Pro- and anti-inflammatory effects of IL-4: from studies in mice to therapy of autoimmune diseases in humans.
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Animals↗
Biomedical subjects
T Biedermann
Publications and source records attributed to T Biedermann.
Very early spondyloarthritis: where the inflammation in the sacroiliac joints starts.
Involvement of the sacroiliac joints (SIJ) is a major and characteristic feature of the spondyloarthritides (SpA). In early ankylosing spondylitis and undifferentiated SpA (uSpA) sacroiliitis is the most common early clinical finding and the presumed first manifestation of the disease. Magnetic resonance imaging has proved useful for visualising inflammation in the SIJ in adults and children. Recently, initial localisation of the inflammation in the SIJ has been described in some detail, but it has not been completely defined to date--either in imaging or in histopathological studies. This is mainly owing to the lack of data in very early disease and the lack of follow up studies. Here we present a patient with early disease, which may augment our understanding of this stage of SpA.
Age of Onset↗
Fetal and neonatal murine skin harbors Langerhans cell precursors.
Resident epidermal Langerhans cells (LC) in adult mice express ADPase, major histocompatibility complex (MHC) class II, and CD205 and CD207 molecules, while the first dendritic leukocytes that colonize the fetal and newborn epidermis are only ADPase(+). In this study, we tested whether dendritic epidermal leukocytes (DEL) are end-stage cells or represent LC precursors. In epidermal sheets of fetal and neonatal mice, we found no apoptotic leukocytes, suggesting that these cells do not die in situ. To address whether DEL can give rise to LC, sorted DEL from murine newborn skin were cultured with cytokines used to generate LC from human CD34(+) precursors. After 7-14 days, DEL proliferated and acquired the morphology and phenotype of cells reminiscent of LC. In concordance with this finding, we show that neonatal epidermis harbors 10-20 times the number of cycling MHC class II(+) leukocytes as adult tissue. To test whether LC can differentiate from skin precursors in vivo, we developed a transplantation model. As it was impossible to transplant fetal epidermis, whole fetal skin was grafted onto adult severe combined immunodeficient mice. As opposed to the uniform absence of donor LC at the time of transplantation, examination of the epidermis from the grafts after 2-4 weeks revealed MHC class II(+) donor cells, which had acquired CD205 and CD207, thus qualifying them as LC. Finally, we present evidence that endogenous LC persist in skin grafts for the observation period of 45 days. These studies show that hematopoietic precursors seed the skin during embryonic life and can give rise to LC.
Animals↗
The German etanercept registry for treatment of juvenile idiopathic arthritis.
OBJECTIVE: To describe a registry set up to monitor children treated with etanercept in Germany and Austria. METHODS: Giannini's criteria, duration of morning stiffness, number of swollen, tender and contracted joints, adverse events, and reasons for discontinuation were assessed. RESULTS: 322 patients with juvenile idiopathic arthritis (JIA) and 12 additional patients with non-JIA rheumatic diagnoses were included. Therapeutic efficacy was observed from one month after treatment was started. The number of patients with significant improvement and the degree of improvement increased during the first year. The mean (SD) number of tender and swollen joints decreased from 9 (9) and 8.4 (9) to 3.0 (6.5) and 4.5 (7) after one month, and to 2.2 (5.5) and 3.3 (5.5) after three months; morning stiffness decreased from 45 (65) minutes to 12 (30) and 7 (19) after one and three months (p<0.001 for all). Using Gianinni's criteria of 30%, 50%, and 70% improvement, a therapeutic response in JIA patients was achieved in, respectively, 66%, 54%, and 30% after one month, 78%, 61%, and 38% after three months, and 83%, 72%, and 52% after six months. Therapeutic efficacy was lower in patients with systemic onset arthritis. Overall tolerability was good: in 592 patient treatment-years there were 69 reports of adverse events in 56 patients, including one CNS demyelination. There were no opportunistic infections or lupus-like reactions. Treatment was discontinued in 53 JIA patients, in 25 because of lack of efficacy. CONCLUSION: Etanercept treatment was safe and led to a significant improvement in most JIA patients resistant to conventional treatment.
Adrenal Cortex Hormones↗
Burden and cost of illness in patients with juvenile idiopathic arthritis.
