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Results for “Adaptive Immunity”

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PubMed2004

The NF-kappaB pathway as a potential target for autoimmune disease therapy.

A battery of proinflammatory agents triggers the activation of NF-kappaB. This inducible transcription factor participates in the expression of an exceptionally large number of target genes, many of them contributing to the regulation of innate and adaptive immunity. Since some target genes also function as NF-kappaB activators, activation of this transcription factor allows the establishment of a signal amplification loop. Dysregulation of the NF-kappaB system and hyperactivated expression of inflammatory mediators are often found in association with some autoimmune diseases, which occur upon mounting of the adaptive immune response against self-antigens. In this review we summarize the relevance of aberrant NF-kappaB signaling for the development and perpetuation of some autoimmune diseases such as rheumatoid arthritis, diabetes mellitus type 1 and Crohn's disease. The assets and drawbacks of systemic or cell-type specific NF-kappaB inhibitors and their potential use in therapy of autoimmune diseases are critically discussed.

Animals↗

PubMed2006

CD1d mediates T-cell-dependent resistance to secondary infection with encephalomyocarditis virus (EMCV) in vitro and immune response to EMCV infection in vivo.

The innate and adaptive immune responses have evolved distinct strategies for controlling different viral pathogens. Encephalomyocarditis virus (EMCV) is a picornavirus that can cause paralysis, diabetes, and myocarditis within days of infection. The optimal innate immune response against EMCV in vivo requires CD1d. Interaction of antigen-presenting cell CD1d with distinct natural killer T-cell ("NKT") populations can induce rapid gamma interferon (IFN-gamma) production and NK-cell activation. The T-cell response of CD1d-deficient mice (lacking all NKT cells) against acute EMCV infection was further studied in vitro and in vivo. EMCV persisted at higher levels in CD1d-knockout (KO) splenocyte cultures infected in vitro. Furthermore, optimal resistance to repeat cycles of EMCV infection in vitro was also shown to depend on CD1d. However, this was not reflected in the relative levels of NK-cell activation but rather by the responses of both CD4(+) and CD8(+) T-cell populations. Repeated EMCV infection in vitro induced less IFN-gamma and alpha interferon (IFN-alpha) from CD1d-deficient splenocytes than with the wild type. Furthermore, the level of EMCV replication in wild-type splenocytes was markedly and specifically increased by addition of blocking anti-CD1d antibody. Depletion experiments demonstrated that dendritic cells contributed less than the combination of NK and NKT cells to anti-EMCV responses and that none of these cell types was the main source of IFN-alpha. Finally, EMCV infection in vivo produced higher levels of viremia in CD1d-KO mice than in wild-type animals, coupled with significantly less lymphocyte activation and IFN-alpha production. These results point to the existence of a previously unrecognized mechanism of rapid CD1d-dependent stimulation of the antiviral adaptive cellular immune response.

Acute Disease↗

PubMed2004

Surfactant protein A, an innate immune factor, is expressed in the vaginal mucosa and is present in vaginal lavage fluid.

Surfactant protein A (SP-A), first identified as a component of the lung surfactant system, is now recognized to be an important contributor to host defence mechanisms. SP-A can facilitate phagocytosis by opsonizing bacteria, fungi and viruses, stimulate the oxidative burst by phagocytes and modulate pro-inflammatory cytokine production by phagocytic cells. SP-A can also provide a link between innate and adaptive immune responses by promoting differentiation and chemotaxis of dendritic cells. Because of the obvious relevance of these mechanisms to the host defence and 'gate keeping' functions of the lower genital tract, we examined human vaginal mucosa for SP-A protein and transcripts and analysed vaginal lavage fluid for SP-A. By immunocytochemistry, SP-A was identified in two layers of the vaginal epithelium: the deep intermediate layer (the site of newly differentiated epithelial cells); and the superficial layer (comprising dead epithelial cells), where SP-A is probably extracellular and associated with a glycocalyx. Transcripts of SP-A were identified by Northern blot analysis in RNA isolated from vaginal wall and shown, by sequencing of reverse transcription-polymerase chain reaction products, to be derived from each of the two closely related SP-A genes, SP-A1 and SP-A2. SP-A was identified in vaginal lavage fluid by two-dimensional gel electrophoresis, and confirmed by mass spectrometry. This study provides evidence, for the first time, that SP-A is produced in a squamous epithelium, namely the vaginal mucosa, and has a localization that would allow it to contribute to both the innate and adaptive immune response. The findings support the hypothesis that in the vagina, as in lung, SP-A is an essential component of the host-defence system. A corollary hypothesis is that qualitative and quantitative alterations of normal SP-A may play a role in the pathogenesis of lower genital tract inflammatory conditions.

