Tolerance and autoimmunity.
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Adjuvants, Immunologic↗
Biomedical subjects
T Kamradt
Publications and source records attributed to T Kamradt.
Regulation and function of T1/ST2 expression on CD4+ T cells: induction of type 2 cytokine production by T1/ST2 cross-linking.
The orphan receptor T1/ST2, a member of the IL-1R family, is preferentially expressed on the surface of murine Th2 cells. In this study, we analyzed the kinetics and function of T1/ST2 expression on Th2 cells in vitro. Whereas naive CD4(+) cells did not express T1/ST2, most CD4(+) cells became T1/ST2(+) upon repeated antigenic stimulation under Th2-polarizing conditions. Flow cytometric analyses revealed that the kinetics of T1/ST2 expression on Th2 cells was delayed compared with the kinetics of type 2 cytokine production. Exogenous IL-6, IL-5, IL-1, and TNF-alpha enhanced the expression of T1/ST2 on Th2 cells, and IL-6 was by far most effective in this regard. However, the expression of T1/ST2 did not depend on the presence of IL-6 and was also detected in IL-6-deficient mice. Most important, cross-linking of T1/ST2 provided a costimulatory signal for Th2 but not Th1 cells and directly induced proliferation and type 2 cytokine production. Thus, T1/ST2 is not only a Th2 cell marker but also plays an important role in the activation of Th2 cells.
Animals↗
Strong acceleration of murine lupus by injection of the SmD1(83-119) peptide.
OBJECTIVE: The mechanisms of IgG anti-double-stranded DNA (anti-dsDNA) antibody induction are incompletely understood. We recently demonstrated a high prevalence of autoantibodies to the C-terminus of SmD1 in patients with systemic lupus erythematosus (SLE) that was closely associated with anti-dsDNA reactivity. The aim of the present study was to analyze the influence of the SmD1 C-terminus on the generation of pathogenic anti-dsDNA antibodies in a murine model of SLE. METHODS: Female lupus-prone prenephritic (NZB x NZW)F1 mice (NZB/NZW mice) as well as female control BALB/c, NZW, and (BALB/c x NZW)F, mice (CWF1 mice) were subcutaneously injected with keyhole limpet hemocyanin (KLH)-coupled SmD1(83-119). Controls received injections of recombinant SmD1 (rSmD1), KLH-rSmD1, KLH-coupled randomized peptide of SmD1(83-119), ovalbumin, or saline. Animals were monitored for survival and proteinuria and for levels of plasma creatinine, urea, and autoantibodies. In addition, histologic examinations were performed and T cell responses against SmD1(83-119) peptide and rSmD1 protein were determined in SmD1(83-119)-treated and -untreated NZB/NZW mice. RESULTS: Immunization with KLH-SmD1(83-119), but not with control peptide, significantly accelerated the natural course of lupus in NZB/NZW mice, with premature renal failure and increased development of anti-dsDNA antibodies. Control strains of mice remained healthy, with no relevant anti-SmD1(83-119) antibodies detectable even after immunization. In contrast to findings in control mice, a T cell response against SmD1(83-119) was already present in unmanipulated NZB/NZW mice, and this response was further amplified after immunization. CONCLUSION: The SmD1(83-119) peptide can influence the pathogenic anti-dsDNA response in the NZB/NZW murine lupus model. The data suggest that an SmD1(83-119)-specific T cell response is critical. Therefore, modulation of these autoantigen-specific T cells by tolerance induction may provide a therapeutic approach to specific immunosuppression in lupus.
Animals↗
A new home for infection research.
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Animals↗
Institution profile: the Max-Planck-Institute for Infection biology and German Center for Rheumatological Research.
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Academies and Institutes↗
Microbial lipopeptides induce the production of IL-17 in Th cells.
Naive Th cells can be directed in vitro to develop into Th1 or Th2 cells by IL-12 or IL-4, respectively. In vivo, chronic immune reactions lead to polarized Th cytokine patterns. We found earlier that Borrelia burgdorferi, the spirochaete that causes Lyme disease, induces Th1 development in alpha beta TCR-transgenic Th cells. Here, we used TCR-transgenic Th cells and oligonucleotide arrays to analyze the differences between Th1 cells induced by IL-12 vs those induced by B. burgdorferi. Transgenic Th cells primed with peptide in the presence of B. burgdorferi expressed several mRNAs, including the mRNA encoding IL-17, at significantly higher levels than Th cells primed with peptide and IL-12. Cytometric single-cell analysis of Th cell cytokine production revealed that IL-17 cannot be categorized as either Th1 or Th2 cytokine. Instead, almost all IL-17-producing Th cells simultaneously produced TNF-alpha and most IL-17(+) Th cells also produced GM-CSF. This pattern was also observed in humans. Th cells from synovial fluid of patients with Lyme arthritis coexpressed IL-17 and TNF-alpha upon polyclonal stimulation. The induction of IL-17 production in Th cells is not restricted to B. burgdorferi. Priming of TCR-transgenic Th cells in the presence of mycobacterial lysates also induced IL-17/TNF-alpha coproduction. The physiological stimulus for IL-17 production was hitherto unknown. We show here for the first time that microbial stimuli induce the expression of IL-17 together with TNF-alpha in both murine and human T cells. Chronic IL-17 expression induced by microbes could be an important mediator of infection-induced immunopathology.
