Dysfunctional Immune Response Research Articles

PD1 blockade improves survival and CD8+ cytotoxic capacity, without increasing inflammation, during normal microbial experience in old mice.

By 2030, individuals 65 years of age or older will make up approximately 20% of the world's population1. Older individuals are at the highest risk for mortality from infections, largely due to the pro-inflammatory, dysfunctional immune response, which is collectively known as immunosenescence2. During aging, CD8+ T cells acquire an exhausted phenotype, including increased expression of inhibitory receptors, such as programmed cell death 1 (PD1), a decline in effector function and elevated expression of inflammatory factors3-7. PD1 reduces T cell receptor activity via SHP2-dependent dephosphorylation of multiple pathways; accordingly, inhibiting PD1 activity through monoclonal antibodies increases CD8+ T cell effector response in young mice8-11. Attempts to improve CD8+ T cell responses by blocking inhibitory receptors are attractive; however, they can lead to adverse immune events due to overamplification of T cell receptor signaling and T cell activation12,13. Here we investigated the effect of monoclonal anti-PD1 immunotherapy during normal microbial experience, otherwise known as exposure to dirty mice, to determine whether it either improves exhausted CD8+ T cell responses in old mice or leads to a heightened inflammatory response and increased mortality.

Analysis of oxidative status, inflammatory cytokines, and Ascaris lumbricoides infection in women at a health district in Bamenda, Northwest, Cameroon

BackgroundClinical outcomes of ascariasis, one of the most common parasitic infections, are remarkably variable ranging from asymptomatic infection to death. Ascariasis can pair absorption of fats, vitamin A, iodine, and lactose digestion and destroys the villi, with significant consequences in pregnancy outcomes, leading to growth retardation, and cognitive impairment, decreased work capacity, and adverse pregnancy outcomes. One of the crucial factors driving the clinical outcomes of ascariasis is the immune response and associated oxidative stress. This study therefore examined the prevalence of ascariasis and associated immune response dysfunction by measuring four inflammatory cytokines alongside with the oxidant and antioxidant biomarkers in women of reproductive age in a health center in Cameroon.ResultsThree-hundred and fifty-five women (pregnant and non-pregnant) were examined for the parasite. Because some participants did not donate blood and due to low volume of blood available, only 127 individuals (62 non-pregnant women and 65 pregnant women) were included for analysis of oxidative biomarkers, and 90 samples were used for the evaluation of inflammatory biomarkers (40 non-pregnant and 50 pregnant). The prevalence of Ascaris lumbricoides was of 13.23%. Ascariasis was associated with high levels in inflammatory cytokines (IL-1β, IL-12, IL-10, and TNF-α) and oxidative markers (TOS, OSI, MDA, and CAT) in both pregnant and non-pregnant women, while high level of NO was only seen in pregnant women. A significant relation was observed between some cytokines and oxidant markers: IL-10 and OSI and IL-12 and NO and between IL-1β and MDA in pregnant women, while in non-pregnant, significant relation was found between Il-10 and NO as well as IL-1β and OSI and NO. Principal component analysis (PCA) underlined a pro-inflammatory cytokine signature (with strongest contributions from IL-1β, IL-10, TNF-α). PCA also highlighted an oxidative stress with strongest contributions from TOS, OSI, SOD, NO, and CAT in pregnant and from OSI, TOS, NO, CAT, and TAC in non-pregnant.ConclusionThese findings demonstrate elevated cytokines (IL-1β, IL-12, IL-10, and TNF-α) and high oxidative stress imbalance, adding further evidence for the role of a pro-inflammatory cytokine signature of oxidative stress in women with A. lumbricoides.

Mapping Human Immunity and the Education of Waldeyer's Ring.

The development and deployment of single-cell genomic technologies have driven a resolution revolution in our understanding of the immune system, providing unprecedented insight into the diversity of immune cells present throughout the body and their function in health and disease. Waldeyer's ring is the collective name for the lymphoid tissue aggregations of the upper aerodigestive tract, comprising the palatine, pharyngeal (adenoids), lingual, and tubal tonsils. These tonsils are the first immune sentinels encountered by ingested and inhaled antigens and are responsible for mounting the first wave of adaptive immune response. An effective mucosal immune response is critical to neutralizing infection in the upper airway and preventing systemic spread, and dysfunctional immune responses can result in ear, nose, and throat pathologies. This review uses Waldeyer's ring to demonstrate how single-cell technologies are being applied to advance our understanding of the immune system and highlight directions for future research.