Adult↗

PubMed2025

A proteomic map of thromboinflammatory signatures in antiphospholipid syndrome: results from antiphospholipid syndrome alliance for clinical trials and international networking (APS ACTION) registry.

INTRODUCTION: Antiphospholipid syndrome (APS) is an autoimmune disease with thromboembolic and obstetric morbidity arising via a model of immunothrombosis. Individuals with APS may present with thrombotic (TAPS), obstetric (OAPS), or microvascular (MAPS) disease, while many have circulating antiphospholipid antibodies (aPL) without APS classification (NoAPS). Multiple pathophysiologic mechanisms have been proposed in APS, including activation by aPL of platelets, endothelial and immune cells, as well as complement and coagulation pathways; however, the pathophysiology of APS, particularly transition of clinical APS from aPL remains unclear. METHODS: Seeking to define the inflammatory signature of APS, we carried out an unbiased proteomic screen of persistently aPL-positive patients with different clinical phenotypes from the international APS Alliance for Clinical Trials and International Networking (ACTION) Registry and compared them to 10 healthy controls. 6398 unique proteins were estimated using an DNA aptamer-based assay. Subsequently, we validated our findings in 34 additional patients. RESULTS: Our data show that the mere presence of aPL confers a distinct thromboinflammatory signature characterized by the activation of coagulation, complement, innate and adaptive immune response pathways shared by all APS subtypes. Pathway enrichment analysis revealed increasing enrichment with rising statistical significance of thrombosis, complement, neutrophil and other innate and adaptive immune activation, as well as extracellular matrix (ECM) organization with increasing clinical severity, suggesting a model of progressive thromboinflammation in evolution of APS from NoAPS to TAPS and MAPS. CONCLUSIONS: Our findings provide novel insights into the pathogenesis of APS and identify potential novel targets for diagnostic and therapeutic intervention in APS across its entire spectrum.

Humans↗

PubMed2026

An Update on Inborn Errors of V(D)J Recombination.

V(D)J recombination is the fundamental process by which developing T and B lymphocytes generate diverse antigen receptors, enabling adaptive immunity. This tightly regulated program operates exclusively in lymphoid precursors during G1 phase and depends on the lymphocyte-specific RAG1-RAG2 recombinase to introduce programmed DNA double-strand breaks at recombination signal sequences, followed by repair through the classical nonhomologous end joining (c-NHEJ) pathway. Disruption of any step in this molecular choreography compromises antigen receptor diversity and underlies a spectrum of inborn errors of immunity (IEIs), ranging from severe combined immunodeficiency (SCID) to immune dysregulation with autoimmunity and granulomatous disease. In this review, we place disorders of V(D)J recombination within the broader framework of T-cell development, detailing the temporal waves of recombinase activity, chromatin accessibility, and DNA damage responses that guide thymocyte differentiation. We discuss pathogenic variants affecting the cleavage phase [RAG1, RAG2, and the recently identified RAG cochaperone NudC domain-containing 3 (NUDCD3)], end processing (ARTEMIS), ligation and repair (LIG4, XLF, XRCC4, PRKDC), and genome surveillance pathways (ATM, MRN complex, RNF168), highlighting genotype-phenotype correlations and mechanisms driving immune deficiency and dysregulation. We briefly review recent diagnostic advances, including newborn screening using T-cell receptor excision circles, repertoire sequencing, and functional assays, alongside current therapeutic strategies. Finally, we outline key unanswered questions and argue that continued integration of clinical observation with molecular discovery is essential to improve outcomes and deepen understanding of adaptive immune development.

Humans↗

PubMed2005

Ontogeny of intestinal epithelium immune functions: developmental and environmental regulation.

