Computational detection of antigen-specific B cell receptors following immunization.

B cell receptors (BCRs) play a crucial role in recognizing and fighting foreign antigens. High-throughput sequencing enables in-depth sampling of the BCRs repertoire after immunization. However, only a minor fraction of BCRs actively participate in any given infection. To what extent can we accurately identify antigen-specific sequences directly from BCRs repertoires? We present a computational method grounded on sequence similarity, aimed at identifying statistically significant responsive BCRs. This method leverages well-known characteristics of affinity maturation and expected diversity. We validate its effectiveness using longitudinally sampled human immune repertoire data following influenza vaccination and SARS-CoV-2 infections. We show that different lineages converge to the same responding Complementarity Determining Region 3, demonstrating convergent selection within an individual. The outcomes of this method hold promise for application in vaccine development, personalized medicine, and antibody-derived therapeutics.

An Ancestral Major Histocompatibility Complex Organization in Cartilaginous Fish: Reconstructing MHC Origin and Evolution.

Cartilaginous fish (sharks, rays, and chimeras) comprise the oldest living jawed vertebrates with a mammalian-like adaptive immune system based on immunoglobulins (Ig), T-cell receptors (TCRs), and the major histocompatibility complex (MHC). Here, we show that the cartilaginous fish "adaptive MHC" is highly regimented and compact, containing (i) a classical MHC class Ia (MHC-Ia) region containing antigen processing (antigen peptide transporters and immunoproteasome) and presenting (MHC-Ia) genes, (ii) an MHC class II (MHC-II) region (with alpha and beta genes) with linkage to beta-2-microglobulin (ß2m) and bromodomain-containing 2, (iii) nonclassical MHC class Ib (MHC-Ib) regions with 450 million-year-old lineages, and (iv) a complement C4 associated with the MHC-Ia region. No MHC-Ib genes were found outside of the elasmobranch MHC. Our data suggest that both MHC-I and MHC-II genes arose after the second round of whole-genome duplication (2R) on a human chromosome (huchr) 6 precursor. Further analysis of MHC paralogous regions across early branching taxa from all jawed vertebrate lineages revealed that Ig/TCR genes likely arose on a precursor of the huchr9/12/14 MHC paralog. The ß2m gene is linked to the Ig/TCR genes in some vertebrates suggesting that it was present at 1R, perhaps as the donor of C1 domain to the primordial MHC gene. In sum, extant cartilaginous fish exhibit a conserved and prototypical MHC genomic organization with features found in various vertebrates, reflecting the ancestral arrangement for the jawed vertebrates.

Immmunometabolism of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a potentially fatal chronic autoimmune disease which is underlain by complex dysfunction of the innate and adaptive immune systems. Although a series of well-defined genetic and environmental factors have been implicated in disease etiology, neither the development nor the persistence of SLE is well understood. Given that several disease susceptibility genes and environmental factors interact and influence inflammatory lineage specification through metabolism, the field of immunometabolism has become a forefront of cutting edge research. Along these lines, metabolic checkpoints of pathogenesis have been identified as targets of effective therapeutic interventions in mouse models and validated in clinical trials. Ongoing studies focus on mitochondrial oxidative stress, activation of the mechanistic target of rapamycin, calcium signaling, glucose utilization, tryptophan degradation, and metabolic cross-talk between gut microbiota and the host immune system.

Loss of αß but not γδ T cells in chickens causes a severe phenotype.

