Immune Failure Research Articles

Efficacy of JAK1/2 inhibition in murine immune bone marrow failure

AbstractImmune aplastic anemia (AA) is a severe blood disease characterized by T-lymphocyte− mediated stem cell destruction. Hematopoietic stem cell transplantation and immunosuppression are effective, but they entail costs and risks, and are not always successful. The Janus kinase (JAK) 1/2 inhibitor ruxolitinib (RUX) suppresses cytotoxic T-cell activation and inhibits cytokine production in models of graft-versus-host disease. We tested RUX in murine immune AA for potential therapeutic benefit. After infusion of lymph node (LN) cells mismatched at the major histocompatibility complex [C67BL/6 (B6)⇒CByB6F1], RUX, administered as a food additive (Rux-chow), attenuated bone marrow hypoplasia, ameliorated peripheral blood pancytopenia, preserved hematopoietic progenitors, and prevented mortality, when used either prophylactically or therapeutically. RUX suppressed the infiltration, proliferation, and activation of effector T cells in the bone marrow and mitigated Fas-mediated apoptotic destruction of target hematopoietic cells. Similar effects were obtained when Rux-chow was fed to C.B10 mice in a minor histocompatibility antigen mismatched (B6⇒C.B10) AA model. RUX only modestly suppressed lymphoid and erythroid hematopoiesis in normal and irradiated CByB6F1 mice. Our data support clinical trials of JAK/STAT inhibitors in human AA and other immune bone marrow failure syndromes.

Immune dysregulation and RNA N6-methyladenosine modification in sepsis.

Sepsis is defined as life-threatening organ dysfunction caused by the host immune dysregulation to infection. It is a highly heterogeneous syndrome with complex pathophysiological mechanisms. The host immune response to sepsis can be divided into hyper-inflammatory and immune-suppressive phases which could exist simultaneously. In the initial stage, systemic immune response is activated after exposure to pathogens. Both innate and adaptive immune cells undergo epigenomic, transcriptomic, and functional reprogramming, resulting in systemic and persistent inflammatory responses. Following the hyper-inflammatory phase, the body is in a state of continuous immunosuppression, which is related to immune cell apoptosis, metabolic failure, and epigenetic reprogramming. Immunosuppression leads to increased susceptibility to secondary infections in patients with sepsis. RNA N6-Methyladenosine (m6A) has been recognized as an indispensable epitranscriptomic modification involved in both physiological and pathological processes. Recent studies suggest that m6A could reprogram both innate and adaptive immune cells through posttranscriptional regulation of RNA metabolism. Dysregulated m6A modifications contribute to the pathogenesis of immune-related diseases. In this review, we summarize immune cell changes and the potential role of m6A modification in sepsis. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Processing > RNA Editing and Modification.

PSX-B-9 A Nanotechnology Base Immunity Measurement (D2Dx) Compared with Total Serum Protein Concentration Using Neonatal Holstein Bull Calves

Abstract The D2Dx immunity test (Nano Discovery Inc.) is a nanotechnology-based assay for quantifying the immune responses to foreign pathogens. In contrast, the measurement of total serum protein (TSP) concentration is used to determine the passive immunity status of neonatal calves. Inadequate colostrum feeding increases the risk of calves having increase disease challenges thereby reducing growth performance and possibly death. Our operation routinely sources 2- to 5-day old Holstein bull calves from numerous Wisconsin sale barns for evaluating nutritional programs and feed additives. The study objective was to compare the D2Dx immunity test with TSP concentration for evaluating the immunity and status of passive immunity of calves. Two 2021 calf studies conducted during summer and fall consisting of 160 total calves (80 calves per study) had 8-10 mL blood samples collected via jugular puncture within 1 day of arrival. Blood serum was immediately analyzed for TSP concentrations using a digital refractometer. Samples were then frozen and later thawed to room temperature for collecting D2Dx measurements. Pearson correlation coefficients were calculated using SAS version 9.4. The D2Dx test was highly correlated with TSP concentrations (r = 0.61, P < 0.01) across both studies indicating the D2Dx test can be used to assess status of passive immunity. The correlation coefficient did vary by study ranging from r = 0.54 (P < 0.01) for summer sourced calves to r = 0.65 (P < 0.01) for fall sourced calves. Average daily gains (ADG) were less (P < 0.01) for summer compared with fall sourced calves (0.692 and 0.853 kg/d for summer and fall, respectively). There was little correlation between passive immunity measurements (D2Dx and TSP) with ADG (r = < -0.04, P > 0.10). The D2Dx test can be used to assess transfer success or failure of passive immunity in neonatal Holstein bull calves.