Induction of regulatory T cells and efficacy of low-dose interleukin-2 in systemic sclerosis: interventional open-label phase 1–phase 2a study

BackgroundSystemic sclerosis (SSc) is a chronic autoimmune disease, with impaired immune response, increased fibrosis and endothelial dysfunction. Regulatory T cells (Tregs), which are essential to control inflammation, tissue repair and...

Porphyromonas gingivalis Strain W83 Infection Induces Liver Injury in Experimental Alcohol-Associated Liver Disease (ALD) in Mice

The liver plays a vital role in the defense against infections. Porphyromonas gingivalis (P. gingivalis), a dominant etiologic oral bacterium implicated in periodontal disease (PD), has been associated with various systemic diseases. This study aimed to investigate the influence of P. gingivalis on alcohol-associated liver diseases (ALD). Mice were fed a Lieber–DeCarli liquid diet containing 5% ethanol for 10 days after an initial adaptation period on a diet with lower ethanol content for 7 days. Two days before tissue sample collection, the mice were administered P. gingivalis strain W83 (Pg) through intraperitoneal injection (IP). Pair-fed mice with Pg infection (PF+Pg) exhibited an activated immune response to combat infections. However, alcohol-fed mice with Pg infection (AF+Pg) showed liver injury with noticeable abscess lesions and elevated serum alanine aminotransferase (ALT) levels. Additionally, these mice displayed liver infiltration of inflammatory monocytes and significant downregulation of proinflammatory cytokine gene expression levels; and AF+Pg mice also demonstrated increased intrahepatic neutrophil infiltration, as confirmed by chloroacetate esterase (CAE) staining, along with elevated gene expression levels of neutrophil cytosol factor 1 (Ncf1), neutrophilic inflammation driver lipocalin 2 (Lcn2), and complement component C5a receptor 1 (C5ar1), which are associated with neutrophilic inflammation. Interestingly, compared to PF+Pg mice, the livers of AF+Pg mice exhibited downregulation of gene expression levels of NADPH oxidase 2 (Cybb), the leukocyte adhesion molecule Cd18, and the Toll-like receptor adaptor Myd88. Consequently, impaired clearance of P. gingivalis and other bacteria in the liver, increased susceptibility to infections, and inflammation-associated hepatic necrotic cell death were observed in AF+Pg mice, which is likely to have facilitated immune cell infiltration and contributed to liver injury. Furthermore, in addition to the Srebf1/Fasn pathway induced by alcohol feeding, Pg infection also activated carbohydrate response element-binding protein (ChREBP) in AF+Pg mice. In summary, this study demonstrates that P. gingivalis infection, acting as a “second hit”, induces dysfunction of immune response and impairs the clearance of bacteria and infections in alcohol-sensitized livers. This process drives the development of liver injury.

COVID-19 liver damage. Features of laboratory and instrumental diagnostics

The aim of the study - to analyze the pathogenesis of liver damage in COVID-19, as well as to study the features of diagnosis. Research materials: literature and own data on the peculiarities of the pathogenesis of liver damage were analyzed, as well as an assessment of laboratory and instrumental diagnostics in patients with COVID-19. The results of the research. In patients, liver damage was manifested by an increase in liver enzymes, as well as a diffuse decrease in its density during CT. The severity of the disease is caused by a cytokine storm caused by a dysfunctional immune response to the virus, viral virulence factors, as well as the presence of concomitant diseases, especially those associated with liver pathology, such as cirrhosis or steatosis. Conclusions. The new COVID-19 coronavirus infection caused by SARS-CoV-2 continues to spread worldwide. The main target is the organs of the respiratory system. However, among the patients with COVID-19, there were lesions of the central nervous system, intestines, myocardium and liver. Liver dysfunction in most cases should be considered as a result of secondary damage due to CVD, ARDS, hypoxia, multiple organ failure, exposure to immune factors, and taking hepatotoxic drugs.

Elimination of the hepatitis B virus: A goal, a challenge.

