0
selected
-
1.
Zinc finger proteins in the host-virus interplay: multifaceted functions based on their nucleic acid-binding property.
Wang, G, Zheng, C
FEMS microbiology reviews. 2021;(3)
Abstract
Zinc finger proteins (ZFPs) are a huge family comprised of massive, structurally diverse proteins characterized by zinc ion coordinating. They engage in the host-virus interplay in-depth and occupy a significant portion of the host antiviral arsenal. Nucleic acid-binding is the basic property of certain ZFPs, which draws increasing attention due to their immense influence on viral infections. ZFPs exert multiple roles on the viral replications and host cell transcription profiles by recognizing viral genomes and host mRNAs. Their roles could be either antiviral or proviral and were separately discussed. Our review covers the recent research progress and provides a comprehensive understanding of ZFPs in antiviral immunity based on their DNA/RNA binding property.
-
2.
Genetics and Pathogenetic Role of Inflammasomes in Philadelphia Negative Chronic Myeloproliferative Neoplasms: A Narrative Review.
Di Battista, V, Bochicchio, MT, Giordano, G, Napolitano, M, Lucchesi, A
International journal of molecular sciences. 2021;(2)
Abstract
The last decade has been very important for the quantity of preclinical information obtained regarding chronic myeloproliferative neoplasms (MPNs) and the following will be dedicated to the translational implications of the new biological acquisitions. The overcoming of the mechanistic model of clonal evolution and the entry of chronic inflammation and dysimmunity into the new model are the elements on which to base a part of future therapeutic strategies. The innate immune system plays a major role in this context. Protagonists of the initiation and regulation of many pathological aspects, from cytokine storms to fibrosis, the NLRP3 and AIM2 inflammasomes guide and condition the natural history of the disease. For this reason, MPNs share many biological and clinical aspects with non-neoplastic diseases, such as autoimmune disorders. Finally, cardiovascular risk and disturbances in iron metabolism and myelopoiesis are also closely linked to the role of inflammasomes. Although targeted therapies are already being tested, an increase in knowledge on the subject is desirable and potentially translates into better care for patients with MPNs.
-
3.
The Trinity of cGAS, TLR9, and ALRs Guardians of the Cellular Galaxy Against Host-Derived Self-DNA.
Kumar, V
Frontiers in immunology. 2020;:624597
Abstract
The immune system has evolved to protect the host from the pathogens and allergens surrounding their environment. The immune system develops in such a way to recognize self and non-self and develops self-tolerance against self-proteins, nucleic acids, and other larger molecules. However, the broken immunological self-tolerance leads to the development of autoimmune or autoinflammatory diseases. Pattern-recognition receptors (PRRs) are expressed by immunological cells on their cell membrane and in the cytosol. Different Toll-like receptors (TLRs), Nod-like receptors (NLRs) and absent in melanoma-2 (AIM-2)-like receptors (ALRs) forming inflammasomes in the cytosol, RIG (retinoic acid-inducible gene)-1-like receptors (RLRs), and C-type lectin receptors (CLRs) are some of the PRRs. The DNA-sensing receptor cyclic GMP-AMP synthase (cGAS) is another PRR present in the cytosol and the nucleus. The present review describes the role of ALRs (AIM2), TLR9, and cGAS in recognizing the host cell DNA as a potent damage/danger-associated molecular pattern (DAMP), which moves out to the cytosol from its housing organelles (nucleus and mitochondria). The introduction opens with the concept that the immune system has evolved to recognize pathogens, the idea of horror autotoxicus, and its failure due to the emergence of autoimmune diseases (ADs), and the discovery of PRRs revolutionizing immunology. The second section describes the cGAS-STING signaling pathway mediated cytosolic self-DNA recognition, its evolution, characteristics of self-DNAs activating it, and its role in different inflammatory conditions. The third section describes the role of TLR9 in recognizing self-DNA in the endolysosomes during infections depending on the self-DNA characteristics and various inflammatory diseases. The fourth section discusses about AIM2 (an ALR), which also binds cytosolic self-DNA (with 80-300 base pairs or bp) that inhibits cGAS-STING-dependent type 1 IFN generation but induces inflammation and pyroptosis during different inflammatory conditions. Hence, this trinity of PRRs has evolved to recognize self-DNA as a potential DAMP and comes into action to guard the cellular galaxy. However, their dysregulation proves dangerous to the host and leads to several inflammatory conditions, including sterile-inflammatory conditions autoinflammatory and ADs.
-
4.
TNIP1 Regulates Cutibacterium acnes-Induced Innate Immune Functions in Epidermal Keratinocytes.