Molecular Characterization and Phylogenetic Analysis of Marek's Disease Virus in Iran.

Marek's disease (MD) is a highly contagious, lymphoproliferative poultry disease caused by the oncogenic herpesvirus, serotype 1 Marek's disease virus (MDV-1), or Gallid herpesvirus 2 (GaHV-2). MDV strains have shown a continued evolution of virulence leading to immune failure, and MD cases continue to occur or surge. Meq, the major MDV-1 oncoprotein, induces T-cell neoplastic transformation through several mechanisms including inhibition of apoptosis, cell cycle regulation, and serum-anchorage independent growth. There is no current information on the MDV serotypes and pathotypes circulating in vaccinated commercial farms in Iran, where the birds are vaccinated at the hatchery with GaHV-2 and Meleagrid herpesvirus 1 (MeHV-1) vaccines. This study reports the molecular characterization of a GaHV-2 strain detected in 19 flocks of Iranian layer farms exhibiting MDV-1-like clinical signs and visceral lymphomas. Based on sequencing and phylogenetic analysis of the Meq gene, the Iranian GaHV-2 isolates could be divided into two separate clades regarding molecular features. The clade containing strains was closely related to Italian, Indian, and Hungarian virulent isolates, and the clade was related to American very virulent plus (vv+) isolates. For the first time, the MDV-1 virus was characterized by an outbreak in poultry flocks in Iran. Although MDV-1 strains obtained in Iran's present outbreak are presumably related to virulent (v) and vv+ pathotypes based on nucleotide, amino acid, and phylogenetic analysis of the viruses, they are not confirmed so far. Thus, it is highly recommended to perform further analyses to demonstrate the pathotype characteristics in vivo.

Biomarkers approach in the diagnosis and prognosis of sepsis: A review

Introduction Sepsis is a systematic host response to infection accompanied by suppression of immune system and organ failure. Rapid diagnosis of sepsis has prompted researchers to use circulating biomarkers for diagnosis sepsis. Method The PubMed, and Google Scholar databases were searched from 2010 until 2020 using the keyorganis “sepsis”, “biomarker”, “pathophysiology”, “pathogenesis”, and “diagnose” with restriction by language to English. For each individual biomarker the databases were searched again by the biomarker name. Results Although CRP and Procalcitonin are the most common biomarkers in the diagnosis of sepsis, other biomarkers such as pro-inflammatory and anti-inflammatory cytokines and chemokines, monocyte and lymphocyte biomarkers, antibody and nucleic acid biomarkers may help in diagnosis of sepsis. Conclusion The biomarkers verified capability in disease progress, prognosis of disorder, risk stratification, and treatment effect rather than diagnosis at early stage of sepsis. Defining molecular properties in septic patients opens up new means to diagnose and manage sepsis in a shorter time compared to conventional methods currently used at hospitals however further clinical evaluation of biomarkers should be performed. Keywords. Sepsis. Biomarkers. Prognosis. Diagnosis

Information Security Decisions with Consideration of Hacker Intrusion Propagation

The spread of network attacks is extremely harmful, which poses a great threat to the assets and reputation of firms. Therefore, making a scientific information security strategy is an important task for the continued and stable development of the firms. This paper develops the SIR model of hacker intrusion propagation and then analyzes the evolution trend of hacker intrusion propagation and the conditions of strategy transfer. The research shows that when immune failure and strategy transfer are not considered, the threshold of hacker intrusion propagation is negatively correlated with the probability of invasion, whereas it is positively correlated with the probability of defense success and the externality during outsourcing. In the case of immune failure, there will always be infected firms in the network, where the threshold of hacker intrusion propagation is affected by the proportion of the infected state and the probability of immune failure. When immune failure and strategy transfer occur simultaneously if the externality is positive and high, information security outsourcing can improve firms’ security benefits; if the externality is negative, the firms should stop cooperating with the managed security service provider (MSSP).