The hepatitis B elimination is a goal proposed by the WHO to be achieved by 2030 through the adoption of synergistic measures for the prevention and chronic HBV infection treatment. Complete cure is characterized by the HBV elimination from the body and is the goal of the chronic hepatitis B treatment, which once achieved, will enable the hepatitis B elimination. This, today, has been a scientific challenge. The difficulty in achieving a complete cure is due to the indefinite maintenance of a covalently closed episomal circular DNA (cccDNA) reservoir and the maintenance and persistence of an insufficient and dysfunctional immune response in chronically infected patients. Among the measures adopted to eliminate hepatitis B, two have the potential to directly interfere with the virus cycle, but with limited effect on HBV control. These are conventional vaccines-blocking transmission and antiviral therapy-inhibiting replication. Vaccines, despite their effectiveness in protecting against horizontal transmission and preventing mother-to-child vertical transmission, have no effect on chronic infection or potential to eliminate the virus. Treatment with antivirals suppresses viral replication, but has no curative effect, as it has no action against cccDNA. Therapeutic vaccines comprise an additional approach in the chronic infection treatment, however, they have only a modest effect on the immune system, enhancing it temporarily. This manuscript aims to address (1) the cccDNA persistence in the hepatocyte nucleus and the immune response dysfunction in chronically infected individuals as two primary factors that have hampered the treatment and HBV elimination from the human body; (2) the limitations of antiviral therapy and therapeutic vaccines, as strategies to control hepatitis B; and (3) the possibly promising therapeutic approaches for the complete cure and elimination of hepatitis B.

Abstract 1533: Characterizing tumor-immune surveillance in Li-Fraumeni syndrome

Abstract Li-Fraumeni Syndrome (LFS) is a cancer predisposition syndrome associated with germline TP53 mutations and increased lifetime risk of developing multiple cancers. p53, the protein encoded by TP53, plays a role in regulating various aspects of immune cell biology. Accordingly, inactivation of p53 in tumor cells shapes interactions with the immune system and influences the anti-tumor immune response. Mutation or deletion of p53 in immune cells also favors tumor development and progression. However, to date, a comprehensive study of immune cell populations and the anti-tumor immune response has not been undertaken in the context of LFS. We hypothesized that germline TP53 mutation carriers possess dysfunctional immune cells and/or immune responses, supporting LFS-associated tumor progression. Our preliminary data indicate a profound defect in tumor-immune surveillance in an LFS murine model. We observed that MC38 cancer cells develop significantly faster into tumors when injected into LFS mice (harboring a gain-of-function mutation Trp53R172H/WT) compared to wildtype (WT) control mice. Importantly, we identified significant alterations in immune cell compositions and phenotypes within the tumor microenvironment as well as immune organs using flow cytometry. We are currently using ex vivo proliferation assays and cytotoxicity assays to investigate the impact of mutant p53 on the tumor-killing ability of immune effector cells. Altogether, an improved understanding of anti-tumor immune dysfunction in the context of germline TP53 mutation may reveal the potential for innovative therapies to target different facets of the immune system to intercept cancer progression in LFS patients. Citation Format: Camilla Giovino, Nicholas Fischer, Noel Ong, Ashby Kissoondoyal, Ran Kafri, David Malkin. Characterizing tumor-immune surveillance in Li-Fraumeni syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1533.

Group 3 innate lymphoid cells in intestinal health and disease.

The gastrointestinal tract is an immunologically rich organ, containing complex cell networks and dense lymphoid structures that safeguard this large absorptive barrier from pathogens, contribute to tissue physiology and support mucosal healing. Simultaneously, the immune system must remain tolerant to innocuous dietary antigens and trillions of normally beneficial microorganisms colonizing the intestine. Indeed, a dysfunctional immune response in the intestine underlies the pathogenesis of numerous local and systemic diseases, including inflammatory bowel disease, food allergy, chronic enteric infections or cancers. Here, we discuss group 3 innate lymphoid cells (ILC3s), which have emerged as orchestrators of tissue physiology, immunity, inflammation, tolerance and malignancy in the gastrointestinal tract. ILC3s are abundant in the developing and healthy intestine but their numbers or function are altered during chronic disease and cancer. The latest studies provide new insights into the mechanisms by which ILC3s fundamentally shape intestinal homeostasis or disease pathophysiology, and often this functional dichotomy depends on context and complex interactions with other cell types or microorganisms. Finally, we consider how this knowledge could be harnessed to improve current treatments or provoke new opportunities for therapeutic intervention to promote gut health.