Intestinal mucosa integrates primary digestive functions with immune functions such as pathogen surveillance, antigen transport and induction of mucosal immunity and tolerance. Intestinal adaptive immunity is elicited in organized mucosa-associated lymphoid tissue (O-MALT) that is composed of antigen-presenting cells and lymphocytes and achieved by effector cells widely distributed in mucosa (diffuse MALT or D-MALT). Interaction between the intestinal epithelium, the O-MALT and the diffuse MALT plays a critical role in establishing an adequate immune response. In regions associated to O-MALT, lympho-epithelial cross-talks lead to acquisition of a specific epithelial phenotype that contributes to O-MALT organization and functionality. Beyond the expression of several innate immune functions, the intestinal epithelium may directly take up and present antigens due to the expression of major histocompatibility complex (MHC) and MHC-related molecules. A complex genetic program that will be outlined in the present review controls the development of immune functions of the intestinal epithelium. The effect of environmental signals on the modulation of this ontogenetic program during development and neonatal life, from bioactive components of amniotic fluid to lactation and bacterial colonization, will be discussed.

Adaptation, Physiological↗

PubMed2006

The eosinophil.

Eosinophils have been considered end-stage cells involved in host protection against parasites. However, numerous lines of evidence have now changed this perspective by showing that eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of diverse inflammatory responses, as well as modulators of innate and adaptive immunity. In this review, we summarize the biology of eosinophils, focusing on the growing properties of eosinophil-derived products, including the constituents of their granules as well as the mechanisms by which they release their pleiotropic mediators. We examine new views on the role of eosinophils in homeostatic function, including developmental biology and innate and adaptive immunity (as well as interaction with mast cells and T cells). The molecular steps involved in eosinophil development and trafficking are described, with special attention to the important role of the transcription factor GATA-1, the eosinophil-selective cytokine IL-5, and the eotaxin subfamily of chemokines. We also review the role of eosinophils in disease processes, including infections, asthma, and gastrointestinal disorders, and new data concerning genetically engineered eosinophil-deficient mice. Finally, strategies for targeted therapeutic intervention in eosinophil-mediated mucosal diseases are conceptualized.

Animals↗

PubMed2007

IL-10 produced by CD4+ and CD8+ T cells emerge as a putative immunoregulatory mechanism to counterbalance the monocyte-derived TNF-alpha and guarantee asymptomatic clinical status during chronic HTLV-I infection.

Although it is believed widely that distinct patterns of the host immune response are associated with the outcome of chronic human T cell lymphotropic virus type 1 (HTLV-I) infection toward asymptomatic or symptomatic neurodegenerative myelopathy (HAM/TSP), the exact mechanism underlying these immunological events still remains unknown. In this study, we have evaluated the cytokine pattern [interleukin (IL)-12, interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha, IL-4 and IL-10] of innate and adaptive immunity cells present at the peripheral blood from non-infected (NI) and HTLV-I infected individuals [asymptomatic (AS), oligosymptomatic (OL) and HAM/TSP-HT], following in vitro short-term incubation in the absence/presence of phorbol myristate acetate (PMA) pan-leucocyte stimulation. In the absence of PMA stimulation, our data demonstrate that despite the overall immunological profile of AS mimicry that observed for NI, the high frequency of IL-12(+) neutrophils and TNF-alpha(+) monocytes are also a hallmark of this group of individuals. However, the outstanding positive correlation between the high frequency of TNF-alpha(+) monocytes and high levels CD4(+) IL-10(+) and CD8(+) IL-10(+) T cells suggests the establishment of immunoregulatory mechanisms that guarantee their asymptomatic clinical status. On the other hand, OL and HT did not present any association between the high frequency and TNF-alpha(+) neutrophils and monocytes and this immunoregulatory profile at their adaptive immunity cells. Upon PMA-index analysis, high levels of type 1 CD4(+) T cells, as well as higher IFN-gamma/IL-10 and TNF-alpha/IL-10 ratios, were observed in HT, and re-emphasize the role of Th1-cytokines from CD4(+) cells to HTLV-I immunity and disease. Moreover, increasing frequency of CD8(+) IFN-gamma(+) and CD8(+) TNF-alpha(+) cells were observed in the HT, which corroborates the marked inflammatory profile underlying this pathological condition and the role of CD8(+) T cells in the pathogenesis of HAM/TSP.

