Systemic Adaptive Immune Responses Research Articles

Systemic Lupus Erythematosus: New Diagnostic and Therapeutic Approaches.

Systemic lupus erythematosus (SLE) is a devastating autoimmune disease that can result in substantial morbidity and mortality. Diagnosis and treatment of SLE are clinical challenges. Patient presentation and response to therapy are heterogeneous because of the complex immune dysregulation that results in SLE disease pathogenesis. An intricate interplay between genetic risk and skewing of adaptive and innate immune system responses leads to overproduction of type I interferons and other cytokines, complement activation, immune-complex deposition, and ultimately inflammation and tissue damage. Here, we review the classification criteria as well as standard and emerging diagnostic tools available to identify patients with SLE. We then focus on medical management, including novel therapeutics, nonpharmacologic interventions, and comorbidity management.

Nanotechnology-Based siRNA Delivery Systems to Overcome Tumor Immune Evasion in Cancer Immunotherapy

Immune evasion is a common reason causing the failure of anticancer immune therapy. Small interfering RNA (siRNA), which can activate the innate and adaptive immune system responses by silencing immune-relevant genes, have been demonstrated to be a powerful tool for preventing or reversing immune evasion. However, siRNAs show poor stability in biological fluids and cannot efficiently cross cell membranes. Nanotechnology has shown great potential for intracellular siRNA delivery in recent years. Nano-immunotherapy can efficiently penetrate the tumor microenvironment (TME) and deliver multiple immunomodulatory agents simultaneously, which appears to be a promising method for combination therapy. Therefore, it provides a new perspective for siRNA delivery in immunomodulation and cancer immunotherapy. The current advances and challenges in nanotechnology-based siRNA delivery strategies for overcoming immune evasion will be discussed in this review. In addition, we also offer insights into therapeutic options, which may expand its applications in clinical cancer treatment.

Interactions among the mycobiome, bacteriome, inflammation, and diet in people living with HIV

ABSTRACT While the intestinal microbiome seems a major driver of persistent immune defects in people with HIV (PWH), little is known about its fungal component, the mycobiome. We assessed the inter-kingdom mycobiome–bacteriome interactions, the impact of diet, and the association with the innate and adaptive immunity in PWH on antiretroviral therapy. We included 24 PWH individuals and 12 healthy controls. We sequenced the Internal Transcribed Spacer 2 amplicons, determined amplicon sequence variants, measured biomarkers of the innate and adaptive immunity in blood and relations with diet. Compared to healthy controls, PWH subjects exhibited a distinct and richer mycobiome and an enrichment for Debaryomyces hansenii, Candida albicans, and Candida parapsilosis. In PWH, Candida and Pichia species were strongly correlated with several bacterial genera, including Faecalibacterium genus. Regarding the links between the mycobiome and systemic immunology, we found a positive correlation between Candida species and the levels of proinflammatory cytokines (sTNF-R2 and IL-17), interleukin 22 (a cytokine implicated in the regulation of mucosal immunity), and CD8+ T cell counts. This suggests an important role of the yeasts in systemic innate and adaptive immune responses. Finally, we identified inter-kingdom interactions implicated in fiber degradation, short-chain fatty acid production, and lipid metabolism, and an effect of vegetable and fiber intake on the mycobiome. Therefore, despite the great differences in abundance and diversity between the bacterial and fungal communities of the gut, we defined the changes associated with HIV, determined several different inter-kingdom associations, and found links between the mycobiome, nutrient metabolism, and systemic immunity.

Abstract 3531: Sensitizing immune unresponsive colorectal cancers to immune checkpoint inhibitors through MAVS overexpression