Excess of body weight is associated with accelerated T-cell senescence in hospitalized COVID-19 patients

BackgroundSeveral risk factors have been involved in the poor clinical progression of coronavirus disease-19 (COVID-19), including ageing, and obesity. SARS-CoV-2 may compromise lung function through cell damage and paracrine inflammation; and obesity has been associated with premature immunosenescence, microbial translocation, and dysfunctional innate immune responses leading to poor immune response against a range of viruses and bacterial infections. Here, we have comprehensively characterized the immunosenescence, microbial translocation, and immune dysregulation established in hospitalized COVID-19 patients with different degrees of body weight.ResultsHospitalised COVID-19 patients with overweight and obesity had similarly higher plasma LPS and sCD14 levels than controls (all p < 0.01). Patients with obesity had higher leptin levels than controls. Obesity and overweight patients had similarly higher expansions of classical monocytes and immature natural killer (NK) cells (CD56+CD16−) than controls. In contrast, reduced proportions of intermediate monocytes, mature NK cells (CD56+CD16+), and NKT were found in both groups of patients than controls. As expected, COVID-19 patients had a robust expansion of plasmablasts, contrasting to lower proportions of major T-cell subsets (CD4 + and CD8+) than controls. Concerning T-cell activation, overweight and obese patients had lower proportions of CD4+CD38+ cells than controls. Contrasting changes were reported in CD25+CD127low/neg regulatory T cells, with increased and decreased proportions found in CD4+ and CD8+ T cells, respectively. There were similar proportions of T cells expressing checkpoint inhibitors across all groups. We also investigated distinct stages of T-cell differentiation (early, intermediate, and late-differentiated – TEMRA). The intermediate-differentiated CD4 + T cells and TEMRA cells (CD4+ and CD8+) were expanded in patients compared to controls. Senescent T cells can also express NK receptors (NKG2A/D), and patients had a robust expansion of CD8+CD57+NKG2A+ cells than controls. Unbiased immune profiling further confirmed the expansions of senescent T cells in COVID-19.ConclusionsThese findings suggest that dysregulated immune cells, microbial translocation, and T-cell senescence may partially explain the increased vulnerability to COVID-19 in subjects with excess of body weight.

Evaluation and Management of Diabetic Neuropathy from the Perspective of People with Diabetes

Diabetic foot ulcers (DFU) and infections are the most common complications of diabetic foot disease. Mortality and financial burdens for both patients and society on the whole are caused by the prevalence of complications. Peripheral neuropathy, peripheral arterial disease, and immune response dysfunction are just a few of the main contributing factors that must be understood in order to effectively treat the condition. In order to treat diabetic foot disease, you must first get a comprehensive physical examination and a detailed history of your condition. Diabetic neuropathy and peripheral vascular disease, as well as any evidence of diabetic foot ulcers or infection, should be examined during this procedure. Patients with diabetes mellitus were studied to see if there was a link between cognitive impairment and the condition of their feet and whether or not they followed their doctor's recommendations for glycemic control. Using a random sample of diabetes patients, researchers conducted a prospective study to see how many people had the condition. The Mini-Mental State Valuation, the Trail Making Judgments, and the Michigan Screening Instrument were used to assess cognitive abilities. In the one-month follow-up, glycated hemoglobin (HB1Ac &gt;7%) was linked to the MMSE and medication adherence, but no link was seen between cognitive function and neuropathy. According to the results of a ROC curve investigation, HB1Ac and the MNSI score both significantly (p&lt; 0.05) mitigate towards eventual adherence to medicine for foot problems. For the purpose of determining if DFU was associated with cognitive impairment, the Chi square valuation was used in the statistical examination. As a determinant of MMSE and MoCA scores, the researchers used linear regression to come to their conclusion. Diabetic foot issues should be managed with good blood sugar control and less acute neuropathy, and this does not seem to be linked to cognitive dysfunction. More study is required in order to personalize treatments for diseases of the central and peripheral nervous systems appropriately. Cognitive dysfunction should be taken into account by doctors and podiatrists while treating diabetic foot problems

SARS-CoV-2 Neutralization by Cell Membrane-Coated Antifouling Nanoparticles.

