Decreased numbers of FoxP3-positive and TLR-2-positive cells in intestinal mucosa are associated with improvement in patients with active inflammatory bowel disease following selective leukocyte apheresis

Background Impaired immunological tolerance to commensal enteric flora is considered one possible pathogenic mechanism of inflammatory bowel disease (IBD). Given that regulatory T cells and Toll-like receptor (TLR)-positive cells are key actors in mucosal immune regulation, we aimed to identify the dynamics of these actors in the intestinal mucosa in relation to clinical improvement following selective leukapheresis treatment. Methods Ten patients with active IBD despite treatment with corticosteroids, immunomodulators, or anti-tumor necrosis factor therapy were assessed by immunohistochemical staining of colorectal mucosal biopsies obtained before and after five sessions (week 7) of granulocyte and monocyte adsorption apheresis (GCAP). The presence of FoxP3-positive regulatory T cells, macrophages, dendritic cells, and TLR-2 and-4 positive cells was determined in relation to short-(week 7) and long-term (week 52) clinical outcome data. Results Following GCAP, the number of FoxP3-(P = 0.012) and TLR-2 (P = 0.008)-positive cells significantly decreased in biopsies after 7 weeks, in parallel with both clinical improvement at week 7 and a longstanding response after 12 months. Conclusions Downregulation of FoxP3 and TLR-2 cells in the colorectal mucosa mirrors both short-and long-term improvement in patients with active IBD responding to GCAP. This observation suggests a potential role of these cells in the pathogenesis of IBD and the induction of immunological tolerance in the mucosa.     

What will studies of Fulani individuals naturally exposed to malaria teach us about protective immunity to malaria?

There are an estimated over 200 million yearly cases of malaria worldwide. Despite concerted international effort to combat the disease, it still causes approximately half a million deaths every year, the majority of which are young children with Plasmodium falciparum infection in sub-Saharan Africa. Successes are largely attributed to malaria prevention strategies, such as insecticide-treated mosquito nets and indoor spraying, as well as improved access to existing treatments. One important hurdle to new approaches for the treatment and prevention of malaria is our limited understanding of the biology of Plasmodium infection and its complex interaction with the immune system of its human host. Therefore, the elimination of malaria in Africa not only relies on existing tools to reduce malaria burden, but also requires fundamental research to develop innovative approaches. Here, we summarize our discoveries from investigations of ethnic groups of West Africa who have different susceptibility to malaria.     

Outcome in adolescence of brachial plexus birth palsy: 69 individuals re-examined after 10–20 years

Background and purpose —

The frequency and severity of a permanent lesion after brachial plexus birth palsy (BPBP) and its impact on activities of daily living are not well documented. We therefore investigated the outcome of BPBP in adolescents, regarding arm function and consequences for activity and participation.

Participants and methods —

Of 30,574 babies born at St. Olavs University Hospital in 1991–2000, 91 had BPBP (prevalence 3 per 1,000), and 69 of these individuals were examined at a median age of 14 (10–20) years. The examination included the modified Mallet classification, range of motion, shoulder rotation and grip strength, Assisting Hand Assessment, and Canadian Occupational Performance Measure. Of the 22 subjects who were not examined, 3 could not be traced and 19 reported having no problems in the affected arm.

Results —

At follow-up, 17 adolescents had a permanent lesion (i.e. individual Mallet subscore below 4) with a median Mallet total score of 15 (9–19), while 52 had good or normal shoulder function (median Mallet total score 25 (23–25)). All participants with a permanent lesion had reduced active shoulder rotation (≤ 15°), 16 had elbow extension deficit, and 10 had subnormal grip strength. External rotation was considerably weaker in the affected shoulder. In addition, they had ineffective use of the affected arm in bimanual activities. Even so, all except 1 were independent in activities of daily living, although 15 experienced minor difficulties.

Interpretation —

Every fourth to fifth child with BPBP had a permanent lesion as an adolescent. External rotation was the most impaired movement. Despite ineffective use of the affected arm in bimanual activities, all of the participants except one were independent in activities of daily living.Brachial plexus birth palsy (BPBP) is caused by a traction injury on the brachial plexus during labor (Metaizeau et al. 1979). The prevalence of BPBP reported varies by a factor of more than 10, from 0.4 to 5.1 per 1,000 live-born (Evans-Jones et al. 2003, Hoeksma et al. 2004, Foad et al. 2008). In Scandinavian populations, a prevalence of 3 per 1,000 live-born has been reported (Lagerkvist et al. 2010, Poyhia et al. 2010).Most children with BPBP have a transient nerve injury, but between 8% and 36% of them will have permanent functional impairments (Michelow et al. 1994, Noetzel et al. 2001, Hoeksma et al. 2004, Poyhia et al. 2010). The extent and severity of the nerve injury, varying from transient neurapraxia to avulsion-type root injuries, are the main predictors of recovery. At the time of diagnosis it is not possible to assess the severity of the injury or to predict the long-term outcome (Sunderland 1991, Hoeksma et al. 2004, Malessy and Pondaag 2011). Some babies may spontaneously recover completely, some may recover partially, and some may need reconstructive nerve surgery. The absence of biceps muscle function at 3 months of age indicates a more severe injury and is also a commonly used indicator for surgical plexus exploration (Gilbert and Tassin 1984, Waters 1999). However, a permanent nerve injury and reduced arm function may also be observed following apparently moderate or less severe injuries.Individuals with a permanent nerve injury after BPBP have various degrees of functional impairment in their affected extremity. These impairments may be due to reduction in muscle strength as well as limited range of motion caused by soft tissue contractures, muscle co-contractions, and secondary osseous deformities (Hardy 1981, Pearl and Edgerton 1998, Hoeksma et al. 2003, Anguelova et al. 2014). Toddlers with incomplete recovery use their affected arm in an asymmetrical way (Lagerkvist et al. 2010). Adults with BPBP have reported problems in activities of daily living (Partridge and Edwards 2004), but there is limited information regarding when these symptoms occur. Moreover, the frequency and the severity of permanent functional impairment in BPBP are not well documented (Pondaag et al. 2004).We studied the long-term outcome of BPBP in adolescents, regarding arm function and consequences for activity and participation.     

