Chimeric antigen receptor T cell (CART) therapy, administration of certain T cell-agonistic antibodies, immune check point inhibitors, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) and Toxic shock syndrome (TSS) caused by streptococcal as well as staphylococcal superantigens share one common complication, that is T cell-driven cytokine release syndrome (CRS) accompanied by multiple organ dysfunction (MOD). It is not understood whether the failure of a particular organ contributes more significantly to the severity of CRS. Also not known is whether a specific cytokine or signaling pathway plays a more pathogenic role in precipitating MOD compared to others. As a result, there is no specific treatment available to date for CRS, and it is managed only symptomatically to support the deteriorating organ functions and maintain the blood pressure. Therefore, we used the superantigen-induced CRS model in HLA-DR3 transgenic mice, that closely mimics human CRS, to delineate the immunopathogenesis of CRS as well as to validate a novel treatment for CRS. Using this model, we demonstrate that (i) CRS is characterized by a rapid rise in systemic levels of several Th1/Th2/Th17/Th22 type cytokines within a few hours, followed by a quick decline. (ii) Even though multiple organs are affected, small intestinal immunopathology is the major contributor to mortality in CRS. (iii) IFN-γ deficiency significantly protected from lethal CRS by attenuating small bowel pathology, whereas IL-17A deficiency significantly increased mortality by augmenting small bowel pathology. (iv) RNA sequencing of small intestinal tissues indicated that IFN-γ-STAT1-driven inflammatory pathways combined with enhanced expression of pro-apoptotic molecules as well as extracellular matrix degradation contributed to small bowel pathology in CRS. These pathways were further enhanced by IL-17A deficiency and significantly down-regulated in mice lacking IFN-γ. (v) Ruxolitinib, a selective JAK-1/2 inhibitor, attenuated SAg-induced T cell activation, cytokine production, and small bowel pathology, thereby completely protecting from lethal CRS in both WT and IL-17A deficient HLA-DR3 mice. Overall, IFN-γ-JAK-STAT-driven pathways contribute to lethal small intestinal immunopathology in T cell-driven CRS.

INTRODUCTION: Spontaneous Coronary Artery Dissection (SCAD) is a non-traumatic separation of coronary arterial wall causing intramural hemorrhage and obstruction of the arterial lumen. The most common presentation of SCAD is Acute Coronary Syndrome (ACS) however it accounts for only 4% of all ACS.CASE PRESENTATION: A 29-year-old Caucasian female with no medical history presented to emergency department (ED) with angina, elevated troponin and anterior STEMI on EKG. She collapsed in the ED with an underlying rhythm of Ventricular Fibrillation. ACLS restored spontaneous circulation. Bed side echocardiogram (ECHO) showed diffusely akinetic left ventricle with an approximate ejection fraction (EF) of 10%. Left heart catheterization (LHC) demonstrated a proximal left main coronary artery dissection spiraling into the left anterior descending, left circumflex and ramus intermedius artery causing complete occlusion of the left coronary system. No occlusive plaque was identified. PCI was done to all 3 arteries however post procedural period was complicated by persistently low Ejection Fraction (EF) of 23%, cardiogenic shock & bleeding and Hypoxia. Extracorporeal membrane oxygenation was considered but it was cancelled as her EF improved to 45% on repeat ECHO. She was weaned off ventilator and discharged home. Second review of LHC revealed string-of-beads appearance of the right iliac artery concerning for fibromuscular dysplasia (FMD) but screening for Ehler-Danlos & Marfan syndrome was negative.DISCUSSION: SCAD is more prevalent in females with a female to male ratio of 9:1. It constitutes 4% of all ACS, 35% of all ACS in females <50 years old & 43% of pregnancy related Myocardial Infarction (MI). SCAD may be genetically linked with FMD and is found together in 62-86% of cases. The mean age of presentation is 52.1 AE 9.2 years however it could be seen in any age group. Extreme emotions, physical stress, intense hormonal fluctuations, drug abuse and post-partum state are some of the known risk factors for SCAD. It is diagnosed with coronary angiography however intravascular ultrasound & optical coherence tomography are useful for the differentiation from atherosclerotic disease. Medical management is preferred however Percutaneous coronary intervention (PCI) may be required for unstable patients with ongoing ischemia, left main lesion or ventricular arrhythmia. Coronary artery bypass graft (CABG) is indicated for the left main stem dissection that has failed or are not amenable to PCI. Emergent CABG is required for PCI related complications in 10-13% of cases and therefore PCI should preferably be performed at centers with on-site cardiothoracic surgery.CONCLUSIONS: SCAD should be suspected in young females presenting with acute MI in absence of cardiac risk factors. FMD should be ruled out in patients with SCAD. Management depends upon the presentation, angiographic findings & clinical course.

Staphylococcal superantigens (SSAgs), produced by Staphylococcus aureus, non-specifically activate 30–50% of all CD4+ and CD8+ T cells expressing certain T cell receptor (TCR) Vb gene families. SSAg-activated T cells rapidly produce large quantities of cytokines and chemokines resulting in a systemic inflammatory response syndrome (SIRS), which culminates in multi organ failure (MOF) and ultimately death. Through this process, SSAgs play a significant role in the immunopathogenesis of pneumonia, sepsis, and toxic shock syndrome. Because most cytokines produced during SIRS act through the Janus Kinase (JAK) signaling pathway, we hypothesized that therapeutics inhibiting JAK functions would attenuate SIRS, MOF, and lower mortality caused by SSAgs. We tested ruxolitinib (RUXO), an FDA-approved selective JAK 1/2 inhibitor. Several in vitro and in vivo studies were performed using HLA-DR3 transgenic mice because SSAgs bind to HLA class II molecules with higher affinity. In vitro, at 100, 10, and 1 mm concentrations, RUXO significantly inhibited SSAg-induced upregulation of CD25 and CD69 on both CD4+ and CD8+ T cell subsets as well as SSAg-induced production of IL-2, IL-17, and IFN-g in a dose-dependent manner at 24 and 48 hours. For in vivo studies, mice (5–6 per group) were gavaged with RUXO (100 mg/kg) or vehicle, twice daily on days −1, 0 and 1, challenged with SSAg (20 mg/mouse, i.p) on day 0 and euthanized on day 2. SSAg-induced SIRS, thymocyte deletion, upregulation of activation markers (CD69 and CD25), and immunopathology were significantly attenuated in RUXO-treated mice compared to vehicle-treated mice. Overall, JAK inhibitors such as ruxolitinib can be used as an adjunct to treat serious diseases caused by SSAg.

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