ARTICLE | doi:10.20944/preprints201805.0456.v1
Subject: Life Sciences, Biotechnology Keywords: monoclonal antibody; immunoglobulin G; glycosylation; Chinese hamster ovary; perfusion cell culture; continuous biomanufacturing
Online: 30 May 2018 (16:52:12 CEST)
A critical quality attribute of therapeutic monoclonal antibodies (mAbs) is the terminal sugar molecules of the N-linked glycan attached to the fragment crystalizable (Fc) region. There exists naturally-occurring heterogeneity in the N-linked glycan structure of mAbs, and such heterogeneity has a significant influence on the clinical safety and efficacy of mAb drugs. We previously proposed a constraint-based modeling method called glycosylation flux analysis (GFA) to characterize the rates (fluxes) of intracellular glycosylation reactions and applied the method to examine the N-linked glycosylation of immunoglobulin G (IgG) in fed-batch Chinese hamster ovary (CHO) fed-batch cultivations. In this work, we significantly improved the computational efficiency of the GFA, and employed the method to analyze the glycosylation of IgG in continuous perfusion CHO cultivations. Perfusion cell cultures have several advantages over the traditional (fed-)batch operation, including higher productivity per unit volume of reactor and more consistent product quality. The GFA showed that as in the fed-batch cultivation, the dynamical changes of IgG glycan heterogeneity in the perfusion culture are mainly attributed to alterations in the galactosylation flux activity. Furthermore, a regression analysis of the galactosylation flux activity using random forest regression linked the dynamics of galactosylation activity with the cell-specific productivity of IgG and the extracellular ammonia concentration.
ARTICLE | doi:10.20944/preprints202112.0181.v1
Subject: Materials Science, Nanotechnology Keywords: Zinc oxide; nanorod; Immunosensors, Electrodeposition, Immunoglobulin-G; Nanostructured materials; Electrochemical sensors.
Online: 10 December 2021 (13:15:47 CET)
Immunoglobulin G (IgG), a type of antibody, represents approximately 75% of serum antibodies in humans, and is the most common type of antibody found in blood circulation Consequently, the development of simple, fast and reliable systems for IgG detection are of considerable interest which can be achieved using electrochemical sandwich-type immunosensors. In this study we have developed an immunosensor sub-strate using an inexpensive and very simple fabrication method based on ZnO nanorods obtained through the electrodeposition of ZnO. The ZnO nanorods were treated by electrodepositing a layer of reduced gra-phene oxide to ensure an easy immobilization of the antibodies. On this substrate, the sandwich configura-tion of the immunosensor was built through different incubation steps, that were all optimized. The im-munosensor is electrochemically active thanks to the presence of gold nanoparticles tagging the secondary antibody, therefore it has been used to measure the current density of the hydrogen development reaction which is indirectly linked to the concentration of H-IgG antigens. In this way the calibration curve was constructed obtaining a linear range of 1-100 ng / ml with a detection limit of few ng / mL and good sensi-tivity.
ARTICLE | doi:10.20944/preprints202112.0500.v1
Subject: Life Sciences, Biophysics Keywords: immunoglobulin G; complement component C1; high-speed atomic force microscopy; CH1; CL
Online: 31 December 2021 (10:36:38 CET)
Immunoglobulin G (IgG) adopts a modular multidomain structure that mediates antigen recognition and effector functions, such as complement-dependent cytotoxicity. IgG molecules are self-assembled into a hexameric ring on antigen-containing membranes, recruiting the complement component, C1q. To provide deeper insights into the initial step of the complement pathway, we report a high-speed atomic force microscopy study for quantitative visualization of the interaction between IgG and the C1 complex composed of C1q, C1r, and C1s. Results showed that C1q in the C1 complex is restricted regarding internal motion and has a stronger binding affinity for on-membrane IgG assemblages than C1q alone, presumably because of smaller conformational entropy loss upon binding. Furthermore, we visualized a 1:1 stoichiometric interaction between C1/C1q and an IgG variant that lacks the entire CH1 domain in the absence of antigen. In addition to the canonical C1q-binding site on Fc, their interactions are mediated through a secondary site on the CL domain that is cryptic in the presence of the CH1 domain. Our findings offer clues for novel-modality therapeutic antibodies.