The availability of genetically modified mice has facilitated the study of mammalian T cells. No model has yet been developed to study these cells in chickens, an important livestock species with a high availability of γδ T cells. To investigate the role of γδ and αß T cell populations in birds, we generated chickens lacking these T cell populations. This was achieved by genomic deletion of the constant region of the T cell receptor γ or ß chain, leading to a complete loss of either γδ or αß T cells. Our results show that a deletion of αß T cells but not γδ T cells resulted in a severe phenotype in KO chickens. The αß T cell KO chickens exhibited granulomas associated with inflammation of the spleen and the proventriculus. Immunophenotyping of αß T cell KO chickens revealed a significant increase in monocytes and expectedly the absence of CD4+ T cells including FoxP3+ regulatory T cells. Surprisingly there was no increase of γδ T cells. In addition, we observed a significant decrease in immunoglobulins, B lymphocytes, and changes in the bursa morphology. Our data reveal the consequences of T cell knockouts in chickens and provide new insights into their function in vertebrates.

FURIN regulates cytotoxic T-lymphocyte effector function and memory cell transition in mice.

The proprotein convertase subtilisin/kexins (PCSKs) regulate biological actions by cleaving immature substrate proteins. The archetype PCSK, FURIN, promotes the pathogenicity of viruses by proteolytically processing viral proteins. FURIN has also important regulatory functions in both innate and adaptive immune responses but its role in the CD8+ CTLs remains enigmatic. We used a T-cell-specific FURIN deletion in vivo to demonstrate that FURIN promotes host response against the CTL-dependent lymphocytic choriomeningitis virus by virtue of restricting viral burden and augmenting interferon gamma (IFNG) production. We also characterized Furin KO CD8+ T cells ex vivo, including after their activation with FURIN regulating cytokines IL12 or TGFB1. Furin KO CD8+ T cells show an inherently activated phenotype characterized by the upregulation of effector genes and increased frequencies of CD44+ , TNF+ , and IFNG+ cells. In the activated CTLs, FURIN regulates the productions of IL2, TNF, and GZMB and the genes associated with the TGFBR-signaling pathway. FURIN also controls the expression of Eomes, Foxo1, and Bcl6 and the levels of ITGAE and CD62L, which implies a role in the development of CTL memory. Collectively, our data suggest that the T-cell expressed FURIN is important for host responses in viral infections, CTL homeostasis/activation, and memory development.

Alterations of Peripheral Lymphocyte Subsets in Isolated Rapid Eye Movement Sleep Behavior Disorder.

BACKGROUND: Adaptive immune dysfunction may play a crucial role in Parkinson's disease (PD) development. Isolated rapid eye movement sleep behavior disorder (iRBD) represents the prodromal stage of synucleinopathies, including PD. Elucidating the peripheral adaptive immune system is crucial in iRBD, but current knowledge remains limited. OBJECTIVE: This study aimed to characterize peripheral lymphocyte profiles in iRBD patients compared with healthy control subjects (HCs). METHODS: This cross-sectional study recruited polysomnography-confirmed iRBD patients and age- and sex-matched HCs. Venous blood was collected from each participant. Flow cytometry was used to evaluate surface markers and intracellular cytokine production in peripheral blood mononuclear cells. RESULTS: Forty-four iRBD patients and 36 HCs were included. Compared with HCs, patients with iRBD exhibited significant decreases in absolute counts of total lymphocytes and CD3+ T cells. In terms of T cell subsets, iRBD patients showed higher frequencies and counts of proinflammatory T helper 1 cells and INF-γ+ CD8+ T cells, along with lower frequencies and counts of anti-inflammatory T helper 2 cells. A significant increase in the frequency of central memory T cells in CD8+ T cells was also observed in iRBD. Regarding B cells, iRBD patients demonstrated reduced frequencies and counts of double-negative memory B cells compared with control subjects. CONCLUSIONS: This study demonstrated alterations in the peripheral adaptive immune system in iRBD, specifically in CD4+ and INF-γ+ CD8+ T cell subsets. An overall shift toward a proinflammatory state of adaptive immunity was already evident in iRBD. These observations might provide insights into the optimal timing for initiating immune interventions in PD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Destabilisation of T cell-dependent humoral immunity in sepsis.