Molecular Characteristics of Hepatitis B Virus among Children Vaccinated with HBsAg Positive in Huzhou, China.

Objective: The HBV genotypes and surface gene mutation among children born after universal HBV vaccination program were not been clearly investigated in Huzhou, China. Thus, the present study was to investigate HBV genotypes and surface gene mutation in vaccinated children in this area.
 Methods: Serum samples were collected from 58 children who were chronic HBV infected in Huzhou. The surface gene of HBV were amplified and direct sequencing. Then, the mutations were analyzed.
 Results: Fifty-six sample were sequenced successfully. The genotype of HBV was genotype B in 45 children and genotype C in 11 children, respectively. Major serotype was adw (42), followed by adr (11) and ayw (3). Sequence analysis showed that 18 amino acid (AA) substitutions sites in major hydrophilic region (MHR) were identified in children (37.5%, 21/56). Most of the substitutions were associated with vaccine immune escape. The genotypes B had a high mutations frequency in the second loop than genotype C. Of note, eight children with low level anti-HBs were still infected with HBV.
 Conclusion: The predominant genotype and serotype were B and adw among children in Huzhou. Genotype B, MHR mutations, and low anti-HBs levels might be related to immunization failure, although the large-scare vaccination program remarkably decreased the infection of HBV in children, strengthen immunization is recommend in children with low level anti-HBs.

High Expression of the Costimulatory Checkpoint Factor DNAM-1 by CD4+ T-Cells from Multiple Myeloma Patients Refractory to Daratumumab-Containing Regimens

Multiple myeloma is an incurable disease characterized by unregulated growth of malignant plasma cells in the bone marrow (BM). Tumor-induced dysfunction of T-cells may be responsible for immune evasion and failure of immunotherapy. Therefore, a better understanding of the phenotype of T-cells at the tumor site is needed. We assessed the expression of immune regulatory receptors on T-cell subsets from peripheral blood (PB) and BM using multicolor flow cytometry. Paired PB and BM samples were collected from newly diagnosed, treatment-naïve myeloma patients (n = 19) and patients progressing during treatment with the CD38 monoclonal antibody daratumumab alone or in combination with other anti-myeloma drugs (n = 39). We observed that CD4+ T-cells from both PB and BM of patients relapsing on daratumumab have a higher expression of the costimulatory checkpoint receptor DNAM-1. The potential role of DNAM-1+CD4+ T-cells in the development of resistance to daratumumab needs further exploration. We also observed that the inhibitory checkpoint receptor TIGIT is more frequently expressed by BM CD8+ T-cells from myeloma patients than PD-1 and CTLA-4, which supports the hypothesis that TIGIT may play a central role in the immune escape of the malignant plasma cells.

Vascular Proteome Responses Precede Organ Dysfunction in a Murine Model of Staphylococcus aureus Bacteremia.

