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PubMed2001

Induction of effective antitumor immune responses in a mouse bladder tumor model by using DNA of an alpha antigen from mycobacteria.

One of the main objectives of cancer immunotherapy is the activation and increase in number of antitumor effector cells. Recently, genetically modified tumor cell vaccines have been proposed for elicitation of antitumor effector cells. Native alpha antigen (alpha Ag) (also known as MPT59 and antigen 85B) of mycobacteria, which cross-reacts among mycobacteria species, may play an important biological role in host-pathogen interaction because it elicits various helper T-cell type 1 immune responses. To assess the induction of antitumor immune responses by alpha Ag, mouse tumor cell lines transfected with cDNA of alpha Ag from Mycobacterium kansasii were established, and the possibility of producing a tumor cell vaccine for induction of antitumor effects was explored. Transfection of tumor cell lines with an alpha Ag gene lead to primary tumor rejection and the establishment of protective immunity to nontransfected original tumor cell lines in Mycobacterium bovis bacillus Calmette-Gurin (BCG)-primed and unprimed mice. Mice immunized with tumor cell lines transfected with the alpha Ag gene showed delayed-type hypersensitivity responses in vivo and proliferative responses together with induction of interferon-gamma of spleen cells against nontransfected wild-type tumor cell lines in in vitro experiments. Moreover, immunization of mice with alpha Ag-expressing tumor cells elicited tumor-specific and cytotoxic T lymphocyte (CTL) epitope peptide-specific CD8+ CTLs. The results of this study provided evidence of the potential usefulness of alpha Ag in tumor cell vaccines.

Animals↗

PubMed2001

Role of EscF, a putative needle complex protein, in the type III protein translocation system of enteropathogenic Escherichia coli.

Type III secretion systems, designed to deliver effector proteins across the bacterial cell envelope and the plasma membrane of the target eukaryotic cell, are involved in subversion of eukaryotic cell functions in a variety of human, animal and plant pathogens. In enteropathogenic Escherichia coli (EPEC), several protein substrates for the secretion apparatus were identified, including EspA, EspB and EspD. EspA is a structural protein and the major component of a large transiently expressed filamentous surface organelle that forms a direct link between the bacterium and the host cell, whereas EspD and EspB seem to form the mature translocation pore. Recent studies of the type III secretion systems of Shigella and Salmonella pathogenicity island (SPI)-1 revealed the existence of a macromolecular complex that spans both bacterial membranes and consists of a basal structure with two upper and two lower rings and a needle-like projection that extends outwards from the bacterial surface. MxiH (Shigella) and PrgI (Salmonella) are the main components of the needle of the type III secretion complex. A needle-like complex has not yet been reported in EPEC. In this study, we investigated EscF, a protein sharing sequence similarity with MxiH and PrgI. We report that EscF is required for type III protein secretion and EspA filament assembly. Moreover, we show that EscF binds EspA, suggesting that EspA filaments are an extension of the type III secretion needle complexes in EPEC.

Amino Acid Sequence↗

PubMed2004

Immunopathological basis of virus-induced myocarditis.

Heart diseases are an important cause of morbidity and mortality in industrialized countries. Dilated cardiomyopathy (DCM), one of the most common heart diseases, may be the consequence of infection-associated myocardits. Coxsackievirus B3 (CVB3) can be frequently detected in the inflamed heart muscle. CVB3-induced acute myocarditis is most likely the consequence of direct virus-induced myocyte damage, whereas chronic CVB3 infection-associated heart disease is dominated by its immunopathological sequelae. Bona fide autoimmunity, for example, directed against cardiac myosin, may favor chronic destructive immune damage in the heart muscle and thereby promote the development of DCM. The immunopathogenesis of myocarditis and subsequent DCM induced either by pathogens or autoantigens can be investigated in well-established animal models. In this article, we review recent studies on the role of viruses, with particular emphasis on CVB3, and different immunological effector mechanisms in initiation and progression of myocarditis.

Animals↗

PubMed2000

Defective intracellular transport and processing of OA1 is a major cause of ocular albinism type 1.