Sepsis is a heterogeneous condition defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. For some, sepsis presents as a predominantly suppressive disorder, whilst others experience a pro-inflammatory condition which can culminate in a 'cytokine storm'. Frequently, patients experience signs of concurrent hyper-inflammation and immunosuppression, underpinning the difficulty in directing effective treatment. Although intensive care unit mortality rates have improved in recent years, one-third of discharged patients die within the following year. Half of post-sepsis deaths are due to exacerbation of pre-existing conditions, whilst half are due to complications arising from a deteriorated immune system. It has been suggested that the intense and dysregulated response to infection may induce irreversible metabolic reprogramming in immune cells. As a critical arm of immune protection in vertebrates, alterations to the adaptive immune system can have devastating repercussions. Indeed, a marked depletion of lymphocytes is observed in sepsis, correlating with increased rates of mortality. Such sepsis-induced lymphopenia has profound consequences on how T cells respond to infection but equally on the humoral immune response that is both elicited by B cells and supported by distinct CD4+ T follicular helper (TFH) cell subsets. The immunosuppressive state is further exacerbated by functional impairments to the remaining lymphocyte population, including the presence of cells expressing dysfunctional or exhausted phenotypes. This review will specifically focus on how sepsis destabilises the adaptive immune system, with a closer examination on how B cells and CD4+ TFH cells are affected by sepsis and the corresponding impact on humoral immunity.

An immunological puzzle: The adaptive immune system fuels Alzheimer's disease pathology.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by a concerning rise in prevalence. It is projected that the number of affected individuals will reach a staggering 150 million by 2050. While recent advancements in monoclonal antibodies targeting Aß have shown some clinical effects, there is an urgent need for improved therapies to effectively address the impeding surge of AD patients worldwide. To achieve this, a deeper understanding of the intricate mechanisms underlying the disease is crucial. In recent years, mounting evidence has underscored the vital role of the innate immune system in AD pathology. However, limited findings persist regarding the involvement of the adaptive immune system. Here, we report on the impact of the adaptive immune system on various aspects of AD by using AppNL-G-F mice crossed into a Rag2-/- background lacking mature adaptive immune cells. In addition, to simulate the continuous exposure to various challenges such as infections that is commonly observed in humans, the innate immune system was activated through the repetitive induction of peripheral inflammation. We observed a remarkably improved performance on complex cognitive tasks when a mature adaptive immune system is absent. Notably, this observation is pathologically associated with lower Aß plaque accumulation, reduced glial activation, and better-preserved neuronal networks in the mice lacking a mature adaptive immune system. Collectively, these findings highlight the detrimental role of the adaptive immune system in AD and underscore the need for effective strategies to modulate it for therapeutic purposes.

Inflammatory and Immune Mechanisms for Atherosclerotic Cardiovascular Disease in HIV.

Atherosclerotic vascular disease disproportionately affects persons living with HIV (PLWH) compared to those without. The reasons for the excess risk include dysregulated immune response and inflammation related to HIV infection itself, comorbid conditions, and co-infections. Here, we review an updated understanding of immune and inflammatory pathways underlying atherosclerosis in PLWH, including effects of viral products, soluble mediators and chemokines, innate and adaptive immune cells, and important co-infections. We also present potential therapeutic targets which may reduce cardiovascular risk in PLWH.

[Immunological foundations of neurological diseases]. / Immunologische Grundlagen neurologischer Erkrankungen.