Animals↗
Multiple cross-reactive self-ligands for Borrelia burgdorferi-specific HLA-DR4-restricted T cells.
T cell recognition of self antigens is a key event in the pathogenesis of autoimmune diseases. To date, the initial events that trigger autoreactive T cells are unknown. The "molecular mimicry" hypothesis predicts that during an infection T cells that recognize both a microbial antigen and a related self peptide become activated and cause autoimmune disease. We have systematically examined the recognition of self antigens by HLA-DR4-restricted T cells specific for peptides of the outer surface protein A (OspA) of Borrelia burgdorferi, the etiological agent of Lyme disease. We used the peptide spot synthesis technique for complete peptide substitution analyses of two immunodominant OspA epitopes. Each amino acid residue of the epitopes was substituted with all 20 naturally occurring amino acids and the altered peptides were tested for recognition by a panel of OspA-specific T cells. The binding motifs (supertopes) revealed by these analyses were used to screen public databases for matching human or murine peptides. Several hundred peptides were identified by this search and synthesized. Of these, 28 were recognized by OspA-specific T cells. Thus, T cell cross-reactivity is a common phenomenon and the existence of cross-reactive epitopes alone does not imply molecular mimicry-mediated pathology and autoimmunity.
Animals↗
Crucial role of the interleukin 1 receptor family member T1/ST2 in T helper cell type 2-mediated lung mucosal immune responses.
T1/ST2 is an orphan receptor of unknown function that is expressed on the surface of murine T helper cell type 2 (Th2), but not Th1 effector cells. In vitro blockade of T1/ST2 signaling with an immunoglobulin (Ig) fusion protein suppresses both differentiation to and activation of Th2, but not Th1 effector populations. In a nascent Th2-dominated response, anti-T1/ST2 monoclonal antibody (mAb) inhibited eosinophil infiltration, interleukin 5 secretion, and IgE production. To determine if these effects were mediated by a direct effect on Th2 cells, we next used a murine adoptive transfer model of Th1- and Th2-mediated lung mucosal immune responses. Administration of either T1/ST2 mAb or T1/ST2-Ig abrogated Th2 cytokine production in vivo and the induction of an eosinophilic inflammatory response, but failed to modify Th1-mediated inflammation. Taken together, our data demonstrate an important role of T1/ST2 in Th2-mediated inflammatory responses and suggest that T1/ST2 may prove to be a novel target for the selective suppression of Th2 immune responses.
Allergens↗
Cross-reactivity of myelin basic protein-specific T cells with multiple microbial peptides: experimental autoimmune encephalomyelitis induction in TCR transgenic mice.
Activation of autoreactive T cells is a crucial event in the pathogenesis of autoimmune diseases. Cross-reactivity between microbial and self Ags (molecular mimicry) is one hypothesis that could explain the activation of autoreactive T cells. We have systematically examined this hypothesis in experimental autoimmune encephalomyelitis using mice bearing exclusively myelin basic protein (MBP)-specific T cells (designated T+ alpha-). A peptide substitution analysis was performed in which each residue of the MBPAc1-11 peptide was exchanged by all 20 naturally occurring amino acids. This allowed the definition of the motif (supertope) that is recognized by the MBPAc1-11-specific T cells. The supertope was used to screen protein databases (SwissProt and TREMBL). By the search, 832 peptides of microbial origin were identified and synthesized. Of these, 61 peptides induced proliferation of the MBPAc1-11-specific transgenic T cells in vitro. Thus, the definition of a supertope by global amino acid substitution can identify multiple microbial mimic peptides that activate an encephalitogenic TCR. Peptides with only two native MBP-residues were sufficient to activate MBPAc1-11-specific T cells in vitro, and experimental autoimmune encephalomyelitis could be induced by immunizing mice with a mimic peptide with only four native MBP residues.
Amino Acid Substitution↗
T1/ST2 expression is enhanced on CD4+ T cells from schistosome egg-induced granulomas: analysis of Th cell cytokine coexpression ex vivo.