Ocular albinism type 1 (OA1) is an X-linked disorder mainly characterized by a severe reduction of visual acuity, hypopigmentation of the retina and the presence of macromelanosomes in the skin and eyes. Various types of mutation have been identified within the OA1 gene in patients with the disorder, including several missense mutations of unknown functional significance. In order to shed light into the molecular pathogenesis of ocular albinism and possibly define critical functional domains within the OA1 protein, we characterized 19 independent missense mutations with respect to processing and subcellular distribution on expression in COS-7 cells. Our analysis indicates the presence of at least two distinct biochemical defects associated with the different missense mutations. Eleven of the nineteen OA1 mutants (approximately 60%) were retained in the endoplasmic reticulum, showing defecNStive intracellular transport and glycosylation, consistent with protein misfolding. The remaining eight of the nineteen OA1 mutants (approximately 40%) displayed sorting and processing behaviours indistinguishable from those of the wild-type protein. Consistent with our recent findings that OA1 represents a novel type of intracellular G protein-coupled receptor (GPCR), we found that most of these latter mutations cluster within the second and third cytosolic loops, two regions that in canonical GPCRs are known to be critical for their downstream signaling, including G protein-coupling and effector activation. The biochemical analysis of OA1 mutations performed in this study provides important insights into the structure-function relationships of the OA1 protein and implies protein misfolding as a major pathogenic mechanism in OA1.

Albinism, Ocular↗

PubMed2004

Degenerative evolution and functional diversification of type-III secretion systems in the insect endosymbiont Sodalis glossinidius.

Sodalis glossinidius, a maternally transmitted endosymbiont of tsetse flies, maintains two phylogenetically distinct type-III secretion systems encoded by chromosomal symbiosis regions designated SSR-1 and SSR-2. Although both symbiosis regions are closely related to extant pathogenicity islands with similar gene inventories, SSR-2 has undergone novel degenerative adaptations in the transition to mutualism. Notably, SSR-2 lacks homologs of genes found in SSR-1 that encode secreted effector proteins known to facilitate the host cell cytoskeletal rearrangements necessary for bacterial entry and uptake into eukaryotic cells. Also, as a result of relaxed selection, SSR-2 has undergone inactivation of genes encoding components of the type-III secretion system needle substructure. In the current study, we used quantitative PCR to determine the expression profiles of ysaV (SSR-1) and invA (SSR-2) transcripts when S. glossinidius infects an insect cell line, and we used an invasion assay to characterize the phenotype of an S. glossinidius mutant that lacks the ability to produce an OrgA protein that is required for function of the SSR-2 secretome. Whereas SSR-1 is required for bacterial invasion of host cells and ysaV is expressed when bacteria contact host cells, SSR-2 is required for bacterial proliferation after entry, and invA is only expressed in the intracellular stage of infection. These results demonstrate that degenerative genetic adaptations in SSR-2 have promoted functional diversification of the Sodalis SSR-2 type-III secretion system.

Animals↗

PubMed2005

Expression levels of avrBs3-like genes affect recognition specificity in tomato Bs4- but not in pepper Bs3-mediated perception.

The tomato Bs4 disease resistance gene mediates recognition of avrBs4-expressing strains of the bacterial spot pathogen Xanthomonas campestris pv. vesicatoria to give a hypersensitive response (HR). Here, we present the characterization of the Bs4 promoter and its application for low-level expression of bacterial type III effector proteins in planta. Real-time polymerase chain reaction showed that Bs4 is constitutively expressed at low levels and that transcript abundance does not change significantly upon infection with avrBs4-containing xanthomonads. A 302-bp promoter fragment was found to be sufficient to promote Bs4 gene function. Previous studies have shown that high, constitutive in planta expression of avrBs3 (AvrBs3 and AvrBs4 proteins are 96.6% identical) via the Cauliflower mosaic virus 35S (35S) promoter triggers a Bs4-dependent HR whereas X. campestris pv. vesicatoria-mediated delivery of AvrBs3 into the plant cytoplasm does not. Here, we demonstrate that, when expressed under control of the weak Bs4 promoter, avrBs3 does not trigger a Bs4-dependent HR whereas avrBs4 does. In contrast, the pepper Bs3 gene, which mediates recognition of AvrBs3- but not AvrBs4-delivering xanthomonads, retains its recognition specificity even if avrBs4 was expressed in planta from the strong 35S promoter. Importantly, Bs4 promoter-driven expression of hax3, hax4 (two recently isolated avrBs3-like genes), avrBs3, and avrBs4 resulted in identical reactions as observed upon infection with X. campestris pv. vesicatoria strains that express the respective avr gene, suggesting that the protein levels expressed under control of the Bs4 promoter are similar to those that are translocated by the bacterial type III secretion system.