OBJECTIVE: To estimate the cost of illness in an incidence based cohort of patients with juvenile idiopathic arthritis. METHODS: Direct costs (healthcare and non-healthcare costs) and indirect costs (productivity loss due to sick leave and work disability) were measured in 215 JIA patients, assessed on an average of 17 years after disease onset. Assessment included a clinical evaluation, a structured interview, and two self completion questionnaires. Annual direct costs were estimated based on the reported use of healthcare services and resources, using average unit prices. Indirect costs were estimated from the number of work days missed-that is, using the human capital approach. RESULTS: The mean total cost of late JIA was estimated to be 3500 per patient and year, of which the direct cost contributed more than half. Patients with still active disease (55%) incurred the major share (90%) of the cost. They had a mean total cost of 5700 per patient year, with those under rheumatological care incurring a cost of 9300. Having a certain JIA subgroup, functional disability, or receipt of specialised care independently contributed to the total cost in active JIA. Highest mean total costs were found in active seropositive polyarthritis (17 000) and extended oligoarthritis (11 000), while the lowest were found in active enthesitis related arthritis (1500) and persistent oligoarthritis (2700). CONCLUSIONS: Estimated 12 month costs in late JIA are considerable, differing among the various JIA subgroups. Treatment strategies in JIA should be analysed for their cost effectiveness in the long term.
Adult↗
[Sacroiliitis in children with spondyloarthropathy: therapeutic effect of CT-Guided intra-articular corticosteroid injection].
PURPOSE: The prospective investigation of the therapeutic effect of CT-guided intra-articular corticosteroid injection into inflammatory sacroiliac (SI) joints compared to conventional treatment with nonsteroidal anti-inflammatory drugs (NSAIDS) in children with juvenile spondyloarthropathy (jSpA) and the determination of the role of dynamic magnetic resonance imaging (MRI) in establishing the indication and monitoring the therapy. MATERIALS AND METHODS: The study comprises 89 children with known jSpA who were diagnosed by MRI to have a unilateral or bilateral sacroiliitis. Therapy with NSAIDS was initiated or continued in all 89 patients. Four weeks after the diagnostic MRI, two groups were distinguished according to the clinical response to NSAIDS, with group 1 consisting of 33 responders and group 2 of 56 non-responders. The patients of group 2 were treated with CT-guided intra-articular corticosteroid injection (low-dose injection) while the therapy with NSAIDS was continued. A total of 83 SI joints were punctured without complications, 27 bilaterally and 29 unilaterally. The indication for the intervention was based on inflammatory activity as determined by MRI. The therapy was monitored by clinical follow-up every 8 to 12 weeks over a period of 20 months. Follow-up by dynamic MRI was performed in all 56 children of group 2 and in 15 of the 33 children of group 1 within 8 +/- 4 months of the initial examination. RESULTS: A total of 87.5% of the children in group 2 showed a statistically significant decrease in their subjective complaints from 6.9 +/- 3.4 to 1.8 +/- 1.7 (p < 0.05) as measured on a visual analog scale (VAS from 0 to 10). Improvement was seen as early as 1.5 +/- 1.0 weeks after the intervention and lasted for a mean of 12 +/- 6 months. The children in group 1 already showed similar improvement of the VAS from 6.8 +/- 3.2 to 1.5 +/- 1.4 (p < 0.05) during the initial four weeks of NSAIDS therapy, with the improvement lasting for the 20-month observation period. The follow-up dynamic MRI (0.1 mmol/kg body weight) during therapy showed a statistically significant lower contrast-enhancement in both groups (group 1: 117 +/- 43 % versus 38 +/- 24 %, p < 0.05; group 2: 127 +/- 59 % versus 38 +/- 22 %, p < 0.05). One third of the patients of group 2 showed progression of joint destruction despite absence of subjective complaints. CONCLUSION: CT-guided intra-articular corticosteroid injection has proven an effective, symptomatic, and uncomplicated therapy of acute sacroiliitis in patients with jSpA. Dynamic MRI has a role in establishing the indication for intervention but its role for any follow-up is restricted to cases with inconclusive clinical response.
Adolescent↗
Hypersensitivity to non-steroidal anti-inflammatory drugs and chronic urticaria cured by treatment of Blastocystis hominis infection.
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Animals↗
Reversal of established delayed type hypersensitivity reactions following therapy with IL-4 or antigen-specific Th2 cells.