Erdei, L, Bolla, BS, Bozó, R, Tax, G, Urbán, E, Kemény, L, Szabó, K
Frontiers in immunology. 2018;:2155
Abstract
Human skin cells recognize the presence of the skin microbiome through pathogen recognition receptors. Epidermal keratinocytes are known to activate toll-like receptors (TLRs) 2 and 4 in response to the commensal Cutibacterium acnes (C. acnes, formerly known as Propionibacterium acnes) bacterium and subsequently to induce innate immune and inflammatory events. These events may lead to the appearance of macroscopic inflammatory acne lesions in puberty: comedos, papules and, pustules. Healthy skin does not exhibit inflammation or skin lesions, even in the continuous presence of the same microbes. As the molecular mechanism for this duality is still unclear, we aimed to identify factors and mechanisms that control the innate immune response to C. acnes in keratinocytes using a human immortalized keratinocyte cell line, HPV-KER, normal human keratinocytes (NHEK) and an organotypic skin model (OSM). TNIP1, a negative regulator of the NF-κB signaling pathway, was found to be expressed in HPV-KER cells, and its expression was rapidly induced in response to C. acnes treatment, which was confirmed in NHEK cells and OSMs. Expression changes were not dependent on the C. acnes strain. However, we found that the extent of expression was dependent on C. acnes dose. Bacterial-induced changes in TNIP1 expression were regulated by signaling pathways involving NF-κB, p38, MAPKK and JNK. Experimental modification of TNIP1 levels affected constitutive and C. acnes-induced NF-κB promoter activities and subsequent inflammatory cytokine and chemokine mRNA and protein levels. These results suggest an important role for this negative regulator in the control of bacterially induced TLR signaling pathways in keratinocytes. We showed that all-trans retinoic acid (ATRA) induced elevated TNIP1 expression in HPV-KER cells and also in OSMs, where TNIP1 levels increased throughout the epidermis. ATRA also reduced constitutive and bacterium-induced levels of TNFα, CCL5 and TLR2, while simultaneously increasing CXCL8 and TLR4 expression. Based on these findings, we propose that ATRA may exhibit dual effects in acne therapy by both affecting the expression of the negative regulator TNIP1 and attenuating TLR2-induced inflammation. Overall, TNIP1, as a possible regulator of C. acnes-induced innate immune and inflammatory events in keratinocytes, may play important roles in the maintenance of epidermal homeostasis.
-
5.
Anti-viral tetris: modulation of the innate anti-viral immune response by A20.
Arguello, M, Paz, S, Ferran, C, Moll, HP, Hiscott, J
Advances in experimental medicine and biology. 2014;:49-64
Abstract
The A20 protein has emerged as an important negative regulator of Toll like receptor (TLR) and retinoic acid-inducible gene 1 (RIG-I)-mediated anti-viral signaling. A20 functions both as a RING-type E3 ubiquitin ligase and as a de-ubiquitinating enzyme. Nuclear factor kappa B (NF-kappaB) and interferon regulatory factor (IRF) pathways are targeted by A20 through mechanisms that appear to be both overlapping and distinct, resulting in the downregulation of interferon alpha/beta (IFNalpha/beta) production. This review specifically details the impact of A20 on the cytosolic RIG-I/MDA5 pathway, a process that is less understood than that of NF-kappaB but is essential for the regulation of the innate immune response to viral infection.
-
6.
Runx and ThPOK: a balancing act to regulate thymocyte lineage commitment.
Egawa, T
Journal of cellular biochemistry. 2009;(6):1037-45
Abstract
CD4-positive helper T cells and CD8-positive cytotoxic T cells comprise the majority of T lymphocytes present in secondary lymphoid organs and are essential for acquired immunity. These two populations are derived from common precursors in the thymus and selected through interaction between their clonal T-cell receptors and major histocompatibility complex molecules. Although intensely studied as a model system for binary cell fate decisions, the mechanisms underlying the helper versus cytotoxic lineage choice in the thymus has been elusive. In the past few years, it has been demonstrated that the Runx family of transcription factors, particularly Runx3, is essential for the generation of cytotoxic lineage T cells, whereas the ThPOK zinc finger transcription factor that plays a crucial role in the differentiation of the helper lineage. Recent works have implied that a cross-regulation between Runx and ThPOK contributes to appropriate thymocyte lineage commitment. In this article, recent findings on the transcription factor networks governing thymocyte lineage decisions are discussed, focusing on the two factors, and provide insights into mechanisms of lineage-specific gene regulation in the process of T-cell commitments.
-
7.
MVA E2 recombinant vaccine in the treatment of human papillomavirus infection in men presenting intraurethral flat condyloma: a phase I/II study.
