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    An Atypical case of Hemophagocytic Lymphohistiocytosis possibly secondary to Systemic Lupus Erythematosus Flare in a Female Patient
    (2023) Kasim, Chaitanya; Ivan, Jared
    Hemophagocytic Lymphohistiocytosis (HLH) is a rare autoimmune disease in which histiocytes and lymphocytes attack the body’s own resulting in severe fever, organ damage, and pancytopenia. Initial signs and symptoms of HLH can mimic common infections, malignancy, hepatitis, or encephalitis making it difficult to distinguish. Case Presentation: A 33-year-old female presented to the hospital for daily recurrent fevers ongoing for 2 weeks. Four weeks prior, patient underwent a dilatation and curettage procedure for a molar pregnancy. Patient endorses 5 kg unintentional weight loss, heavy night sweats, nausea, vomiting, and chills. She immigrated to the U.S. from Nepal three years prior. Upon admission, her labs were significant for pancytopenia. Her physical exam was significant for bilateral axillary lymphadenopathy. She was subsequently started on broad-spectrum antibiotics due to concern for possible endometritis. All infectious workup was unremarkable. After 5 days of antibiotic treatment, she continued having cyclical fevers without resolution of symptoms. CT imaging revealed bilateral lymphadenopathy that was concerning for possible malignancy. Her lymph node biopsy was significant for necrotizing granulomatous lymphadenitis (NGL). NGL is very nonspecific and includes a wide array of differentials from malignancy, infectious etiology, or autoimmune disease. Bone marrow biopsy was significant for pancytopenia and depleted iron stores While waiting for her biopsy results, autoimmune work up was initiated as patient reported diffuse joint stiffness, dry mouth, and a malar rash. Autoimmune work up was significant for elevated ANA titer and elevated IL2- receptor. However, C3, C4, RF, anti-ds DNA, anti-Smith, and CCP within normal limits. Initially, rheumatology believed this was not a lupus flare as C3 and C4 levels were normal. About 8 days after admission, the patient started experiencing right upper quadrant pain and labs revealed significant transaminitis and proteinuria. However, autoimmune hepatitis panel was negative. On day 15 of admission, the patient’s malar rash resolved and she was afebrile for 2 days. Due to her clinical improvement, Adult onset Still’s disease and Kikuchi’s lymphadenitis were high on the differential, which usually spontaneously resolve. However, on day 17 of admission, patient started to experience high grade fevers and became very hypotensive. Her labs showed worsening transaminitis, elevated triglycerides at 517, and elevated ferritin level above 40,000. Due to her worsening clinical condition, she was started on high dose steroids and hydroxychloroquine for HLH and possible acute lupus flare. After initiation of treatment, patient started to show signs of clinical improvement and labs were trending in the right direction. The patient met 4/17 diagnostic criteria for lupus and 5/8 diagnostic criteria for HLH. However, it was hard to determine in HLH was primary, secondary to an acute lupus flare, or secondary to stress from a miscarriage. Although the patient met diagnostic criteria for lupus; normal complement levels make a lupus flare less likely. In HLH, bone marrow biopsy usually shows the presence of macrophages, but hers only showed pancytopenia and iron depletion. This case emphasizes that clinicians cannot always rely on typical diagnostic findings and sometimes must treat based on a risk-benefit analysis.
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    Expression of Immune Receptors in Response to Chemotherapy Treatment in B and T Acute Lymphoblastic Leukemia
    (2023) Ahmed, Nourhan; Mathew, Stephen O.
    Acute Lymphoblastic Leukemia (ALL) represents the most common pediatric cancer. Most patients (85%) develop B-cell ALL, however, T-cell ALL tends to be more aggressive and show less promising prognosis. Significant improvements in chemotherapy regimens caused a leap in the 5-year survival rates to surpass 90%. However, relapse significantly lowers the chances of survival to less than 50% due to resistance developed by malignant cells to chemotherapy. Natural Killer (NK) cells represent the cytotoxic compartment of innate immunity. As opposed to T cells, NK cells can recognize and kill malignant cells without the need for antigen presentation. NK cells currently represent a promising immunotherapy alternative to traditional chemotherapy. They directly kill cancer cells through activation/inhibition signals or through cytokine release and mediating an adaptive response. As targets of interest for our research, we chose LLT1, CD155 and PCNA as NK-inhibitory receptors and CS1, 2B4 as activation receptors. Previously, we have shown a significant decrease of LLT1, 2B4 and CS1 on T lymphoblasts of ALL patients collected from 42 subjects after induction chemotherapy and compared with samples from 20 healthy subjects. Based on the preliminary data, in this study we are investigating the effect of chemotherapy on the expression of those activating and inhibitory receptors. Cell surface protein expression and mRNA expression of these NK receptors pre- and post-Doxorubicin and Vincristine treatment of B and T ALL cell lines have been analyzed. Resistance to chemotherapy is one of the major reasons for failure of treatment in cancer recurrence. However, the cytotoxic potential of NK cells can be harnessed to overcome the chemo-resistance seen in leukemic cells.
