Cytokine Surge Research Articles

Time-course analysis of antibody and cytokine response after the third SARS-CoV-2 vaccine dose

The widespread administration of an additional dose of the SARS-CoV-2 vaccine has been promoted across adult populations, demonstrating a robust immune response against COVID-19. Longitudinal studies provide crucial data on the durability of immune response after the third vaccination. This study aims to explore the antibody response, neutralizing activity, and cytokine response against the SARS-CoV-2 ancestral strain (wild-type) and its variants during the timeline before and after the administration of the third vaccine dose. Anti-spike antibody titers and neutralizing antibodies blocking ACE2 binding to spike antigens were measured in 62 study participants at baseline, and on days 7, 21, and 180 post-vaccination. Cytokine levels were assessed at the same points except for day 180, with an additional measurement on day 3 post-vaccination. The analysis revealed no substantial variation in anti-spike antibody titer against the SARS-CoV-2 ancestral strain between the pre-vaccination phase and three days following the third dose. However, a significant nine-fold increase in these titers was observed by day 7, maintained until day 21. Although a decrease was observed by day 180, all participants still had detectable antibody levels. A similar trend was noted for neutralizing antibodies, with a four-fold rise by day 7 post-vaccination. At day 180, a diminution of neutralizing antibody titers was evident for both wild-type and all variants, including Omicron subvariant. A transient increase in cytokine activity, notably involving components of the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway, such as CXCL10 and IL-10, was observed within three days after the third dose. This study underscores a distinct amplification of humoral immune response seven days following the third SARS-CoV-2 vaccine dose and observes a decline in neutralizing antibody titers 180 days following the third dose, thus indicating the temporal humoral effectiveness of booster vaccination. A short-term cytokine surge, notably involving the JAK/STAT pathway, highlights the dynamic immune modulation post-vaccination.

SIK2 Controls the Homeostatic Character of the POMC Secretome Acutely in Response to Pharmacological ER Stress Induction.

The neuronal etiology of obesity is centered around a diet-induced inflammatory state in the arcuate nucleus of the hypothalamus, which impairs the functionality of pro-opiomelanocortine neurons (POMCs) responsible for whole-body energy homeostasis and feeding behavior. Intriguingly, systemic salt inducible kinase 2 (SIK2) knockout mice demonstrated reduced food intake and energy expenditure along with modestly dysregulated metabolic parameters, suggesting a causal link between the absence of SIK2 activity in POMCs and the observed phenotype. To test this hypothesis, we conducted a comparative secretomics study from POMC neurons following pharmacologically induced endoplasmic reticulum (ER) stress induction, a hallmark of metabolic inflammation and POMC dysregulation in diet-induced obese (DIO) mice. Our data provide significant in vitro evidence for the POMC-specific SIK2 activity in controlling energy metabolism and feeding in DIO mice by regulating the nature of the related POMC secretome. Our data also suggest that under physiological stress conditions, SIK2 may act as a gatekeeper for the secreted inflammatory factors and signaling molecules critical for cellular survival and energy homeostasis. On the other hand, in the absence of SIK2, the gate opens, leading to a surge of inflammatory cytokines and apoptotic cues concomitant with the dysregulation of POMC neurons.

Temporal Immune Profiling in the CSF and Blood of Patients with Aneurysmal Subarachnoid Hemorrhage.

Delayed cerebral ischemia (DCI) is a significant complication of aneurysmal subarachnoid hemorrhage (aSAH). This study profiled immune responses after aSAH and evaluated their association with DCI onset. Twelve aSAH patients were enrolled. Leukocyte populations and cytokine levels were analyzed in cerebrospinal fluid (CSF) and peripheral blood (PB) on days 3, 5, 7, 10, and 14 post-aSAH. Peripheral blood mononuclear cells (PBMCs) were collected and their cytokine production quantified following stimulation. Mixed-effects models revealed distinct immune cell dynamics in CSF compared to blood. Natural killer T cell frequency increased over time in CSF only, while monocyte/macrophage numbers increased in both CSF and PBMCs. CD4+ HLA II+ T cells increased in circulation. Unstimulated PBMCs showed increased IL-1β, IL-6, and TNFα production, peaking at 7 days post-aSAH, coinciding with typical DCI onset. Ex vivo stimulation of PBMCs showed that only IL-6 significantly changed over time. In CSF, cytokines peaked 5 days post-injury, preceding immune cell profile alterations. Our findings reveal a time-dependent immune response following aSAH, with distinct within-patient patterns in CSF and PB. The early CSF cytokine peak preceding immune cell changes suggests a potential mechanistic link and identifies the cytokine response as a promising therapeutic target. This cytokine surge may drive immune cell expansion and prime PBMCs for increased inflammatory activity, potentially contributing to DCI risk. Future studies should explore the importance and sources of specific cytokines in driving immune activation. These insights may inform the development of targeted immunomodulatory strategies for preventing or managing DCI in aSAH patients.

