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PubMed2005

Neutrophil-mediated maturation of chemerin: a link between innate and adaptive immunity.

Dendritic cells and macrophages are professional APCs that play a central role in initiating immune responses, linking innate and adaptive immunity. Chemerin is a novel chemoattractant factor that specifically attracts APCs through its receptor ChemR23. Interestingly, chemerin is secreted as a precursor of low biological activity, prochemerin, which upon proteolytic removal of a C-terminal peptide, is converted into a potent and highly specific agonist of its receptor. Given the fact that APCs are often preceded by polymorphonuclear cells (PMN) in inflammatory infiltrates, we hypothesized that PMN could mediate chemerin generation. We demonstrate here that human degranulated PMNs release proteases that efficiently convert prochemerin into active chemerin. The use of specific protease inhibitors allowed us to identify the neutrophil serine proteases cathepsin G and elastase as responsible for this process. Mass spectrometry analysis of processed prochemerin showed that each protease generates specifically a distinct form of active chemerin, differing in their C terminus and initially identified in human inflammatory fluids. These findings strongly suggest that bioactive chemerin generation takes place during the early stages of inflammation, underscoring the functional contribution of chemerin as a bridge between innate and adaptive immunity.

Adaptation, Physiological↗
PubMed2005

Innate and adaptive immunity: specificities and signaling hierarchies revisited.

The conventional classification of known immune responses by specificity may need re-evaluation. The immune system can be classified into two subsystems: the innate and adaptive immune systems. In general, innate immunity is considered a nonspecific response, whereas the adaptive immune system is thought of as being very specific. In addition, the antigen receptors of the adaptive immune response are commonly viewed as 'master sensors' whose engagement dictates lymphocyte function. Here we propose that these ideas do not genuinely reflect the organization of immune responses and that they bias our view of immunity as well as our teaching of immunology. Indeed, the level of specificity and mode of signaling integration used by the main cellular participants in the adaptive and innate immune systems are more similar than previously appreciated.

Animals↗
PubMed2002

The T cell as a bridge between innate and adaptive immune systems: implications for the kidney.

The T cell as a bridge between innate and adaptive immune systems: Implications for the kidney. The immune system is classically divided into innate and adaptive components with distinct roles and functions. T cells are major components of the adaptive immune system. T cells are firmly established to mediate various immune-mediated kidney diseases and are current targets for therapy. Ischemic acute renal failure, a major cause of native kidney and allograft dysfunction, is mediated in part by inflammatory components of the innate immune system. However, recent data from experimental models in kidney as well as liver, intestine, brain and heart implicate T cells as important mediators of ischemia reperfusion injury. These data reveal new insights into the pathogenesis of ischemic acute renal failure, as well as identify novel and feasible therapeutic approaches. Furthermore, the identification of T cells as a mediator of early alloantigen-independent tissue injury demonstrates that the functional capacity of T cells spreads beyond adaptive immunity into the realm of the innate immune response.

Adaptation, Physiological↗
PubMed1999

Evolution of the innate and adaptive immune systems: relationships between potential immune molecules in the lowest metazoan phylum (Porifera) and those in vertebrates.

Porifera (sponge) form the lowest metazoan phylum and share a common ancestor with other metazoan phyla. In the present study, it is reported that sponges possess molecules that are similar in structure to those molecules involved in the immune system in mammals. Experiments with the marine sponges Geodia cydonium and Suberites domuncula have been performed on tissue (auto- and allografting) as well as on a cellular level. The studies revealed that sponges are provided with elements of the mammalian innate immune system, such as molecules containing scavenger receptor cysteine-rich domains. Furthermore, macrophage-derived cytokine-like molecules have been identified that are up-regulated during the grafting process. In addition, the (2'-5')oligoadenylate synthetase system exists in sponges. "Precursors" of the second type of immune response in mammals, the adaptive immune system, have been traced in sponges. It is shown that the expression of a lymphocyte-derived cytokine from mammals is up-regulated during non-self-recognition in S. domuncula. Finally, in G. cydonium, two classes of receptors that comprise Ig-like domains have been identified: the receptor tyrosine kinases and the non-enzymic sponge adhesion molecules. They contain two polymorphic Ig-like domains that are grouped to the variable set of immunoglobulins. The expression of these molecules is also up-regulated during the grafting process. It is concluded that sponges are already provided with a series of elements used in higher vertebrates for both the innate and the adaptive immune recognition.