Bacterial Proteins↗

PubMed2001

Effective in vitro clearance of Porphyromonas gingivalis by Fc alpha receptor I (CD89) on gingival crevicular neutrophils.

Porphyromonas gingivalis has been implicated as a causative pathogen in periodontitis. Immunotherapeutic approaches have recently been suggested to aid in the clearance of P. gingivalis from disease sites. Because antibody-Fc receptor (FcR) interactions play a role in the effector functions of polymorphonuclear neutrophils (PMN), we evaluated which FcR on PMN from gingival crevicular fluid (GCF) serves as an optimal target molecule for FcR-directed immunotherapy. GCF PMN and peripheral blood (PB) PMN from adult periodontitis patients were analyzed for their immunoglobulin G (IgG) and IgA FcR (Fc gamma R and Fc alpha R, respectively) expression and function by studying IgG- and IgA-mediated elimination of P. gingivalis. GCF PMN exhibited higher Fc alpha RI and Fc gamma RI levels and lower Fc gamma RIIa and Fc gamma RIIIb levels than PB PMN. Functional studies revealed that GCF PMN exhibited less of a capacity to phagocytose and kill IgG1-opsonized P. gingivalis than PB PMN. IgA1-mediated phagocytosis and killing capacity was, however, comparable between GCF PMN and PB PMN. In summary, these in vitro results document that Fc alpha RI represents a candidate target for FcR-directed immunotherapy for the clearance of P. gingivalis.

Adult↗

PubMed2025

Arabidopsis CNL receptor SUT1 confers immunity in hydathodes against the vascular pathogen Xanthomonas campestris pv. campestris.

Bacterial plant pathogens exploit natural openings, such as pores or wounds, to enter the plant interior and cause disease. Plants guard these openings through defense mechanisms. However, bacteria from the genus Xanthomonas have specialized in that they enter their host via a special entry point, the hydathode-an organ at the leaf margin involved in xylem sap guttation. Hydathodes can mount an immune response against bacteria, including non-adapted and adapted pathogens like X. campestris pv. campestris (Xcc) that cause vascular disease. Previously, it was shown that the RKS1/ZAR1 immune complex confers vascular resistance against Xcc by recognizing XopAC activity, a type III effector (T3E). However, in absence of XopAC recognition, Arabidopsis Col-0 hydathodes still display resistance against Xcc. Here we mapped the causal gene using an inoculation method that promotes Xcc hydathode entry. Using a population of Recombinant Inbred Lines (RILs) of a cross between a susceptible (Oy-0) and resistant accession (Col-0), a major QTL for Xcc resistance was found on the right arm of Chromosome 5 in Col-0. Combining this result with a genome-wide association analysis yielded a single candidate gene encoding a coiled-coil nucleotide-binding leucine-rich repeat (CNL-type) immune receptor protein called SUPPRESSOR OF TOPP4 1 (SUT1). Expression of SUT1 was confirmed in hydathodes. We reveal that RKS1/ZAR1 and SUT1 confer different levels of Xcc resistance in different tissue types. Both RKS1/ZAR1 and SUT1 are alone sufficient for Xcc resistance in Col-0 hydathodes. However, RKS1/ZAR1 resistance is also effective in tissue types that represent late infection stages, i.e., xylem and mesophyll. In contrast, SUT1 resistance is not effective in the xylem, while weakly additive to RKS1/ZAR1 in the mesophyll. We thus identify a novel R gene, SUT1, that confers Xcc resistance primarily early in the infection during hydathode colonization.

Plant Diseases↗

PubMedDate not supplied

Molecular basis of Trypanosoma cruzi and Leishmania interaction with their host(s): exploitation of immune and defense mechanisms by the parasite leading to persistence and chronicity, features reminiscent of immune system evasion strategies in cancer diseases.