The potential immunological mechanisms of sepsis.

Sepsis is described as a life-threatening organ dysfunction and a heterogeneous syndrome that is a leading cause of morbidity and mortality in intensive care settings. Severe sepsis could incite an uncontrollable surge of inflammatory cytokines, and the host immune system's immunosuppression could respond to counter excessive inflammatory responses, characterized by the accumulated anti-inflammatory cytokines, impaired function of immune cells, over-proliferation of myeloid-derived suppressor cells and regulatory T cells, depletion of immune effector cells by different means of death, etc. In this review, we delve into the underlying pathological mechanisms of sepsis, emphasizing both the hyperinflammatory phase and the associated immunosuppression. We offer an in-depth exploration of the critical mechanisms underlying sepsis, spanning from individual immune cells to a holistic organ perspective, and further down to the epigenetic and metabolic reprogramming. Furthermore, we outline the strengths of artificial intelligence in analyzing extensive datasets pertaining to septic patients, showcasing how classifiers trained on various clinical data sources can identify distinct sepsis phenotypes and thus to guide personalized therapy strategies for the management of sepsis. Additionally, we provide a comprehensive summary of recent, reliable biomarkers for hyperinflammatory and immunosuppressive states, facilitating more precise and expedited diagnosis of sepsis.

Rutin Nanoparticles Alleviate Cadmium-Induced Oxidative and Immune Damage in Broilers' Bursa of Fabricius via Modulating Hsp70/TLR4/NF-κB Signaling Pathway.

Cadmium (Cd) is a serious environmental pollutant affecting various tissues/organs in broilers and compromising their immunological function and productivity. Therefore, the current study aimed to investigate Cd-induced immunotoxicity and potential immunoprotective effect of rutin nanoparticles (RNPs) in the bursal tissue of broilers. A total number of 150 chicks from the Hubbard breed were randomly divided into 5 groups. Group I was fed on standard basal diet (SD) with normal drinking water (DW), Group II received SD containing RNPs (50mg/kg feed) with DW, Group III fed on SD and DW containing Cd (150mg/L), Group IV co-treated with rutin-enforced SD (50mg/kg diet) and DW containing Cd (150mg/L), and finally, Group V co-supplemented with RNP-enhanced SD (50mg/kg diet) DW containing Cd (150mg/L). Productive performance, economic efficiency, oxidative biomarkers, histopathological changes, and the expression level of TLR-4, HSP-70, caspase 3, NF-κB, Bcl-2, and Bax were assessed in the BF tissue. Cd led to severe production and economic losses in exposed birds with a marked surge of oxidative biomarkers, pro-inflammatory cytokines, and histopathological changes in the bursal tissue which could be explained through upregulation of the Hsp70/TLR4/NF-κB molecular pathway in the BF tissue. Meanwhile, RNPs could alleviate most of these changes and prevail optimistic immunomodulatory properties which subsequently could enhance broilers' productivity when incorporated in their diets.

Paradigm of immune dysregulation in coronavirus disease-2019 infection

The coronavirus disease 2019 (COVID-19) pandemic cost 7–8 million deaths worldwide, creating an unprecedented health and economic crisis. Affecting 700 million people globally, the magnitude of this pandemic is far from anything that humanity has encountered in recent times. A detailed investigation revealed that more than the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, the hyperactive immune system mediated injury as the real cause of mortality. Cytokine storm following viral infection leads to the surge of proinflammatory cytokines resulting in acute respiratory distress syndrome (ARDS) and lung injury. Anti-inflammatory intervention with anti-interleukin-6 (anti-IL-6) receptor monoclonal antibodies (mAbs; e.g., sarilumab and tocilizumab) and anti-IL-6 mAbs (i.e., siltuximab) and/or steroid-based approach leads to substantial protection and prevent death thereby implying the role of inflammation in COVID-19. In this review, the authors have summarized the dysregulated immune system in COVID-19 infection, investigating in detail the virus-host immune cross talks and presenting the possibilities of therapeutic intervention.