BACKGROUND: Neurodegenerative diseases represent an increasing challenge in ageing societies, as only limited treatment options are currently available. OBJECTIVE: New research methods and interdisciplinary interaction of different disciplines have changed the way neurological disorders are viewed and paved the way for the comparatively new field of neuroimmunology, which was established in the early 1980s. Starting from neurological autoimmune diseases, such as multiple sclerosis, knowledge about the involvement of immunological processes in other contexts, such as stroke or traumatic brain injury, has been significantly expanded in recent years. MATERIAL AND METHODS: This review article provides an overview of the role of the immune system and the resulting potential for novel treatment approaches. RESULTS: The immune system plays a central role in fighting infections but is also able to react to the body's own signals under sterile conditions and cause inflammation and subsequent adaptive immune responses through the release of immune mediators and the recruitment and differentiation of certain immune cell types. This can be beneficial in initiating healing processes; however, chronic inflammatory conditions usually have destructive consequences for the tissue and the organism and must be interrupted. CONCLUSION: It is now known that different cells of the immune system play an important role in neurological diseases. Regulatory mechanisms, which are mediated by regulatory T cells or Th2 cells, are usually associated with a good prognosis, whereas inflammatory processes and polarization towards Th1 or Th17 have a destructive character. Novel immunomodulators, which are also increasingly being used in cancer treatment, can now be used in a tissue-specific manner and therefore offer great potential for use in neurological diseases.

A joint effort: The interplay between the innate and the adaptive immune system in Lyme arthritis.

Articular joints are a major target of Borrelia burgdorferi, the causative agent of Lyme arthritis. Despite antibiotic treatment, recurrent or persistent Lyme arthritis is observed in a significant number of patients. The host immune response plays a crucial role in this chronic arthritic joint complication of Borrelia infections. During the early stages of B. burgdorferi infection, a major hinder in generating a proper host immune response is the lack of induction of a strong adaptive immune response. This may lead to a delayed hyperinflammatory reaction later in the disease. Several mechanisms have been suggested that might be pivotal for the development of Lyme arthritis and will be highlighted in this review, from molecular mimicry of matrix metallopeptidases and glycosaminoglycans, to autoimmune responses to live bacteria, or remnants of Borrelia spirochetes in joints. Murine studies have suggested that the inflammatory responses are initiated by innate immune cells, but this does not exclude the involvement of the adaptive immune system in this dysregulated immune profile. Genetic predisposition, via human leukocyte antigen-DR isotype and microRNA expression, has been associated with the development of antibiotic-refractory Lyme arthritis. Yet the ultimate cause for (antibiotic-refractory) Lyme arthritis remains unknown. Complex processes of different immune cells and signaling cascades are involved in the development of Lyme arthritis. When these various mechanisms are fully been unraveled, new treatment strategies can be developed to target (antibiotic-refractory) Lyme arthritis more effectively.

The weaker-binding Fc γ receptor IIIa F158 allotype retains sensitivity to N-glycan composition and exhibits a destabilized antibody-binding interface.

Antibodies engage Fc γ receptors (FcγRs) to elicit healing cellular immune responses following binding to a target antigen. Fc γ receptor IIIa/CD16a triggers natural killer cells to destroy target tissues with cytotoxic proteins and enhances phagocytosis mediated by macrophages. Multiple variables affect CD16a antibody-binding strength and the resulting immune response, including a genetic polymorphism. The predominant CD16a F158 allotype binds antibodies with less affinity than the less common V158 allotype. This polymorphism likewise affects cellular immune responses and clinical efficacy of antibodies relying on CD16a engagement, though it remains unclear how V/F158 affects CD16a structure. Another relevant variable shown to affect affinity is composition of the CD16a asparagine-linked (N)-glycans. It is currently not known how N-glycan composition affects CD16a F158 affinity. Here, we determined N-glycan composition affects the V158 and F158 allotypes similarly, and N-glycan composition does not explain differences in V158 and F158 binding affinity. Our analysis of binding kinetics indicated the N162 glycan slows the binding event, and shortening the N-glycans or removing the N162 glycan increased the speed of binding. F158 displayed a slower binding rate than V158. Surprisingly, we found N-glycan composition had a smaller effect on the dissociation rate. We also identified conformational heterogeneity of CD16a F158 backbone amide and N162 glycan resonances using NMR spectroscopy. Residues exhibiting chemical shift perturbations between V158 and F158 mapped to the antibody-binding interface. These data support a model for CD16a F158 with increased interface conformational heterogeneity, reducing the population of binding-competent forms available and decreasing affinity.