ABSTRACTVascular dysfunction and organ failure are two distinct, albeit highly interconnected, clinical outcomes linked to morbidity and mortality in human sepsis. The mechanisms driving vascular and parenchymal damage are dynamic and display significant molecular cross talk between organs and tissues. Therefore, assessing their individual contribution to disease progression is technically challenging. Here, we hypothesize that dysregulated vascular responses predispose the organism to organ failure. To address this hypothesis, we have evaluated four major organs in a murine model of Staphylococcus aureus sepsis by combining in vivo labeling of the endothelial cell surface proteome, data-independent acquisition (DIA) mass spectrometry, and an integrative computational pipeline. The data reveal, with unprecedented depth and throughput, that a septic insult evokes organ-specific proteome responses that are highly compartmentalized, synchronously coordinated, and significantly correlated with the progression of the disease. These responses include abundant vascular shedding, dysregulation of the intrinsic pathway of coagulation, compartmentalization of the acute phase response, and abundant upregulation of glycocalyx components. Vascular cell surface proteome changes were also found to precede bacterial invasion and leukocyte infiltration into the organs, as well as to precede changes in various well-established cellular and biochemical correlates of systemic coagulopathy and tissue dysfunction. Importantly, our data suggest a potential role for the vascular proteome as a determinant of the susceptibility of the organs to undergo failure during sepsis.IMPORTANCE Sepsis is a life-threatening response to infection that results in immune dysregulation, vascular dysfunction, and organ failure. New methods are needed for the identification of diagnostic and therapeutic targets. Here, we took a systems-wide approach using data-independent acquisition (DIA) mass spectrometry to track the progression of bacterial sepsis in the vasculature leading to organ failure. Using a murine model of S. aureus sepsis, we were able to quantify thousands of proteins across the plasma and parenchymal and vascular compartments of multiple organs in a time-resolved fashion. We showcase the profound proteome remodeling triggered by sepsis over time and across these compartments. Importantly, many vascular proteome alterations precede changes in traditional correlates of organ dysfunction, opening a molecular window for the discovery of early markers of sepsis progression.

Systematic lupus erythematous patients following COVID-19 vaccination: Its flares up and precautions

Systemic lupus erythematosus (SLE) is an autoimmune disease that can cause both direct and indirect inflammatory damage to multiple organs. Clinical symptoms in the skin, joints, kidneys, and central nervous system, as well as serological indicators such as antinuclear antibodies (ANA), notable antibodies to dsDNA, are used to diagnose SLE. mRNA SARS-CoV-2 vaccines have been shown to trigger SLE flares and the development of new rheumatic diseases. SARS-CoV-2 mRNA vaccinations increase type I interferon (INF), which is not only known to have a role in the antiviral response but is also a crucial cytokine in the pathophysiology of SLE. Furthermore, both the mRNA and adenovirus vaccines boost the production of type 1 interferons, which are required for the spread of SARS-CoV-2. The danger of not administering the COVID-19 vaccination to SLE patients is significantly larger than the likelihood of its adverse effects, which are most likely caused by intrinsic immune failure, demographic disease activity, medications, linked organ damage, and comorbidities. The adverse effects of COVID-19 vaccination in SLE patients are common (about 50%), although they do not interfere with daily functioning in the majority of cases. Several precautions can be taken to avoid the complications associated with COVID-19 vaccinations.

Metabolic reprogramming consequences of sepsis: adaptations and contradictions

During sepsis, the importance of alterations in cell metabolism is underappreciated. The cellular metabolism, which has a variable metabolic profile in different cells and disease stages, is largely responsible for the immune imbalance and organ failure associated with sepsis. Metabolic reprogramming, in which glycolysis replaces OXPHOS as the main energy-producing pathway, is both a requirement for immune cell activation and a cause of immunosuppression. Meanwhile, the metabolites produced by OXPHOS and glycolysis can act as signaling molecules to control the immune response during sepsis. Sepsis-induced "energy shortage" leads to stagnated cell function and even organ dysfunction. Metabolic reprogramming can alleviate the energy crisis to some extent, enhance host tolerance to maintain cell survival functions, and ultimately increase the adaptation of cells during sepsis. However, a switch from glycolysis to OXPHOS is essential for restoring cell function. This review summarized the crosstalk between metabolic reprogramming and immune cell activity as well as organ function during sepsis, discussed the benefits and drawbacks of metabolic reprogramming to show the contradictions of metabolic reprogramming during sepsis, and assessed the feasibility of treating sepsis through targeted metabolism. Using metabolic reprogramming to achieve metabolic homeostasis could be a viable therapy option for sepsis.

Role of vector in transmission of viral hemorrhagic fever

Viral hemorrhagic fever is considered from zoonotic diseases which infect both human and animal, it is transmitted via vector (mosquito, tick) according to type of viral hemorrhagic fever, such as dengue fever and yellow fever are transmitted by bite of mosquito, but CCHF is transmitted by bite of tick, the viruses belong to four families include Arenaviridae, Bunyaviridae, Flaviviridae, and Filoviridae, can also be transmitted from human to human by direct contact with blood and body fluids. In severe cases of disease may be lead to threatening human life due to malfunction in immune system and failure in kidney and other organs. While in animal that cause in economic losses. To reduce severity of disease by control of vector and should be use vaccine to prevent disease.

