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PubMed1987

Immunologic mechanisms in intestinal diseases.

The intestine is a unique immunologic organ that comprises an afferent and efferent compartment and provides the host with the ability to respond through several different effector mechanisms against environmental factors. We discuss mechanisms in three intestinal diseases in this overview of the mucosal immune system. Genetic and immunologic factors are important in the pathogenesis of celiac disease, which is characterized by damage to the mucosa of the small intestine with resultant malabsorption. Pathogenic microbes are important environmental agents that interact with the intestinal mucosa and initiate local immune responses. Advances in the understanding of the mucosal immune response to these pathogenic microbes have produced a clear picture of the way in which this specialized immune system works in concert with systemic immunity. As to the autoimmune nature of inflammatory bowel disease, no specific antigen has been shown to incite the inflammatory reactions and neither the target cells nor the effector mechanism involved have been identified. Several factors exist, however, to suggest an autoimmune mechanism and the role of mucosal immunologic factors in this disease.

Autoimmune Diseases↗

PubMed2006

Adenosine signalling in airways.

Current research endeavours indicate that adenosine elicits strong inflammatory responses in the lung and might be involved in the pathogenic mechanisms of chronic inflammatory disorders of the airways such as asthma and chronic obstructive pulmonary disease (COPD). The contribution of adenosine-associated effector mechanisms to the initiation, persistence and progression of the inflammatory response is highly heterogeneous and is dictated by the expression pattern of four different adenosine receptors. Selective activation or blockade of these sites can therefore be exploited in an attempt to generate novel therapies for asthma and COPD. In addition, an important development is the use of adenosine (or AMP) as a diagnostic test for discriminating asthma from COPD, and as an accurate biomarker to monitor corticosteroid requirements in asthma. It is likely that therapies interfering with adenosine signalling in the airways will offer a considerable advance in the management of asthma and COPD.

Adenosine↗

PubMed2004

Gene discovery and expression analysis of immune-relevant genes from Biomphalaria glabrata hemocytes.

The immune effector cells (hemocytes) of the snail host Biomphalaria glabrata are known to play a key role in recognition and elimination of larval helminths such as the human blood fluke Schistosoma mansoni. To identify novel immune-relevant genes, we undertook an expressed sequence tag program. A hemocyte cDNA library was constructed using snails that were not exposed to a particular pathogen or parasite but maintained in non-axenic conditions. Putative function could be assigned to 53% of the 1613 high quality cDNAs analysed. Based on sequence similarities, we identified 31 immune-relevant genes corresponding either to cellular defence effectors, proteases and protease inhibitors, pattern recognition receptors, cell adhesion molecules or immune regulators. In order to further investigate the potential involvement of these genes in snail-trematode immunobiological interactions, we analysed their expression in unchallenged and parasite-challenged snails, using the immunosuppressive trematode Echinostoma caproni and snail strains selected for resistance or susceptibility to this parasite. Real-time PCR analysis of expression ratios at 7 time-points post-exposure revealed both (i) genes displaying constitutive expression differences between the two strains; and (ii) genes differentially modulated after parasite exposure.

Animals↗

PubMed1999

[Immunological bases and classification of allergy].

The task of the immune system consists of destroying foreign structures in order to prevent the invasion of living organisms by pathogens. This destruction often provokes adverse effects defined as hypersensitivity reactions. The classification of hypersensitivity reactions proposed by Gell and Coombs is based on effector mechanisms. Although this framework remains largely used, recent work demonstrated the occurrence of profound similarities between different classes of hypersensitivity reactions. Indeed, all these reactions involve the activation of adhesion mechanisms intended to allow the local recruitment of blood leukocytes and cytokine production. The concept of a separation between two different modes of immune response induced by two different T lymphocyte subpopulations (TH1 and TH2) proved useful in understanding hypersensitivity reactions, although it represents only an approximation. Recent results were an incentive to develop new diagnostic and therapeutic strategies whose usefulness will be evaluated in the near future.