Subject: Medicine & Pharmacology, Allergology Keywords: triple-negative breast cancer; prognosis; immune system; immunoglobulin kappa C
Online: 31 May 2021 (12:27:49 CEST)
We studied the prognostic impact of tumor immunoglobulin kappa C (IGKC) mRNA expression as a marker of the humoral immune system in the FinHer trial patient population, where 1,010 patients with early breast cancer were randomly allocated to either docetaxel-containing or vinorelbine-containing adjuvant chemotherapy. HER2-positive patients were additionally allocated to either trastuzumab or no trastuzumab. Hormone receptor-positive patients received tamoxifen. IGKC was evaluated in 909 tumors using quantitative real-time polymerase chain reaction, and the influence on distant disease-free survival (DDFS) was examined using univariable and multivariable Cox regression and Kaplan-Meier estimates. Interactions were analyzed using Cox regression. IGKC expression, included as continuous variable, was independently associated with DDFS in a multivariable analysis including also age, molecular subtype, grade, and pT and pN stage (HR 0.930, 95% CI 0.870 – 0.995, P = 0.034). An independent association with DDFS was also found in a subset analysis of triple-negative breast cancers (TNBC) (HR 0.843, 95% CI 0.724 – 0.983, P = 0.029), but not in luminal (HR 0.957, 95% CI 0.867 – 1.056, P = 0.383) or HER2-positive (HR 0.933, 95% CI 0.826 – 1.055, P = 0.271) cancers. No significant interaction between IGKC and chemotherapy or trastuzumab administration was detected (Pinteraction = 0.855 and 0.684, respectively). These results show that humoral immunity beneficially influences the DDFS of patients with early TNBC.
ARTICLE | doi:10.20944/preprints202105.0345.v1
Subject: Materials Science, Biomaterials Keywords: Respiratory Failure; COVID19; Intravenous Immunoglobulin Therapy
Online: 14 May 2021 (15:04:29 CEST)
Adjunctive therapy with polyclonal intravenous immunoglobins (IVIg) is currently used for preventing or managing infections and sepsis, especially in immunocompromised patients. The pathobiology of COVID19 and the mechanisms of action of Ig led to consider this adjunctive therapy also in patients with respiratory failure by SARS-CoV2 infection. This manuscript report the rationale, the available data and the results of a structured consensus on intravenous Ig therapy in patients with severe COVID19. METHODS A panel of multidisciplinary experts defined the clinical phenotypes of COVID19 patients with severe respiratory failure and, after literature review, voted for the agreement on the rationale and the potential role of IVIg therapy for each phenotype. Due to the scarce evidence available, a modified RAND/UCLA appropriateness method was used. RESULTS Three different phenotypes of COVID19 patients with severe respiratory failure were identified: patients with an abrupt and dysregulated hyperinflammatory response (early phase), patients with suspected immune-paralysis (late phase), and patients with sepsis by hospital-acquired superinfection (sepsis by bacterial superinfection). The rationale for intravenous Ig therapy in the early phase was considered uncertain whereas the panellists considered appropriate its use in the late phase and patients with sepsis/septic shock by bacterial superinfection. CONCLUSION As with other immunotherapies, IVIg adjunctive therapy may a potential role in the managing of COVID19 patients. The ongoing trials will clarify the appropriate target population and the true effectiveness.
REVIEW | doi:10.20944/preprints201809.0477.v1
Subject: Medicine & Pharmacology, Dentistry Keywords: oral lichen planus; immunoglobulin; serum; saliva
Online: 25 September 2018 (06:17:41 CEST)
Background and Aim: Immunoglobulins (IgA, IgG, and IgM) are significant anti-inflammatory factors. The meta-analysis aimed to assess the serum and salivary levels of Igs as more important immunoglobulins in patients affected by oral lichen planus (OLP) compared to the healthy controls. Materials and Methods: Four databases, including PubMed/Medline, Scopus, Web of Science, and Cochrane Library as well as Iranian databases were checked up to January 2018 without language restriction. The quality of each involved study was done using the NOS questionnaire. A random-effects model analysis was done by RevMan 5.3 software applying the mean difference (MD) plus 95% confidence intervals (CIs). The CMA 2.0 software was applied to calculate the publication bias among the studies. Results: Out of 70 studies found in the databases, eight studies were involved and analyzed in the meta-analysis. The meta-analysis included 282 OLP patients and 221 healthy controls. The pooled MDs of serum levels of IgA, IgG, and IgM were -0.13 g/L [95%CI: -0.24, -0.02; P = 0.02], 1.01 g/L [95%CI: -0.91, 2.93; P = 0.30], and -0.06 g/L [95%CI: -0.25, 0.14; P = 0.56], respectively; whereas, the salivary IgA and IgG levels were 71.54 mg/L [95%CI: 12.01, 131.07; P = 0.02] and 0.59 mg/L [95%CI: -0.20, 1.38; P = 0.14], respectively. Conclusions: Considering the few studies performed on saliva, the results suggested that the salivary levels, especially IgA level had a higher diagnostic value than the serum levels. Therefore, the salivary immunoglobulins can play a significant function in the OLP pathogenesis.