Delayed-type hypersensitivity reactions (DTHR) are mediated by IFN-gamma-producing CD4+ (Th1) or CD8+ T cells (Tc1) and can be prevented by steering T cells toward an IL-4-producing Th2 or Tc2 phenotype. It is currently accepted that T cells can be directed toward a Th2 or Tc2 phenotype only during the initiation of an immune response. Once established, the cytokine pattern of immune reactions is believed to be stable. Therefore, inhibition of DTHR by the induction of Th2/Tc2 responses, termed immune deviation, is considered only as a prevention but not as a therapy of harmful DTHR. Here we demonstrate that therapeutic immune deviation can reverse established contact hypersensitivity (CHS), a Th1/Tc1-mediated DTHR. One or two weeks after induction of CHS, mice received either a single cycle of IL-4 therapy or adoptive transfer of antigen-specific Th2 cells. This treatment generated a novel state of immunity that provided long-lasting protection against tissue destruction and neutrophil recruitment during subsequent antigen exposures. Therapeutic immune deviation of established CHS was dependent on CD4+ T cells and the induction of endogenous IL-4 synthesis. Thus, a population of immunoregulatory Th2 cells persists during advanced inflammatory responses that can be used for therapeutic deviation of established DTHR.
Adoptive Transfer↗
IL-4 instructs TH1 responses and resistance to Leishmania major in susceptible BALB/c mice.
Immunity to infection with intracellular pathogens is regulated by interleukin 12 (IL-12), which mediates protective T helper type 1 (TH1) responses, or IL-4, which induces TH2 cells and susceptibility. Paradoxically, we show here that when present during the initial activation of dendritic cells (DCs) by infectious agents, IL-4 instructed DCs to produce IL-12 and promote TH1 development. This TH1 response established resistance to Leishmania major in susceptible BALB/c mice. When present later, during the period of T cell priming, IL-4 induced TH2 differentiation and progressive leishmaniasis in resistant mice. Because immune responses developed via the consecutive activation of DCs and then T cells, the contrasting effects of IL-4 on DC development and T cell differentiation led to immune responses that had opposing functional phenotypes.
Animals↗
Mast cells control neutrophil recruitment during T cell-mediated delayed-type hypersensitivity reactions through tumor necrosis factor and macrophage inflammatory protein 2.
Polymorphonuclear leukocytes (PMNs) characterize the pathology of T cell-mediated autoimmune diseases and delayed-type hypersensitivity reactions (DTHRs) in the skin, joints, and gut, but are absent in T cell-mediated autoimmune diseases of the brain or pancreas. All of these reactions are mediated by interferon gamma-producing type 1 T cells and produce a similar pattern of cytokines. Thus, the cells and mediators responsible for the PMN recruitment into skin, joints, or gut during DTHRs remain unknown. Analyzing hapten-induced DTHRs of the skin, we found that mast cells determine the T cell-dependent PMN recruitment through two mediators, tumor necrosis factor (TNF) and the CXC chemokine macrophage inflammatory protein 2 (MIP-2), the functional analogue of human interleukin 8. Extractable MIP-2 protein was abundant during DTHRs in and around mast cells of wild-type (WT) mice but absent in mast cell-deficient WBB6F(1)-Kit(W)/Kit(W-)(v) (Kit(W)/Kit(W)(-v)) mice. T cell-dependent PMN recruitment was reduced >60% by anti-MIP-2 antibodies and >80% in mast cell-deficient Kit(W)/Kit(W)(-v) mice. Mast cells from WT mice efficiently restored DTHRs and MIP-2-dependent PMN recruitment in Kit(W)/Kit(W)-(v) mice, whereas mast cells from TNF(-/)- mice did not. Thus, mast cell-derived TNF and MIP-2 ultimately determine the pattern of infiltrating cells during T cell-mediated DTHRs.
Animals↗
In BALB/c mice, IL-4 production during the initial phase of infection with Leishmania major is necessary and sufficient to instruct Th2 cell development resulting in progressive disease.
In contrast to intact BALB/c mice, BALB/c mice rendered deficient in Vbeta4+ CD4+ T cells develop a Th1 response to infection with Leishmania major and are resistant. Vbeta4-deficient BALB/c mice are unable to generate the early IL-4 transcription occurring in Vbeta4 Valpha8 CD4+ T cells of BALB/c mice within 1 day of infection. Here we demonstrate that treatment of Vbeta4-deficient BALB/c mice with IL-4 during the first 64 h after infection instructs Th2 cell development and susceptibility to infection. The demonstrated inability of IL-4 to reverse the resistant phenotype of BALB/c mice treated with anti-CD4 mAb the day before infection suggest that these effects of IL-4 require its interaction with CD4+ T cells. In contrast to draining lymph node cells from BALB/c mice, cells from Vbeta4-deficient BALB/c mice remain responsive to IL-12 following infection. Strikingly, administration of IL-4 to Vbeta4-deficient BALB/c mice renders their lymph node cells unresponsive to IL-12 by down-regulating IL-12R beta2-chain expression. This study directly demonstrates that in BALB/c mice IL-4 is necessary and sufficient to initiate the molecular events steering Th2 cell maturation and susceptibility to L. major.