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    T cell alterations in a mouse model of neglect-related early life stress
    (2023) Choe, Jamie Y.; Donkor, Michael; Jones, Harlan P.
    Exposure to severe or chronically stressful life events during childhood—referred to as early life stress (ELS)—is associated with negative effects on health across the life course. Neglect is a significant source of ELS during childhood and accounts for over 75% of maltreatment-related child abuse in the United States. Animal models of ELS emulate the nature of childhood neglect through scheduled separation. A major challenge in studying the impact of stress on immune competency has been the difficulty of developing a reliable mouse model. The thymus is responsible for producing self-tolerant T cells and is critical for adaptive immunity. Developing T cells can be identified based on CD4/CD8 expression status which corresponds to defined stages in thymocyte maturation. We developed a novel murine model of neglect-related ELS based on the maternal separation with early weaning (MSEW) paradigm featuring scheduled dam-pup separation and early weaning to a high carbohydrate diet. This study investigates the effect of ELS on surface markers for thymic T cell development and distribution. Pups were produced by in-house breeding and subjected to one of two distinct ELS conditions: (1) daily dam-pup separation with early weaning (MSEW) or (2) the early weaning condition alone (EW) at postnatal day (PD) 14. Control pups were maintained on the dam’s milk to the standard wean date (PD21). Tissues were collected at PD21 after euthanasia. Flow cytometry revealed significant differences in the distribution of PD21 thymocytes between the double-positive CD4+CD8+ (DP) and single-positive (SP) compartments. Our data indicate that neglect-related ELS can disrupt the baseline distribution of developing T cells within defined thymic compartments and suggests ELS exposure may have downstream ramifications on T cell immunity.
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    Active suppression of adaptive immunity by Borrelia burgdorferi in the murine host
    (2023) Williams, Megan; Zhang, Yan; Kilgore, Rebecca; Allen, Michael
    Purpose: Borrelia burgdorferi(Bb), the spirochetal agent of Lyme disease, utilizes a variety of tactics to evade and suppress the host immune response which enable it to persist chronically. These tactics can include complement inhibition, antigenic variation, extracellular matrix degradation, and adaptive immune suppression. Adaptive immune suppression by Bb is still not well understood. Previous studies have shown that lymph node (LN) germinal centers generated in response to Bb collapse one-month post-infection. The resulting humoral immune response is characterized by unusually strong and persistent IgM production and lack of long-lived immunity. Here we aimed to better characterize how Bb manipulates the host humoral immune response, ultimately resulting in failure to clear the infection. Methods: Mice were infected with Bb and concomitantly immunized with recombinant SARS-CoV-2 spike protein to measure the antibody response to the immunization and how it may be dampened by infection with Bb. We also immunized mice at 2-, 4-, and 6-weeks post-infection to test how long this humoral immune suppression lasts. Using RT-qPCR, we also examined changes to gene expression in murine LNs 15 days post-infection to better characterize what may be causing this observed immune dysfunction. Results: Suppression of host antibody production against the rSARS-CoV-2 spike protein peaked at 2 weeks post-infection but continued for all timepoints measured. We also found that live Bb, but not heat-killed (HK) Bb, broadly suppressed many genes related to T cell homing and function. Genes which play a critical role in the establishment and maintenance of T cell zones within the LNs, Ccl19 and Ccr7, were significantly downregulated. This was interesting considering previous studies have provided evidence of disorganization of LN architecture and the disruption of T cell zones beginning around 10 days post-infection. In addition, both Il2 and Il2ra were significantly downregulated, which is typically observed during the resolution of infection and indicates a lack of antigenic restimulation. Conclusion: These data suggest potential T cell disruption by Bb, which may play a role in the failure to mount an appropriate humoral immune response to the infection.