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Immunologic research into pathogenic mechanisms operating in autoimmune-mediated atherosclerosis initially focused on adaptive immunity. Current interest is directed to more basic inflammatory mechanisms. Chronic inflammation (innate immunity-associated) may trigger initial events that can lead to atherosclerotic cardiovascular disease. This chronic inflammation may start early in life and be perpetuated by classic atherosclerosis risk factors. Lipid peroxidation of low-density lipoprotein seems to be a key event in the initiation and progression of atherosclerosis. Oxidized low-density lipoprotein triggers inflammatory and immunogenic events that promote endothelial dysfunction and the synthesis and secretion of pro-inflammatory cytokines, leading to an autoimmune response capable of accelerating the intracellular accumulation of lipids within atherosclerotic plaques. Oxidized low-density lipoprotein binds β2-glycoprotein I to form circulating complexes found in both autoimmune and non-autoimmune atherosclerosis. It is likely that β2-glycoprotein I and/or these complexes contribute to early atherogenesis by stimulating pro-inflammatory innate immunity through endogenous sensors and inflammasome/interleukin-1 pathways. We discuss the chronic inflammatory (innate) and autoimmune (adaptive) responses operating in atherosclerosis to discern the role of autoimmunity in atherosclerotic cardiovascular disease.

Pathogens and associated outbreaks of infectious disease exert selective pressure on human populations, and any changes in allele frequencies that result may be especially evident for genes involved in immunity. In this regard, the 1346-1353 Yersinia pestis-caused Black Death pandemic, with continued plague outbreaks spanning several hundred years, is one of the most devastating recorded in human history. To investigate the potential impact of Y. pestis on human immunity genes, we extracted DNA from 36 plague victims buried in a mass grave in Ellwangen, Germany in the 16th century. We targeted 488 immune-related genes, including HLA, using a novel in-solution hybridization capture approach. In comparison with 50 modern native inhabitants of Ellwangen, we find differences in allele frequencies for variants of the innate immunity proteins Ficolin-2 and NLRP14 at sites involved in determining specificity. We also observed that HLA-DRB1*13 is more than twice as frequent in the modern population, whereas HLA-B alleles encoding an isoleucine at position 80 (I-80+), HLA C*06:02 and HLA-DPB1 alleles encoding histidine at position 9 are half as frequent in the modern population. Simulations show that natural selection has likely driven these allele frequency changes. Thus, our data suggest that allele frequencies of HLA genes involved in innate and adaptive immunity responsible for extracellular and intracellular responses to pathogenic bacteria, such as Y. pestis, could have been affected by the historical epidemics that occurred in Europe.

Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance 1 – 4 . This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to targeted therapies 5 – 8 , but remains incompletely defined. Here, we identify a subclass of endogenous retroviruses (ERVs) that engages innate immune signaling in these cells. Stimulated 3 prime antisense retroviral coding sequences (SPARCS) are oriented inversely in 3′ untranslated regions of specific genes enriched for regulation by STAT1 and EZH2. Derepression of these loci results in double-stranded RNA generation following IFN-γ exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5′ long terminal repeat of the antisense ERV. Engagement of MAVS and STING activates downstream TBK1, IRF3, and STAT1 signaling, sustaining a positive feedback loop. SPARCS induction in human tumors is tightly associated with major histocompatibility complex class 1 expression, mesenchymal markers, and downregulation of chromatin modifying enzymes, including EZH2. Analysis of cell lines with high inducible SPARCS expression reveals strong association with an AXL/MET-positive mesenchymal cell state. While SPARCS-high tumors are immune infiltrated, they also exhibit multiple features of an immune-suppressed microenviroment. Together, these data unveil a subclass of ERVs whose derepression triggers pathologic innate immune signaling in cancer, with important implications for cancer immunotherapy. Retroelements located in antisense orientation within interferon-regulated genes are reactivated in a subset of cancer cells and initiate a STING- and MAVS-dependent feed-forward inflammatory loop, driving antitumor immunity and exhaustion.

The humoral arm of innate immunity includes diverse molecules with antibody-like functions, some of which serve as disease severity biomarkers in coronavirus disease 2019 (COVID-19). The present study was designed to conduct a systematic investigation of the interaction of human humoral fluid-phase pattern recognition molecules (PRMs) with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Of 12 PRMs tested, the long pentraxin 3 (PTX3) and mannose-binding lectin (MBL) bound the viral nucleocapsid and spike proteins, respectively. MBL bound trimeric spike protein, including that of variants of concern (VoC), in a glycan-dependent manner and inhibited SARS-CoV-2 in three in vitro models. Moreover, after binding to spike protein, MBL activated the lectin pathway of complement activation. Based on retention of glycosylation sites and modeling, MBL was predicted to recognize the Omicron VoC. Genetic polymorphisms at the MBL2 locus were associated with disease severity. These results suggest that selected humoral fluid-phase PRMs can play an important role in resistance to, and pathogenesis of, COVID-19, a finding with translational implications.Stravalaci et al. examined recognition of SARS-CoV-2 by human soluble innate pattern recognition receptor. They report that pentraxin 3 and mannose-binding protein recognize viral nucleoprotein and spike, respectively. Mannose-binding lectin has antiviral activity, and human genetic polymorphisms of MBL2 are associated with more severe COVID-19.