The global outbreak of the COVID-19 pandemic has indisputably wreaked havoc on societies worldwide, compelling the scientific community to seek urgently needed therapeutic agents with low-cost and low-side effect profiles. Numerous approaches have been investigated in the quest to prevent or treat COVID-19, but many of them exhibit unwelcome side effects, such as dysfunctional viral immune responses and inflammation. Herein, we present the preparation of solid natural human pulmonary alveolar epithelial cell (ATII) membrane-coated PLGA NPs (PLGA NPs@ATII-M), which demonstrate remarkable affinity and competitiveness to neutralize the SARS-CoV-2 S1 protein-coated NPs (SCMMA NPs-S1), which are employed as a surrogate for coronavirus particles. In addition, we first considered the antifouling properties of these types of NPs, and we found that this membrane-coated NP formulation boasts excellent antifouling capabilities, which serve to protect their neutralization properties out of shielding by protein coronas in blood circulation. Moreover, this formulation is easily prepared and stored with a low-cost profile and exhibits good specificity, high targeting efficiency, and potentially side effect avoiding, thus making it a highly promising candidate for COVID-19 treatment.

Immunosurveillance encounters cancer metabolism.

Tumor cells reprogram nutrient acquisition and metabolic pathways to meet their energetic, biosynthetic, and redox demands. Similarly, metabolic processes in immune cells support host immunity against cancer and determine differentiation and fate of leukocytes. Thus, metabolic deregulation and imbalance in immune cells within the tumor microenvironment have been reported to drive immune evasion and to compromise therapeutic outcomes. Interestingly, emerging evidence indicates that anti-tumor immunity could modulate tumor heterogeneity, aggressiveness, and metabolic reprogramming, suggesting that immunosurveillance can instruct cancer progression in multiple dimensions. This review summarizes our current understanding of how metabolic crosstalk within tumors affects immunogenicity of tumor cells and promotes cancer progression. Furthermore, we explain how defects in the metabolic cascade can contribute to developing dysfunctional immune responses against cancers and discuss the contribution of immunosurveillance to these defects as a feedback mechanism. Finally, we highlight ongoing clinical trials and new therapeutic strategies targeting cellular metabolism in cancer.

SERUM FERRITIN AND SERUM LACTATE DEHYDROGENASE LEVELS AMONG COVID-19 PATIENTS

Objectives: The aim of this study was to estimate serum ferritin and serum lactate dehydrogenase (LDH) values among COVID-19-positive and COVID-19-negative subjects. Methods: The study was conducted on 152 cases; 76 were COVID-19 diseased, and 76 were COVID-19 free. Serum ferritin and serum LDH levels were estimated. Result: Average ferritin levels among COVID-19 diseased were 529.33 ng/ml compared to 450.92 ng/ml among negative individuals. Similarly, the LDH level among positive persons was 338.50 IU/L and 303.30 IU/L among hostile people. Conclusion: The uncontrolled and dysfunctional immune response is connected with macrophage activation and hyperferritinemic syndrome. Elevated LDH readings seem to reflect that multiple organ injury and failure may play a more prominent role in influencing the clinical outcomes in patients with COVID-19.

COVID-19 pathogenesis.

The pathogenesis of COVID-19 involves a complex interplay between host factors and the SARS-CoV-2 virus, leading to a multitude of clinical manifestations beyond the respiratory system. This chapter provides an overview of the risk factors, genetic predisposition, and multisystem manifestations of COVID-19, shedding light on the underlying mechanisms that contribute to extrapulmonary manifestations. The chapter discusses the direct invasion of SARS-CoV-2 into various organs as well as the indirect mechanisms such as dysregulation of the renin-angiotensin-aldosterone system (RAAS), immune response dysfunctions within the innate and adaptive immune systems, endothelial damage, and immunothrombosis. Furthermore, the multisystem manifestations of COVID-19 across different organ systems, including the cardiovascular, renal, gastrointestinal, hepatobiliary, nervous, endocrine and metabolic, ophthalmic, ear-nose-throat, reproductive, hematopoietic, and immune systems are discussed in detail. Each system exhibits unique manifestations that contribute to the complexity of the disease.