A number of features occurring during host-parasite interactions in Chagas disease caused by the protozoan parasite, Trypanosoma cruzi, and Leishmaniasis, caused by a group of kinetoplastid protozoan parasites are reminiscent of those observed in cancer diseases. In fact,although the cancer is not a single disease, and that T.cruzi and Leishmania are sophisticated eukaryotic parasites presenting a high level of genotypic variability the growth of the parasites in their host and that of cancer cells share at least one common feature, that is their mutual capacity for rapid cell division. Surprisingly, the parasitic diseases and cancers share some immune evasion strategies. Consideration of these immunological alterations must be added to the evaluation of the pathogenic processes. The molecular and functional characterization of virulence factors and the study of their effect on the arms of the immune system have greatly improved understanding of the regulation of immune effectors functions. The purpose of this review is to analyze some of the current data related to the regulatory components or processes originating from the parasite that control or interfere with host cell physiology. Attempts are also made to delineate some similarities between the immune evasion strategies that parasites and tumors employ. The elucidation of the mode of action of parasite virulence factors toward the host cell allow not only provide us with a more comprehensive view of the host-parasite relationships but may also represent a step forward in efforts aimed to identify new target molecules for therapeutic intervention.

Animals↗

PubMed2006

Interferon alpha and its contribution to autoimmunity.

It is now well accepted that interferon (IFN)alpha plays a critical role in the pathogenesis and perpetuation of specific autoimmune diseases, including systemic lupus erythematosus (SLE), autoimmune thyroid disease and type 1 diabetes. IFNalpha-based treatments are widely used for the treatment of chronic viral infections, particularly chronic hepatitis C virus infection; however, several case reports have emerged describing autoimmune conditions that have developed during IFNalpha therapy. The data support the pathogenic potential of IFNalpha in autoimmunity, although it is clear that genetic and environmental factors are also key to the development of autoimmune conditions. Several points of interaction between IFNalpha and immune effector cells have been experimentally defined, the functional consequences of many of which remain poorly understood. This review describes the most recent data in support of an important role for IFNalpha in autoimmunity, particularly SLE, and the potential mechanisms by which IFNalpha contributes to immune dysfunction. Future approaches to IFNalpha modulation as a therapeutic strategy for use in the treatment of autoimmune diseases are also discussed.

Animals↗

PubMed2004

Apoptosis and estrogen deficiency in primary Sjögren syndrome.

PURPOSE OF REVIEW: Primary Sjögren syndrome is an autoimmune disorder characterized by lymphocytic infiltrates and destruction of the salivary and lacrimal glands, and systemic production of autoantibodies to the ribonucleoprotein particles SS-A/Ro and SS-B/La. The purpose of this review is to discuss recent advances in the pathogenesis of primary Sjögren syndrome. RECENT FINDINGS: Although several candidate autoantigens including alpha-fodrin have been reported in Sjögren syndrome, the pathogenic roles of the autoantigens in initiation and progression of SS are still unclear. It is possible that individual T cells activated by an appropriate self antigen can proliferate and form a restricted clone. Recent evidence suggests that the apoptotic pathway plays a central role in tolerizing T cells to tissue-specific self antigen, and may drive the autoimmune phenomenon. Cleavage of certain autoantigens during apoptosis may reveal immunocryptic epitopes that could potentially induce autoimmune response. The studies reviewed imply that Fas-mediated cytotoxicity and caspase-mediated alpha-fodrin proteolysis are involved in the progression of tissue destruction in Sjögren syndrome. Fas ligand (FasL), and its receptor Fas are essential in the homeostasis of the peripheral immune system. It can be considered that a defect in activation-induced cell death of effector T cells may result in the development of autoimmune exocrinopathy in Sjögren syndrome. SUMMARY: Although the mechanisms by which estrogen deficiency influences autoimmune lesions remain unclear, it is possible that antiestrogenic actions might be a potent factor in the formation of pathogenic autoantigens.

Animals↗

PubMed2004

Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs.

Microglia are the resident macrophage-like population in the CNS. Microglia remain quiescent until injury or infection activates the cells to perform effector inflammatory and APC functions. Our previous studies have shown that microglia infected with a neurotropic strain of Theiler's murine encephalomyelitis virus secreted innate immune cytokines and up-regulated costimulatory molecules and MHC class II, enabling the cells to present viral and myelin Ags to CD4+ T cells. Recently, TLRs have been shown to recognize pathogen-associated molecular patterns and initiate innate immune responses upon interaction with infectious agents. We examined TLR expression on brain microglia and their functional responses upon stimulation with various TLR agonists. We report that mouse microglia express mRNA for all of the recently identified TLRs, TLR1-9, used for recognition of bacterial and viral molecular patterns. Furthermore, stimulation of quiescent microglia with various TLR agonists, including LPS (TLR4), peptidoglycan (TLR2), polyinosinic-polycytidylic acid (TLR3), CpG DNA (TLR9), and infection with viable Theiler's murine encephalomyelitis virus, activated the cells to up-regulate unique patterns of innate and effector immune cytokines and chemokines at the mRNA and protein levels. In addition, TLR stimulation activated up-regulation of MHC class II and costimulatory molecules, enabling the microglia to efficiently present myelin Ags to CD4+ T cells. Thus, microglia appear to be a unique and important component of both the innate and adaptive immune response, providing the CNS with a means to rapidly and efficiently respond to a wide variety of pathogens.