2',5'-Oligoadenylate Synthetase↗
PubMed2004

Interplay of natural killer cells and their receptors with the adaptive immune response.

Although natural killer (NK) cells are defined as a component of the innate immune system, they exhibit certain features generally considered characteristic of the adaptive immune system. NK cells also participate directly in adaptive immune responses, mainly by interacting with dendritic cells. Such interactions can positively or negatively regulate dendritic cell activity. Reciprocally, dendritic cells regulate NK cell function. In addition, 'NK receptors' are frequently expressed by T cells and can directly regulate the functions of these cells. In these distinct ways, NK cells and their receptors influence the adaptive immune response.

Adaptation, Physiological↗
PubMed2006

A structural perspective on MHC class Ib molecules in adaptive immunity.

The highly polymorphic MHC class Ia molecules have a central role in adaptive immunity. By contrast, the closely related MHC class Ib molecules, which show limited polymorphism, are best known for regulating innate immune responses. Nevertheless, a recent area of interest is the emerging role of class Ib molecules in adaptive immunity, particularly in response to tumours and pathogens such as Mycobacteria, Listeria and Salmonella. Here, we review recent findings in this area, highlighting the structure of a T-cell receptor complexed with a cytomegalovirus peptide bound to the class Ib molecule, HLA-E. Collectively, these findings have implications for immunity, transplantation and autoimmunity, and our understanding of the evolution and plasticity of the molecular interactions mediating adaptive immunity.

Animals↗
PubMed2006

Virulent Salmonella enterica serovar typhimurium evades adaptive immunity by preventing dendritic cells from activating T cells.

Dendritic cells (DCs) constitute the link between innate and adaptive immunity by directly recognizing pathogen-associated molecular patterns (PAMPs) in bacteria and by presenting bacterial antigens to T cells. Recognition of PAMPs renders DCs as professional antigen-presenting cells able to prime naïve T cells and initiate adaptive immunity against bacteria. Therefore, interfering with DC function would promote bacterial survival and dissemination. Understanding the molecular mechanisms that have evolved in virulent bacteria to evade activation of adaptive immunity requires the characterization of virulence factors that interfere with DC function. Salmonella enterica serovar Typhimurium, the causative agent of typhoid-like disease in the mouse, can prevent antigen presentation to T cells by avoiding lysosomal degradation in DCs. Here, we show that this feature of virulent Salmonella applies in vivo to prevent activation of adaptive immunity. In addition, this attribute of virulent Salmonella requires functional expression of a type three secretion system (TTSS) and effector proteins encoded within the Salmonella pathogenicity island 2 (SPI-2). In contrast to wild-type virulent Salmonella, mutant strains carrying specific deletions of SPI-2 genes encoding TTSS components or effectors proteins are targeted to lysosomes and are no longer able to prevent DCs from activating T cells in vitro or in vivo. SPI-2 mutant strains are attenuated in vivo, showing reduced tissue colonization and enhanced T-cell activation, which confers protection against a challenge with wild-type virulent Salmonella. Our data suggest that impairment of DC function by the activity of SPI-2 gene products is crucial for Salmonella pathogenesis.

Animals↗
PubMed2006

Flag in the crossroads: flagellin modulates innate and adaptive immunity.

PURPOSE OF REVIEW: To consider observations suggesting that the bacterial protein flagellin, the primary structural component of flagella, plays a major role in mediating gut inflammation associated with infection by enteric pathogens and in inflammatory bowel disease. RECENT FINDINGS: Biochemical dissection of an in-vitro model of bacterial-epithelial interactions revealed flagellin, via ligation of Toll-like receptor 5, to be a major means of activating the innate immune responses defining active intestinal inflammation. Application of the novel technique of serologic expression cloning to murine models of colitis discovered that flagellin is also a dominant target of the adaptive immune responses that drive colitis in such models. Human studies observed that flagellin was also a major antigenic target of immune responses associated with Crohn's disease. Carriers of dominant-negative Toll-like receptor 5 gene exhibit reduced natural acquisition of immunity to flagellin, indicating that the adaptive immune response to flagellin is likely driven, in part, by Toll-like receptor 5. In some genetic backgrounds dominant-negative Toll-like receptor 5 associated negatively with Crohn's disease, suggesting that immune responses to flagellin are not only associated with Crohn's disease, but can promote the pathogenic response. SUMMARY: Flagellin is a major activator of innate immunity thus driving pathogen-induced acute inflammation and, perhaps, the active flares of inflammatory bowel disease. Flagellin is also a dominant antigen of the Crohn's disease-associated adaptive immune response, thus placing this molecule at the crossroads of the innate and adaptive immune responses that are the hallmark of intestinal inflammation.