Animals↗
MR imaging of septic sacroiliitis.
OBJECTIVE: To investigate the diagnostic value of magnetic resonance (MR) imaging in detecting septic sacroiliitis and to determine whether the MR characteristics allow this entity to be differentiated from sacroiliitis in spondylarthropathy (SpA). PATIENTS AND DESIGN: The imaging findings of 11 patients with septic sacroiliitis were retrospectively analyzed by two experienced radiologists. Radiographic surveys of the pelvis as well as computed tomography (CT) and MR images of the sacroiliac joints were available in all cases. Seven of the patients additionally underwent a follow-up MR examination. The MR imaging protocol comprised combinations of coronal and transverse T1-weighted spin-echo (SE) or fast SE sequences, T2-weighted gradient-echo (GE) sequences and short tau inversion recovery sequence (STIR) sequences as well as dynamic contrast-enhanced T1-weighted acquisitions. RESULTS: Three patients with a short disease history showed anterior and/or posterior subperiosteal infiltrations ("lava cleft phenomenon"), transcapsular infiltrations of juxtaarticular muscle layers, which obscured the fasciae, and periarticular bone marrow edema. The eight patients with more advanced stages of sacroiliitis additionally showed abscess formation, sequestration, and erosion. At follow-up MR examination (n=7) under systemic antibiotic treatment, the morphologic characteristics showed progression (n=1), regression (n=4), unchanged findings (n=1), or a mixed response (n=1). Clinical improvement precedes resolution of the MR findings. CONCLUSIONS: Anterior and/or posterior subperiosteal infiltrations and transcapsular infiltrations of juxtaarticular muscle layers were depicted in all patients. These MR imaging findings are characteristic of septic sacroiliitis and may be used to differentiate this entity from sacroiliitis in SpA.
Adolescent↗
Primary and secondary Sjögren's syndrome in children--a comparative study.
Sjögren's syndrome is a chronic inflammatory systemic autoimmune disease mainly affecting the exocrine and, particularly, the salivary and lacrimal glands. The condition usually occurs in adults. In 1994, the criteria for this syndrome were redefined in a multicenter European study. In children, Sjögren's syndrome is a rare and probably underdiagnosed disease. To date, Sjögren's syndrome in children has only been described in case reports and in the comparative presentation of various study results. So far, no study of a comparative classification into primary and secondary Sjögren's syndrome has been carried out in a patient population of any size. Sjögren's syndrome should be considered in the differential diagnosis of children with recurrent parotitis, keratoconjunctivitis sicca, or pronounced and early tooth decay associated with xerostomia. In this study of 23 children and adolescents under the age of 16 with the clinical symptoms and laboratory findings of Sjögren's syndrome, we differentiate between primary and secondary Sjögren's syndrome. The value of the individual methods of assessing the oral and the ophthalmological components and the manifestation of the underlying rheumatic condition are discussed on the basis of the EULAR criteria. The EULAR diagnostic criteria are of limited applicability in children because reliable anamnestic data are frequently lacking. Another problem in diagnosing Sjögren's syndrome is the short-term detection of serological alterations and clinical symptoms. Even if young patients do not completely fulfill the required criteria, Sjögren's syndrome can be assumed or confirmed in the presence of positive testing for oral and ocular manifestations and recurrent salivary gland enlargement.
Adolescent↗
Livedoid vasculopathy in a patient with factor V mutation (Leiden).
BACKGROUND: Frequently, no underlying disease can be detected in patients with livedoid vasculopathy. For these forms, an unknown vaso-occlusive or thrombogenic process has been accused to play a role. Thus, a patient with livedoid vasculopathy was examined for different parameters which can be involved in coagulopathies. METHODS: Laboratory studies for different autoantigen reactive immunoglobulins, cryoglobulins, and circulating immune complexes were carried out. Besides dermatopathologic examination, a biopsy specimen was analyzed by direct immunofluorescence for immunoglobulin (Ig) and complement deposits. Furthermore, hemostaseological function tests including activated protein C (APC) resistance were undertaken. RESULTS: Positive only at very low titres were antinuclear antibodies and c-ANCA, all other parameters were within normal ranges or negative. Direct immunofluorescence revealed IgM, C3 and fibrogen deposits. Hemostaseological function tests demonstrated a pathologic activated protein c resistance and PCR analysis a heterozygous defect of the factor V (Leiden). CONCLUSIONS: The diagnosis of livedoid vasculopathy associated with factor V mutation (Leiden) was made. Since the underlying cause for livedoid vasculopathy often remains unknown, we suggest that hemostaseological function tests including APC resistance and factor V gene mutation analysis should be carried out. Further studies have to follow in order to elucidate the role of mutant factor V in livedoid vasculopathy and in cutaneous ulcerations.