Adult↗

PubMed2006

Characterization of the interaction of single tryptophan containing mutants of IpaC from Shigella flexneri with phospholipid membranes.

Shigella flexneri causes dysentery after invading the epithelial cells of the human colon. Enterocyte invasion is induced by the bacterial effector IpaC (invasion plasmid antigen C), which triggers Shigella entry into epithelial cells by a rather poorly understood mechanism. IpaC is also involved in pathogen escape into the host cell cytoplasm following uptake, and this property may be reflected in its ability to disrupt phospholipid vesicles in vitro. Purified recombinant IpaC interacts with liposome vesicles to cause the release of small molecules trapped inside. This interaction requires that the liposomes possess an acidic phospholipid component. To better understand the events involved in the disruption of liposomes by IpaC, single tryptophan mutants were generated to permit the use of intrinsic fluorescence, circular dichroism, and ultraviolet absorption spectroscopies to examine the effect that phospholipid membrane association has on IpaC structure and stability. These mutants were also used to determine how amino acid substitutions within specific regions of IpaC influence its activity in vivo. The outcomes of this study include findings that cholesterol greatly impacts IpaC association with phospholipid membranes, tryptophan incorporation into specific regions of IpaC (especially near the C-terminus) can greatly impact its in vivo activity, and interaction with phospholipid membranes causes differing degrees of change in the fluorescence of tryptophan residues introduced at specific sites within IpaC. These data, together with fluorescence quenching analyses, provide new functional and structural information concerning IpaC and its insertion into phospholipid membranes.

Amino Acid Substitution↗

PubMed2000

B-cell activation by T-cell-independent type 2 antigens as an integral part of the humoral immune response to pathogenic microorganisms.

Antigens that are expressed on the surface of pathogens in an organized, highly repetitive form can activate specific B cells by cross-linking of antigen receptors in a multivalent fashion. B cells respond to these multivalent antigens in the absence of MHC class II-restricted T-cell help by a mechanism that depends on the expression of a functional Bruton's tyrosine kinase (Btk). Accordingly, this class of immunogens has been designated T-cell-independent type 2 (TI-2) antigens. The unique properties of the B-cell response to TI-2 antigens are critically dependent on the formation of a small number of antigen receptor clusters, each of which contains approximately 10 to 20 antigen-bound membrane Ig (mIg) molecules. These clusters induce local membrane association of multiple activated Btk molecules, which results in long-term mobilization of intracellular ionized calcium. Such persistent calcium fluxes efficiently recruit transcription factors and thereby induce T-cell-independent B-cell activation and proliferation. While this first signal of multivalent mIg cross-linking can induce B-cell proliferation, we propose that a second signal is required for a TI-2 Ig secretory response. We have found that engagement of members of the Toll-like receptor (TLR) family could provide second signals that selectively induce Ig secretion in B cells that were activated by multivalent, but not by bivalent, antigen receptor engagement. This finding demonstrates a general mechanism by which TLRs recognize molecular motifs on the surface of pathogens and provide the TI-2-activated B cell with a second signal. In addition, TLR-dependent recognition of these non-self motifs by cells of the innate immune system can induce these cells to provide alternative and/or additional second signals in the TI-2 response. The complement system provides another link between the B cell and the innate immune system, and facilitates the mIg signal transduction by recruitment of CD21 in the immune response. Thus, the TI-2 response provides the host with a combination of "the best of both worlds": the recruitment of the fine specificity of the adaptive immune response and the utilization of both the speed of the innate immune system and the wealth of cytokines produced by its member cells upon stimulation by pathogenic organisms or their products. By combining these two pathways, the TI-2 response enables the host to rapidly produce antigen-specific Ig effector molecules that can be secreted at a sufficient rate to keep up with the rapid multiplication of invading infectious microorganisms, and will also prevent the intracellular spreading of a significant part of this population.

Animals↗

PubMed2003

Effect of iron treatment on circulating cytokine levels in ESRD patients receiving recombinant human erythropoietin.