In patients with acute myocardial infarction interleukin-8 levels are related to impaired renal function and predict recurrent infarction or death at 1-year follow-up - a case-control study

Abstract Introduction Acute myocardial infarction (AMI) induces a surge of inflammatory cytokines. IL-8, secreted by endothelial cells and monocyte-macrophages, rapidly recruits immune cells to the infarcted tissue. Previous studies in chronic kidney disease reported IL-8 to be associated with an increased inflammatory burden. Little is known about the diagnostic and prognostic value of IL-8 plasma levels in patients with AMI. Purpose We aimed to explore the diagnostic and prognostic value of IL-8 plasma levels in AMI patients. Methods Patients with AMI (STEMI and NSTEMI) were included from the SPUM-ACS cohort selecting a time window <24 h from symptom onset to blood sampling before PCI. Patients with malignancies or on immunosuppressive therapies were excluded. 160 patients with recurrent AMI or death within 1-year follow-up (cases) were compared to 160 counterparts with favorable outcome matched for age, sex, AMI subtype, and pain onset time (controls). 45 healthy blood donors (HD) without cardiovascular disease were added as an age- and sex-matched reference group. Heparin-plasma was used for Mesoscale U Plex cytokine analyses. The median and interquartile ranges (IQR) were compared using the non-parametric Kruskal-Wallis test. Relation of baseline characteristics to IL-8 levels within cases and controls was assessed with linear regression analyses. Kaplan-Meier curves were computed, selecting the cut-off value in consideration of the overall median IL-8 level. Results Cases (median=59.5, IQR=112.0 pg/mL) showed higher IL-8 plasma levels than HD (median=38.6, IQR=25.1 pg/mL, p=0.0006, Figure 1). Cases also had higher plasma IL-8 levels compared to controls (median=41.2, IQR=51.7 pg/mL, p=0.0006, Figure 1). Considering the median IL-8 level (50.1 pg/ml) as cut-off, cases with higher IL-8 had higher rates of recurrent MI or all-cause death than those with lower IL-8 levels within one year (log-rank p=0.002, Figure 2) with divergence between the subgroups seen early within the first two months. After correction for possible confounding factors (BMI, hypertension history, dyslipidaemia, diabetes, smoking, use of statins, LDL, Troponin, LVEF, and NT-proBNP), eGFR (estimated glomerular filtration rate) remained the only predictor for increased IL-8 (SRC: -0.178, p=0.016) in AMI patients. Conclusions In patients with AMI increased IL-8 levels predict subsequent MI or death at one-year follow-up. Lower eGFR is related to elevated IL-8 levels. Patients with AMI may thus profit from early IL-8 blocking therapies, particularly in the setting of impaired renal function.

Abstract 2480: Chemotherapy increases invasive cancer stem cells in breast cancer

