-immune signalling and expression of pro-inflammatory cytokines. SARS-CoV-2 proteins: Spike, M and nsp6, nsp12 and nsp13 inhibit IFR3-mediated Type-1-interferon defence, but hyper-activate intracellular signalling, which leads to dysfunctional expression of pro-inflammatory cytokines, particularly IL-1β IL-6, IL-8, and TNFα. Ezrin, a sub-membrane adaptor-protein, organises multi-protein-complexes such as ezrin+NHERF1+NHE+CFTR, which control the density and location of ACE2 receptor expression on the luminal surface of airway-epithelial-cells, as well as determining susceptibility to SARS-CoV-2 infection. This protein complex is vital for lung-surfactant production for efficient gas-exchange. Ezrin also forms multi-protein-complexes that regulate signalling kinases; Ras, PKC, PI3K, and PKA. m-RAGE is a pattern-recognition-receptor of the innate immune system that is triggered by AGEs, which are chemically modified proteins common in the elderly and obese. Vasoactive Intestinal Peptide (VIP) is a 28-amino acid peptide released by intrinsic neurons in the human airways. 
  • 1.2K
  • 22 Apr 2022
Topic Review
Non-Small Cell Lung Cancer
Lung cancer is divided to Non-Small Cell Lung Cancer (NSCLC) comprising about 85% of lung cancer cases, and small cell lung cancer (15% of lung cancer cases). Non-small cell lung cancer (NSCLC) has several subtypes: a. Adenocarcinoma, b. Squamous cell carcinoma, c. Large cell carcinoma, or d. mixed histology. Treatment of localized NSCLC is surgical resection, stereotactic ablative radiation therapy, or combination of chemotherapy and radiation (chemoradiation). Treatment of advanced / metastatic disease includes targeted therapies, chemotherapy and immunotherapy. 
  • 1.2K
  • 17 Feb 2021
Topic Review
Immune Checkpoint Inhibitors
There are several forms of Immune checkpoint inhibitors (ICIs) targeting at several checkpoint proteins or receptors including programmed cell death 1 (PD-1), PD-1 ligand (PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), B and T cell lymphocyte attenuator (BTLA), V-domain Ig suppressor of T cell activation (VISTA), lymphocyte activation gene 3 (LAG3) and T cell immunoglobulin and mucin domain 3 (TIM-3) [5,6,7,8,9]. ICIs, specifically PD-1, PDL-1 and CTLA-4 inhibitors have been approved for the treatment of a variety of solid tumors, initially beginning with melanoma in 2011. Both PD-1 and CTLA-4 are negative costimulatory molecules that when inhibited enhance T cell activation and the eventual killing of tumor cells [10].ICIs can be used in patients with chemotherapy-resistant tumors through tissue agnostic approval for MSI-H and high mutational burden tumors [14]. ICIs have shown that they are not only efficacious but have superior safety profile as well [15]. Most of the ICIs are well tolerated, however, they have distinct side effects compared to traditional cytotoxic chemotherapies [16,17].
  • 1.2K
  • 27 Oct 2020
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