Adaptation, Physiological↗
PubMed2003

TOLL-like receptors linking innate and adaptive immune response.

Invading pathogens are controlled by the innate and adaptive arms of the immune system. Adaptive immunity, which is mediated by B and T lymphocytes, recognises pathogens by rearranged high affinity receptors. However, the establishment of adaptive immunity is often not rapid enough to eradicate microorganisms as it involves cell proliferation, gene activation and protein synthesis. More rapid defense mechanisms are provided by innate immunity, which recognises invading pathogens by germ-line-encoded pattern recognition receptors (PRR). Recent evidence shows that this recognition can mainly be attributed to the family of TOLL-like receptors (TLR). Binding of pathogen-associated molecular patterns (PAMP) to TLR induces the production of reactive oxygen and nitrogen intermediates (ROI and RNI), pro-inflammatory cytokines, and up-regulates expression of co-stimulatory molecules, subsequently initiating the adaptive immunity. In this review, we will summarize the discovery and the critical roles of the TLR family in host defense, briefly allude to signaling mechanisms mediating the response to TLR ligands, and will provide an update on current knowledge regarding the ligand specificity of these receptors and their role in immunity of domestic animals, particularly cattle.

Animals↗
PubMed2026

Immune subtyping of colorectal adenoma identifies a subtype with activated adaptive immunity ahead of progressing to cancer.

BACKGROUND: Colorectal adenomas (CRA) represent precursor lesions with varying risks of malignant transformation. However, molecular subtyping, particularly immune-related classification, remains underexplored in adenomas. This study aims to characterize the immune landscape of CRA through immune subtyping and evaluate its association with cancer progression, gene expression signatures, and functional pathways. METHODS: We conducted a retrospective analysis of transcriptomic data from multiple cohorts of CRA samples. Immune subtypes were identified using non-negative matrix factorization (NMF) based on immune-related genes. Diverse deconvolution algorithms were used to estimate immune cell infiltration. The immune status alteration in premalignant lesion was further consolidated by single-cell transcriptome data. Differential gene expression analysis was performed between subtypes, followed by functional enrichment analyses (Gene Ontology [GO] and Kyoto Encyclopedia of Genes and Genomes [KEGG]). RESULTS: Two distinct immune subtypes were identified: an immune-enriched subtype characterized by high lymphocyte infiltration and elevated expression of immune-related genes, and an immune-deficient subtype with suppressed immune activity. Differential expression analysis revealed significant upregulation of immune response genes (e.g., CD4, CD86, HLA-DRA) in the immune-enriched subtype. GO and KEGG analyses highlighted enrichments in leukocyte transendothelial migration, chemokine signaling, and antigen processing and presentation pathways. Single-cell result revealed an early occurrence of TIGIT activation and exhausted CD8 T cell features in adenoma when compared to normal tissue. CONCLUSION: This study delineates distinct immune subtypes within CRAs. The immune-enriched subtype demonstrates activated adaptive immunity and may reflect a higher potential for immune surveillance, while the immune-deficient subtype exhibits stromal features suggestive of progressive transformation. These findings provide insights into early immune microenvironment alterations and may inform strategies for risk stratification and immunoprevention in colorectal carcinogenesis.

Colorectal adenoma↗
PubMed1998

What do the paralogous regions in the genome tell us about the origin of the adaptive immune system?

During the last decade, our understanding of the immune system of ectothermic vertebrates has advanced significantly. It is now clear that all jawed vertebrates are equipped with the adaptive immune system characterized by the MHC molecules and the rearranging receptors. In contrast, there is no molecular evidence that suggests the existence of adaptive immunity in jawless vertebrates. How did the adaptive immune system emerge? Our recent work suggests that one of the driving forces that enabled the emergence of the adaptive immune system was one or more genome-wide or large-scale chromosomal duplications presumed to have taken place in a common ancestor of jawed vertebrates.

Adaptation, Physiological↗
PubMed2003

Evolution of complement as an effector system in innate and adaptive immunity.