Abstract Background: Metastasis is the leading cause of breast cancer (BC) death. To successfully metastasize, tumor cells must have both invasive and stem-like phenotypes. BC cells that express MenaINV, an invasive isoform of the actin regulatory protein Mena, have an enhanced ability to migrate and intravasate within the primary tumor, and extravasate at secondary sites. BC cells with a stem-like phenotype can withstand anoikis during hematogenous dissemination and initiate metastatic growth. Therefore, MenaINVHigh cancer stem cells (CSCs) have high metastatic potential and can be considered the most dangerous cells in the tumor. We recently showed that MenaINV and the CSC program can be induced independently in BC cells via direct contact with tumor associated macrophages (TAMs). Though chemotherapy improves survival, recent evidence shows that for some BC patients, chemotherapy may increase metastatic dissemination, though the reasons for this are unclear. Chemotherapy causes extensive cell death and a proinflammatory cytokine surge that recruits macrophages to the primary tumor and enhances the assembly of the tumor cell dissemination portals TMEM doorways. Given that TAM-tumor cell contact induces MenaINV and the CSC program in BC cells, we hypothesized that chemotherapy promotes dissemination by increasing TAM-tumor cell contact, leading to the induction of MenaINVHigh cells, CSCs, and “double positive” MenaINVHigh CSCs. Methods: We used two models of BC (MMTV-PyMT mice bearing spontaneous mammary tumors, and HT17 patient-derived xenografts) which recapitulate metastatic triple-negative BC in mice. Mice were treated with paclitaxel (10 mg/kg, IV) every 5 days for a total of 3 treatments. Mouse subgroups received an additional treatment of liposomes with the macrophage-depleting agent clodronate (200 µL, 18.4 µM concentration, IP), or PBS control liposomes, every 2 days. Mammary tumors were evaluated for: (1) TAM density, (2) number of “single positive” cells - defined as those expressing high levels of Sox9 (CSC marker) or MenaINV (invasion marker) - and (3) the number of “double positive” MenaINVHigh CSCs (Sox9HighMenaINVHigh). Results: We found that chemotherapy increased TAM density, and this corresponded with an increase in “double positive” MenaINVHigh CSCs. Upon macrophage depletion, MenaINVHigh CSCs fell to below baseline levels regardless of chemotherapy treatment. Chemotherapy did not increase “single positive” cells. Conclusion: The induction of prometastatic MenaINVHigh CSCs during chemotherapy is macrophage dependent. The finding that chemotherapy only affected double positive cells suggests that MenaINV and the CSC program are induced together, rather than independently, by TAMs. Further work is required to determine the mechanism of this co-induction. These results lay the groundwork for novel microenvironment-based therapies to alleviate the prometastatic effects of chemotherapy in BC. Citation Format: Madeline Friedman, Camille L. Duran, Ved P. Sharma, John S. Condeelis, Maja H. Oktay, George S. Karagiannis, David Entenberg. Chemotherapy increases invasive cancer stem cells in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2480.

Novel pathophysiological insights into CAR-T cell associated neurotoxicity.

Chimeric antigen receptor (CAR) T cell therapy represents a scientific breakthrough in the treatment of advanced hematological malignancies. It relies on cell engineering to direct the powerful cytotoxic T-cell activity toward tumor cells. Nevertheless, these highly powerful cell therapies can trigger substantial toxicities such as cytokine release syndrome (CRS) and immune cell-associated neurological syndrome (ICANS). These potentially fatal side effects are now better understood and managed in the clinic but still require intensive patient follow-up and management. Some specific mechanisms seem associated with the development of ICANS, such as cytokine surge caused by activated CAR-T cells, off-tumor targeting of CD19, and vascular leak. Therapeutic tools are being developed aiming at obtaining better control of toxicity. In this review, we focus on the current understanding of ICANS, novel findings, and current gaps.

Renalase Challenges the Oxidative Stress and Fibroproliferative Response in COVID-19.

The hallmark of the coronavirus disease 2019 (COVID-19) pathophysiology was reported to be an inappropriate and uncontrolled immune response, evidenced by activated macrophages, and a robust surge of proinflammatory cytokines, followed by the release of reactive oxygen species, that synergistically result in acute respiratory distress syndrome, fibroproliferative lung response, and possibly even death. For these reasons, all identified risk factors and pathophysiological processes of COVID-19, which are feasible for the prevention and treatment, should be addressed in a timely manner. Accordingly, the evolving anti-inflammatory and antifibrotic therapy for severe COVID-19 and hindering post-COVID-19 fibrosis development should be comprehensively investigated. Experimental evidence indicates that renalase, a novel amino-oxidase, derived from the kidneys, exhibits remarkable organ protection, robustly addressing the most powerful pathways of cell trauma: inflammation and oxidative stress, necrosis, and apoptosis. As demonstrated, systemic renalase administration also significantly alleviates experimentally induced organ fibrosis and prevents adverse remodeling. The recognition that renalase exerts cytoprotection via sirtuins activation, by raising their NAD+ levels, provides a “proof of principle” for renalase being a biologically impressive molecule that favors cell protection and survival and maybe involved in the pathogenesis of COVID-19. This premise supports the rationale that renalase's timely supplementation may prove valuable for pathologic conditions, such as cytokine storm and related acute respiratory distress syndrome. Therefore, the aim for this review is to acknowledge the scientific rationale for renalase employment in the experimental model of COVID-19, targeting the acute phase mechanisms and halting fibrosis progression, based on its proposed molecular pathways. Novel therapies for COVID-19 seek to exploit renalase's multiple and distinctive cytoprotective mechanisms; therefore, this review should be acknowledged as the thorough groundwork for subsequent research of renalase's employment in the experimental models of COVID-19.