Activated Protein C Resistance↗
[Exertion-induced anaphylaxis after eating pork and beef].
HISTORY AND CLINICAL FINDINGS: A 72-year-old woman developed generalized urticaria. Quincke oedema, shortness of breath and hypotension two hours after eating a meal containing pork and after mild physical activity (ironing) in-between. She was treated by an emergency physician and then admitted to hospital for one day of monitoring her condition. During the past several years such episodes of generalized urticaria had recurred twice to four times a year. INVESTIGATIONS: Pin-prick tests gave an immediate-type reaction to beef but not to pork. Specific serum IgE antibodies were demonstrated to pork and beef, cat's epithelia, milk albumin and casein. Oral provocation tests were negative for pork and beef. But when pork and beef were eaten mild physical activity (bicycle ergometry at 20 W), generalized urticaria occurred after eating pork and beef, but not after drinking milk. TREATMENT AND COURSE: Exercise-induced anaphylaxis to pork and beef was diagnosed. No allergic reaction has occurred in more than 12 months of avoiding eating these meats. CONCLUSION: The picture of exercise-induced anaphylaxis caused by food allergy can be precipitated by even mild activity. This must be taken into account in the diagnosis of systemic rapid-reaction response and in the performance of provocation tests.
Aged↗
Mastocytosis associated with severe wasp sting anaphylaxis detected by elevated serum mast cell tryptase levels.
A markedly elevated serum level of mast cell tryptase (77.6 microg/L; 95th percentile in normals 13.5 microg/L) was detected in a patient treated for 5 years with wasp venom immunotherapy because of severe anaphylaxis following a wasp sting. Retrospective analysis of stored serum samples taken during the course of immunotherapy revealed that the tryptase level had been elevated for at least 3 years. Despite several dermatological examinations, skin changes of mastocytosis had been missed. Re-examination of the patient revealed sparse macules on the thorax and thighs; Darier's sign was negative. Histologically, mast cell accumulation in these lesions was demonstrable. No signs of systemic mastocytosis were detected. The most appropriate diagnosis was telangiectasia macularis eruptiva perstans. Even in patients with highly elevated tryptase levels, mastocytosis may go undiagnosed. As mastocytosis predisposes to severe anaphylaxis, the condition should be looked for in patients with such reactions by clinical examination and measurement of serum tryptase levels.
Adult↗
Use of contrast-enhanced MR imaging to detect sacroiliitis in children.
PURPOSE: To verify the diagnostic value of contrast-enhanced MR imaging compared with conventional radiography in the diagnosis of sacroiliitis in children. DESIGN AND PATIENTS: Radiography and MR imaging of the sacroiliac joints were performed in 185 children subdivided into the following groups according to the modified European Spondyloarthropathy (SpA) Study Group (ESSG) criteria: group 1, undifferentiated spondyloarthropathy (uSpA) (n=53, 94.5% HLA-B27+); group 2, differentiated SpA (n=45, 93.3% HLA-B27+); group 3, patients with no signs of SpA other than oligoarthritis (n=39, 92.3% HLA-B27+); group 4, HLA-B27+ controls with various other non-SpA diagnoses (n=22); and group 5, HLA-B27-controls with various other non-SpA diagnoses (n=26). Radiographs were evaluated on the basis of the modified New York criteria independently by three experienced radiologists masked to the clinical data. In a second step, the same radiologists independently evaluated the MR images without knowledge of the clinical data and radiographic findings using the recently published criteria developed by our group. These criteria allow differentiation of acute and chronic inflammatory changes. RESULTS: Radiography demonstrated sacroiliitis in 18 patients: 4 of 53 in group 1 (7.5%), 14 of 45 in group 2 (31%), but none in groups 3, 4 and 5. In contrast, MR imaging demonstrated acute and/or chronic sacroiliitis in 44 patients: 18 of 53 in group 1 (34%), 21 of 45 in group 2 (46.7%) and 5 of 39 in group 3 (12.8%), but none in groups 4 and 5. The percentage of sacroiliitis detected by MR imaging was significantly higher than that detected by radiography (P<0.001). CONCLUSION: Contrast-enhanced MR imaging is a useful method for detecting sacroiliitis in children. Advantages of contrast-enhanced MR imaging compared with conventional radiography are a higher sensitivity due to the ability to document early and acute changes and the absence of radiation exposure.
Adolescent↗