For a long time, the complement system in mammals has been regarded as a biological system that plays an essential role in innate immunity. More recently, it has been recognized that the complement system contributes heavily to the generation and development of an acquired immune response. In fact, this ancient mechanism of defense has evolved from a primitive mechanism of innate immune recognition in invertebrate species to that of an effector system that bridges the innate with the adaptive immune response in vertebrate species. When and how did complement evolve into a shared effector system between innate and adaptive immunity? To answer this question, our group is interested in understanding the role of complement in innate and adaptive immune responses in an evolutionary relevant species: the teleost fish. The attractiveness of this species as an animal model is based on two important facts. First, teleost fish are one of the oldest animal species to have developed an adaptive immune response. Second, the complement system of teleost fish offers a unique feature, which is the structural and functional diversity of its main effector protein, C3, the third component of the complement system.

Animals↗
PubMed1998

Roles of innate and adaptive immunity in respiratory mycoplasmosis.

Current evidence suggests that host defense in respiratory mycoplasmosis is dependent on both innate and humoral immunity. To further delineate the roles of innate and adaptive immunity in antimycoplasmal defenses, we intranasally infected C3H/HeSnJ-scid/scid (C3H-SCID), C3H/HeSnJ (C3H), C57BL/6J-scid/scid (C57-SCID), and C57BL/6N (C57BL) mice with Mycoplasma pulmonis and at 14 and 21 days postinfection performed quantitative cultures of lungs and spleens, quantification of lung lesions, and histopathologic assessments of all other major organs. We found that numbers of mycoplasmas in lungs were associated with genetic background (C3H susceptible, C57BL resistant) rather than functional state of adaptive immunity, indicating that innate immunity is the main contributor to antimycoplasmal defense of the lungs. Extrapulmonary dissemination of mycoplasmas with colonization of spleens and histologic lesions in multiple organs was a common occurrence in all mice. The absence of adaptive immune responses in severe combined immunodeficient (SCID) mice resulted in increased mycoplasmal colonization of spleens and lesions in extrapulmonary sites, particularly spleens, hearts, and joints, and also reduced lung lesion severity. The transfer of anti-M. pulmonis serum to infected C3H-SCID mice prevented extrapulmonary infection and disease, while the severity of lung lesions was restored by transfer of naive spleen cells to infected C3H-SCID mice. Collectively, our results strongly support the conclusions that innate immunity provides antimycoplasmal defense of the lungs and humoral immunity has the major role in defense against systemic dissemination of mycoplasmal infection, but cellular immune responses may be important in exacerbation of mycoplasmal lung disease.

Animals↗
PubMed2003

Adaptive immune response of Vgamma2Vdelta2 T cells: a new paradigm.

The role of gammadelta T cells in adaptive immunity remains uncertain. Recent studies have demonstrated that a unique subset of gammadelta T cells in primates can mount adaptive immune responses during mycobacterial infections. This Review discusses notable similarities and differences in adaptive immune responses between non-peptide-specific gammadelta T cells and peptide-specific alphabeta T cells, and discusses both the molecular basis for gammadelta T-cell responses and potential functions of these enigmatic cells.

Animals↗
PubMed2005

Molecular interactions between dendritic cells and Salmonella: escape from adaptive immunity and implications on pathogenesis.

Dendritic cells (DCs) constitute the link between innate and adaptive immunity by directly recognizing pathogen-associated molecular patterns (PAMPs) on bacteria and by processing and presenting bacterial antigens to T cells. Recognition of PAMPs renders DCs as professional antigen-presenting cells with the ability to prime naive T cells and to initiate the adaptive immune response against pathogen-derived antigens. For this reason, any interference with DC function might be advantageous for bacterial survival and dissemination. Identification of the molecular interactions occurring between DCs and bacterial pathogens is necessary to understand the mechanisms that virulent bacteria have evolved to prevent recognition by the adaptive immune system. This could be helpful in the identification of possible new targets that might lead to the design of effective therapies aimed at preventing or treating serious infections by these pathogens. In this article, we focus on Salmonella enterica serovar Typhimurium, the causative agent of typhoid-like disease in the mouse, and how it is able to escape from DC-mediated antigen presentation by avoiding lysosomal degradation. This feature of virulent Salmonella requires the functional expression of the Type Three Secretion System (TTSS) and effector proteins encoded within the Salmonella pathogenicity island 2 (SPI-2). Recent studies have demonstrated that impairment of DC function by the activity of SPI-2 gene products is crucial for Salmonella pathogenesis.

Animals↗
PubMed1998

What brought the adaptive immune system to vertebrates?--The jaw hypothesis and the seahorse.