Abstract Background: The majority of colorectal carcinomas (CRCs) are insensitive to anti-PD-1/PD-L1 immune checkpoint inhibitor (ICI) antibodies. While there are many causes for ICI insensitivity, recent studies suggest that the suppression of innate immunity through a loss of innate immune adaptor expression could be a root cause of this insensitivity and an important factor in the evolution of tumor immunosuppression. Methods: We interrogated mitochondrial antiviral signaling gene (MAVS) expression through bioinformatics analyses of multiple datasets to validate its suppression in clinical samples. We then engineered MAVS expressing tumor cells and tested its ability to elicit innate and adaptive anti-tumor immunity using both in vitro and in vivo approaches, which we then confirmed using MAVS expressing viral vectors. Finally, we observed that MAVS stimulated PD-L1expression in different types of tumor cells and then assessed the combination of PD-L1 ICI antibodies with MAVS tumor expression in vivo. Results: MAVS was significantly downregulated in CRCs, but its re-expression could stimulate broad cellular interferon-related responses, in both murine and patient-derived CRCs. In vivo, local MAVS expression elicited significant anti-tumor responses in both immune-sensitive and insensitive CRC models, through the stimulation of an interferon responsive axis that elicited tumor antigen-specific adaptive immunity. Critically, we found that tumor-intrinsic MAVS expression triggered systemic adaptive immune responses that enabled abscopal CD8+ T cell cytotoxicity against distant CRCs. As MAVS also induced PD-L1 expression, we further found synergistic anti-tumor responses in combination with anti-PD-L1 ICIs. Conclusion: These data demonstrate that intratumoral MAVS expression results in local and systemic tumor antigen-specific T cell responses, which could be combined with PD-L1 ICI to permit effective anti-tumor immunotherapy in ICI resistant cancers. We are further exploring to overcome the ICI insensitivity of other types of solid tumor, with MAVS-delivery strategies other than viral vectors. Citation Format: Bin-Jin Hwang, Li-Chung Tsao, Chaitanya Acharya, Timothy Trotter, Pankaj Agarwal, Tao Wang, Junping Wei, Xiao-Yi Yang, Gang-jun Lei, Takuya Osada, Herbert Kim Lyerly, Michael A. Morse, Zachary Hartman. Sensitizing immune unresponsive colorectal cancers to immune checkpoint inhibitors through MAVS overexpression [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 3531.

NASAL NANO-VACCINE PREVENTS PRIMARY BREAST TUMOR FROM MAKING THE LUNG ITS NEW HOME

Abstract Despite medical advances in the diagnosis and treatment of cancer, metastatic breast cancers remain a leading cause of death in the U.S. Increasingly, novel immune-based treatments which harness the patient’s immune system have promise for improving survivorship. Such therapies take advantage of the immune system’s natural defense mechanisms to halt progression of breast cancer. This is through the early activation of innate immune cells such as natural killer cells and the subsequent activation of the adaptive immune responses such as T and B lymphocytes. Researchers have taken advantage of these immune mechanisms of tumor defense as a complementary approach to current radio-chemo treatments, which have shown to be limited by adverse off-target effects on patients. Ongoing research in our laboratory is focused on using nanotechnology to develop immune-based vaccines to target local immune protection against metastatic lung disease. Because the lung is naturally tolerogenic, making it easy for disseminated tumor cells to grow, the expectation is that boosting immune responses at the lungs before seeding tumors from primary organs would mitigate metastasis and reduce mortality risks. Using an experimental murine breast cancer model of metastasis, we examined the effect of intranasal vaccination to induce local and systemic adaptive immune responses. We hypothesized that an intranasal vaccine protocol would increase antigen-specific adaptive responses across the respiratory tract. Our results demonstrated that intranasal vaccination provides protection against secondary lung metastasis due to increased accumulation functional CD4+ and CD8+ T cells in the lungs as shown by flow cytometry and ELISA techniques. Supported by National Institute of Cancer Research of the Health under Award 1 P20 CA233355-01

Modulating the systemic and local adaptive immune response after fracture improves bone regeneration during aging.

Tissue injury leads to the well-orchestrated mobilization of systemic and local innate and adaptive immune cells. During aging, immune cell recruitment is dysregulated, resulting in an aberrant inflammatory response that is detrimental for successful healing. Here, we precisely define the systemic and local immune cell response after femur fracture in young and aging mice and identify increased toll-like receptor signaling as a potential culprit for the abnormal immune cell recruitment observed in aging animals. Myd88, an upstream regulator of TLR-signaling lies at the core of this aging phenotype, and local treatment of femur fractures with a Myd88 antagonist in middle-aged mice reverses the aging phenotype of impaired fracture healing, thus offering a promising therapeutic target that could overcome the negative impact of aging on bone regeneration.

