Biomedical subjects

Axel Roers

Publications and source records attributed to Axel Roers.

8 recordsLinked to original sources

PubMed2007

Accelerated wound closure in mice deficient for interleukin-10.

The impact of the local inflammatory response on the process of wound healing has been debated for decades. In particular, the question whether infiltrating macrophages and granulocytes promote or impede tissue repair has received much attention. In the present study, we show that wound healing is accelerated in mice deficient for the anti-inflammatory cytokine interleukin (IL)-10. IL-10-/- mice closed excisional wounds significantly earlier compared with IL-10-competent control littermates. This effect was attributable to accelerated epithelialization as well as enhanced contraction of the wound tissue in the mutant animals. Increased alpha-smooth muscle actin expression in IL-10-deficient mice suggests that augmented myofibroblast differentiation is responsible for the enhanced contraction of wounds in mutant mice. The number of macrophages infiltrating the wound tissue was significantly increased in IL-10-/- mice compared with control littermates suggesting that this cell type mediates the accelerated tissue repair. These results show for the first time that IL-10 can impede wound repair.

Actins↗

PubMed2006

Integrin alpha2beta1 deficiency does not affect contact hypersensitivity.

Collagens in the extracellular matrix are thought to play an important role in regulating inflammatory responses by affecting cell adhesion and migration. The contact between collagens and cells is established mainly by alpha1beta1, alpha2beta1 and alpha11beta1integrin receptors. Here, we analyzed the contact hypersensitivity (CHS) reaction in mice that were genetically deficient in the collagen receptor alpha2beta1. Integrin alpha2beta1 is widely expressed and has been suggested to play an important role in mediating inflammatory responses. CHS was induced by applying dinitrofluorobenzene to abdominal skin and challenging with the same reagent on ear skin. Macroscopically and histologically, ear swelling in alpha2beta1-deficient mice did not differ from that in wild-type control mice. Immunohistological detection of infiltrated T lymphocytes, neutrophils and mast cells in inflamed ear skin revealed similar numbers in controls and integrin alpha2beta1-deficient animals. Our results suggest that the adhesive functions of integrin alpha2beta1 are dispensable for the CHS response; they may be compensated for by the collagen receptor alpha1beta1 or other collagen receptors.

Animals↗

PubMed2006

Interleukin-10 derived from macrophages and/or neutrophils regulates the inflammatory response to LPS but not the response to CpG DNA.

Interleukin-10 (IL-10) is an important regulator of immune responses secreted by different cell types. We have previously shown that mice with selective inactivation of the IL-10 gene in T cells suffer from deregulated T cell responses similar to those observed in IL-10(-/-) animals. Unlike IL-10(-/-) mice, however, T cell-specific mutants do not mount an enhanced innate immune response to LPS, which must, therefore, be subject to control by IL-10 from non-T cells. Herein we show that subcutaneous injection of LPS, which causes moderate local inflammation in WT and T cell-specific IL-10 mutant mice, results in augmented inflammatory infiltration and extensive tissue necrosis in mice with deficiency for IL-10 in macrophages and neutrophils. Correspondingly, we observed an enhanced sensitivity of the macrophage/neutrophil-specific IL-10 mutants to systemic LPS exposure when compared with WT animals. In contrast, the inflammatory response of these mutants to CpG oligodeoxynucleotides was not different from that of WT mice. While IL-10(-/-) mice developed massive inflammation, necrosis and increased serum cytokine levels after subcutaneous CpG injection, only moderate responses were observed in macrophage/neutrophil-specific IL-10 mutant and WT mice. These results show that different innate immune responses can be subject to control by IL-10 from different cellular sources.

Adjuvants, Immunologic↗

PubMed2005

[The Jo-1 Syndrome--immunological findings and clinical manifestations].

El The Jo-1 syndrome is an autoimmune disease which is characterized by the presence of autoantibodies against the Jo-1 antigen. The designation Jo-1 is derived from the name of the first patient (John P.) who was tested positive for this antibody. This patient suffered from polymyositis and fibrosing alveolitis. The Jo-1 antigen was identified as histidyl-transfer-RNA synthetase present in the cytosol. The Jo-1 syndrome is a member of a family of autoimmune diseases, called anti-synthetase syndromes. These syndromes are characterized by autoantibodies directed against aminoacyl-transfer-RNA synthetases. The etiology of the Jo-1 syndrome is unknown. The most frequent clinical manifestation is myositis, which may present as polymyositis or dermatomyositis. In addition to muscle involvement, interstitial lung disease is frequently found and critical for the prognosis. Furthermore, symptoms of other autoimmune disorders such as polyarthritis may occur. Similar to polymyositis and dermatomyositis, the Jo-1 syndrome may present as myositis overlap syndrome. In these cases, antibodies against U1-RNP are detected. The Jo-1 syndrome responds to treatment with corticosteroids and, if necessary, azathioprine, methotrexate or cyclophosphamide. The clinical manifestations of the Jo-1 syndrome are illustrated by two clinical cases.