Ali Gharavi and colleagues report a genome-wide association analysis of IgA nephropathy in over 20,000 individuals of European and East Asian ancestry. They identify genome-wide significant signals at three new loci near VAV3 , CARD9 and ITGAM - ITGAX and correlations between genetic risk and pathogen diversity. We performed a genome-wide association study (GWAS) of IgA nephropathy (IgAN), the most common form of glomerulonephritis, with discovery and follow-up in 20,612 individuals of European and East Asian ancestry. We identified six new genome-wide significant associations, four in ITGAM - ITGAX , VAV3 and CARD9 and two new independent signals at HLA-DQB1 and DEFA . We replicated the nine previously reported signals, including known SNPs in the HLA-DQB1 and DEFA loci. The cumulative burden of risk alleles is strongly associated with age at disease onset. Most loci are either directly associated with risk of inflammatory bowel disease (IBD) or maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The geospatial distribution of risk alleles is highly suggestive of multi-locus adaptation, and genetic risk correlates strongly with variation in local pathogens, particularly helminth diversity, suggesting a possible role for host–intestinal pathogen interactions in shaping the genetic landscape of IgAN.

Despite the fundamental role of vaccines in the decline of infant mortality, parents may decide to decline vaccination for their own children. Many factors may influence this decision, such as the belief that the infant immune system is weakened by vaccines, and concerns have been raised about the number of vaccines and the early age at which they are administered. Studies focused on the infant immune system and its reaction to immunizations, summarized in this review, show that vaccines can overcome those suboptimal features of infant immune system that render them more at risk of infections and of their severe manifestations. In addition, many vaccines have been shown to improve heterologous innate and adaptive immunity resulting in lower mortality rates for fully vaccinated children. Thus, multiple vaccinations are necessary and not dangerous, as infants can respond to several antigens as well as when responding to single stimuli. Current immunization schedules have been developed and tested to avoid vaccine interference, improve benefits and reduce side effects compared to single administrations. The infant immune system is therefore capable, early after birth, of managing several antigenic challenges and exploits them to prompt its development.

Antimicrobial peptides (AMPs) are found widespread in nature and possess antimicrobial and immunomodulatory activities. Due to their multifunctional properties, these peptides are a focus of growing body of interest and have been characterized in several fish species. Due to their similarities in amino-acid composition and amphipathic design, it has been suggested that neuropeptides may be directly involved in the innate immune response against pathogen intruders. In this review, we report the molecular characterization of the fish-specific AMP piscidin1, the production of an antibody raised against this peptide and the immunohistochemical identification of this peptide and enkephalins in the neuroepithelial cells (NECs) in the gill of several teleost fish species living in different habitats. In spite of the abundant literature on Piscidin1, the biological role of this peptide in fish visceral organs remains poorly explored, as well as the role of the neuropeptides in neuroimmune interaction in fish. The NECs, by their role as sensors of hypoxia changes in the external environments, in combination with their endocrine nature and secretion of immunomodulatory substances would influence various types of immune cells that contain piscidin, such as mast cells and eosinophils, both showing interaction with the nervous system. The discovery of piscidins in the gill and skin, their diversity and their role in the regulation of immune response will lead to better selection of these immunomodulatory molecules as drug targets to retain antimicrobial barrier function and for aquaculture therapy in the future.

Background Leprosy is a chronic infectious disease caused by Mycobacterium leprae ( M. leprae ) that reached an epidemic scale in the Middle Ages. Nowadays, the disease is absent in Europe and host genetic influences have been considered as a contributing factor to leprosy disappearance. In this study, we perform a case–control association analysis between multiple human leukocyte antigen (HLA) alleles and leprosy in a medieval European population. The sample comprises 302 individuals from 18 archaeological sites in Denmark ( N  = 16) and Germany ( N  = 2). Results Our results indicate that HLA-B*38 is associated with leprosy risk. Furthermore, we detect three novel variants that were possibly involved in leprosy risk or protection: HLA-A*23, DRB1*04, and DRB1*13. We also note a subtle temporal change in frequency for several alleles previously associated with infectious diseases, inflammatory disorders, and cancer in present-day populations. Conclusions This study demonstrates the potential of ancient DNA in the identification of genetic variants involved in predisposition to diseases that are no longer present in Europe but remain endemic elsewhere. Although it is difficult to pinpoint the reason behind the temporal frequency shift, past epidemics of infectious diseases have likely influenced the HLA pool in present-day Europe.

Carica papaya, a tropical fruit-bearing plant, has attracted significant attention for its diverse phytomedical properties and its ability to regulate both innate and adaptive immunity, making it a promising natural therapeutic agent. C. papaya is rich in bioactive compounds that play a multifaceted role in immunomodulation. These bioactive constituents have demonstrated efficacy not only against the dengue virus but also against other viral infections, including COVID-19 (Corona Virus Disease 2019), Human Immunodeficiency Virus (HIV), Zika virus, and others. The antiviral effects of C. papaya are achieved through its ability to enhance host immunity, mitigate inflammation, reduce oxidative stress, inhibit viral replication, and modulate immune responses. These mechanisms highlight its potential as a candidate for antiviral therapies, paving the way for further exploration of its pharmacological applications and promoting eco-friendly, accessible healthcare solutions for combating viral diseases. This review highlights the antiviral potential of C. papaya extracts in inhibiting viral replication and modulating immune responses, emphasizing the need for further studies and clinical trials to validate their efficacy against other medically significant viruses causing human diseases.

Development of a vaccine against Staphylococcus aureus has proven to be difficult, in no small measure due to our lack of understanding of the human immune response to this pathogen. Because the human immune response is distinct from other species often used for pre-clinical animal models, including non-human primates, it will be necessary to perform studies in humans to guide vaccine development. One can view the staphylococcal vaccine clinical trials as an opportunity to study human immune response to S. aureus infections, which of course provide outcome data. In order to gain maximal information from these clinical trials, biological materials should be taken during the trial. In this commentary article, we explore a mechanism for such collection.