SARS-CoV-2 spike protein accelerates systemic sclerosis by increasing inflammatory cytokines, Th17 cells, and fibrosis

BackgroundCoronavirus disease 2019 (COVID-19) induces a dysfunctional immune response, inflammation, autoantibody production, and coagulopathy, which are symptoms that bear resemblance to those of autoimmune diseases, including systemic sclerosis (SSc).MethodsWhile there is a single case report suggesting an association between COVID-19 and SSc, the effects of COVID-19 on SSc are not yet fully understood. Human embryonic kidney 293 (HEK293) cells were transfected with the SARS-CoV-2 spike protein gene, in the presence of TGF-β. The expression levels of fibrosis-related proteins were measured via Western blotting. A bleomycin (BLM)-induced SSc mouse model was employed, wherein mice were injected with the gene encoding the SARS-CoV-2 spike protein and the ACE2 receptor. The levels of fibrosis, autoantibodies, thrombotic factors, and inflammatory cytokines in tissues and serum were analyzed.ResultsIn vitro, the expression levels of fibrosis marker proteins were elevated in the spike protein group compared to the control group. In vivo, the skin thickness of SSc mice increased following exposure to the SARS-CoV-2 spike protein. Furthermore, the levels of autoantibodies and thrombotic factors, such as anti-phospholipid antibodies (APLA), were significantly increased in the presence of the protein. Flow cytometry analysis revealed increased expression of the proinflammatory cytokine IL-17 in the skin, lungs, and blood. Moreover, tissue fibrosis and levels of inflammatory cytokines in skin and lung tissues were markedly escalated in SSc mice subjected to the protein.ConclusionCOVID-19 may accelerate the development and progression of SSc by intensifying fibrosis through the upregulation of inflammation, autoantibody production, and thrombosis.

The effect of metformin on senescence of T lymphocytes

BackgroundImmunosenescence occurs as people age, leading to an increased incidence of age-related diseases. The number of senescent T cells also rises with age. T cell senescence and immune response dysfunction can result in a decline in immune function, especially in anti-tumor immune responses. Metformin has been shown to have various beneficial effects on health, such as lowering blood sugar levels, reducing the risk of cancer development, and slowing down the aging process. However, the immunomodulatory effects of metformin on senescent T cells still need to be investigated.MethodsPBMCs isolation from different age population (n = 88); Flow Cytometry is applied to determine the phenotypic characterization of senescent T lymphocytes; intracellular staining is applied to determine the function of senescent T cells; Enzyme-Linked Immunosorbent Assay (ELISA) is employed to test the telomerase concentration. The RNA-seq analysis of gene expression associated with T cell senescence.ResultsThe middle-aged group had the highest proportion of senescent T cells. We found that metformin could decrease the number of CD8 + senescent T cells. Metformin affects the secretion of SASP, inhibiting the secretion of IFN-γ in CD8 + senescent T cells. Furthermore, metformin treatment restrained the production of the proinflammatory cytokine IL-6 in lymphocytes. Metformin had minimal effects on Granzyme B secretion in senescent T cells, but it promoted the production of TNF-α in senescent T cells. Additionally, metformin increased the concentration of telomerase and the frequency of undifferentiated T cells. The results of RNA-seq showed that metformin promoted the expression of genes related to stemness and telomerase activity, while inhibiting the expression of DNA damage-associated genes.ConclusionOur findings reveal that metformin could inhibit T cell senescence in terms of cell number, effector function, telomerase content and gene expression in middle-aged individuals, which may serve as a promising approach for preventing age-related diseases in this population.

Single-cell transcriptomics of peripheral blood mononuclear cells indicates impaired immune and inflammatory responses in alcohol-associated hepatitis