Adult↗

PubMed2001

CD14: a bridge between innate immunity and adaptive IgE responses.

Total IgE levels are known to be under genetic control. Linkage studies have indicated that one or more loci on chromosome 5q may control total IgE, as well as asthma and bronchial hyperresponsiveness to non-specific stimuli. Our group has undertaken a systematic analysis of chromosome 5q, and has recently characterized five single nucleotide polymorphisms at position -1619, -1359, -1145, -809, and -159 in the promoter of the gene encoding CD14, the myeloid pattern recognition receptor that is critical for efficient innate immune responses to lipopolysaccharide and bacterial ligands. Individuals homozygous for the three major CD14 haplotypes found in the Children Respiratory Study population (n = 390) were analyzed for serum levels of total IgE and soluble CD14. A strong inverse correlation was found between these two parameters, i.e. carriers of the -1359T/-1145A/-159C haplotype had the highest levels of IgE, and the lowest levels of sCD14. Conversely, carriers of the -1359G/-1145G/-159T haplotype had the highest levels of sCD14 and the lowest IgE values. Our results suggest that genetic variation in CD14, a key gene of innate immunity, may modulate the effects that exposure to bacterial ligands has on the development of Th2 responses.

Child↗

PubMed2005

Early innate immune response and redistribution of inflammatory cells in the bony fish gilthead seabream experimentally infected with Vibrio anguillarum.

An obvious difference between the immune system of fish and mammals is that fish lack both bone marrow and lymph nodes; in their place, the head-kidney acts as a major haematopoietic and lymphoid organ in adult fish, whereas the thymus, spleen and mucosa-associated lymphoid tissues are common to both fish and mammals. This suggests that differences exist in antigen presentation and naive lymphocyte stimulation, a prerequisite for the initiation of adaptive immune responses. Intraperitoneal injection of the bony fish gilthead seabream (Sparus aurata L.) with intact Vibrio anguillarum, as a particulate bacterial antigen, results in the mobilisation of head-kidney leucocytes to the peritoneal cavity and priming of their respiratory burst activity. We have also observed the rapid infiltration of acidophilic granulocytes, which are leucocytes functionally equivalent to mammalian neutrophils, into the spleen. These cells may be involved in antigen capture and transport to the spleen, since an apparent association between mobilised acidophilic granulocytes, bacterial antigens and proliferating lymphocytes has been seen in this organ. Collectively, these results suggest that, in addition to being actively involved in bacterial clearance, fish phagocytic granulocytes play a role in the initiation and support of the adaptive immune response.

Animals↗

PubMed2006

When T cells recognize a pattern, they might cause trouble.

The mechanisms of self and non-self discrimination by T cells remain a fascinating topic for immunologists. How the immune system achieves protection of the host against an ever-changing realm of pathogens using a rather limited repertoire of T-cell receptors and at the same time avoids inflicting damage against its own tissues is equally puzzling. Although a better understanding of these questions has come from studies of the extent of cross reactivity of T-cell clones specific for foreign or self antigens, and also from examination of the different antigen avidities by which they recognize either type of antigen, many details are still lacking. Recently, there has been investigation into how T cells of the adaptive immune system can recognize functional protein domains or amino acid patterns. This type of T-cell reactivity is reminiscent of the pattern recognition that is firmly established as an important function of innate immune receptors such as Toll-like receptors. Many functional protein domains are conserved in evolution and are shared by a wide spectrum of pathogens, as well as by proteins of animals and humans. Hence, pattern recognition by adaptive immune cells might represent an efficient mechanism for host protection by the above-mentioned limited number of T-cell receptors. However, the fact that such functional domains occur so frequently in nature also implies that pattern recognition by T cells might cause autoimmunity, and recent data support this hypothesis.

Amino Acids↗

PubMed2005

Innate autoimmunity.