Leveraging Antibody, B Cell and Fc Receptor Interactions to Understand Heterogeneous Immune Responses in Tuberculosis

Despite over a century of research, Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), continues to kill 1.5 million people annually. Though less than 10% of infected individuals develop active disease, the specific host immune responses that lead to Mtb transmission and death, as well as those that are protective, are not yet fully defined. Recent immune correlative studies demonstrate that the spectrum of infection and disease is more heterogenous than has been classically defined. Moreover, emerging translational and animal model data attribute a diverse immune repertoire to TB outcomes. Thus, protective and detrimental immune responses to Mtb likely encompass a framework that is broader than T helper type 1 (Th1) immunity. Antibodies, Fc receptor interactions and B cells are underexplored host responses to Mtb. Poised at the interface of initial bacterial host interactions and in granulomatous lesions, antibodies and Fc receptors expressed on macrophages, neutrophils, dendritic cells, natural killer cells, T and B cells have the potential to influence local and systemic adaptive immune responses. Broadening the paradigm of protective immunity will offer new paths to improve diagnostics and vaccines to reduce the morbidity and mortality of TB.

Changes in Specific Biomarkers Indicate Cardiac Adaptive and Anti-inflammatory Response of Repeated Recreational SCUBA Diving.

ObjectiveRecreational SCUBA (rSCUBA) diving has become a highly popular and widespread sport. Yet, information on molecular events underlying (patho)physiological events that follow exposure to the specific environmental conditions (hyperbaric conditions, coldness, immersion, and elevated breathing pressure), in which rSCUBA diving is performed, remain largely unknown. Our previous study suggested that repeated rSCUBA diving triggers an adaptive response of cardiovascular and immune system. To elucidate further molecular events underlying cardiac and immune system adaptation and to exclude possible adverse effects we measured blood levels of specific cardiac and inflammation markers.MethodsThis longitudinal intervention study included fourteen recreational divers who performed five dives, one per week, on the depth 20–30 m that lasted 30 min, after the non-dive period of 5 months. Blood samples were taken immediately before and after the first, third, and fifth dives. Copeptin, immunoglobulins A, G and M, complement components C3 and C4, and differential blood count parameters, including neutrophil-to-lymphocyte ratio (NLR) were determined using standard laboratory methods. Cell-free DNA was measured by qPCR analysis and N-glycans released from IgG and total plasma proteins (TPP), were analyzed by hydrophilic interaction ultra-performance liquid chromatography.ResultsCopeptin level increased after the first dive but decreased after the third and fifth dive. Increases in immunoglobulins level after every dive and during whole studied period were observed, but no changes in C3, C4, and cfDNA level were detected. NLR increased only after the first dive. IgG and TPP N-glycosylation alterations toward anti-inflammatory status over whole studied period were manifested as an increase in monogalyctosylated and core-fucosylated IgG N-glycans and decrease in agalactosylated TPP N-glycans.ConclusionrSCUBA diving practiced on a regular basis promotes anti-inflammatory status thus contributing cardioprotection and conferring multiple health benefits.

Sensitizing immune unresponsive colorectal cancers to immune checkpoint inhibitors through MAVS overexpression

BackgroundThe majority of colorectal carcinomas (CRCs) are insensitive to programmed death protein-1/programmed death-ligand 1 (anti-PD-1/PD-L1) immune checkpoint inhibitor (ICI) antibodies. While there are many causes for ICI insensitivity, recent studies...

Minthostachys verticillata Griseb (Epling.) (Lamiaceae) essential oil orally administered modulates gastrointestinal immunological and oxidative parameters in mice