BACKGROUND: Anemia in patients with end-stage renal disease (ESRD) is treated with recombinant human erythropoietin (rhEPO) often in combination with iron. However, iron catalyzes the formation of toxic radicals, which might promote vascular damage, is a nutrient for microorganisms, and negatively affects immune pathways, thus increasing the risk for severe infections. METHODS: We investigated 28 patients on chronic hemodialysis who were randomized to receive either rhEPO alone (N = 15) or rhEPO in combination with intravenous iron (N = 13) for a period of 12 weeks. We analyzed iron therapy associated changes in cytokine patterns and endogenous radical formation. RESULTS: Tumor necrosis factor-alpha (TNF-alpha) levels were increased in ESRD patients at study entry and then decreased significantly over time in subjects receiving additional iron, while they increased with rhEPO alone. In contrast, we found serum concentrations of the anti-inflammatory cytokine interleukin (IL)-4 to increase with iron therapy. A significant negative correlation between iron availability, as determined by transferrin saturation, and TNF-alpha levels (P = 0.008) and a positive one between transferring saturation and IL-4 (P = 0.02) pointed to the potential role of iron to induce immunologic changes. Interestingly, iron therapy resulted in a slight decrease in the amounts of endogenous peroxides, which may be referred to reduced TNF-alpha concentrations since peroxide concentrations were positively correlated to TNF-alpha levels (P = 0.046) and negatively to transferrin saturation (P = 0.02). CONCLUSION: Iron supplementation in ESRD patients down-regulates proinflammatory immune effector pathways and stimulates the expression of the anti-inflammatory cytokine IL-4. Such a condition is detrimental for host response toward invading pathogens. However, tissue damage by radicals such as endogenous peroxides may be reduced in this condition due to impaired TNF-alpha formation.

Aged↗

PubMed2005

Variation in IL-1beta gene expression is a major determinant of genetic differences in arthritis aggressivity in mice.

In humans and in animal models, susceptibility to arthritis is under complex genetic control, reflecting influences on the immunological processes that initiate autoimmunity and on subsequent inflammatory mechanisms in the joints. The effector phases are conveniently modeled by the K/BxN serum transfer system, a robust model well suited for genetic analysis where arthritis is initiated by pathogenic Ig. Here, we mapped the genetic loci distinguishing the high-responder BALB/c vs. low-responder SJL strains. After computational modeling of potential breeding schemes, we adapted a stepwise selective breeding strategy, with a whole-genome scan performed on a limited number of animals. Several genomic regions proved significantly associated with high sensitivity to arthritis. One of these regions, on distal chr2, was centered on the interleukin 1 gene family. Quantitation of transcripts of the Il1a and Il1b candidate genes revealed a 10-fold greater induction of Il1b mRNA in BALB/c than in SJL splenocytes after injection of LPS, whereas Il1a showed much less difference. The differential activity of the Il1b gene was associated with a particular sequence haplotype of noncoding polymorphisms. The BALB/c haplotype was found in 75% of wild-derived strains but was rare among conventional inbred strains (4/33 tested, one of which is DBA/1, the prototype arthritis-susceptible strain) and was associated with vigorous Il1b responses in a panel of inbred strains. Inbred strains carrying this allele were far more responsive to serum-transferred arthritis, confirming its broad importance in controlling arthritis severity.

Animals↗

PubMed2001

A highly specific one-step PCR - assay for the rapid discrimination of enteropathogenic Yersinia enterocolitica from pathogenic Yersinia pseudotuberculosis and Yersinia pestis.

Based on differences within the yopT-coding region of Yersinia. enterocolitica, Y pseudotuberculosis and Y pestis, a rapid and sensitive one-step polymerase chain reaction assay with high specificity for pathogenic Y enterocolitica was developed. By this method pathogenic isolates of Y enterocolitica can be easily identified and discriminated from other members of this genus. The entire coding sequence of the yopT effector gene of Y. pseudotuberculosis Y36 was determined.

Animals↗

PubMed2005

Recruitment of Gr-1+ monocytes is essential for control of acute toxoplasmosis.