CASE REPORT | doi:10.20944/preprints202006.0260.v1
Subject: Medicine & Pharmacology, Other Keywords: SARS-CoV-2; COVID-19; pulse therapy; corticosteroids; immunoglobulin
Online: 21 June 2020 (11:06:08 CEST)
Three patients with severe life-threatening COVID-19 who failed to achieve substantial improvement on tocilizumab, received pulse therapy with corticosteroids (methylprednisolone, 1000 mg/day IV for three consecutive days) and intravenous immunoglobulin (20 g/day IV). This was associated with a prompt resolution of respiratory failure, elimination of cytokine release syndrome, and reversal of pulmonary CT changes. The treatment was generally safe and well tolerated. There was no evidence of protracted persistence of the virus in the patients who received pulse therapy. Randomized controlled trials are necessary to specify the efficacy and safety of high-dose methylprednisolone and intravenous immunoglobulin in the treatment of severe life-threatening COVID-19 separately or in combination.
REVIEW | doi:10.20944/preprints201612.0132.v1
Subject: Medicine & Pharmacology, Allergology Keywords: wheat allergy; specific immunoglobulin E; children; gluten-related disorders
Online: 28 December 2016 (10:37:23 CET)
IgE-mediated wheat allergy is a gluten-related disorder. Wheat is one of the five most common food allergens in children. However, the natural history of IgE-mediated wheat allergy has seldom been described in the research literature. This study presents the current state of knowledge about the IgE-mediated wheat allergy in children.
ARTICLE | doi:10.20944/preprints201905.0103.v2
Subject: Life Sciences, Molecular Biology Keywords: L-arginine, embryonic development, intracytoplasmic vacuoles, immunoglobulin, heat shock proteins
Online: 10 May 2019 (14:03:49 CEST)
The objective of this study was to evaluate the effect of in ovo injection of L-arginine (L-Arg) into Ross broiler eggs at different embryonic developmental stages on their survival, hatchability, and body weight (BW). Additionally, we have analyzed the levels of serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT), protein expression of heat shock proteins (HSPs), also we have the determined micronuclei (MN) and nuclear abnormality (NA). Results showed that survival and hatching rates as well as body weight were increased on the 14th day incubation compared to 8th and 18th day incubation at lower concentration of L-Arg. Moreover, the levels of SGOT and SGPT were also significantly (P < 0.05) increased at 14th day incubation at the same concentration (100μg/μl/egg) of injection. In addition, IgM levels were increased on the 14th day incubation compared to other days. The protein expressions of HSP-47, HSP-60, and HSP-70 in the liver were significantly down-regulated whereas the expression of myogenin and MyoD were significantly up-regulated on the 14th day after incubation in treated with all different doses such as 100μg, 1000μg and 2500μg/μl/egg namely 3T1, 3T2 and 3T3 respectively. However, the treatment with low dose of L-Arg down-regulated expression levels of those proteins on the 14th day incubation. Histopathology of liver by hematoxylin and eosin (H&E) straining showed that the majority of liver damage, specifically intracytoplasmic vacuoles, were observed in 3T1, 3T2, and 3T3. The minimum dose of 100 μg/ml/egg on the 14th day of incubation significantly prevented intracytoplasmic vacuole damages. These results demonstrate that in ovo administration of L-Arg at (100μg/μl/egg) may be an effective method to increase chick BW, hatch rate, increasing muscle growth related proteins and promote the immune response through increasing IgM on the 14th day of incubation period.