Th cells are categorized into subsets based on the cytokine production of in vitro-differentiated Th populations. For in vivo-differentiated Th subsets, little is known about the heterogeneity of cytokine production in single cells. We recently described a molecule, T1/ST2, that is preferentially expressed on the surface of Th2 cells. Here we combined high-gradient magnetic cell separation with four-color single-cell cytometry to analyze simultaneously three intracellular cytokines and T1/ST2 surface expression on CD4+ cells from lungs containing granulomas induced by Schistosoma mansoni eggs. T1/ST2 was highly up-regulated on CD4+ T cells from hepatic granulomas and granulomatous lungs. T1/ST2+ cells from granulomatous lungs preferentially produced type 2 cytokines ex vivo. In the total CD4+ population, coexpression of type 1 and type 2 cytokines occurred frequently. However, such coproduction was drastically reduced in T1/ST2+ cells compared with T1/ST2- cells. Coexpression of type 1 and type 2 cytokines was also rare in cells simultaneously producing two cytokines of one type. These findings indicate that individual CD4+ T cells in vivo have different levels of commitment to a certain Th phenotype. Coexpression of two type 2 cytokines or production of one type 2 cytokine together with surface expression of T1/ST2 indicate advanced commitment to the Th2 phenotype.
Animals↗
Arthritis of the finger joints: a comprehensive approach comparing conventional radiography, scintigraphy, ultrasound, and contrast-enhanced magnetic resonance imaging.
OBJECTIVE: A prospective study was performed comparing conventional radiography, 3-phase bone scintigraphy, ultrasound, and magnetic resonance imaging (MRI) with precontrast and dynamic postcontrast examinations in 60 patients with various forms of arthritis including rheumatoid arthritis (RA), spondyl-arthropathy, and arthritis associated with connective tissue disease. METHODS: A total of 840 finger joints were examined clinically and by all 4 imaging methods. Experienced investigators blinded to the clinical findings and diagnoses analyzed all methods independently of each other. The patients were divided into 2 groups. Group 1 included 32 patients (448 finger joints) without radiologic signs of destructive arthritis (Larsen grades 0-1) of the evaluated hand and wrist and group 2 included 28 patients (392 finger joints) with radiographs revealing erosions (Larsen grade 2) of the evaluated hand and/or wrist. RESULTS: Clinical evaluation, scintigraphy, MRI, and ultrasound were each more sensitive than conventional radiography in detecting inflammatory soft tissue lesions as well as destructive joint processes in arthritis patients in group 1. All differences were statistically significant. We found ultrasound to be even more sensitive than MRI in the detection of synovitis. MRI detected erosions in 92 finger joints (20%; 26 patients) in group 1 that had not been detected by conventional radiography. CONCLUSION: Our data indicate that MRI and ultrasound are valuable diagnostic methods in patients with arthritis who have normal findings on radiologic evaluation.
Adult↗
Th1/Th2 balance in infection.
Cytokines produced by T helper (Th) cells are of critical importance for the outcome of many infectious diseases. Producing the "right" set of cytokines in response to an infectious agent can be a matter of life or death. The Th1/Th2 dichotomy, although an oversimplification has proven useful in the analysis of immune responses to infections. In some infectious diseases, most notably leishmaniasis or infections with gastrointestinal helminths, one Th subset is indispensable for clearing the infection, whereas the opposite Th subset is detrimental. More frequently, both Th1 and Th2 responses are required at different time points to effectively eradicate an infectious agent. The granuloma responses to either Mycobacterium tuberculosis or Schistosoma mansoni provide illustrative examples and are discussed in this review. There is accumulating evidence for frequent coexpression of Th1 and Th2 cytokines during the in vivo immune response to infections. The mechanisms by which infectious agents modulate Th1/Th2 phenotype development are summarized here. Finally, we review here the current evidence for cytokine imbalances induced by infections as pathogenic or protective factors in autoimmunity and allergy.
Animals↗
Sacroiliitis - it's not all B 27.
We describe an HLA-B27 positive patient in whom posttraumatic pyogenic sacroiliitis led to complete unilateral sacroiliac joint ankylosis in the absence of any signs indicative of HLA-B27 associated spondyloarthropathy. Sacroiliitis is the pathologic hallmark - and usually one of the earliest pathologic manifestations - of ankylosing spondylitis (AS). Bilateral sacroiliitis is typical for ankylosing spondylitis. The frequency of asymmetric sacroiliitis may be higher in other inflammatory disorders, e.g., reactive arthritis, Reiters syndrome, spondylitis associated with psoriasis, or inflammatory bowel disease. Most but not all of these disorders show an increased prevalence among individuals who have inherited the HLA-B27 gene. In the context of this case, we discuss the differential diagnosis of unilateral sacroiliitis.
Adult↗
T1/ST2 is preferentially expressed on murine Th2 cells, independent of interleukin 4, interleukin 5, and interleukin 10, and important for Th2 effector function.