Type 2 Diabetes Contributes to Altered Adaptive Immune Responses and Vascular Inflammation in Patients With SARS-CoV-2 Infection.

SARS-CoV-2, which initially emerged in November of 2019, wreaked havoc across the globe by leading to clinical acute respiratory distress syndrome and continues to evade current therapies today due to mutating strains. Diabetes mellitus is considered an important risk factor for progression to severe COVID disease and death, therefore additional research is warranted in this group. Individuals with diabetes at baseline have an underlying inflammatory state with elevated levels of pro-inflammatory cytokines and lower levels of anti-inflammatory cytokines, both of which cause these individuals to have higher susceptibility to SARS- CoV2 infection. The detrimental effects of SARS-CoV-2 has been attributed to its ability to induce a vast cell mediated immune response leading to a surge in the levels of pro-inflammatory cytokines. This paper will be exploring the underlying mechanisms and pathophysiology in individuals with diabetes and insulin resistance making them more prone to have worse outcomes after SARS- CoV2 infection, and to propose an adjunctive therapy to help combat the cytokine surge seen in COVID-19. It will also look at the immunomodulatory effects of glutathione, an antioxidant shown to reduce immune dysregulation in other diseases; Vitamin D, which has been shown to prevent COVID-19 patients from requiring more intensive care time possibly due to its ability to decrease the expression of certain pro-inflammatory cytokines; and steroids, which have been used as immune modulators despite their ability to exacerbate hyperglycemia.

Corona Virus Disease (COVID-19): A past and Present Prospective

Background: Corona virusis identified since 2002 and from seven strain severe acute respiratory syndrome corona virus and middle east respiratory syndrome corona virus causes severity in patients and then in December 2019, an outbreak of severe acute respiratory syndrome Corona virus 2 infection ensued in Wuhan, China and spread crosswise China and beyond. On February 12, 2020, WHO officially named the disease caused by the novel Corona virusas Corona virus Disease 2019 (COVID-19). Main Text: This form of virus comes up its growth when expose to any of the naturally expose material and the precaution for this is only single oriented, that is keeping yourself hygienic by washing your hands by utilizing high grade sanitizer. The literature survey revealed that Corona virus strain mainly severe acute respiratory syndrome corona virus and middle east respiratory syndrome Corona virus and human corona virus preserve on various surfaces like metal, glass or plastic for about 9 days but inactivation of virus by utilizing various virucide. On infection, the virus has a surge of proinflammatory cytokines and chemokines, which do damage to lung tissue, deterioration of lung function, and then eventually go to lung failure. Drug discovery against the virus is a challenging line of work owing to frequent recombination events. The evolution of a vaccine is another significant facet. Research is in ongoing stage to develop vaccine and medicines for COVID 19. In such circumstances, other system of medicineis widely used, like Allopathy, Ayurveda and Unani. Unani system of medicine utilized some measures for health protection during epidemics. In Unani medicine, during an epidemic, apart from isolation and quarantine, three measures are of utmost importance, impurification of surroundings using certain herbal drugs as fumigants or sprays, health promotion and immune-modulation, and use of health-protecting drugs and symptom-specific drugs. Conclusion: We require more structural biological details which put up rush up the drug or vaccine development process against corona virus. Thus, objective of this follow-up article is to focus on past to present perspective on corona virus pandemic.

Ocular transmissibility of COVID-19: possibilities and perspectives.

Since the initial outbreak of coronavirus disease 2019 (COVID-19), extensive research has emerged from across the globe to understand the pathophysiology of this novel coronavirus. Transmission of this virus is a subject of particular interest as researchers work to understand which protective and preventative measures are most effective. Despite the well understood model of aerosol-respiratory mediated transmission, the exact mechanism underlying the inoculation, infection and spread of COVID-19 is currently unknown. Given anatomical positioning and near constant exposure to aerosolized pathogens, the eye may be a possible gateway for COVID-19 infection. This critical review explores the possibility of an ocular-systemic or ocular–nasal–pulmonic pathway of COVID-19 infection and includes novel insights into the possible immunological mechanisms leading to cytokine surge.