Subject: Medicine & Pharmacology, Allergology Keywords: antibodies; COVID-19; glycans; immunoglobulin M; SARS-CoV-2; pneumonia; prediction; protection
Online: 24 April 2020 (10:25:27 CEST)
The natural history of COVID-19 caused by SARS-CoV-2 is extremely variable, ranging from asymptomatic infection, to pneumonia, and to complications eventually fatal. We propose here the first model, explaining how the outcome of first, crucial 10-15 days after infection, hangs on the balance between the cumulative dose of viral exposure and the efficacy of the local innate immune response (natural IgA and IgM antibodies, MBL). If SARS-CoV-2 runs the blockade of this innate immunity and spreads from the upper airways to the alveoli in the early phases of the infections, it can replicate with no local resistance, causing pneumonia and releasing high amounts of antigens. The delayed and strong adaptive immune response (high affinity IgM and IgG antibodies) that follows, causes severe inflammation and triggers mediator cascades (complement, coagulation, and cytokine storm) leading to complications often requiring intensive therapy and being, in some patients, fatal. Strenuous exercise and high flow air in the incubation days and early stages of COVID-19, facilitates direct penetration of the virus to the lower airways and the alveoli, without impacting on the airway’s mucosae covered by neutralizing antibodies. This allows the virus to bypass the efficient immune barrier of the upper airways mucosa in young and healthy athletes. In conclusion, whether the virus or the adaptative immune response reach the lungs first, is a crucial factor deciding the fate of the patient. This “quantitative and time-sequence dependent” model has several implications for prevention, diagnosis, and therapy of COVID-19.
REVIEW | doi:10.20944/preprints201611.0099.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: pneumonia; acute respiratory distress syndrome; pathogenesis; protein-homeostasis-system; corticosteroid; intravenous immunoglobulin
Online: 18 November 2016 (10:18:58 CET)
Acute respiratory distress syndrome (ARDS) is caused by infectious insults, such as pneumonia from various pathogens or related to other noninfectious events. Clinical and histopathologic characteristics are similar across severely affected patients, suggesting that a common mode of immune reaction may be involved in the immunopathogenesis of ARDS. There may be etiologic substances that have an affinity for respiratory cells and induce lung cell injury in cases of ARDS. These substances originate not only from pathogens, but also from injured host cells. At the molecular level, these substances have various sizes and biochemical characteristics, classifying them as protein substances and non-protein substances. Immune cells and immune proteins may recognize and act on these substances, including pathogenic proteins and peptides, depending upon the size and biochemical properties of the substances (this theory is known as the protein-homeostasis-system hypothesis). The severity or chronicity of ARDS depends on the amount of etiologic substances with corresponding immune reactions, the duration of the appearance of specific immune cells, or the repertoire of specific immune cells that control the substances. Therefore, treatment with early systemic immune modulators (corticosteroids and/or intravenous immunoglobulin) as soon as possible may reduce aberrant immune responses in the potential stage of ARDS.
ARTICLE | doi:10.20944/preprints202008.0408.v1
Subject: Life Sciences, Virology Keywords: covid-19 antibody; coronavirus; immunoglobulin; police officer; quality of life; SARS-CoV-2
Online: 19 August 2020 (09:55:16 CEST)
The coronavirus of severe acute respiratory syndrome 2 (SARS-CoV-2), known as COVID-19, has spread rapidly around the world, leading to social detachment and the home office replacing face-to-face work. The performance of police officers faces limitations to the new requirements, while recognizing the need to ensure health and quality of life. Thus, the present study aimed to verify the panorama of the spread of COVID-19 among federal police officers by analyzing the presence of symptoms, individual protection measures (IPM), suspect screening measures (SSM) and examination for total antibodies (IgA, IgG and IgM). For this, data were collected through a questionnaire customized for this situation, blood for serological testing and measurements of clinical data from 56 federal police officers in the municipality of Marília (São Paulo, Brazil). There was no positive result in the Anti-SARS-CoV-2 serological test in any sample participant. The mean value of the Body Mass Index (27.2 ± 5.4 kg / m2) suggests overweight and obesity, in addition to the presence of hypertension in 16.1%, diabetes in 3.6%, asthma in 3.6 % and obesity by 25%, which represents an important risk of complications for COVID-19. The use of a mask is the most frequent IPM (96.4%) and most of the sample has used a cloth or home mask (90.9%). However, 47.3% have not performed the correct cleaning of the masks and 5.5% have not taken any care with mask hygiene. It can be concluded that care in relation to the professional activities of federal police to date has prevented the spread of SARS-CoV-2 and that they must be maintained or increased because risk factors, which involve quality of life and worsening of the contamination condition, were detected in the participants.