Relevance of tissue-resident memory CD8 T cells in the onset of Parkinson's disease and examination of its possible etiologies: infectious or autoimmune?

Tissue-resident memory CD8 T cells are responsible for local immune surveillance in different tissues, including the brain. They constitute the first line of defense against pathogens and cancer cells and play a role in autoimmunity. A recently published study demonstrated that CD8 T cells with markers of residency containing distinct granzymes and interferon-γ infiltrate the parenchyma of the substantia nigra and contact dopaminergic neurons in an early premotor stage of Parkinson's disease. This infiltration precedes α-synuclein aggregation and neuronal loss in the substantia nigra, suggesting a relevant role for CD8 T cells in the onset of the disease. To date, the nature of the antigen that initiates the adaptive immune response remains unknown. This review will discuss the role of tissue-resident memory CD8 T cells in brain immune homeostasis and in the onset of Parkinson's disease and other neurological diseases. We also discuss how aging and genetic factors can affect the CD8 T cell immune response and how animal models can be misleading when studying human-related immune response. Finally, we speculate about a possible infectious or autoimmune origin of Parkinson's disease.

The landscape of innate and adaptive immune cell subsets in patients with adult-onset Still's disease.

OBJECTIVE: Adult-onset Still's disease (AOSD) is a systemic autoinflammatory disorder. The understanding of the changes in adaptive immune cells and the crosstalk between innate and adaptive immune systems in AOSD is limited. This study aimed to examine the peripheral immune cell composition and inflammatory protein levels in AOSD patients. METHODS: Twenty-nine active AOSD patients were enrolled. Flow cytometry was used to analyze the cell populations in peripheral blood. Antibody chips were utilized to detect the protein expression profile in serum. RESULTS: In active AOSD patients, there was an increase in the percentage of classical and non-classical monocytes among peripheral blood mononuclear cells. The proportion of natural killer (NK) cells decreased, with an increase in CD56dim NK1 cells and a decrease in CD56bright NK2 cells compared with healthy controls (HC). The percentage of naïve central memory T cells was decreased, while the percentage of effector and effector memory T cells was increased among adaptive lymphocytes. The proportion of naïve B and memory B cells was decreased, while plasma cells were increased in AOSD patients, indicating activation of the adaptive immune system. Additionally, the serum levels of 40 proteins were elevated in AOSD patients, primarily involved in cytokine-cytokine receptor interaction, inflammatory response, and regulation of MAPK cascade. CONCLUSION: Our findings showed the activation of the innate and adaptive immune system in AOSD. The protein-protein interaction analysis suggested potential communication between innate and adaptive cell subsets. These findings provide new insights into the pathogenesis of the disease and the development of targeted therapies.

Evaluation of innate and adaptive immune system interactions in the tumor microenvironment via a 3D continuum model.

Immune cells in the tumor microenvironment (TME) are known to affect tumor growth, vascularization, and extracellular matrix (ECM) deposition. Marked interest in system-scale analysis of immune species interactions within the TME has encouraged progress in modeling tumor-immune interactions in silico. Due to the computational cost of simulating these intricate interactions, models have typically been constrained to representing a limited number of immune species. To expand the capability for system-scale analysis, this study develops a three-dimensional continuum mixture model of tumor-immune interactions to simulate multiple immune species in the TME. Building upon a recent distributed computing implementation that enables efficient solution of such mixture models, major immune species including monocytes, macrophages, natural killer cells, dendritic cells, neutrophils, myeloid-derived suppressor cells (MDSC), cytotoxic, helper, regulatory T-cells, and effector and regulatory B-cells and their interactions are represented in this novel implementation. Immune species extravasate from blood vasculature, undergo chemotaxis toward regions of high chemokine concentration, and influence the TME in proportion to locally defined levels of stimulation. The immune species contribute to the production of angiogenic and tumor growth factors, promotion of myofibroblast deposition of ECM, upregulation of angiogenesis, and elimination of living and dead tumor species. The results show that this modeling approach offers the capability for quantitative insight into the modulation of tumor growth by diverse immune-tumor interactions and immune-driven TME effects. In particular, MDSC-mediated effects on tumor-associated immune species' activation levels, volume fraction, and influence on the TME are explored. Longer term, linking of the model parameters to particular patient tumor information could simulate cancer-specific immune responses and move toward a more comprehensive evaluation of immunotherapeutic strategies.