IL-1β induced by PRRSV co-infection inhibited CSFV C-strain proliferation via the TLR4/NF-κB/MAPK pathways and the NLRP3 inflammasome

PRRSV and CSFV are both the main pathogens of pigs and pose great threats to the pig industry. Previous studies have shown that PRRSV infection or attenuated virus vaccination can reduce the antibody level of attenuated CSFV vaccine and even cause immune failure. The higher pro-inflammatory cytokines induced by PRRSV might play a significant role in inhibiting the proliferation of CSFV-C. However, the molecular mechanism has not been elucidated yet. Here, the effect of IL-1β, a central mediator of immune-regulating inflammatory responses, on CSFV-C proliferation was investigated, as well as the mechanisms responsible for the production of IL-1β in the PRRSV and CSFV-C co-infection systems. The results showed that co-infection could significantly increase IL-1β production both at mRNA and protein levels with the infection progressing, and the IL-1β upregulation was mainly triggered by PRRSV infection. Additional experiments indicated that IL-1β inhibited the proliferation of CSFV-C in a cell-type independent manner at the replication and release stages. Furthermore, the IL-1β production induced via the TLR4/MyD88 pathway and the downstream signaling pathways NF-κB, ERK1/2, P38, and JNK were involved by treatment with specific inhibitors or siRNA knockdown assays. Finally, we clarified that the NLRP3 inflammasome played a meaningful role in the maturation and release of IL-1β. Together, the accumulated results provided a deeper understanding of the vaccination failure of CSFV caused by PRRSV co-infection as well as targets for the development of novel approaches for the vaccination and control of CSF.

Astragalus polysaccharide alleviated the inhibition of CSFV C-strain replication caused by PRRSV via the TLRs/NF‑κB/TNF-α pathways

It is a common phenomenon that PRRSV infection can interfere with the protective efficacy of the CSFV vaccine in clinical settings, and no effective treatment is available. In our previous study, we found that PRRSV infection could inhibit the replication of CSFV-C by promoting the high expression of inflammatory cytokines. In order to further investigate whether Chinese medicine could alleviate the inhibition effect, the PAM39 cells model, which was co-infected with PRRSV and CSFV-C, was established. The effects of Chinese medicine on this co-infection model, as well as the effect of astragalus polysaccharide on the TLRs/NF-κB/TNF-α pathways, were investigated. Our results demonstrated that PAM39 cells inoculated with different pathogenic PRRSV significantly inhibited the replication of CSFV-C and up-regulated the major inflammatory mediators, including TNF-α. For the following studies, 50 µM of astragalus polysaccharide was selected from six kinds of representative Chinese medicine based on their cytotoxicity, viral titers, and inflammatory mediators. Further experiments indicated that astragalus polysaccharide could alleviate the inhibition of CSFV-C replication in the co-infection group with no influence on cell viability. In addition, astragalus polysaccharide treatment clearly reduced P65 phosphorylation and down-regulated the expression of TLR7, TLR9, and TNF-α in co-infection group, implying that the TLRs/NF-κB/TNF-α pathways may play an important role in astragalus polysaccharide's anti-inflammatory response. In conclusion, astragalus polysaccharide treatment alleviated PRRSV-mediated inhibition of CSFV-C replication via the TLRs/NF-κB/TNF-α pathways, and the molecular mechanism of PRRSV co-infection leading to the failure of CSFV vaccine immunization was partially elucidated, providing a scientific basis for effective CSF prevention and control in pig farms.

Exosomal miRNA-146a is downregulated in clear cell renal cell carcinoma patients with severe immune-related adverse events.

