Ger T. Rijkers

Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome

Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS; MIM 260920) is an autosomal recessive disorder characterized by recurrent episodes of fever associated with lymphadenopathy, arthralgia, gastrointestinal dismay and skin rash. Diagnostic hallmark of HIDS is a constitutively elevated level of serum immunoglobulin D (IgD), although patients have been reported with normal IgD levels. To determine the underlying defect in HIDS, we analysed urine of several patients and discovered increased concentrations of mevalonic acid during severe episodes of fever, but not between crises. Subsequent analysis of cells from four unrelated HIDS patients revealed reduced activities of mevalonate kinase (MK; encoded by the gene MVK), a key enzyme of isoprenoid biosynthesis. Sequence analysis of MVK cDNA from the patients identified three different mutations, one of which was common to all patients. Expression of the mutant cDNAs in Escherichia coli showed that all three mutations affect the activity of the encoded proteins. Moreover, immunoblot analysis demonstrated a deficiency of MK protein in patient fibroblasts, indicating a protein-destabilizing effect of the mutations.

CD4+CD25bright regulatory T cells actively regulate inflammation in the joints of patients with the remitting form of juvenile idiopathic arthritis.

This study investigates the role of CD4+CD25+ regulatory T cells during the clinical course of juvenile idiopathic arthritis (JIA). Persistent oligoarticular JIA (pers-OA JIA) is a subtype of JIA with a relatively benign, self-remitting course while extended oligoarticular JIA (ext-OA JIA) is a subtype with a much less favorable prognosis. Our data show that patients with pers-OA JIA display a significantly higher frequency of CD4+CD25bright T cells with concomitant higher levels of mRNA FoxP3 in the peripheral blood than ext-OA JIA patients. Furthermore, while numbers of synovial fluid (SF) CD4+CD25bright T cells were equal in both patient groups, pers-OA JIA patients displayed a higher frequency of CD4+CD25int T cells and therefore of CD4+CD25total in the SF than ext-OA JIA patients. Analysis of FoxP3 mRNA levels revealed a high expression in SF CD4+CD25bright T cells of both patient groups and also significant expression of FoxP3 mRNA in the CD4+CD25int T cell population. The CD4+CD25bright cells of both patient groups and the CD4+CD25int cells of pers-OA JIA patients were able to suppress responses of CD25neg cells in vitro. A markedly higher expression of CTLA-4, glucocorticoid-induced TNFR, and HLA-DR on SF CD4+CD25bright T regulatory (Treg) cells compared with their peripheral counterparts suggests that the CD4+CD25+ Treg cells may undergo maturation in the joint. In correlation with this mature phenotype, the SF CD4+CD25bright T cells showed an increased regulatory capacity in vitro compared with peripheral blood CD4+CD25bright T cells. These data suggest that CD4+CD25bright Treg cells play a role in determining the patient’s fate toward either a favorable or unfavorable clinical course of disease.

Effect of conjugate pneumococcal vaccine followed by polysaccharide pneumococcal vaccine on recurrent acute otitis media: a randomised study.

BACKGROUND Pneumococcal conjugate vaccine prevents recurrent acute otitis media (AOM) in infants immunised at 2, 4, 6, and 12-15 months of age. We aimed to find out whether this vaccine also prevents AOM in older children who have had previous episodes of AOM. METHODS In this double-blind, randomised study, we enrolled 383 patients aged 1-7 years who had had two or more episodes of AOM in the year before entry. Randomisation was stratified in four groups according to age (12-24 months vs 25-84 months) and the number of previous AOM episodes (two or three episodes vs four or more episodes). Children received either 7-valent pneumococcal conjugate vaccine followed by 23-valent pneumococcal polysaccharide vaccine, or hepatitis A or B vaccines. They were followed up for 18 months for recurrence of AOM. We also cultured samples of middle-ear fluid and nasopharyngeal swabs to assess association of pneumococcal serotypes with AOM after vaccination. FINDINGS We noted no reduction of AOM episodes in the pneumococcal vaccine group compared with controls (intention-to-treat analysis: rate ratio 1.25, 95% CI 0.99-1.57). Although nasopharyngeal carriage of pneumococci of serotypes included in the conjugate-vaccine was greatly reduced after pneumococcal vaccinations, immediate and complete replacement by non-vaccine pneumococcal serotypes took place. INTERPRETATION These data do not lend support to the use of pneumococcal conjugate vaccine to prevent otitis media in previously unvaccinated toddlers and children with a history of recurrent AOM.