Ethnopharmacological relevanceMinthostachys verticillata (Griseb.) Epling (Lamiaceae) is a plant used in folk medicine for digestive or respiratory disorders. In addition, it is incorporated as condiment, in foods, as beverage flavoring or mate. The ethnopharmacological interest of M. verticillata resides in its essential oil (EO). Part of group has demonstrated the immunomodulatory ability of EO giving this oil a biological potential not known until that moment and conducted studies to evaluate their possible application in diseases of veterinary interest. However, the immunomodulatory effects of EO administered orally have not been fully characterized. Aim of the studyThis study evaluated the impact of EO oral administration on gastrointestinal and immune health through measurement of immunological and oxidative parameters in mice. Material and methodsThe EO was extracted from the leaves, slender stems and flowers of M. verticillata by hydrodistillation and chemical analyzed by gas chromatography-mass spectrometry (GC-MS). Prior to in vivo study, the cytotoxic effect of EO was determined using the human colon carcinoma Caco-2 cell line. For in vivo study, three groups of male Balb/c mice (n = 3) were orally administered with saline solution (control group) and EO (5 or 10 mg/kg/day) during 10 consecutive days. Subsequently, histological and hematological parameters, cytokines production, oxidative markers and CD4+ and CD8+ T cells were evaluated. ResultsThe chemical analysis of EO revealed the presence of a high content of monoterpenes, being the main pulegone (76.12%) and menthone (14.28%). The EO oral administration improved mice growth performance and modulated systemic adaptive immune response by increasing in the total leukocyte number. A high percentage of CD4+ T cells were observed whereas the number of CD8+ T cells was not altered. EO did not alter the morpho-physiology of intestine and improved total antioxidant capacity by decreasing MDA concentrations. In addition, EO decreased the IL-6 levels and increased in the IL-4 and IL-10 concentrations. ConclusionResults indicate that M. verticillata EO modulate inflammatory and oxidative parameters constituting a natural alternative which could be applied to improve gastrointestinal and immune functionality in animals.

P354 Immunological response to vaccination against SARS-COV-2 infection in Inflammatory Bowel Disease patients under immunosuppressive therapy: should we prioritize an additional booster injection?

BackgroundThe severe acute respiratory syndrome coronavirus, 2 (SARS-COV-2) infection may lead to the development of the novel coronavirus disease, 2019 (COVID-19). Currently, little to no data is available regarding safety and efficacy of SARS-COV-2 vaccination in Inflammatory Bowel Disease (IBD) patients, which may present differences between subgroups, as these patients may exhibit impaired innate and adaptive immune system responses. Lower immunological response could, in this specific population, require an additional booster injection.MethodsWe conducted a prospective study including adult patients with Crohn’s disease (CD) and Ulcerative Colitis (UC) who have undergone complete vaccination against SARS-COV-2 infection with BioNTech® vaccine. Patients with previous SARS-COV-2 infection were excluded. Medical data regarding age, sex, IBD classification and current medication for IBD were collected.A control group with healthy individuals matched for age and sex was also analyzed.Blood samples were collected, 30 days after complete vaccination to quantify IgG antibody titers for SARS-COV-2 in both groups (IBD and non-IBD).ResultsOur final sample included, 81 IBD and, 32 non-IBD patients, 55 (48.7%) of them females, with a mean age of, 40.2±13.0 years. From the IBD patients, 58(71.6%) had CD and, 23(28.4%) had UC.IBD patients had significantly lower anti-SARS-COV-2 IgG levels when compared to the control group (8950±9366 vs, 14834±11679 AU/mL; p=0.003).Regarding IBD medication, significant lower levels of SARS-COV-2 IgG antibodies when compared to control patients were found in patients under thiopurines (9074±9779 AU/mL; p=0.011); methotrexate (1987±2568 AU/mL; p=0.002); infliximab (7208±7276 AU/mL; p=0.001); and corticosteroids (1065±933 AU/mL; p=0.001). Additionally, patients under combined therapy (infliximab plus thiopurines) presented with significantly lower antibodies titers when compared to patients treated with thiopurines in monotherapy (8130±11048 vs, 10563±5680 AU/mL; p=0.039).No significant differences were found in IBD patients under salicylates (10195±7371 AU/mL; p=0.226); adalimumab (15644±21467 AU/mL; p=0.336); vedolizumab (10464±9087 AU/mL; p=0.286) and ustekinumab (11366±10016 AU/mL; p=0.390).ConclusionIBD patients presented with significantly lower anti-SARS-COV-2 IgG levels, 1 month after complete vaccination against SARS-COV-2 infection compared to healthy controls. Thiopurines, methotrexate, infliximab and corticosteroid treatment were associated with significantly lower antibodies levels. These findings may express the benefit of an additional booster injection in this population.