Alcohol-associated hepatitis (AH) is often diagnosed at advanced stages, and severe AH usually carries poor prognosis and high short-term mortality. In addition, it is challenging to understand the molecular mechanisms of immune dysregulation and inflammation in AH due to the cellular complexity and heterogeneity. Using single-cell RNA sequencing, previous studies found that AH causes dysfunctional innate immune response in monocytes, involving activation of pattern recognition receptors (PRRs) and cytokine signaling pathways. To better understand the coordinated systemic immune response in AH patients, we performed combined single-cell transcriptome, cell-surface protein, and lymphocyte antigen receptor analysis of peripheral blood mononuclear cell (PBMC) samples. Our results showed inflammatory cytokines and chemokines were highly expressed in AH, including IL-2, IL-32, CXC3R1 and CXCL16 in monocytes and NK cells, whereas HLA-DR genes were reduced in monocytes. In addition, we also found altered differentiation of T-helper cells (TH1 and TH17), which could further lead to neutrophil recruitment and macrophage activation. Lastly, our results also suggest impaired NK-cell activation and differentiation in AH with reduced gene expression of KLRC2 and increased gene expression of KLRG1. Our findings indicate different mechanisms may be involved in impaired immune and inflammatory responses for the cellular subtypes of the PBMCs in AH.

Long COVID-19 Infections and Organizing Pneumonia in a Series of Patients with Indolent Lymphoma Treated with Rituximab

Background: Patients with hematologic malignancies have an increased risk of complications and mortality from COVID-19 (SARS-CoV-2). These patients are often more susceptible to protracted COVID-19 infections (e.g., long COVID-19). In addition, patients treated with the CD20-targeted immunotherapy rituximab in B-cell lymphomas are at greater risk for a protracted clinical course with COVID-19, including care in the ICU for respiratory failure. Hypogammaglobulinemia is an independent predictor of increased risk for long-COVID19. Immune depletion both leads to a persistent detection of SARS-CoV-2 and an inability to mount a sustained immune response. Other authors have reported on the appearance of a delayed organizing pneumonia (OP) after acute COVID-19 infection, but these patients were not immunocompromised by rituximab. In this case series, we report on three patients with indolent lymphoma who had the delayed presentation of long COVID-19 after an acute infection. All three were previously treated with rituximab, and each case was notable for prolonged OP that was refractory to steroid therapy. Methods: Summative data for the three patient cases was aggregated from the medical record including available physician notes, diagnostic body imaging, and laboratory data. Results: In total, we found three cases of long COVID-19 in patients with indolent lymphoma from our institution (Table 1). Patient 1 received just two doses of rituximab, Patient 2 received three doses of rituximab, and Patient 3 was treated with rituximab intermittently for nearly three years. All three patients experienced their first COVID-19 infections in August 2022 and had low IgG. This was followed by complications including acute hypoxemic respiratory failure, pulmonary embolism, and organizing pneumonia in these patients two to three months thereafter. These patients continue to have ongoing chronic hypoxemic respiratory failure requiring immune suppression and continuous oxygen support. Conclusions: Immune depletion with rituximab in patients with indolent lymphomas can put them at significant risk of long COVID-19, OP, and chronic hypoxemic respiratory failure after contracting SARS-Cov-2. Such patients may benefit from prolonged immune suppression, but the exact duration remains unclear. The mechanism of long COVID-19 and refractory OP is unclear and complex. Possible mechanisms may include inadequate clearance of virus or a dysfunctional immune response. Table 1: Lymphoma patients who received rituximab and then developed long COVID-19

Targeting Nrf2 Signaling Pathway in Cancer Prevention and Treatment: The Role of Cannabis Compounds.

The development and progression of cancer are associated with the dysregulation of multiple pathways involved in cell proliferation and survival, as well as dysfunction in redox balance, immune response, and inflammation. The master antioxidant pathway, known as the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, regulates the cellular defense against oxidative stress and inflammation, making it a promising cancer prevention and treatment target. Cannabinoids have demonstrated anti-tumor and anti-inflammatory properties, affecting signaling pathways, including Nrf2. Increased oxidative stress following exposure to anti-cancer therapy prompts cancer cells to activate antioxidant mechanisms. This indicates the dual effect of Nrf2 in cancer cells-influencing proliferation and apoptotic processes and protecting against the toxicity of anti-cancer therapy. Therefore, understanding the complex role of cannabinoids in modulating Nrf2 might shed light on its potential implementation as an anti-cancer support. In this review, we aim to highlight the impact of cannabinoids on Nrf2-related factors, with a focus on cancer prevention and treatment. Additionally, we have presented the results of several research studies that combined cannabidiol (CBD) with other compounds targeting Nrf2. Further studies should be directed toward exploring the anti-inflammatory effects of cannabinoids in the context of cancer prevention and therapy.