Here we report the results of the pilot project of exosomal miRNA expression levels in clear cell renal cell carcinoma (ccRCC) patients with different clinical response to ICIs (nivolumab) and treatment related toxicity. Immune-related adverse events (irAEs) are a major cause of immune checkpoint inhibitors cancellation and therapy failure. Modern studies demonstrate evidence that exosomes are of great importance in the formation of tumor resistance to ICIs drugs and therapy. We performed exosomal miRNA-146a expression analysis using qPCR on 86 ccRCC patients and revealed a statistically significant (p = 0.01) decreased expression level in ccRCC patients with CTCAE grade 3–4 (M±SEM 1.71 ± 0.13) compared to CTCAE grade 0–2 group (M±SEM 2.30 ± 0.24). The expression levels of miRNA-126, miRNA-218 and miRNA-410 did not show statistically significant differences in the comparison groups (p > 0.05). Association analysis of rs2910164 in the miRNA-146a gene demonstrated that CC genotype and C allele carriers had higher risk of developing severe irAEs (p = 0.03, OR = 6.12; p = 0.01, OR = 2.42, respectively) compare with GG and GC carriers. That is the first attempt to identify biomarkers of ICIs treatment efficacy for ccRCC in the Volga-Ural region based on exosomal miRNAs analysis.

Characteristics and Genomic Diversity of Measles Virus From Measles Cases With Known Vaccination Status in Shanghai, China.

Although the highly effective measles vaccine has dramatically reduced the incidence of measles, measles, and outbreaks continue to occur in individuals who received the measles vaccine because of immunization failure. In this study, patients who have definite records of immunization were enrolled based on measles surveillance in Shanghai, China, from 2009 to 2017, and genomic characteristics regarding viruses retrieved from these cases provided insights into immunization failure. A total of 147 complete genomes of measles virus (MV) were obtained from the laboratory-confirmed cases through Illumina MiSeq. Epidemiological, and genetic characteristics of the MV were focused on information about age, gender, immunization record, variation, and evolution of the whole genome. Furthermore, systematic genomics using phylogeny and selection pressure approaches were analyzed. Our analysis based on the whole genome of 147 isolates revealed 4 clusters: 2 for the genotype H1 (clusters named H1-A, including 73 isolates; H1-B, including 72 isolates) and the other 2 for D8 and B3, respectively. Estimated nucleotide substitution rates of genotype H1 MV derived using genome and individual genes are lower than other genotypes. Our study contributes to global measles epidemiology and proves that whole-genome sequencing was a useful tool for more refined genomic characterization. The conclusion indicates that vaccination may have an effect on virus evolution. However, no major impact was found on the antigenicity in Shanghai isolates.

Adverse Childhood Events, Post-Traumatic Stress Disorder, Infectious Encephalopathies and Immune-Mediated Disease.

Adverse Childhood Events (ACE), Post-Traumatic Stress Disorder (PTSD), and infectious encephalopathies are associated with immune-mediated diseases. Data supporting this are reviewed, and an integrated hypothesis is provided. All three can be associated with intrusive symptoms and temporal lobe pathology. ACE and PTSD are accompanied by an impaired mental capacity to differentiate external danger vs. safety. Infectious encephalopathies are accompanied by a failure of adaptive immunity and an impaired immune capacity to differentiate internal danger vs. safety. All three conditions are associated with impairments to differentiate danger vs. safety and adapt effectively. There are reciprocal interactions between ACE, PTSD, and infectious encephalopathies with accompanying persistent immune activation. This is associated with immune dysregulation, chronic hyperarousal, activation of the stress response, and impairments of the fear recognition and response neural circuits, hypothalamic–pituitary–adrenal axis, amygdala, and hippocampus. The pathophysiological processes can result in a broad spectrum of chronic neuropsychiatric and somatic symptoms and diseases. Understanding the psychodynamic, neurological, neuroimmune, inflammatory and autoimmune components of this interactive process expands the effective treatment opportunities.