Aged↗

PubMed2005

Immunotherapy of hypersensitivity to hymenoptera venom.

Insect sting allergy is a common condition with a risk of life-threatening anaphylaxis. After a severe reaction, the fear of being restung can significantly reduce quality of life. Venom immunotherapy (VIT) is a highly effective treatment of the underlying type I-sensitisation. This review addresses the mechanisms of immune modulation by VIT and outlines current clinical application. Although highly effective in the majority of patients, VIT fails in a few individuals. It can also cause systemic allergic side effects, restricting its application to physicians trained in the treatment of anaphylaxis. This review discusses several new strategies to overcome these problems, which are presently a promising focus of research. These include the use of new adjuvants, of recombinant and genetically engineered venom allergens, as well as vaccination with peptides.

Animals↗

PubMed2004

T cell-specific inactivation of the interleukin 10 gene in mice results in enhanced T cell responses but normal innate responses to lipopolysaccharide or skin irritation.

Interleukin (IL)-10 is a regulator of inflammatory responses and is secreted by a variety of different cell types including T cells. T regulatory cells have been shown to suppress immune responses by IL-10-dependent, but also IL-10-independent, mechanisms. Herein, we address the role of T cell-derived IL-10 in mice with an inactivation of the IL-10 gene restricted to T cells generated by Cre/loxP-mediated targeting of the IL-10 gene. Splenocytes from this T cell-specific mutant secrete increased amounts of proinflammatory cytokines after activation in vitro compared with show enhanced contact hypersensitivity reactions, and succumb to severe immunopathology upon infection with Toxoplasma gondii. Despite intact IL-10 genes in other cell types, the dysregulation of T cell responses observed in the T cell-specific IL-10 mutant closely resembles the phenotype in complete IL-10 deficiency. However, in contrast to complete IL-10 deficiency, sensitivity to endotoxic shock and irritant responses of the skin are not enhanced in the T cell-specific IL-10 mutant. Our data highlight the importance of T cell-derived IL-10 in the regulation of T cell responses and demonstrate that endotoxic shock and the irritant response of the skin are controlled by IL-10 from other cell types.

Animals↗

PubMed2004

Multiple sclerosis: brain-infiltrating CD8+ T cells persist as clonal expansions in the cerebrospinal fluid and blood.

We surveyed the T cell receptor repertoire in three separate compartments (brain, cerebrospinal fluid, and blood) of two multiple sclerosis patients who initially had diagnostic brain biopsies to clarify their unusual clinical presentation but were subsequently confirmed to have typical multiple sclerosis. One of the brain biopsy specimens had been previously investigated by microdissection and single-cell PCR to determine the clonal composition of brain-infiltrating T cells at the single-cell level. Using complementarity-determining region 3 spectratyping, we identified several identical, expanded CD8+ (but not CD4+) T cell clones in all three compartments. Some of the expanded CD8+ T cells also occurred in sorted CD38+ blood cells, suggesting that they were activated. Strikingly, some of the brain-infiltrating CD8+ T cell clones persisted for >5 years in the cerebrospinal fluid and/or blood and may thus contribute to the progression of the disease.

Amino Acid Sequence↗

PubMed2003

Clonal tracking of autoaggressive T cells in polymyositis by combining laser microdissection, single-cell PCR, and CDR3-spectratype analysis.

Clonal expansions of CD8+ T cells have been identified in muscle and blood of polymyositis patients by PCR techniques, including T cell receptor (TCR) complementarity-determining region (CDR)3 length analysis (spectratyping). To examine a possible pathogenic role of these clonally expanded T cells, we combined CDR3 spectratyping with laser microdissection and single-cell PCR of individual myocytotoxic T cells that contact, invade, and destroy a skeletal muscle fiber. First, we screened cDNA from muscle biopsy specimens by CDR3 spectratyping for expanded TCR beta chain variable region (BV) sequences. To pinpoint the corresponding T cells in tissue, we stained cryostat sections with appropriate anti-TCR BV mAbs, isolated single BV+ T cells that directly contacted or invaded a muscle fiber by laser-assisted microdissection, and amplified their TCR BV chain sequences from rearranged genomic DNA. In this way, we could relate the oligoclonal peaks identified by CDR3-spectratype screening to morphologically characterized microdissected T cells. In one patient, a large fraction of the microdissected T cells carried a common TCR-BV amino acid CDR3 motif and conservative nucleotide exchanges in the CDR3 region, suggesting an antigen-driven response. In several cases, we tracked these T cell clones for several years in CD8+ (but not CD4+) blood lymphocytes and in two patients also in consecutive muscle biopsy specimens. During immunosuppressive therapy, oligoclonal CDR3-spectratype patterns tended to revert to more polyclonal Gaussian distribution-like patterns. Our findings demonstrate that CDR3 spectratyping and single-cell analysis can be combined to identify and track autoaggressive T cell clones in blood and target tissue. This approach should be applicable to other inflammatory and autoimmune disorders.

Adult↗