Circulating murine monocytes comprise two largely exclusive subpopulations that are responsible for seeding normal tissues (Gr-1-/CCR2-/CX3CR1high) or responding to sites of inflammation (Gr-1+/CCR2+/CX3CR1lo). Gr-1+ monocytes are recruited to the site of infection during the early stages of immune response to the intracellular pathogen Toxoplasma gondii. A murine model of toxoplasmosis was thus used to examine the importance of Gr-1+ monocytes in the control of disseminated parasitic infection in vivo. The recruitment of Gr-1+ monocytes was intimately associated with the ability to suppress early parasite replication at the site of inoculation. Infection of CCR2-/- and MCP-1-/- mice with typically nonlethal, low doses of T. gondii resulted in the abrogated recruitment of Gr-1+ monocytes. The failure to recruit Gr-1+ monocytes resulted in greatly enhanced mortality despite the induction of normal Th1 cell responses leading to high levels of IL-12, TNF-alpha, and IFN-gamma. The profound susceptibility of CCR2-/- mice establishes Gr-1+ monocytes as necessary effector cells in the resistance to acute toxoplasmosis and suggests that the CCR2-dependent recruitment of Gr-1+ monocytes may be an important general mechanism for resistance to intracellular pathogens.

Acute Disease↗

PubMed2006

Neutrophil-derived leukotriene B4 is required for inflammatory arthritis.

Neutrophils serve as a vanguard of the acute innate immune response to invading pathogens. Neutrophils are also abundant at sites of autoimmune inflammation, such as the rheumatoid joint, although their pathophysiologic role is incompletely defined and relevant effector functions remain obscure. Using genetic and pharmacologic approaches in the K/BxN serum transfer model of arthritis, we find that autoantibody-driven erosive synovitis is critically reliant on the generation of leukotrienes, and more specifically on leukotriene B4 (LTB4), for disease induction as well as perpetuation. Pursuing the cellular source for this mediator, we find via reconstitution experiments that mast cells are a dispensable source of leukotrienes, whereas arthritis susceptibility can be restored to leukotriene-deficient mice by intravenous administration of wild-type neutrophils. These experiments demonstrate a nonredundant role for LTB4 in inflammatory arthritis and define a neutrophil mediator involved in orchestrating the synovial eruption.

Animals↗

PubMed2026

Rs_MEP1 Is Required for the Pathogenesis of Rhizoctonia solani AG1-IA in Plants.

Rhizoctonia solani AG1-IA is a polyphagous necrotrophic fungal pathogen that causes sheath blight disease in rice. Efforts are being made to identify pathogenicity-associated genes in R. solani and modulate them to develop a disease control strategy. Here, we investigated the roles of some predicted pathogenicity-associated genes of R. solani that have previously been reported to be upregulated during infection in rice. The tobacco rattle virus-based host-induced gene silencing of the selected pathogenicity-associated genes revealed that silencing of Rs_MEP1, a zinc-containing Peptidase_M43 domain metalloprotease, severely compromises R. solani infection in tomato. Moreover, double-stranded RNA-mediated silencing of Rs_MEP1 prevented R. solani infection in rice. The signal sequence trap assay indicated the secretory nature of Rs_MEP1, and the reporter assay suggested its localization in the plant apoplast. Notably, Agrobacterium-mediated transient overexpression of Rs_MEP1 induces necrotic cell death responses in plants. We provide evidence that Rs_MEP1 interacts with the GH19 family of rice chitinases and potentially modulates their functions. Overall, our study emphasizes that Rs_MEP1 facilitates R. solani in promoting necrotic responses and targets rice GH19 chitinases to impart disease susceptibility in plants. [Formula: see text] Copyright © 2026 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Rhizoctonia↗

PubMed2003

CesAB is an enteropathogenic Escherichia coli chaperone for the type-III translocator proteins EspA and EspB.