Mesenchymal Stem Cell Immunomodulation: A Novel Intervention Mechanism in Cardiovascular Disease.

Mesenchymal stem cells (MSCs) are the member of multipotency stem cells, which possess the capacity for self-renewal and multi-directional differentiation, and have several characteristics, including multi-lineage differentiation potential and immune regulation, which make them a promising source for cell therapy in inflammation, immune diseases, and organ transplantation. In recent years, MSCs have been described as a novel therapeutic strategy for the treatment of cardiovascular diseases because they are potent modulators of immune system with the ability to modulating immune cell subsets, coordinating local and systemic innate and adaptive immune responses, thereby enabling the formation of a stable inflammatory microenvironment in damaged cardiac tissues. In this review, the immunoregulatory characteristics and potential mechanisms of MSCs are sorted out, the effect of these MSCs on immune cells is emphasized, and finally the application of this mechanism in the treatment of cardiovascular diseases is described to provide help for clinical application.

The Complement System, T Cell Response, and Cytokine Shift in Normotensive versus Pre-Eclamptic and Lupus Pregnancy.

Successful pregnancy requires an immunological shift with T helper CD4+ bias based on disbalance Th1/Th17 versus Th2/T regulatory (Tregs) required to induce tolerance against the semi-allogeneic fetus and placenta and to support fetal growth. Considered a pregnancy-specific hypertensive disorder, pre-eclampsia is characterized by multifaceted organ involvement related to impaired maternal immune tolerance to paternal antigens triggered by hypoxic placental injury as well as excessive local and systemic anti-angiogenic and inflammatory factor synthesis. Both systemic and local Th1/Th2 shift further expands to Th17 cells and their cytokines (IL-17) complemented by suppressive Treg and Th2 cytokines (IL-10, IL-4); alterations in Th17 and Tregs cause hypertension during pregnancy throughout vasoactive factors and endothelial dysfunction, providing an explanatory link between immunological and vascular events in the pathobiology of pre-eclamptic pregnancy. Apart from immunological changes representative of normotensive pregnancy, lupus pregnancy is generally defined by higher serum pro-inflammatory cytokines, lower Th2 polarization, defective and lower number of Tregs, potential blockade of complement inhibitors by anti-phospholipid antibodies, and similar immune alterations to those seen in pre-eclampsia. The current review underpins the immune mechanisms of pre-eclampsia focusing on local (placental) and systemic (maternal) aberrant adaptive and innate immune response versus normotensive pregnancy and pregnancy in systemic autoimmune conditions, particularly lupus.

Citral modulates human monocyte responses to Staphylococcus aureus infection

Staphylococcus aureus is a Gram-positive bacterium that is considered an important human pathogen. Due to its virulence and ability to acquire mechanisms of resistance to antibiotics, the clinical severity of S. aureus infection is driven by inflammatory responses to the bacteria. Thus, the present study aimed to investigate the modulating role of citral in inflammation caused by S. aureus infection. For this, we used an isolate obtained from a nasal swab sample of a healthy child attending a day-care centre in Vitória da Conquista, Bahia, Brazil. The role of citral in modulating immunological factors against S. aureus infection was evaluated by isolating and cultivating human peripheral blood mononuclear cells. The monocytes were treated with 4%, 2%, and 1% citral before and after inoculation with S. aureus. The cells were analysed by immunophenotyping of monocyte cell surface molecules (CD54, CD282, CD80, HLA-DR, and CD86) and cytokine dosage (IL-1β, IL-6, IL-10, IL-12p70, IL-23, IFN-γ, TGF-β, and TNF-α), and evaluated for the expression of 84 genes related to innate and adaptive immune system responses. GraphPad Prism software and variables with P values < 0.05, were used for statistical analysis. Our data demonstrated citral’s action on the expression of surface markers involved in recognition, presentation, and migration, such as CD14, CD54, and CD80, in global negative regulation of inflammation with inhibitory effects on NF-κB, JNK/p38, and IFN pathways. Consequently, IL-1β, IL-6, IL-12p70, IL-23, IFN-γ, and TNF-α cytokine expression was reduced in groups treated with citral and groups treated with citral at 4%, 2%, and 1% and infected, and levels of anti-inflammatory cytokines such as IL-10 were increased. Furthermore, citral could be used as a supporting anti-inflammatory agent against infections caused by S. aureus. There are no data correlating citral, S. aureus, and the markers analysed here; thus, our study addresses this gap in the literature.