ARTICLE | doi:10.20944/preprints202011.0685.v1
Subject: Biology, Anatomy & Morphology Keywords: teleost fish; Notothenioidei; genome modifications; IgT; exonic remnant; immunoglobulin domain; Antarctic marine environment; molecular evolution
Online: 27 November 2020 (11:31:09 CET)
Cryonotothenioidea is the main group of fishes that thrive in the extremely cold Antarctic environment, thanks to the acquisition of peculiar morphological, physiological and molecular adaptations. We have previously disclosed that IgM, the main immunoglobulin isotype in teleosts, display typical cold-adapted features. Recently, we have analyzed the gene encoding the heavy chain constant region (CH) of the IgT isotype from the Antarctic teleost Trematomus bernacchii (family Nototheniidae), characterized by the near-complete deletion of the CH2 domain. Here, we aimed to track the loss of the CH2 domain along notothenioid phylogeny and to identify its ancestral origins. To this end, we obtained the IgT gene sequences from several species belonging to the Antarctic families Nototheniidae, Bathydraconidae and Artedidraconidae. All species display a CH2 remnant of variable size, encoded by a short Cτ2 exon, which retains functional splicing sites and therefore is included in the mature transcript. We also considered representative species from the three non-Antarctic families: Eleginopsioidea (Eleginops maclovinus), Pseudaphritioidea (Pseudaphritis urvillii) and Bovichtidae (Bovichtus diacanthus and Cottoperca gobio). Even though only E. maclovinus, the sister taxa of Cryonotothenioidea, shared the partial loss of Cτ2, the other non-Antarctic notothenioid species displayed early molecular signatures of this event. These results shed light on the evolutionary path that underlies the origins of this remarkable gene structural modification.
REVIEW | doi:10.20944/preprints201909.0144.v1
Subject: Life Sciences, Immunology Keywords: immunoglobulin; IVIG; LcrV; PcrV; translocation; type III secretory toxin; type III secretion system; V-antigen
Online: 14 September 2019 (19:18:28 CEST)
The mechanisms underlying the effects of γ-globulin therapy for bacterial infections are thought to involve bacterial cell lysis via complement activation, phagocytosis via bacterial opsonization, toxin neutralization, and antibody-dependent cell-mediated cytotoxicity. Nevertheless, recent advances in the study of pathogenicity in gram-negative bacteria have raised the possibility of an association between γ-globulin and bacterial toxin secretion. Over time, new toxin secretion systems like the type III secretion system have been discovered in many pathogenic gram-negative bacteria. With this system, the bacterial toxins are directly injected into the cytoplasm of the target cell through a special secretory apparatus without any exposure to the extracellular environment and, therefore, with no opportunity for antibodies to neutralize the toxin. However, because antibodies against the V-antigen, which is located on the needle-shaped tip of the bacterial secretion apparatus, can inhibit toxin translocation, this raises the hope that the toxin might be susceptible to antibody targeting. Because multi-drug resistant bacteria are now prevalent, inhibiting this secretion mechanism is attractive as an alternative or adjunctive therapy against lethal bacterial infections. Thus, it would not be unreasonable to define the blocking effect of anti-V-antigen antibodies as the fifth mechanism for immunoglobulin action against bacterial infections.