Gda-201, a Novel Metabolically Enhanced Allogeneic Natural Killer (NK) Cell Product Yields High Remission Rates in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma (NHL): 2-Year Survival and Correlation with Cytokine IL7

Gda-201, a Novel Metabolically Enhanced Allogeneic Natural Killer (NK) Cell Product Yields High Remission Rates in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma (NHL): 2-Year Survival and Correlation with Cytokine IL7

DEXAMETHASONE AND AMPHOTERICIN B TO THE RESCUE: A CASE OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS

TOPIC: Critical Care TYPE: Fellow Case Reports INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a rare disease characterized by immune system overstimulation resulting in widespread inflammation, a cytokine surge, and multisystem organ failure. HLH is associated with significant mortality, so early recognition and a multidisciplinary approach to treatment are key for improved survival. CASE PRESENTATION: A 59-year-old kidney and pancreas transplant recipient presented with diarrhea, fevers, altered mental status, and acute kidney injury. He was transferred to the ICU due to respiratory distress and was started on antibiotics. CT scan of the chest and abdomen showed a small right lower lobe consolidation and mild splenomegaly. Sputum, urine, and blood cultures were negative. Serum fungitell was elevated and Aspergillus galactomannan serum antigen was positive. Serum Histoplasma antigen was >25ng/mL and urine Histoplasma antigen was 7.8ng/mL. Amphotericin B was started and hematology was consulted for presumed HLH secondary to histoplasmosis with elevated ferritin (7559 ng/mL) and triglycerides (227). Bone marrow aspirate demonstrated foamy histocytes and hemophagocytic histiocytes as well dimorphic fungal forms in the interstitium and within a granuloma on GMS stain consistent with Histoplasma. Dexamethasone was initiated at 10mg/m2. Soluble IL-2R was 14,120 U/mL. He clinically improved on dexamethasone and was transitioned from amphotericin to itraconazole. DISCUSSION: At least 5 out of 8 of the following criteria must be met for a diagnosis of HLH: fever, splenomegaly, cytopenia, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis in bone marrow, spleen or lymph nodes, low/absent NK-cell activity, ferritin ≥ 500 mg/L, and soluble CD25 ≥2400 U/mL. This patient had 6/8 of the diagnostic criteria for HLH: fever, splenomegaly, hypertriglyceridemia, ferritin >500, high soluble IL-2 receptor, and hemophagocytosis in bone marrow. A multidisciplinary discussion involving critical care, hematology, and transplant infectious disease was held about initiating Etoposide due to rising ferritin (based on evidence supporting the use of Etoposide in pediatric patients with HLH), however, data is lacking regarding how to treat adult patients with HLH and histoplasmosis. He was clinically improving without Etoposide and there was concern that Etoposide would make his histoplasmosis more difficult to treat, so he was not given Etoposide. Histoplasma is a known but rare cause of HLH (<50 published cases). Due to the rarity of HLH and its risk for mortality, it is important to have a high index of suspicion to test for HLH in an immunosuppressed patient who presents with fevers. CONCLUSIONS: Working with a multidisciplinary team was essential to both the diagnosis and management of HLH due Histoplasma due to a lack of evidence about optimal treatment. Research is needed to improve outcomes for patients with HLH due to Histoplasma. REFERENCE #1: Hayden, A., Park, S., Giustini, D., Lee, A. Y., & Chen, L. Y. (2016). Hemophagocytic syndromes (HPSs) including hemophagocytic lymphohistiocytosis (HLH) in adults: A systematic scoping review. Blood reviews, 30(6), 411–420. https://doi.org/10.1016/j.blre.2016.05.001 REFERENCE #2: Bergsten, E., Horne, A., Aricó, M., Astigarraga, I., Egeler, R. M., Filipovich, A. H., Ishii, E., Janka, G., Ladisch, S., Lehmberg, K., McClain, K. L., Minkov, M., Montgomery, S., Nanduri, V., Rosso, D., & Henter, J. I. (2017). Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study. Blood, 130(25), 2728–2738. https://doi.org/10.1182/blood-2017-06-788349 REFERENCE #3: Filipovich A. H. (2009). Hemophagocytic lymphohistiocytosis (HLH) and related disorders. Hematology. American Society of Hematology. Education Program, 127–131. https://doi.org/10.1182/asheducation-2009.1.127 DISCLOSURES: No relevant relationships by Maureen McElligott, source=Web Response No relevant relationships by Meilinh Thi, source=Web Response