Immunological response of 35 and 42 days old Asian seabass (Lates calcarifer, Bloch 1790) fry following immersion immunization with Streptococcus iniae heat-killed vaccine.

Early disease prevention by vaccination requires understanding when fry fish develop specific immunity to a given pathogen. In this research, we explored the immune responses of Asian seabass (Lates calcarifer) at the stages of 35- and 42- days post-hatching (dph) to an immersive heat-killed Streptococcus iniae (Si) vaccine to determine whether fish can produce specific antibodies against the pathogen. The vaccinated fish of each stage (V35 and V42) were immersed with the Si vaccine at 107 CFU/ml for 3 h, whereas the control groups (C35 and C42) were immersed with tryptic soy broth (TSB) in the same manner. Specific antibodies were measured by enzyme-linked immunosorbent assay (ELISA) before and post-immunization (i.e., 0, 7, and 14 days post-immunization, dpi). Expression of innate (TNFα and IL-1ß) and adaptive (MHCI, MHCII, CD4, CD8, IgM-like, IgT-like, and IgD-like) immune-related genes were evaluated at the same time points with the addition of 1 dpi. The results showed that a subset of immunized fish from both V35 and V42 fry could elicit specific antibodies (IgM) against Si at 14 dpi. All tested innate and adaptive immune genes upregulated at 7 dpi among fish in V35 group. Interestingly, 42 dph fish appeared to respond to the Si vaccine faster than that of 35 dph, as a significant increase in transcripts was observed in CD4, IL-1ß, IgM-like, and IgD-like at 1 dpi; and specific antibody titers of some fish, although not all, were higher than a threshold (p = 0.05) since 7 dpi. In conclusion, this study reveals that 35-42 dph Asian seabass fry can elicit specific immunity to Si immersion vaccine, suggesting that early vaccination of 35 dph fry Asian seabass is feasible.

Immunotherapy for keratinocyte cancers. Part I: Immune-related epidemiology, risk factors, pathogenesis, and immunotherapy management of keratinocyte cancers.

The important role of the immune system in the surveillance and control of keratinocyte cancers (KCs), namely squamous and basal cell carcinomas, is increasingly appreciated, as new immunotherapies have recently become available. As the field of immunotherapy is rapidly evolving, this review synthesizes key concepts and highlights important cellular components within the immune system responsible for attacking KCs. We review the most current data on the epidemiology, risk factors, and immunotherapy management for KCs. Patients will seek advice from dermatologists to help explain why immunotherapies work for KCs and whether they might be appropriate for different clinical scenarios. Collaboration with medical colleagues across different disciplines to evaluate KCs for response to immunotherapy and early recognition of immune-related adverse events will help to optimize patient outcomes.

Molecular Mechanisms for the Vicious Cycle between Insulin Resistance and the Inflammatory Response in Obesity.