REVIEW | doi:10.20944/preprints202107.0271.v1
Subject: Life Sciences, Biochemistry Keywords: bovine colostrum; bacterium; pathogens; probiotic bacteria; cost-effective processing; heat treatment; pasteurization; contamination control; immunoglobulin; enzyme
Online: 12 July 2021 (17:46:44 CEST)
The purpose of bovine colostrum, being the milk secreted by a cow after giving birth, is to transfer passive immunity to the calf. The calves have an insufficient immune system as they lack immunoglobulins (Igs). Subsequently, the supply of good quality bovine colostrum is obligatory. The quality of colostrum is classified by low bacterial counts and adequate Ig concentrations. Bacterial contamination can contain a variety of human pathogens or high counts of spoilage bacteria, which becomes more challenging with emerging use of bovine colostrum as food and food supplements. There is also a growing risk for the spread of zoonotic diseases originating from bovines. For this reason, processing based on heat treatment or other feasible techniques are required. This review provides an overview of literature on the microbial quality of bovine colostrum and processing methods to improve its microbial quality and keep its nutritional values as food. The highlights of this review are: high quality colostrum is a valuable raw material in food products and supplements, the microbial safety of bovine colostrum is increased using appropriate processing, suitable effective heat-treatment, which does not destroy the high nutrition value of colostrum, the heat treatment processes are cost-effective compared to other methods, and heat treatment can be performed in both small- and large-scale production
REVIEW | doi:10.20944/preprints202001.0203.v1
Subject: Life Sciences, Immunology Keywords: immunoglobulin (Ig); nonsense-mediated mRNA decay (NMD); nonsense-associated altered splicing (NAS); B lymphocytes; plasma cells
Online: 18 January 2020 (10:21:18 CET)
The presence of premature termination codons (PTCs) in transcripts is dangerous for the cell as they encode potentially deleterious truncated proteins that can act with dominant-negative or gain-of-function effects. To avoid synthesis of these shortened polypeptides, several RNA surveillance systems can be activated to decrease the level of PTC-containing mRNAs. Nonsense-mediated mRNA decay (NMD) ensures an accelerated degradation of mRNAs harboring PTCs by using several key NMD factors such as up-frameshift (UPF) proteins. Another pathway called nonsense-associated altered splicing (NAS) upregulates transcripts that have skipped disturbing PTCs by alternative splicing. Therefore, these RNA quality control processes eliminate abnormal PTC-containing mRNAs from the cells by using positive and negative responses. In this review, we will describe the general mechanisms of NMD and NAS and their respective involvement in the decay of aberrant immunoglobulin and TCR transcripts in lymphoid cells.
ARTICLE | doi:10.20944/preprints202205.0277.v1
Subject: Life Sciences, Genetics Keywords: immunoglobulin A nephropathy; expression quantitative trait loci; summary data-based Mendelian randomization; genome-wide association study; functional mapping
Online: 20 May 2022 (12:13:06 CEST)
Background: Immunoglobulin A nephropathy (IgAN) is a complex autoimmune disease, and the exact pathogenesis remains to be elucidated. Methods: We conducted summary data-based Mendelian randomization (SMR) analysis and performed functional mapping and annotation using FUMA to explore genetic loci that are po-tentially involved in the pathogenies of IgAN. Both analyses used summarized data of a recent genome-wide association study (GWAS) on IgANs, which included 477,784 Europeans (15,587 cases and 462,197 controls) and 175,359 East Asians (71 cases and 175,288 controls). We performed separate SMR analysis using CAGE and GTEx eQTL data. Results: Using the CAGE eQTL data, our SMR analysis identified 32 probes tagging 25 unique genes that were pleiotropically/potentially causally associated with IgAN, with the top three probes being ILMN_2150787 (tagging HLA-C, PSMR=2.10×10-18), ILMN_1682717 (tagging IER3, PSMR=1.07×10-16) and ILMN_1661439 (tagging FLOT1, PSMR=1.16×10-14). Using GTEx eQTL data, our SMR analysis identified 24 probes tagging 24 unique genes, with the top three probes being ENSG00000271581.1 (tagging XXbac-BPG248L24.12, PSMR=1.44×10-10), ENSG00000186470.9 (tagging BTN3A2, PSMR=2.28×10-10), and ENSG00000224389.4 (tagging C4B, PSMR=1.23×10-9). FUMA analysis identified 3 independent, significant and lead SNPs, 2 genomic risk loci and 39 genes. Conclusion: We identified many genetic variants/loci that are potentially involved in the patho-genesis of IgAN.