Meeting Program and Abstracts

Graves' disease is an autoimmune condition characterized by hyperthyroidism due to higher levels of circulating autoantibodies that bind to and activate the thyrotropin receptors (TSH receptors) on the surface of thyroid follicular cells. We report a unique case of Graves' disease after the cytokine surge due to an infection with COVID-19. We present a case of a 45-year-old male with a past medical history of hypertension who developed graves' disease after being diagnosed with COVID-19, a highly infectious viral disease caused by SARS- COV 2. Physical examinations showed, patient to be tachycardiac, with an irregular pulse of 155 beats per minute. The patient had a mild resting bilateral hand tremor but did not have any sign of Graves' ophthalmopathy or dermopathy. Electrocardiogram tracing showed the heart rhythm in atrial fibrillation, and the Burch-Wartofsky Point Scale indicated a score of 25 reflecting an impending thyroid storm. Laboratory work-up conducted on the same day showed an undetectable TSH level with elevated free thyroxine (FT4) and free triiodothyronine (FT3). The patient was then started on medical therapy with Propranolol and Methimazole. This is a case of COVID-19 followed by graves hyperthyroidism. This case raises the possibility of triggering of autoimmunity due to cytokine surge seen in genetically susceptible COVID-19 patients. Hence one needs to recognize and treat the autoimmune conditions that might be seen in COVID-19 patients.

Interferon- gamma-induced protein-10 (IP-10) serum level and natural killer cell count as predictive factors for the severity of COVID-19

Background: The immune mechanisms underlying the pathology of COVID-19 are currently under immense scrutiny. Following NK and T cell activation, a surge of proinflammatory cytokines, and chemokines such IP-10, are found to increase. These cytokines stimulate the adaptive immune response and recruit other immune cells to the site of infection. Paradoxically, NK cells are known to be decreased in the peripheral circulation of severely ill COVID patients. It is not clear if this decrease in number is due to cell depletion or due to recruitment to sites of inflammation. The purpose of this study was to determine if there is a correlation between IP-10 levels and peripheral NK cell numbers and if this correlates with diseases severity. Methods: The study involved 30 patients divided into 2 groups (moderate and severe) depending on disease severity, as well as 15 age- and gender-matched controls. Serum IP-10 levels were assessed by ELISA and determination of NK cell numbers were determined by flow cytometry. Results: The results demonstrate an inverse relationship between NK cell numbers and IP-10 levels. Moreover, severely ill patients characteristically displayed decreased peripheral NK cell numbers and increased serum IP-10 levels in a manner that correlates with disease severity. Conclusion: The results demonstrate that disease severity is associated with increased production of chemokines such as IP-10 in the serum which may be involved in the recruitment of NK cells to peripheral tissues such as the lung, which may partially explain the decreased NK cell number associated with severe pathology.

Absence of Interleukin-6 Protects Murine Bone Marrow Erythropoiesis Under Inflammation, in a Process Reversible By Iron Mediated Reactive Oxygen Species Upregulation