The adaptive immune system has evolved highly specific pattern recognition proteins and receptors that, when triggered, provide a first line of host defense against pathogens. Studies reveal that these innate recognition proteins are also self-reactive and can initiate inflammation against self-tissues in a similar manner as with pathogens. This specific event is referred to as "innate autoimmunity." In this review, we describe two classes of autoimmune responses, that is, reperfusion injury and fetal loss syndrome, in which the recognition and injury are mediated by innate immunity. Both disorders are common and are clinically important. Reperfusion injury (RI) represents an acute inflammatory response after a reversible ischemic event and subsequent restoration of blood flow. Findings that injury is IgM and complement dependent and that a single natural antibody prepared from a panel of B-1 cell hybridomas can restore injury in antibody-deficient mice suggest that RI is an autoimmune-type disorder. Fetal loss syndrome is also an antibody- and complement-dependent disorder. Although both immune and natural antibodies are likely involved in recognition of phospholipid self-antigens, inhibition of the complement pathway in rodent models can block fetal loss. As new innate recognition proteins and receptors are identified, it is likely that innate responses to self represent frequent events and possibly underlie many of the known chronic autoimmune disorders normally attributable to dysregulation of adaptive immunity.

Animals↗

PubMed2005

The role of T lymphocytes in bone metabolism.

Recent findings from animal models suggest that the bone loss induced by estrogen deficiency may stem in large measure from a pathological upregulation of the adaptive immune response. While the role of activated T cells in the osteoporosis driven by inflammatory conditions and infection has been well documented, only recently has the role of T cells in the bone destruction associated with estrogen deficiency begun to be appreciated. In vivo and in vitro models of postmenopausal osteoporosis demonstrate that estrogen deficiency leads to an increase in the adaptive immune function that culminates in an increased production of tumor necrosis factor alpha (TNF) by activated T cells. TNF increases osteoclast (OC) formation and bone resorption both directly and by augmenting the sensitivity of maturing OCs to the essential osteoclastogenic factor receptor activator of nuclear factor kappaB ligand. The activation and expansion of TNF-producing T cells are key steps in estrogen deficiency-driven bone loss and are regulated by multiple interacting cytokines including transforming growth factor-beta, interleukin-7, and interferon-gamma, as well as by the process of antigen presentation. Herein, we review the experimental evidence that suggests estrogen prevents bone loss by regulating T-cell function and immune cell bone interactions.

Animals↗

PubMed2006

Interaction of foot-and-mouth disease virus with dendritic cells.

Despite several decades of investigation, the manner in which foot-and-mouth disease virus (FMDV) interacts with the innate and adaptive immune compartments is not completely understood. The importance of elucidating this relationship is emphasized by the inability of current FMDV vaccines to provide long-term protection and the recent outbreaks of FMDV in formerly disease-free countries. Dendritic cells (DCs) are professional antigen-presenting cells that have evolved to monitor the environment and provide a link between the innate and adaptive immune systems. Comprehending the cross-talk between DC and FMDV will provide valuable information towards understanding the host response to the virus and will aid in the design of effective tools and vaccines to block virus spread.

Animals↗

PubMed2004

Human dendritic cells are less potent at killing Candida albicans than both monocytes and macrophages.

Dendritic cells (DC) function as professional phagocytes to kill Candida albicans and subsequently present it to the adaptive immune system. Monocytes, macrophages and DC were generated from five individual donors and their Candida-killing capacity and cytokine release were assessed. Compared to monocytes and macrophages, DC from healthy volunteers were significantly less effective in C. albicans--stimulated cytokine release, killing of C. albicans blastoconidia and damaging of C. albicans hyphae. In conclusion, while important as antigen-presenting cells and initiators of the adaptive immune system, DC are poor in both intracellular killing and damaging of C. albicans hyphae. Effective handling of large numbers of C. albicans is the prime task of the innate immune system consisting of large numbers of neutrophils and monocytes.

Candida albicans↗

PubMed2000

Multiple roles for Bordetella lipopolysaccharide molecules during respiratory tract infection.