ARTICLE | doi:10.20944/preprints202208.0324.v1
Subject: Life Sciences, Immunology Keywords: T cytotoxic cells; Leukocyte-associated Immunoglobulin-like Receptor-1; LAIR-1; Hepatitis C virus genotype 4; HCV G4; hepatocellular carcinoma; cirrhosis; immune inhibitory checkpoints; inflammation; prognosis; insulin resistance
Online: 17 August 2022 (11:38:10 CEST)
Background and Aim. Since virus-related hepatocellular carcinoma (HCC) pathogenesis involves liver inflammation, therefore, post-hepatitis C virus (HCV) infection would be a cause for liver cirrhosis that would progress to HCC. Cytotoxic T cells (Tc) are known to be involved in post-HCV complications and HCC pathogenesis. The inhibitory checkpoint Leukocyte-Associated Immunoglobulin-like Receptor-1 (LAIR-1) is expressed on Tc. Therefore, we aimed to determine whether the Tc expression level of LAIR-1 is associated with HCC progression post-HCV and moreover, to evaluate LAIR-1 expression as a non-invasive biomarker for HCC progression in the context of liver cirrhosis post-HCV genotype 4 (G4) in Egyptian patients’ peripheral venous blood liquid biopsy. We studied LAIR-1 expression on Tc related to the progression of liver cirrhosis in a case-controlled study enrolled 64 patients with post-HCV G4-HCC and 37 patients with post-HCV G4-liver cirrhosis. Methods: LAIR-1 expression was analyzed by flow cytometry. Results: LAIR-1 expression on Tc and the percentage of Tc positive for LAIR-1 (LAIR-1+Tc %) were significantly higher in the post-HCV G4-HCC group compared to the post-HCV G4-liver cirrhosis
REVIEW | doi:10.20944/preprints202105.0183.v1
Subject: Life Sciences, Biochemistry Keywords: Intravenous Immunoglobulin (IVIg); Human Leukocyte Antigen-I (HLA-1); Polyreactive mAbs; Monospecific mAbs; Shared epitopes; Immunosuppression; T-cells; B-memory cells; T-regulatory Cells; Blastogenesis, proliferation, Antibody production
Online: 10 May 2021 (12:30:03 CEST)
HLA class-I (HLA-I) polyreactive monoclonal antibodies (mAbs) reacting to all HLA-I alleles were developed by immunizing HLA-E monomeric heavy chain (HC) (Open Conformers, OCs). Two of the mAbs (TFL-006 and TFL-007) bound to the HC’s coated on a solid matrix. The binding was inhibited by a peptide 117AYDGKDY123, present in all alleles of the six HLA-I isoforms but masked by 2-microglobulin -m) in intact HLA-I trimers (Closed Conformers, CCs). Identical HLA-I polyreactivity is observed in IVIg administered to lower anti-HLA antibodies (Abs) in HLA-sensitized patients, but the mechanism is unknown. We hypothesized that the mAbs that mimic IVIg HLA-I polyreactivity might mimic the immunomodulatory functions of IVIg. We tested the relative binding affinity of the mAbs and IVIg for both OCs- and CCs and compared their effects on (a) the phytohemagglutinin (PHA)-activation T-cells, (b) the production of anti-HLA-II antibody (Ab) by B-memory cells, and anti-HLA-I Ab by immortalized B-cells, and (c) the upregulation of CD4+, CD25+, and Fox P3+ T-regs. The mAbs bound only to OCs, whereas IVIg is bound to both CCs and OCs. The mAbs suppressed blastogenesis and proliferation of PHA-activated T-cells, anti-HLA Ab production by B-cells and expanded the T-regs, better than IVIg. We conclude that a humanized version of the TFL-mAbs could be an ideal therapeutic IVIg-mimetic.
REVIEW | doi:10.20944/preprints202005.0244.v1
Subject: Biology, Anatomy & Morphology Keywords: COVID-19; SARS-CoV-2; antigen; monovalent; oligovalent; protein; kilodalton (kDa); Th1 response; Th2 response; B cell activation; B cell receptor (BCR); macrophage; dendritic cell; apoptosis; subcapsular sinus; immunoglobulin; interleukin; cytokine; Cytokine Storm Syndrome (CSS); allergen; immune paralysis; vaccine; polymer
Online: 14 May 2020 (15:19:53 CEST)
COVID-19 sepsis immune response remains unclear. Here we propose a new perspective in host response against pathogenic proteins that may lead to a vaccine design by polymerization of antigens of <70 kDa. In COVID-19, initial Th1 response kills infected cells releasing viral proteins. SARS-CoV-2 viral structural proteins are Spike (140 kDa), Nucleocapsid (50 kDa), Membrane (25 kDa) and Envelope (10 kDa). B cell receptor cannot capture antigens >70 kDa. The Spike protein (140 kDa) cannot be captured by B cells and triggers inflammatory Th1 response via the macrophages. Only proteins with a size <70 kDa can activate B cell receptor and trigger Th2 adaptative humoral response. Moreover, M-25 kDa and E-12 kDa glycoproteins can activate IgM-BCR like oligovalent or monovalent antigens. The sustained infected cells lysis overfeeds high levels of viral proteins <70 kDa, increases B cells activation and, in the shift from Th1 to Th2 immune response, triggers the cytokine storm. The continuous BCR activation increases IL-10 releasing and may lead to immune paralysis.