A common approach for fighting tuberculosis and leprosy: controlling endoplasmic reticulum stress in myeloid-derived suppressor cells.

Leprosy and tuberculosis are infectious diseases that are caused by bacteria, and both share primary risk factors. Mediators of these diseases are regulated by a heterogeneous immature population of myeloid cells called myeloid-derived suppressor cells (MDSCs) that exhibit immunosuppressive activity against innate and adaptive immunity. During pathological conditions, endoplasmic reticulum (ER) stress occurs in MDSCs, and high levels of ER stress affect MDSC-linked immunosuppressive activity. Investigating the role of ER stress in regulating immunosuppressive functions of MDSCs in leprosy and tuberculosis may lead to new approaches to treating these diseases. Herethe authors discuss the immunoregulatory effects of ER stress in MDSCs as well as the possibility of targeting unfolded protein response elements of ER stress to diminish the immunosuppressive activity of MDSCs and reinvigorate diminished adaptive immune system responses that occur in leprosy and tuberculosis.

Pathophysiological and Clinical Aspects of Chronic Rhinosinusitis: Current Concepts.

Adult chronic rhinosinusitis (CRS) is a chronic inflammation of the mucosa of the nose and paranasal sinuses. According to the latest EPOS guidelines CRS should be regarded as primary or secondary with distinction between diffuse and localized disease. Further pathophysiologic research identified different inflammatory patterns leading to the term “endotyping of CRS.” The primary focus of endotyping is to define a dominant inflammatory type allowing for better orientation of therapy. The current approach proposes the differentiation between type 2 (eosinophilic) and non-type 2 inflammatory responses. In this review pathophysiological concepts of CRS will be discussed, focusing on the different inflammatory endotypes of T cells with special attention to the eosinophilic type 2 inflammatory response. The contribution of innate and adaptive immune system responses is presented. The possibility of endotyping based on sinonasal secretions sampling is brought to attention because it is indicative of corticosteroid responsiveness and available to most ENT surgeons. Furthermore, the clinical aspects of the three distinct phenotypes are analyzed in view of their characteristics, the related endoscopic findings, typical radiological imaging, histopathology findings, their relation toward allergy and obvious therapeutical implications. This overview will enable clinicians to relate pathophysiological patterns with clinical observations by explaining the different inflammatory mechanisms, hence providing a better understanding of therapy.

Repeated exposure to inactivated Streptococcus pneumoniae induces asthma-like pathological changes in mice in the presence of IL-33

While environmental aeroallergens and epithelial alarmins such as IL-33 are firmly implicated in asthma, the possible role of Streptococcus pneumoniae (S. pneumoniae) antigens is less clear. To explore this, wild-type BALB/c mice were repeatedly challenged per-nasally with IL-33 and inactivated S. pneumoniae, either agent alone or diluent control. Some animals were rested then later re-challenged with inactivated S. pneumoniae alone. Serum concentrations of S. pneumoniae lysates-specific IgE were measured in patients with asthma and control subjects. Interestingly, in the presence of IL-33, repeated exposure to inactivated S. pneumoniae induced asthma-like pathological changes accompanied by a systemic adaptive immune response. Subsequent re-exposure of the sensitized animals to inactivated S. pneumoniae alone was able to induce such changes. The concentration of S. pneumoniae lysates-specific IgE was significantly elevated in the asthma patients. These data suggest that antigens derived from infectious microorganisms may participate in generating the mucosal inflammation which characterizes asthma.

The Promise and Challenges of Cyclic Dinucleotides as Molecular Adjuvants for Vaccine Development.