Animals↗

PubMed2004

Rapid development of T cell memory.

Prime-boost immunization is a promising strategy for inducing and amplifying pathogen- or tumor-specific memory CD8 T cell responses. Although expansion of CD8 T cell populations following the second Ag dose is integral to the prime-boost strategy, it remains unclear when, after priming, memory T cells become competent to proliferate. In this study, we show that Ag-specific CD8 T cells with the capacity to undergo extensive expansion are already present at the peak of the primary immune response in mice. These early memory T cells represent a small fraction of the primary immune response and, at early time points, their potential to proliferate is obscured by large effector T cell populations that rapidly clear Ag upon reimmunization. With sufficient Ag boosting, however, secondary expansion of these memory cells can be induced as early as 5-7 days following primary immunization. Importantly, both early and delayed boosting result in similar levels of protective immunity to subsequent pathogen challenge. Early commitment and differentiation of memory T cells during primary immunization suggest that a short duration between priming and boosting is feasible, providing potential logistic advantages for large-scale prime-boost vaccination of human populations.

Animals↗

PubMed2006

Comparative genomics of host-specific virulence in Pseudomonas syringae.

While much study has gone into characterizing virulence factors that play a general role in disease, less work has been directed at identifying pathogen factors that act in a host-specific manner. Understanding these factors will help reveal the variety of mechanisms used by pathogens to suppress or avoid host defenses. We identified candidate Pseudomonas syringae host-specific virulence genes by searching for genes whose distribution among natural P. syringae isolates was statistically associated with hosts of isolation. We analyzed 91 strains isolated from 39 plant hosts by DNA microarray-based comparative genomic hybridization against an array containing 353 virulence-associated (VA) genes, including 53 type III secretion system effectors (T3SEs). We identified individual genes and gene profiles that were significantly associated with strains isolated from cauliflower, Chinese cabbage, soybean, rice, and tomato. We also identified specific horizontal gene acquisition events associated with host shifts by mapping the array data onto the core genome phylogeny of the species. This study provides the largest suite of candidate host-specificity factors from any pathogen, suggests that there are multiple ways in which P. syringae isolates can adapt to the same host, and provides insight into the evolutionary mechanisms underlying host adaptation.

Gene Expression Profiling↗

PubMed2003

Nramp1 functionality increases inducible nitric oxide synthase transcription via stimulation of IFN regulatory factor 1 expression.

Natural-resistance associated macrophage protein 1 (Nramp1) encodes a transmembrane phagolysosomal protein exerting resistance toward infections with intracellular pathogens by a mechanism not fully elucidated so far. We used the murine macrophage cell line RAW264.7, stably transfected with functional (RAW-37) or nonfunctional (RAW-21) Nramp1, to study for differences in the expression of NO, a central antimicrobial effector molecule of macrophages. Following stimulation with IFN-gamma and LPS, Nramp1-expressing cells exhibit higher enzymatic activity of inducible NO synthase (iNOS) and increased cytoplasmic iNOS mRNA levels than RAW-21 cells. Time-course experiments showed that iNOS-mRNA levels remain increased in RAW-37 cells after prolonged cytokine stimulation while they decrease in RAW-21 cells. Reporter gene assays with iNOS-promoter luciferase constructs demonstrated an increased and prolonged promoter activity in Nramp1-resistant vs susceptible cells. This was paralleled by increased IFN regulatory factor 1 (IRF-1) expression and binding affinity to the iNOS promoter in RAW-37 cells, which may be related to enhanced STAT-1 binding affinity in these cells. A point mutation within the IRF-1 binding site of the iNOS promoter abolished the differences in iNOS transcription between RAW-21 and RAW-37 cells. Cells carrying functional Nramp1 express increased amounts of NO, which may be related to STAT-1-mediated stimulation of IRF-1 expression with subsequent prolonged activation of iNOS transcription. Enhanced NO expression may partly underlie the protection against infection with intracellular pathogens by Nramp1 functionality.