Enteropathogenic Escherichia coli (EPEC) are extracellular pathogens that colonize mucosal surfaces of the intestine via formation of attaching and effacing (A/E) lesions. The genes responsible for induction of the A/E lesions are located on a pathogenicity island, termed the locus of enterocyte effacement (LEE), which encodes the adhesin intimin and the type III secretion system needle complex, translocator and effector proteins. One of the major EPEC translocator proteins, EspA, forms a filamentous conduit along which secreted proteins travel before they arrive at the translocation pore in the plasma membrane of the host cell, which is composed of EspB and EspD. Prior to secretion, many type III proteins, including translocators, are maintained in the bacterial cytoplasm by association with a specific chaperone. In EPEC, chaperones have been identified for the effector proteins Tir, Map and EspF, and the translocator proteins EspD and EspB. In this study, CesAB (Orf3 of the LEE) was identified as a chaperone for EspA and EspB. Specific CesAB-EspA and CesAB-EspB protein interactions are demonstrated. CesAB was essential for stability of EspA within the bacterial cell prior to secretion. Furthermore, a cesAB mutant failed to secrete EspA, as well as EspB, to assemble EspA filaments, to induce A/E lesion following infection of HEp-2 cells and to adhere to, or cause haemolysis of, erythrocytes.

Bacterial Adhesion↗

PubMed2002

Role of Yops and adhesins in resistance of Yersinia enterocolitica to phagocytosis.

Yersinia enterocolitica is a pathogen endowed with two adhesins, Inv and YadA, and with the Ysc type III secretion system, which allows extracellular adherent bacteria to inject Yop effectors into the cytosol of animal target cells. We tested the influence of all of these virulence determinants on opsonic and nonopsonic phagocytosis by PU5-1.8 and J774 mouse macrophages, as well as by human polymorphonuclear leukocytes (PMNs). The adhesins contributed to phagocytosis in the absence of opsonins but not in the presence of opsonins. In agreement with previous results, YadA counteracted opsonization. In every instance, the Ysc-Yop system conferred a significant level of resistance to phagocytosis. Nonopsonized single-mutant bacteria lacking either YopE, -H, -T, or -O were phagocytosed significantly more by J774 cells and by PMNs. Opsonized bacteria were phagocytosed more than nonopsonized bacteria, and mutant bacteria lacking either YopH, -T, or -O were phagocytosed significantly more by J774 cells and by PMNs than were wild-type (WT) bacteria. Opsonized mutants lacking only YopE were phagocytosed significantly more than were WT bacteria by PMNs but not by J774 cells. Thus, YopH, -T, and -O were involved in all of the phagocytic processes studied here but YopE did not play a clear role in guarding against opsonic phagocytosis by J774. Mutants lacking YopP and YopM were, in every instance, as resistant as WT bacteria. Overexpression of YopE, -H, -T, or -O alone did not confer resistance to phagocytosis, although it affected the cytoskeleton. These results show that YopH, YopT, YopO, and, in some instances, YopE act synergistically to increase the resistance of Y. enterocolitica to phagocytosis by macrophages and PMNs.

Actins↗

PubMed2004

Helicobacter pylori induces apoptosis of human monocytes but not monocyte-derived dendritic cells: role of the cag pathogenicity island.

Monocytes are circulating precursors of the dendritic cell subset, professional antigen-presenting cells with a unique ability to initiate the innate and adaptive immune response. In this study, we have investigated the effects of wild-type Helicobacter pylori strains and their isogenic mutants with mutations in known bacterial virulence factors on monocytes and monocyte-derived dendritic cells. We show that H. pylori strains induce apoptosis of human monocytes by a mechanism that is dependent on the expression of a functional cag pathogenicity island. This effect requires an intact injection organelle for direct contact between monocytes and the bacteria but also requires a still-unidentified effector that is different from VacA or CagA. The exposure of in vitro-generated monocyte-derived dendritic cells to H. pylori stimulates the release of inflammatory cytokines by a similar mechanism. Of note is that dendritic cells are resistant to H. pylori-induced apoptosis. These phenomena may play a critical role in the evasion of the immune response by H. pylori, contributing to the persistence of the infection.