Albarran Y Carvajal, A, de la Garza, A, Cruz Quiroz, BJ, Vazquez Zea, E, Díaz Estrada, I, Mendez Fuentez, E, López Contreras, M, Andrade-Manzano, A, Padilla, S, Varela, AR, et al
BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy. 2007;(1):47-59
Abstract
BACKGROUND Human papillomavirus (HPV) is the etiologic agent for warts and cervical cancer. In Mexico, the death rate from cervical cancer is extremely high, and statistical data show that since 1990 the number of deaths is increasing. Condylomas and cancer of the penis are the most common lesions presented in men; bladder and prostate cancer in men are also associated with the presence of HPV. Since HPV is transmitted by sexual intercourse, treating both partners is necessary in order to eliminate the virus in the population. Approaches to this include preventative vaccines such as Gardasil, and therapeutic vaccines to treat established infections in both men and women. This will be the only way to decrease the numbers of deaths due to this malignancy. PATIENTS AND METHODS We conducted a phase I/II clinical trial to evaluate the potential use of the recombinant vaccinia viral vaccine MVA E2 (composed of modified vaccinia virus Ankara [MVA] expressing the E2 gene of bovine papillomavirus) to treat flat condyloma lesions associated with oncogenic HPV in men. Fifty male patients with flat condyloma lesions were treated with either MVA E2 therapeutic vaccine or fluorouracil (5-fluorouracil). Thirty men received the therapeutic vaccine, at a total of 10(6) virus particles per dose, administered directly into the urethra once every week over a 4-week period. Twenty control patients were treated with 5% fluorouracil 1mL twice weekly over a 4-week period directly into the urethra. Reduction of lesions or absence of papillomavirus infection was monitored by colposcopy and histologic analysis. The immune response after MVA E2 treatment was determined by measuring the antibodies against the MVA E2 virus and by analyzing the lymphocyte cytotoxic activity against cancer cells bearing oncogenic papillomavirus. Presence of papillomavirus was determined by the Hybrid Capture method. RESULTS Twenty-eight of 30 patients showed no lesion or presence of papillomavirus as diagnosed by colposcopy and brush histologic examination after 4 weeks of MVA E2 treatment. These patients showed complete elimination of flat condyloma in the urethra and no acetowhite spots were detected over the prepuce. In two other patients the acetowhite spots and flat condyloma did not diminish. All patients developed antibodies against the MVA E2 vaccine and E2 protein, and generated a specific cytotoxic response against papilloma-transformed cells. Viral DNA was not detected in MVA E2-treated patients. In the control group, 13 of 20 patients were free of lesions. Three of these patients had recurrence of lesions after 3 months of treatment and none of the patients developed specific antibodies against cancer cells. In contrast, patients treated with MVA E2 did not show any recurrence of lesions after 1 year of treatment. In addition, none of the patients had local or systemic adverse effects according to the WHO classification 1-4. CONCLUSIONS Therapeutic vaccination with MVA E2 proved to be very effective in stimulating the immune system against papillomavirus, and in generating regression of flat condyloma lesions in men.
-
8.
[Transfer RNA-associated anti-Wa antibody in patients with scleroderma and the target antigen NEFA/Nucleobindin-2].
Imura, Y, Mimori, T
Nihon Rinsho Men'eki Gakkai kaishi = Japanese journal of clinical immunology. 2007;(3):151-5
-
-
Free full text
-
Abstract
Many autoantibodies associated with nucleic acids are found in autoimmune diseases, and are important for analyzing pathophysiologic mechanisms. Toll-like receptors (TLRs) are receptor molecules for innate immunity and some of them recognize nucleic acids. Nucleic acids in autoantigens may stimulate TLR and activate antigen presenting cells as adjuvants. The Wa antigen was found as a transfer RNA (tRNA)-binding protein by RNA immunoprecipitation and identified as NEFA/Nucleobindin-2. Although the function of NEFA/Nucleobindin-2 is still not clear, it may be involved in secretion of proteins along with calcium metabolism and in protein translation by tRNA-binding ability.
-
9.
Frequency of SOX Group B (SOX1, 2, 3) and ZIC2 antibodies in Turkish patients with small cell lung carcinoma and their correlation with clinical parameters.
Vural, B, Chen, LC, Saip, P, Chen, YT, Ustuner, Z, Gonen, M, Simpson, AJ, Old, LJ, Ozbek, U, Gure, AO
Cancer. 2005;(12):2575-83
-
-
Free full text
-
Abstract
BACKGROUND Expression of neuroectodermal markers is a key feature of small cell lung carcinoma (SCLC). Although immune responses against a number of these proteins have been associated with paraneoplastic neuronal disease (PND), most patients with SCLC have anti-neuroectodermal antibodies in the absence of PND. Whether these immune responses affect the clinical outcome in SCLC is critical in understanding the potential value of these proteins as cancer vaccine targets as well as in the pathogenesis of PND. METHODS The authors investigated the frequency of immunoglobulin G autoantibodies against Sry-like high-mobility group box (SOX)1, 2, 3 and Zinc-finger gene of the cerebellum (ZIC)2 proteins in stored serum samples from 90 patients utilizing the lambda-phage plaque assay. Data obtained from patient records were utilized to measure clinical correlates of seroreactivity. RESULTS Antibodies to SOX1 were present in 28% of patients and another 28% had anti-ZIC2 antibodies, classifying these as some of the most frequent antibody responses observed in SCLC. None had autoimmune paraneoplastic disease. Antibody titers were frequently as high as > or = 1:10(6) and were stable for < or = 6 months after diagnosis. Seroreactivity against either SOX1 or ZIC2 correlated with younger age, lower lactate dehydrogenase levels, and better response to initial therapy. CONCLUSIONS The frequent and stable presence of SOX Group B and/or ZIC2 antibodies in SCLC, but not in healthy individuals examined, indicates they are serological markers of SCLC. However, the correlation between known clinical parameters of less aggressive disease and seroreactivity suggests that these antibodies are indicators of better prognosis in SCLC and warrants further studies to clarify the nature of the underlying immune responses.