A hypothesis is discussed that the adaptive immune system of vertebrates evolved in the gastrointestinal regions of primitive jawed fish (placoderms) due to increased localized injuries and infections which were inadvertently brought about by the novel jaw structures and the predatory life style. The question whether the modern jawless fish, cyclostomes, have adaptive immunity or not is briefly but critically reviewed. The discovery that the gut-associated immune tissues in mammals constitute the primary immune tissues for the local T cells and that some epithelial gamma delta T cells have a unique propensity is summarized and discussed in relation to the jaw hypothesis. Initial study of the seahorse (Hippocampus) indicates that the gut-associated immune tissues may be absent in this teleost species, suggesting an evolutionary link between the adaptive immune system and the jaw structure or eating habit.

Adaptation, Physiological↗
PubMed2004

Understanding asthma pathogenesis: linking innate and adaptive immunity.

PURPOSE OF REVIEW: Treatment and even prevention of allergic asthma will require a detailed understanding of disease pathogenesis and in particular identification of factors that govern T-helper type 2 (Th2) immunity. This review defines the priming and differentiation steps necessary to develop antiallergen Th2 immunity and highlights recently identified stimuli that satisfy these requirements. RECENT FINDINGS: Striking discoveries in innate immunity have advanced our understanding of how adaptive immune responses are initiated, yet only recently have these principles been applied to allergic disease. Signaling through certain innate immune receptors, the toll-like receptors (TLR) have been shown to modulate Th2-mediated disease in animal models. The dendritic cell has emerged as the central player in the intricate interplay between the adaptive and innate systems of immunity. Recent studies have also uncovered alternative pathways of initiating allergen sensitization that depend entirely on adaptive, rather than innate immune, triggers. SUMMARY: The adaptive immune system cannot initiate a response without the "permission" of the innate immune system, and this holds true for Th2 responses to aeroallergens, although induction of Th2 immunity in response to TLR signaling varies with the type and dose of TLR ligand. However, under conditions of ongoing Th2 inflammation, the adaptive immune system can act as its own adjuvant and provide the necessary activating signals to initiate an immune response to foreign protein antigens. This may be the mechanism underlying the clinically observed phenomenon of polysensitization in atopic patients and provides another therapeutic target in asthma.

Animals↗
PubMed2026

Pan-cancer analysis identifies APOC1 as a TAM-derived modulator of adaptive immune resistance and predictor of therapeutic response.

BACKGROUND: Apolipoprotein C1 (APOC1) has been implicated in several malignancies, yet its expression patterns, clinical significance, and immunomodulatory roles across cancer types remain poorly characterized. METHODS: We performed a comprehensive multi-omic analysis of APOC1 across 33 cancer types integrating transcriptomic, proteomic, genomic, epigenomic, and pharmacogenomic data from TCGA, GTEx, CPTAC, and multiple independent external cohorts. Immune infiltration was assessed using seven complementary algorithms. Spatial transcriptomics and single-cell RNA sequencing were employed to determine the cellular source of APOC1 expression. RESULTS: APOC1 upregulation in most cancers was associated with cancer type-specific prognosis. After adjustment for clinical covariates and macrophage infiltration, high APOC1 remained an independent adverse factor in KIRC, LGG, and STAD. APOC1 expression positively correlated with genomic instability hallmarks, including homologous recombination deficiency and aneuploidy, with these associations largely independent of immune infiltration; in contrast, associations with tumor mutational burden were substantially confounded by macrophage abundance. Immune infiltration analysis revealed a pattern consistent with adaptive immune resistance: APOC1 correlated positively with immune-activating signatures (STAT1, MHC-II, TCR signaling) and immunosuppressive M2 macrophages and Tregs, yet negatively with anti-tumor effectors (activated NK cells, dendritic cells). Spatial transcriptomics and single-cell RNA sequencing identified tumor-associated macrophages (TAMs) as the primary cellular source of APOC1, with transcripts co-localizing with CD68 in tissue sections. APOC1 expression correlated with multiple immune checkpoint molecules and was elevated in responders to immune checkpoint blockade, consistent with an inflamed yet regulated tumor microenvironment. Pharmacogenomic analyses revealed that APOC1-high tumors display distinct drug response profiles, characterized by resistance to MAPK pathway inhibitors and potential sensitivity to the HDAC inhibitor Entinostat. CONCLUSION: This pan-cancer analysis establishes APOC1 as a context-dependent biomarker and a TAM-derived modulator of adaptive immune resistance, with prognostic and therapeutic implications across malignancies. APOC1-expressing TAMs represent a potential target for combination immunotherapy strategies.

APOC1↗