T helper (Th) cells can be categorized according to their cytokine expression. The differential induction of Th cells expressing Th1 and/or Th2 cytokines is key to the regulation of both protective and pathological immune responses. Cytokines are expressed transiently and there is a lack of stably expressed surface molecules, significant for functionally different types of Th cells. Such molecules are of utmost importance for the analysis and selective functional modulation of Th subsets and will provide new therapeutic strategies for the treatment of allergic or autoimmune diseases. To this end, we have identified potential target genes preferentially expressed in Th2 cells, expressing interleukin (IL)-4, IL-5, and/or IL-10, but not interferon-gamma. One such gene, T1/ST2, is expressed stably on both Th2 clones and Th2-polarized cells activated in vivo or in vitro. T1/ST2 expression is independent of induction by IL-4, IL-5, or IL-10. T1/ST2 plays a critical role in Th2 effector function. Administration of either a mAb against T1/ST2 or recombinant T1/ST2 fusion protein attenuates eosinophilic inflammation of the airways and suppresses IL-4 and IL-5 production in vivo following adoptive transfer of Th2 cells.
Animals↗
Autoreactivity versus autoaggression: a different perspective on human autoantigens.
Antigen-specific B and T cell responses against myelin basic protein, as well as responses against beta-islet-cells or joint tissue, are commonly found both in patients with autoimmune disease and in normal control subjects with disease-associated HLA-DR/DQ alleles. Thus, autoreactive immune responses are not disease-specific; however, the presence of certain autoantibodies may have prognostic value and may aid in disease management.
Animals↗
Detection of Borrelia burgdorferi by polymerase chain reaction in synovial membrane, but not in synovial fluid from patients with persisting Lyme arthritis after antibiotic therapy.
OBJECTIVES: To identify possible sites of bacterial persistence in patients with treatment resistant Lyme arthritis. It was determined whether Borrelia burgdorferi DNA may be detectable by polymerase chain reaction (PCR) in synovial membrane (SM) when PCR results from synovial fluid (SF) had become negative after antibiotic therapy. METHODS: Paired SF and SM specimens and urine samples from four patients with ongoing or recurring Lyme arthritis despite previous antibiotic therapy were investigated. A PCR for the detection of B burgdorferi DNA was carried out using primer sets specific for the ospA gene and a p66 gene of B burgdorferi. RESULTS: In all four cases, PCR with either primer set was negative in SF and urine, but was positive with at least one primer pair in the SM specimens. In all patients arthritis completely resolved after additional antibiotic treatment. CONCLUSIONS: These data suggest that in patients with treatment resistant Lyme arthritis negative PCR results in SF after antibiotic therapy do not rule out the intraarticular persistence of B burgdorferi DNA. Therefore, in these patients both SF and SM should be analysed for borrelial DNA by PCR as positive results in SM are strongly suggestive of ongoing infection.
Adult↗
Cytokines and arthritis: is the Th1/Th2 paradigm useful for understanding pathogenesis?
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Animals↗
T cell cytokine pattern in the joints of patients with Lyme arthritis and its regulation by cytokines and anticytokines.
OBJECTIVE: To investigate whether type 1 helper (Th1) or Th2 cytokines are found in the joints of patients with Lyme arthritis, and whether the cytokine pattern can be modulated by cytokines or anticytokines. METHODS: The cytokine pattern in the joints of 10 patients with Lyme arthritis was investigated. Expression of interferon-gamma (IFN gamma), tumor necrosis factor alpha (TNF alpha), interleukin-4 (IL-4), and IL-10 was measured by enzyme-linked immunosorbent assay (ELISA), after stimulation of synovial fluid mononuclear cells (SFMC) with Borrelia burgdorferi (Bb) in the supernatant. Expression of cytokine messenger RNA and protein in synovial membrane (SM) and nonstimulated SFMC was studied using semiquantitative reverse transcriptase-polymerase chain reaction and immunohistologic techniques. The effects of recombinant cytokines or neutralizing anticytokine antibodies on cytokine production in Bb-stimulated SFMC were investigated by ELISA. RESULTS: SFMC produced high amounts of IFN gamma and TNF alpha, but little or no IL-4, upon stimulation with Bb antigen, indicating a Th1-type cytokine pattern. In SM, IFN gamma was detectable in all patients, while the other cytokines were less frequently found. Serial sections of SM revealed that all cytokines were located in the same area. The Th1 response, especially the production of TNF alpha, could be down-regulated in vitro by both endogenous and exogenous IL-10, but not by IL-4 or anti-IL-12. CONCLUSION: A Th1-type cytokine pattern was found in the joints of patients with Lyme arthritis. This Th1 response could be down-regulated by IL-10, suggesting insufficient IL-10 production in vivo.
Adolescent↗