Inflammatory states seen in infections and chronic disorders are often characterized by a condition called anemia of Inflammation (AI). Using a mouse model of AI generated by a single injection of the heat killed pathogen Brucella abortus (BA), we have previously shown that mice lacking IL6 (IL6 -KO mice) exhibited protected erythropoiesis in the bone marrow (BM) and a faster recovery from anemia compared to controls. To study the mechanism of IL6 mediated improved erythropoiesis under AI, we investigated erythroid recovery in WT and IL6 -KO mice injected with BA. 72 hours following BA administration, both genotypes showed impaired BM erythropoiesis associated by a surge in inflammatory cytokines such as IFNγ and TNFα and a concurrent increase in mitochondrial ROS (reactive oxygen species), specifically superoxide (SO) in erythroid progenitors. Cytokines levels were normalized after 24 hours. However, during the second phase of erythroid recovery (10-14 days following BA treatment), mice showed a second surge of inflammatory cytokines. During this phase, IL6 -KO mice showed significantly improved BM erythropoiesis and normalization of ROS levels. We analyzed SO levels by Mitosox red, generic ROS production using the chloromethyl derivative of 2′,7′-dichlorofluorescin diacetate and total protein oxidation (by looking at total protein carbonylation) by Western blot. These results were in sharp contrast to WT animals which continued to show upregulated ROS, total protein oxidation and slackened erythroid recovery.Given the extensive association of iron overloading conditions and oxidative stress, we investigated the improved erythroid recovery within IL6 -KO mice in the context of increased iron absorption. We asked if and how BM erythropoiesis would change in IL6 -KO mice lacking Hepcidin (Hamp), a key iron regulatory hormone whose absence induces iron overload. In double knock out mice lacking both IL6 and Hamp (DKO), we observed an initial improved erythroid recovery in the BM, as indicated by increased number of total BM erythroid progenitors and reticulocytes, and improved RBC lifespan. However, all of these factors regressed after 10 days, with a simultaneous increase of cytokine production. The deterioration of erythropoiesis in the BM was accompanied by a concurrent increase in ROS. Of note, compared to non-treated mice, erythroid progenitors in the spleen of DKO-BA did not show increased ROS levels, and this was associated with an increased number of splenic erythroid progenitors and RBC. These results point to a potential role in the microenvironment in influencing erythropoiesis under inflammation. Furthermore, these results suggest that while lack of IL6 protects BM erythropoiesis, iron overload could antagonize it. In fact, iron overloaded IL6 -KO mice (with iron dextran) did show an impairment in BM erythroid recovery and upregulation of ROS, similarly to the DKO. Finally, we hypothesized that while there is a distinct positive correlation between upregulated ROS and weakened BM erythropoiesis, this comes into effect only in the context of inflammation. In other words, we speculated that some level of ROS upregulation is otherwise a physiological byproduct of erythropoietic stress associated with the onset of anemia. In line with this theory, we found that ROS levels were indeed upregulated in BM erythroid progenitors of phlebotomized animals. Our data suggests a model of erythroid recovery under AI wherein inflammation exacerbates ROS production triggered by stress erythropoiesis, and that this phenomenon exquisitely impairs BM erythropoiesis. This negative effect on BM erythropoiesis is mitigated by the absence of IL6, but the lack of IL6 mediated protective function is reversible under conditions of iron overload (Figure 1).Our results, in combination with the upregulation of TNFa, suggest the involvement of non-apoptotic ROS associated programmed cell death such as necroptosis or ferroptosis, which are under investigation. We also have preliminary data pointing to mechanism of increased erythroid iron uptake that could potentially contribute to oxidative stress under AI. With these additional studies, we hope to further characterize the mechanisms surrounding improved BM erythropoiesis in the absence of ROS and IL6. Our studies could potentially characterize cellular responses that can be targeted in conditions of inflammation for therapeutic benefits. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Abstract #1017450: COVID-19 Associated Grave’s Disease Identified in a 45-year-old Male

Graves’ disease is an autoimmune condition characterized by hyperthyroidism due to higher levels of circulating autoantibodies that bind to and activate the thyrotropin receptors (TSH receptors) on the surface of thyroid follicular cells. We report the first known case of Graves’ disease as a result of the cytokine surge after infection with COVID-19.

Animal Models of COVID-19 II. Comparative Immunology.

Developing strong animal models is essential for furthering our understanding of how the immune system functions in response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. The alarming speed at which SARS-CoV-2 has spread, and the high mortality rate of severe Coronavirus Disease 2019 (COVID-19), has required both basic science and clinical research to move at an unprecedented pace. Models previously developed to study the immune response against SARS-CoV have been rapidly deployed to now study SARS-CoV-2. To date, both small and large animal models are remarkably consistent when infected with SARS-CoV-2; however, certain models have proven more useful when answering specific immunological questions than others. Small animal models, such as Syrian hamsters, ferrets, and mice carrying the hACE2 transgene, appear to reliably recapitulate the initial cytokine surge seen in COVID-19 as well as show significant innate and adaptive cell infiltration in to the lung early in infection. Additionally, these models develop strong antibody responses to the virus, are protected from reinfection, and genetically modified versions exist that can be used to ask specific immunological questions. Large animal models such as rhesus and cynomologus macaques and African green monkeys are critical to understanding how the immune system responds to SARS-CoV-2 infection because they are considered to be the most similar to humans. These models are considered the gold standard for assessing vaccine efficacy and protection, and recapitulate the initial cytokine surge, immune cell infiltration into the lung, certain aspects of thrombosis, and the antibody and T-cell response to the virus. In this review, we discuss both small and large animal model studies previously used in SARS-CoV-2 research that may be useful in elucidating the immunological contributions to hallmark syndromes observed with COVID-19.