Cholinergic receptor activation on epithelia protects against cytokine-induced barrier dysfunction.

AIM: Various types of cholinergic receptors are expressed on intestinal epithelia. Their function is not completely understood. We hypothesize that cholinergic receptor activation on epithelium may serve a protective function in cytokine-induced barrier dysfunction. METHODS: The effect of cholinergic receptor activation on cellular barrier function in epithelial cells was assessed by measuring electrical impedance, and by determining para-cellular transport in transwell experiments. Cell lysates treated with cytokine and/or cholinergic agonists were analysed for cyto- and chemokine production, and tight junction (TJ) protein rearrangement was assessed. Primary colonic epithelial cells were isolated from surgically resected colon tissue of patients with inflammatory bowel disease. RESULTS: IL-1ß induced production of chemokines (CXCL-1, CXCL-10, IL-8, CCL-7) and led to a rearrangement of TJ proteins (occludin and ZO-1). This response was inhibited by pre-treatment with muscarinic, rather than nicotinic, acetylcholine receptor agonists. Treatment with IL-1ß enhanced paracellular permeability (4kD dextran) and reduced impedance across the monolayer, which was counteracted by pre-incubation with acetylcholine, or muscarinic receptor agonist bethanechol. The protective effect of acetylcholine was antagonized by atropine, underscoring muscarinic receptor involvement. IL-1ß induced transcription of myosin light chain kinase and phosphorylation of myosin light chain, and this cytokine-induced phosphorylation of MLC was inhibited by muscarinic receptor agonists. Furthermore, in epithelial cells from resection material of patients with Crohn's disease and ulcerative colitis, high expression of CXCL-8 was associated with a reduced choline acetyl transferase expression, suggesting an aberrant epithelial production of ACh in inflammatory context. CONCLUSION: Acetylcholine acts on muscarinic receptors on epithelial cells to maintain epithelial barrier function under inflammatory conditions.

Excreted/secreted Trichuris suis products reduce barrier function and suppress inflammatory cytokine production of intestinal epithelial cells.

The administration of helminths is considered a promising strategy for the treatment of autoimmune diseases due to their immunomodulatory properties. Currently, the application of the helminth Trichuris suis as a treatment for Crohn's disease is being studied in large multi-center clinical trials. The intestinal epithelium forms an efficient barrier between the intestinal lumen containing the microbial flora and helminths, and dendritic cells (DCs) present in the lamina propria that determine the TH response. Here, we investigated how excreted/secreted (E/S) products of T. suis affect the barrier function of intestinal epithelial cells (IECs) in order to reach the DCs and modulate the immune response. We show that T. suis E/S products reduce the barrier function and the expression of the tight junction proteins EMP-1 and claudin-4 in IEC CMT93/69 monolayers in a glycan-dependent manner. This resulted in an increased passage of soluble compounds to the basolateral side that affected DC function. In addition, T. suis E/S suppressed LPS-induced pro-inflammatory cytokine production by CMT93/69 cells, whereas the production of the TH2 response-inducing cytokine thymic stromal lymphopoietin (TSLP) was induced. Our studies indicate that T. suis E/S glycans affect the function of the intestinal epithelium in order to modulate DC function. Identification of the T. suis E/S glycans that modulate IEC and DC function may lead to a strategy to reduce symptoms of autoimmune and allergic immune diseases by orally administrated helminth-derived factors without the need of infection with live helminths.

Juvenile dermato/polymyositis: a retrospective analysis of 33 cases with special focus on initial CPK levels.

Retrospective analysis of 33 patients with juvenile dermato/polymyositis showed 45% complete recovery, 26% remission (steroid dependent), 6% wheelchair-dependency, 3% deaths and 10% development of other connective tissue diseases after a mean follow up of 4 years. Patients who received 2 mg/kg of prednisone had the worst prognosis but since they apparently represent a subgroup it is questionable whether high dose prednisone was the cause of the poor prognosis. This subgroup is characterized by high CPK serum levels (a 10-fold increase or more) and an acute type of onset. An initial high ANA titer was found to predict the later development of other connective tissue disorders.