Antigens, Bacterial↗

PubMed2003

Complement components and their autoantibodies.

The purpose of the immune system is to defend the host from constantly changing microbial pathogens. Autoimmune diseases develop as a consequence of the production of antibodies and/or cells that react with self-antigens, and may recruit other effector mechanisms that result in tissue damage. Thus, in this context, autoimmunity represents an immune response to self-antigens that is sufficient to cause disease. This article is specifically devoted to autoantibodies directed against complement components.

Algorithms↗

PubMed2002

Novel molecular targets for systemic lupus erythematosus.

For a long time the complement cascade has been believed to be the predominant pathway to inflammation and tissue destruction in autoimmune diseases such as systemic lupus erythematosus. Recently, new evidences show that FcRs may share the primacy with complement cascade, playing an equal or greater role in the disease process. The generation of specific mouse strains deficient in individual components has clarified the different role played by complement and Fc receptors in their interaction with ICs, illustrating that complement is essential for innate immunity against microbial pathogens, requiring natural antibodies to mediate its protective effects, whereas FcyRs have evolved as the principal system for coupling antigen-antibody complexes to effector cells and initiate the inflammatory cascade. Validation of FcRs as new therapeutic targets for autoimmune diseases, in particular for Systemic Lupus Erythematosus (SLE), has been provided by a large number of studies where the biological action of soluble forms of FcyRs or of monoclonal antibodies targeting Fc receptors has been assessed. Additional support to the role of FcRs in SLE has been provided by data obtained with compounds derived from combinatorial chemistry, such as TG19320, a tetrameric tripeptide which interferes with IgG/FcgammaR interaction in vitro and prevents glomerulonephritis in vivo in a SLE susceptible mouse strain. These findings might open the way to new therapeutic approaches for disorders where the role of FcRs has been established, including not only autoimmune diseases like systemic lupus erythematosus, rheumatoid arthritis, multiple myeloma, but also acquired immunodeficiency syndrome (AIDS).

Animals↗

PubMed2006

CD4+CD25+ regulatory T cells inhibit the antigen-dependent expansion of self-reactive T cells in vivo.

A deficiency of CD4+CD25+ regulatory T cells (CD25+ Tregs) in lymphopenic mice can result in the onset of autoimmune gastritis. The gastric H/K ATPase alpha (H/Kalpha) and beta (H/Kbeta) subunits are the immunodominant autoantigens recognized by effector CD4+ T cells in autoimmune gastritis. The mechanism by which CD25+ Tregs suppress autoimmune gastritis in lymphopenic mice is poorly understood. To investigate the antigenic requirements for the genesis and survival of gastritis-protecting CD25+ Tregs, we analyzed mice deficient in H/Kbeta and H/Kalpha, as well as a transgenic mouse line (H/Kbeta-tsA58 Tg line 224) that lacks differentiated gastric epithelial cells. By adoptive transfer of purified T cell populations to athymic mice, we show that the CD25+ Treg population from mice deficient in either one or both of H/Kalpha and H/Kbeta, or from the H/Kbeta-tsA58 Tg line 224 mice, is equally effective in suppressing the ability of polyclonal populations of effector CD4+ T cells to induce autoimmune gastritis. Furthermore, CD25+ Tregs, from either wild-type or H/Kalpha-deficient mice, dramatically reduced the expansion of pathogenic H/Kalpha-specific TCR transgenic T cells and the induction of autoimmune gastritis in athymic recipient mice. Proliferation of H/Kalpha-specific T cells in lymphopenic hosts occurs predominantly in the paragastric lymph node and was dependent on the presence of the cognate H/Kalpha Ag. Collectively, these studies demonstrate that the gastritis-protecting CD25+ Tregs do not depend on the major gastric Ags for their thymic development or their survival in the periphery, and that CD25+ Tregs inhibit the Ag-specific expansion of pathogenic T cells in vivo.

Adoptive Transfer↗