Animals↗

PubMed1996

Dissection of the pathologies induced by transmembrane and wild-type tumor necrosis factor in transgenic mice.

With increasing awareness that seemingly diverse immune-mediated diseases involve similar pathogenetic mechanisms, and the identification of a growing number of key effector molecules, it is becoming possible to design and generate effective transgenic models for such diseases. Tumor necrosis factor (TNF) plays a prominent role in immune and host defense responses and there is strong evidence that abnormal TNF production contributes to disease initiation and progression in rheumatoid arthritis, systemic inflammatory response syndrome, diabetes, multiple sclerosis, and many other immune-mediated disorders. The generation of TNF transgenic mice, in which TNF production is deregulated, has provided us with direct evidence that, in vivo, this cytokine can indeed trigger the development of such complex disease phenotypes. Transgenic mice that have been engineered to overexpress human or murine TNF molecules in peripheral joints, T cells, or neurons of the central nervous system represent important animal models for human rheumatoid arthritis, systemic inflammation, and multiple sclerosis, respectively. In addition to establishing a central role for TNF in such diseases, these animal models have already proved valuable for identifying additional important disease-effector molecules, and for gaining an insight into the complex in vivo mechanisms that are involved in disease pathogenesis. For example, in the case of arthritis, TNF has been found to transmit its pathogenic effects entirely through interleukin-1, which may therefore represent an additional important target for therapeutic intervention in the human disease. In summary, TNF transgenic models of human disease are expected to serve as important in vivo tools for defining details of disease pathogenesis, potential targets for therapeutic intervention and for evaluating the possible involvement of additional genetic and environmental factors on the disease state.

Animals↗

PubMed2006

Signal integration between IFNgamma and TLR signalling pathways in macrophages.

Macrophages are major effector cells of the innate immune system, and appropriate regulation of macrophage function requires the integration of multiple signalling inputs derived from the recognition of host factors (e.g. interferon-gamma/IFNgamma) and pathogen products (e.g. toll-like receptor/TLR agonists). The profound effects of IFNgamma pre-treatment ("priming") on TLR-induced macrophage activation have long been recognised, but many of the mechanisms underlying the priming phenotype have only recently been identified. This review summarises the known mechanisms of integration between the IFNgamma and TLR signalling pathways. Synergy occurs at multiple levels, ranging from signal recognition to convergence of signals at the promoters of target genes. In particular, the cross-talk between the IFNgamma, and LPS and CpG DNA signalling pathways is discussed.

Animals↗

PubMed2005

Where do T cells stand in rheumatoid arthritis?

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by destruction of cartilage and bone. The destructive lesions result from both immune responses and non-antigen-specific inflammatory processes. Little is known about the primary cause of RA. Although the primacy of T-cell-related events early in the disease remains debated, strong evidence indicates that autoantigen recognition by specific T cells is crucial to the pathophysiology of rheumatoid synovitis. We will discuss evolving concepts about T-cell involvement in RA and the roles for various T cell subsets in the development of joint abnormalities. The hypothesis that RA is a T-cell driven disease was put forward when studies of RA synovium showed numerous T cells carrying activation markers. These T cells were found to participate in the complex network of cell- and mediator-driven events leading to joint destruction. Conceivably, these T cells may be stimulated by an autoantigen (whether specific to the joints or ubiquitous), a highly conserved foreign protein cross-reacting with its human homolog, or a neo-antigen expressed as a result of posttranslational events. For many years, animal models have provided valuable evidence supporting a role for T cells in RA. We will review three murine models of arthritis caused by different mechanisms. In collagen-induced arthritis, the immune response to a joint antigen is mediated by pathogenic Th1 cells that elicit severe inflammatory synovitis. Spontaneous arthritis in K/BxN T-cell-receptor transgenic mice is related to an adaptive immune response against a ubiquitous protein whose end-stage effector mechanisms are heavily dependent on the innate immune system. In the SKG model of autoimmune inflammatory arthritis, a point mutation in the gene encoding a key signal-transduction molecule in T cells causes defective T cell selection in the thymus, which releases polyclonal autoreactive T cells. Studies in these and other animal models have established that a variety of T-cell subsets whose roles vary with cell location and disease stage can contribute to synovitis. Finally, in addition to direct autoimmune attack by effector T cells, arthritis may result from defective homeostatic control of immunity by regulatory T cells.

Animals↗