Nasal discharge and obstruction as presenting symptoms of Wegener's granulomatosis in childhood.

A case with nasal manifestations as presenting symptoms of Wegener's granulomatosis in childhood is discussed. The diagnostic and treatment modalities are reviewed with emphasis on the specific problems concerning the side effects of treatment on the child.

Defective antipneumococcal polysaccharide antibody response in children with recurrent respiratory tract infections.

BACKGROUND: Recurrent pyogenic infections are known to occur in patients with an impaired response to polysaccharide antigens. We investigated the occurrence of deficient responses to pneumococcal capsular polysaccharides in patients with recurrent respiratory tract and recurrent systemic infections. METHODS: Forty-five patients, 1.7 to 17.1 years of age, were immunized with 23-valent pneumococcal polysaccharide vaccine. Antibody levels to seven pneumococcal serotypes (3, 4, 6A, 9N, 14, 19F, 23F) were determined by ELISA before and after immunization. In addition, patients received a booster immunization with diphtheria toxoid, tetanus toxoid, and poliomyelitis virus vaccine. RESULTS: Thirty-five patients had normal serum immunoglobulin levels. Five of these patients (14%) had low antipneumococcal preimmunization antibody levels and failed to respond to pneumococcal vaccination, whereas the response to booster immunization with protein antigens was appropriate. Three patients were younger than 3 years old, and one had a family history of IgG2 deficiency. Low IgG developed in a fifth patient during follow-up. Ten patients had a humoral immunodeficiency. Seven of these patients failed to respond to pneumococcal vaccination. CONCLUSIONS: We conclude that a defective immune response to polysaccharide antigens in patients requires long-term follow-up to distinguish transient maturational delay from a persistent selective impaired response to polysaccharide antigens, which on occasion may precede the development of humoral immunodeficiency disease.

[Juvenile dermatomyositis, systemic lupus erythematosus and mixed connective tissue disease]. / Juveniele dermatomyositis, systemische lupus erythematosus en mixed connective tissue disease.

This paper covers the current insights into the classification, etiology, management and prognosis of juvenile dermatomyositis (JDMS) systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD). Since specific diagnostic tests for these autoimmune diseases are not available, diagnosis depends on the presence of defined criteria. Drug therapy in JDMS consists of prednisone at a low dosage (1 mg/kg/day). In SLE different therapeutic approaches are known depending on the occurrence of life threatening symptoms. The prognosis of MCTD is good, it is of prime importance to avoid overdosage of corticosteroids, since drug treatment is often not needed.

[HIV infections in childhood]. / Infecties met HIV op de kinderleeftijd.

After the presentation of 3 case histories of children who became infected with HIV through different modes of transmission the disease is further discussed. Special attention is paid on epidemiology, transmission pathways, pathophysiology, making the diagnosis, clinical symptoms, therapy and prognosis of HIV infected children.

Clinical and immunological studies in patients with an increased serum IgD level.

Increased levels of serum IgD can be found in single patients with a variety of clinical syndromes and in the disease entity designated hyper-IgD syndrome which is associated with periodic fever and lymphadenopathy. We investigated 17 patients, both children and adults, with high serum IgD levels ranging from 220 to 5300 IU/ml. Eight patients had periodic fever and lymphadenopathy, four showed a humoral immunodeficiency, and the remainder had a variety of clinical abnormalities. Serum IgA levels were consistently high in all patients except in those with an immunodeficiency. Serum IgD complexes were detectable in each serum, which indicates that the occurrence is not pathognomic for the syndrome of periodic fever. Antibody formation against the primary antigen Helix pomatia hemocyanine and the secondary antigen tetanus toxoid showed no abnormalities in the patients without an immunodeficiency. Bone marrow origin of serum IgD was strongly suggested by enumeration of IgD-containing plasma cells. We conclude that no apparent relationship exists between the several clinical syndromes and increased serum IgD.