Abstract 1591: Convergence of antigenic diversity and Tex-cell stability fatally constrains immune surveillance in non-small cell lung cancer (TRACERx) and HIV-1 infection (Protocol C)

Abstract T cells recognize cognate antigen and elicit effector function to eliminate target cells. In chronic infection and cancer, exhausted T cells with impaired effector function and narrow TCR repertoires must respond to vast and diverse antigenic landscapes, favoring immune escape. Here we test whether T cell exhaustion and antigenic diversity converge to drive fatal immune failure in chronic infection and cancer. We leveraged over 600 primary longitudinal samples from the Protocol C (IAVI) and TRACERx (CRUK) studies to track the natural course of HIV-1 infection and non-small cell lung cancer (NSCLC), respectively, using high parameter flow cytometry, genome sequencing and TCRseq, complemented with focused scRNAseq and antigen specific profiling. In both diseases systemic Tcf1-Tox+Eomes+PD1+ T (Tex) cells track antigen burden and predict adverse outcome, independent of host clinical status. In HIV-1 infection, Tex cells are clonally restricted and rapid Gag RNA sequence divergence accompanies higher viral loads and lower CD4 counts. Similarly, in lung cancer peripheral Tex cells harbor hyper-expanded TCRs, contract after resection and reconstitute at recurrence with strikingly preserved clonal hierarchies, creating a ‘specificity gap’ that could be exploited by subclonal evolution. Commensurate with this model, we discover that a high level of systemic Tex cells coupled with either elevated Gag diversity in HIV-1 infection, or higher mutational or copy number heterogeneity in lung cancer defines patients with the poorest clinical outcome. We propose a unifying model of immune failure in chronic infection and cancer where genomic diversity and T cell exhaustion co-ordinately diminish human immune protection. Citation Format: James L. Reading, Rachel Rosenthal, Oriol Pich, Samuel Gamble, Seng Anakin Ung, Teerapon Sahwangarrom, Betty Gration, Yien Ning Sophia Wong, Lucas Black, Benny Chain, Jonathan Hare, Sergio A. Quezada, Charles Swanton. Convergence of antigenic diversity and Tex-cell stability fatally constrains immune surveillance in non-small cell lung cancer (TRACERx) and HIV-1 infection (Protocol C) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1591.

Microenvironmental Features Driving Immune Evasion in Myelodysplastic Syndromes and Acute Myeloid Leukemia.

Bone marrow, besides the known functions of hematopoiesis, is an active organ of the immune system, functioning as a sanctuary for several mature immune cells. Moreover, evidence suggests that hematopoietic stem cells (the bone marrow’s functional unit) are capable of directly sensing and responding to an array of exogenous stimuli. This chronic immune stimulation is harmful to normal hematopoietic stem cells, while essential for the propagation of myeloid diseases, which show a dysregulated immune microenvironment. The bone marrow microenvironment in myelodysplastic syndromes (MDS) is characterized by chronic inflammatory activity and immune dysfunction, that drive excessive cellular death and through immune evasion assist in cancer cell expansion. Acute myeloid leukemia (AML) is another example of immune response failure, with features that augment immune evasion and suppression. In this review, we will outline some of the functions of the bone marrow with immunological significance and describe the alterations in the immune landscape of MDS and AML that drive disease progression.

Clustered Regularly Interspaced Short Palindromic Repeat/Cas12a Mediated Multiplexable and Portable Detection Platform for GII Genotype Porcine Epidemic Diarrhoea Virus Rapid Diagnosis.

Porcine epidemic diarrhoea virus (PEDV) is a member of the genus Alphacoronavirus in the family Coronaviridae. It causes acute watery diarrhoea and vomiting in piglets with high a mortality rate. Currently, the GII genotype, PEDV, possesses a high separation rate in wild strains and is usually reported in immunity failure cases, which indicates a need for a portable and sensitive detection method. Here, reverse transcription–recombinase aided amplification (RT-RAA) was combined with the Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)/Cas12a system to establish a multiplexable, rapid and portable detection platform for PEDV. The CRISPR RNA (crRNA) against Spike (S) gene of GII PEDV specifically were added into the protocol. This system is suitable for different experimental conditions, including ultra-sensitive fluorescence, visual, UV light, or flow strip detection. Moreover, it exhibits high sensitivity and specificity and can detect at least 100 copies of the target gene in each reaction. The CRISPR/Cas12a detection platform requires less time and represents a rapid, reliable and practical tool for the rapid diagnosis of GII genotype PEDV.