The comprehensive anabolic effects of insulin throughout the body, in addition to the control of glycemia, include ensuring lipid homeostasis and anti-inflammatory modulation, especially in adipose tissue (AT). The prevalence of obesity, defined as a body mass index (BMI) ≥ 30 kg/m2, has been increasing worldwide on a pandemic scale with accompanying syndemic health problems, including glucose intolerance, insulin resistance (IR), and diabetes. Impaired tissue sensitivity to insulin or IR paradoxically leads to diseases with an inflammatory component despite hyperinsulinemia. Therefore, an excess of visceral AT in obesity initiates chronic low-grade inflammatory conditions that interfere with insulin signaling via insulin receptors (INSRs). Moreover, in response to IR, hyperglycemia itself stimulates a primarily defensive inflammatory response associated with the subsequent release of numerous inflammatory cytokines and a real threat of organ function deterioration. In this review, all components of this vicious cycle are characterized with particular emphasis on the interplay between insulin signaling and both the innate and adaptive immune responses related to obesity. Increased visceral AT accumulation in obesity should be considered the main environmental factor responsible for the disruption in the epigenetic regulatory mechanisms in the immune system, resulting in autoimmunity and inflammation.

CD4 T-Cell Subsets and the Pathophysiology of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is an umbrella term for the chronic immune-mediated idiopathic inflammation of the gastrointestinal tract, manifesting as Crohn's disease (CD) or ulcerative colitis (UC). IBD is characterized by exacerbated innate and adaptive immunity in the gut in association with microbiota dysbiosis and the disruption of the intestinal barrier, resulting in increased bacterial exposure. In response to signals from microorganisms and damaged tissue, innate immune cells produce inflammatory cytokines and factors that stimulate T and B cells of the adaptive immune system, and a prominent characteristic of IBD patients is the accumulation of inflammatory T-cells and their proinflammatory-associated cytokines in intestinal tissue. Upon antigen recognition and activation, CD4 T-cells differentiate towards a range of distinct phenotypes: T helper(h)1, Th2, Th9, Th17, Th22, T follicular helper (Tfh), and several types of T-regulatory cells (Treg). T-cells are generated according to and adapt to microenvironmental conditions and participate in a complex network of interactions among other immune cells that modulate the further progression of IBD. This review examines the role of the CD4 T-cells most relevant to IBD, highlighting how these cells adapt to the environment and interact with other cell populations to promote or inhibit the development of IBD.

In the SARS-CoV-2 Pandora Pandemic: Can the Stance of Premorbid Intestinal Innate Immune System as Measured by Fecal Adnab-9 Binding of p87:Blood Ferritin, Yielding the FERAD Ratio, Predict COVID-19 Susceptibility and Survival in a Prospective Population Database?

SARS-CoV-2 severity predictions are feasible, though individual susceptibility is not. The latter prediction allows for planning vaccination strategies and the quarantine of vulnerable targets. Ironically, the innate immune response (InImS) is both an antiviral defense and the potential cause of adverse immune outcomes. The competition for iron has been recognized between both the immune system and invading pathogens and expressed in a ratio of ferritin divided by p87 (as defined by the Adnab-9 ELISA stool-binding optical density, minus the background), known as the FERAD ratio. Associations with the FERAD ratio may allow predictive modeling for the susceptibility and severity of disease. We evaluated other potential COVID-19 biomarkers prospectively. Patients with PCR+ COVID-19 tests (Group 1; n = 28) were compared to three other groups. In Group 2 (n = 36), and 13 patients displayed COVID-19-like symptoms but had negative PCR or negative antibody tests. Group 3 (n = 90) had no symptoms and were negative when routinely PCR-tested before medical procedures. Group 4 (n = 2129) comprised a pool of patients who had stool tests and symptoms, but their COVID-19 diagnoses were unknown; therefore, they were chosen to represent the general population. Twenty percent of the Group 4 patients (n = 432) had sufficient data to calculate their FERAD ratios, which were inversely correlated with the risk of COVID-19 in the future. In a case report of a neonate, we studied three biomarkers implicated in COVID-19, including p87, Src (cellular-p60-sarcoma antigen), and Abl (ABL-proto-oncogene 2). The InImS of the first two were positively correlated. An inverse correlation was found between ferritin and lysozyme in serum (p < 0.05), suggesting that iron could have impaired an important innate immune system anti-viral effector and could partially explain future COVID-19 susceptibility.