Cyclic dinucleotides (CDNs), originally discovered as bacterial second messengers, play critical roles in bacterial signal transduction, cellular processes, biofilm formation, and virulence. The finding that CDNs can trigger the innate immune response in eukaryotic cells through the stimulator of interferon genes (STING) signalling pathway has prompted the extensive research and development of CDNs as potential immunostimulators and novel molecular adjuvants for induction of systemic and mucosal innate and adaptive immune responses. In this review, we summarize the chemical structure, biosynthesis regulation, and the role of CDNs in enhancing the crosstalk between host innate and adaptive immune responses. We also discuss the strategies to improve the efficient delivery of CDNs and the recent advance and future challenges in the development of CDNs as potential adjuvants in prophylactic vaccines against infectious diseases and in therapeutic vaccines against cancers.

Immune cells in lens injury repair and fibrosis

Immune cells, both tissue resident immune cells and those immune cells recruited in response to wounding or degenerative conditions, are essential to both the maintenance and restoration of homeostasis in most tissues. These cells are typically provided to tissues by their closely associated vasculatures. However, the lens, like many of the tissues in the eye, are considered immune privileged sites because they have no associated vasculature. Such absence of immune cells was thought to protect the lens from inflammatory responses that would bring with them the danger of causing vision impairing opacities. However, it has now been shown, as occurs in other immune privileged sites in the eye, that novel pathways exist by which immune cells come to associate with the lens to protect it, maintain its homeostasis, and function in its regenerative repair. Here we review the discoveries that have revealed there are both innate and adaptive immune system responses to lens, and that, like most other tissues, the lens harbors a population of resident immune cells, which are the sentinels of danger or injury to a tissue. While resident and recruited immune cells are essential elements of lens homeostasis and repair, they also become the agents of disease, particularly as progenitors of pro-fibrogenic myofibroblasts. There still remains much to learn about the function of lens-associated immune cells in protection, repair and disease, the knowledge of which will provide new tools for maintaining the core functions of the lens in the visual system.

POS1250 VITAMIN D DEFICIENCY IS MAINLY ASSOCIATED WITH SEVERE LUNG INVOLVEMENT, LONGER DISEASE DURATION AND RISK OF DEATH IN ELDERLY COVID-19 PATIENTS

Background:Vitamin D regulates the innate and adaptive immune system responses and low vitamin D levels have been associated with the increased risk of respiratory tract infections (1). Vitamin D deficiency has been recently reported to interfere with the prognosis of COVID-19 (2,3).Objectives:The aim of this study was to correlate the 25OH-vitamin D serum levels with lung involvement and disease severity, in a cohort of elderly patients hospitalized for SARS-CoV-2 infection.Methods:Sixty-five COVID-19 patients (mean age 76±13 years) and sixty-five sex- and age-matched control subjects (CNT) were included in the study. Respiratory parameters (PaO2, SO2, PaCO2, PaO2/FiO2), clinical and laboratory parameters (including 25OH-vitamin D, D-dimer, C-reactive protein) and type of radiological pulmonary involvement were collected at hospital admission. Statistical analysis was performed by non-parametric tests.Results:Vitamin D sufficiency (&gt;30 ng/ml), insufficiency (between 20 and 30 ng/ml), deficiency (between 10 and 20 ng/ml) and severe deficiency (&lt;10 ng/ml) were observed respectively in 11, 11, 21 and 57 % of COVID-19 patients. Vitamin D serum levels were found significantly lower in COVID-19 patients than in CNT (median 8 vs 16 ng/ml, p=0.001). A statistically significant positive correlation was observed between vitamin D serum levels and SO2 (p=0.05), PaO2 (p=0.03), PaO2/FiO2 (p=0.02). A statistically significant negative correlation was found between vitamin D serum levels and severity of radiologic pulmonary involvement: vitamin D was significantly lower in COVID-19 patients with either diffuse/severe interstitial lung involvement (p=0.05) or multiple lung consolidations (p=0.0001) than in those with mild radiological lung involvement. Significantly lower vitamin D serum levels were found in COVID-19 patients who died during hospitalization, compared to those who survived (median 3 vs 8 ng/ml, p=0.05). Finally, a statistically significant negative correlation was found between vitamin D serum levels and D-dimer (p=0.04), C-reactive protein (p=0.04) and disease duration (p=0.05).Conclusion:This study confirms that severe vitamin D deficiency is associated with more severe lung involvement, longer disease duration and risk of death in elderly COVID-19 patients.