Bordetella pertussis, Bordetella parapertussis, and Bordetella bronchiseptica are closely related subspecies that cause respiratory tract infections in humans and other mammals and express many similar virulence factors. Their lipopolysaccharide (LPS) molecules differ, containing either a complex trisaccharide (B. pertussis), a trisaccharide plus an O-antigen-like repeat (B. bronchiseptica), or an altered trisaccharide plus an O-antigen-like repeat (B. parapertussis). Deletion of the wlb locus results in the loss of membrane-distal polysaccharide domains in the three subspecies of bordetellae, leaving LPS molecules consisting of lipid A and core oligosaccharide. We have used wlb deletion (Deltawlb) mutants to investigate the roles of distal LPS structures in respiratory tract infection by bordetellae. Each mutant was defective compared to its parent strain in colonization of the respiratory tracts of BALB/c mice, but the location in the respiratory tract and the time point at which defects were observed differed significantly. Although the Deltawlb mutants were much more sensitive to complement-mediated killing in vitro, they displayed similar defects in respiratory tract colonization in C5(-/-) mice compared with wild-type (wt) mice, indicating that increased sensitivity to complement-mediated lysis is not sufficient to explain the in vivo defects. B. pertussis and B. parapertussis Deltawlb mutants were also defective compared to wt strains in colonization of SCID-beige mice, indicating that the defects were not limited to interactions with adaptive immunity. Interestingly, the B. bronchiseptica Deltawlb strain was defective, compared to the wt strain, in colonization of the respiratory tracts of BALB/c mice beginning 1 week postinoculation but did not differ from the wt strain in its ability to colonize the respiratory tracts of B-cell- and T-cell-deficient mice, suggesting that wlb-dependent LPS modifications in B. bronchiseptica modulate interactions with adaptive immunity. These data show that biosynthesis of a full-length LPS molecule by these three bordetellae is essential for the expression of full virulence for mice. In addition, the data indicate that the different distal structures modifying the LPS molecules on these three closely related subspecies serve different purposes in respiratory tract infection, highlighting the diversity of functions attributable to LPS of gram-negative bacteria.

Animals↗

PubMed2004

An intravaginal live Candida challenge in humans leads to new hypotheses for the immunopathogenesis of vulvovaginal candidiasis.

Acute and recurrent vulvovaginal candidiasis (VVC) remains a significant problem in women of childbearing age. While clinical studies of women with recurrent VVC (RVVC) and animal models have provided important data about a limited protective role of adaptive immunity, there remains a paucity of information on the protective mechanisms or factors associated with susceptibility to infection. In the present study, an intravaginal live Candida challenge in healthy adult women showed a differential susceptibility to symptomatic VVC, where 3 (15%) of 19 women with no history of VVC acquired a symptomatic infection compared to 6 (55%) of 11 women with an infrequent history of VVC. Furthermore, these studies revealed that protection against infection is noninflammatory while symptomatic infection correlates with a vaginal infiltration of polymorphonuclear neutrophils (PMNs) and a high vaginal fungal burden. Thus, the presence of symptomatic infection appears more dependent on host factors than on properties of the organism. Finally, vaginal lavage fluid from women with a symptomatic infection, but not those asymptomatically colonized, promoted the chemotaxis of PMNs. These results suggest that rather than RVVC/VVC being caused by an aberrant adaptive immune response, symptoms that define infection appear to be due to an aggressive innate response by PMNs.

Adaptation, Physiological↗

PubMed2004

Pathogenesis of filoviral haemorrhagic fevers.

The filoviruses, marburgvirus and ebolavirus, cause epidemics of haemorrhagic fever with high case-fatality rates. The severe illness results from a complex of pathogenetic mechanisms that enable the virus to suppress innate and adaptive immune responses, infect and kill a broad variety of cell types, and elicit strong inflammatory responses and disseminated intravascular coagulation, producing a syndrome resembling septic shock. Most experimental data have been obtained on Zaire ebolavirus, which causes uniformly lethal disease in experimentally infected non-human primates but produces a broader range of outcomes in naturally infected human beings. 10-30% of patients can survive the illness by mobilising adaptive immune responses, and there is limited evidence that mild or symptomless infections also occur. The other filoviruses that have caused human disease, Sudan ebolavirus, Ivory Coast ebolavirus, and marburgvirus, produce a similar illness but with somewhat lower case-fatality rates. Variations in outcome during an epidemic might be due partly to genetically determined differences in innate immune responses to the viruses. Recent studies in non-human primates have shown that blocking of certain host responses, such as the coagulation cascade, can result in reduced viral replication and improved host survival.

Africa↗