Vascular endothelial growth factor is highly expressed in muscle tissue of patients with polymyositis and patients with dermatomyositis

OBJECTIVE: To investigate the expression of vascular endothelial growth factor (VEGF) in muscle biopsy specimens and serum from patients with polymyositis and patients with dermatomyositis compared with that in healthy control subjects. METHODS: Muscle biopsy specimens from 33 patients with polymyositis or dermatomyositis and 15 healthy control subjects and serum samples from 56 patients and 56 healthy control subjects were analyzed. Patients were categorized into 3 groups, depending on disease duration and the presence or absence of inflammatory infiltrates. The expression of VEGF and the vessel marker CD31 in muscle was analyzed by immunohistochemistry, the expression of VEGF messenger RNA (mRNA) was analyzed by in situ hybridization, and serum levels of VEGF were determined by enzyme-linked immunosorbent assay. RESULTS: Patients with polymyositis or dermatomyositis in the early or chronic phase without inflammatory infiltrates had a decreased total number of capillaries compared with healthy individuals. In patients with early disease without inflammatory infiltrates, the number of VEGF-expressing muscle fibers was increased compared with that in control subjects, whereas VEGF expression was unchanged in the chronic phase of disease. In patients with established disease with inflammatory infiltrates, total VEGF expression was high compared with that in healthy control subjects. In healthy control subjects, VEGF was expressed in endothelial cells and in occasional muscle fibers. VEGF mRNA was expressed in muscle fibers in both healthy individuals and patients. The level of serum VEGF was significantly increased in patients compared with control subjects. CONCLUSION: Our observations support a role of VEGF in the early phases of polymyositis and dermatomyositis. A reduced number of capillaries could lead to induction of VEGF expression in muscle fibers. Furthermore, differences in molecular expression during certain phases of disease may help in the development of specific therapeutic algorithms in the treatment of myositis.     

Cytokine production in muscle tissue of patients with idiopathic inflammatory myopathies

Objective. To study cytokine expression in muscle tissues of patients with inflammatory myopathies and to compare the profiles of patients with polymyositis (PM), inclusion body myositis (IBM), and dermatomyositis (DM). Methods. We performed indirect immunohistochemistry studies of muscle tissue sections with a panel of 16 different cytokine-specific monoclonal antibodies, directed against interleukin-1α, (IL-1α), IL-1β, IL-1 receptor antagonist (IL-1ra), IL-2, IL-3, IL-4, IL-6, IL-8, IL-10, IL-13, interferon-γ (IFNγ), tumor necrosis factor α (TNFα), granulocyte-macrophage colonystimulating factor (GM-CSF), transforming growth factor β1 (TGFß1), TGFß2, and TGFß3 in 5 untreated patients each with PM, DM, and IBM and in 4 normal controls. Fresh frozen muscle tissue sections were fixed in formaldehyde before the procedure. The use of saponin as a detergent to permeabilize the cell membranes enabled identification of intracellular cytokine production. Results. The most prominent finding was the expression of IL-1α observed in all patients but in none of the normal controls. In all patients with PM, DM, and IBM, IL-1α was expressed in endothelial cells of capillaries, arterioles, and venules in areas surrounded by inflammatory cells, and also in areas with no or scarce inflammatory cells in both endomysium and perimysium. Furthermore, IL-1α was also expressed in mononuclear inflammatory cells in all 15 cases. IL-1β was observed in inflammatory cells in 10 of the 15 patients but, in contrast to IL-1α, it was not expressed in blood vessel walls. TGFß1, TGFß2, and TGFß3 were strongly positive in all 15 patients, but only scattered cells were positive in the normal controls. The remaining cytokines were observed only in relatively few cells and only in occasional patients (although the patients were selected for the presence of large infiltrates), and in none of the controls. The patterns were similar in PM, DM, and IBM. Conclusion. Cytokine expression in muscle tissue of patients with inflammatory myopathy is dominated by IL-1α, IL-1β, and TGFß1–3. The predominant IL-1α expression in the blood vessels indicates an importance of the endothelial cells in the inflammatory process in PM, IBM, and DM. A sustained, local release of T cell-derived cytokines may not be a requirement for tissue injury in the inflammatory myopathies. There does not appear to be a qualitative difference in cytokine expression patterns in PM, IBM, and DM.