Guidance for Substantiating the Evidence for Beneficial Effects of Probiotics: Prevention and Management of Infections by Probiotics

The rationale for the use of probiotics in the management of infectious diseases is supported by their potential to influence and stabilize the composition of gut microbiota, enhance colonization resistance, and modulate immune function parameters. A literature review was conducted to determine the efficacy of using probiotics in selected infections: 1) infectious diarrhea in infants and children, 2) travelers diarrhea, 3) necrotizing enterocolitis in infants, 4) Helicobacter pylori infection, 5) respiratory tract infections in adults and children, 6) ear, nose, and throat infections, and 7) infectious complications in surgical and critically ill patients. The different types of infections that have been subject to clinical studies with different probiotics obviously prevent any generic conclusions. Furthermore, the lack of consistency among studies focusing on 1 specific infection, in study design, applied probiotic strains, outcome parameters, and study population, along with the still limited number of studies, preclude clear and definite conclusions on the efficacy of probiotics and illustrate the need for better-aligned study designs and methodology. Exceptions were the management of infectious diarrhea in infants and travelers diarrhea, antibiotic-associated diarrhea, and necrotizing enterocolitis. Sufficient consistent data exist for these applications to conclude that certain probiotics, under certain conditions, and in certain target populations, are beneficial in reducing the risk of infection. In addition, some evidence exists, although conclusions are premature, for the management of Helicobacter pylori infection and possible reduction of treatment side effects. Certain probiotics may also reduce the risk of various symptoms of respiratory tract infections in adults and children, including ear, nose, and throat infections, although data are currently far too limited to distill any clinical recommendations in this area. Positive but also negative results have been obtained in prevention of infectious complications in surgical and critically ill patients. For future studies it is recommended that researchers provide adequate power, identify pathogens, and report both clinical outcomes and immune biomarkers relating to putative underlying mechanisms.

Identification of strong interleukin-10 inducing lactic acid bacteria which down-regulate T helper type 2 cytokines.

Background Decreased exposure to microbial stimuli has been proposed to be involved in the increased prevalence of atopic disease. Such a relationship was indicated by enhanced presence of typical probiotic bacteria in the intestinal flora correlating with reduced prevalence of atopic disease. Recent clinical trials suggested that probiotic bacteria may decrease and prevent allergic symptoms, but which (different) species or strains may contribute is poorly understood.

The effects of selected probiotic strains on the development of eczema (the PandA study)

Background:  Modification of the intestinal microbiota by administration of probiotic bacteria may be a potential approach to prevent allergic disease. We aimed to study primary prevention of allergic disease in high‐risk children by pre‐ and postnatal supplementation of selected probiotic bacteria.

Recognition of human 60 kD heat shock protein by mononuclear cells from patients with juvenile chronic arthritis

A postulated mechanism for autoimmune disorders is that the immunoreactivity develops against bacterial antigens which show a high degree of sequence homology with mammalian proteins. The mycobacterial 65 kD heat shock protein (hsp) has been implicated in several forms of arthritis. Substantial amounts of the human 60 kD homologue (hsp60) were produced by insertion of the gene into Escherichia coli. To investigate the hypothesis that T-cell reactivity is directed against the endogenous hsp, T-cell proliferation of synovial-fluid and peripheral-blood mononuclear cells in response to hsp60 was studied in samples from six patients with juvenile chronic arthritis (JCA) and nine adult patients with rheumatoid arthritis (RA). There was no T-lymphocyte proliferative response to purified fractions of hsp60 in mononuclear cells from RA patients or healthy children and young adults. However, both synovial-fluid and peripheral-blood mononuclear cells from JCA patients showed substantial proliferative responses. There was a significant correlation between the stimulation indices for human hsp60 and for mycobacterial hsp65 (r = 0.948, p less than 0.02). A similar correlation for hsp60 and mycobacterial hsp70 did not achieve significance. Immunohistochemistry showed that hsp65 and hsp70 homologues were expressed in the synovial membrane in these patients but not in controls. These findings suggest a sequence of events in which hsps become expressed during synovial inflammation and function as autoantigens. In JCA this may be manifested by specific T-cell reactivity which apparently is lost in the more bone-eroding and non-remitting adult disease.

Juvenile chronic arthritis: T cell reactivity to human HSP60 in patients with a favorable course of arthritis.

Synovial fluid and peripheral blood mononuclear cell proliferative responses to the 60-kD human heat shock protein (HSP60) were studied in 23 patients with juvenile chronic arthritis (JCA) and 7 non-JCA control patients. All patients showed active arthritis at the time of study. The patients were divided into two groups according to the presence (group A) or absence (group B) of T lymphocyte reactivity to human HSP60. We show that reactivity to human HSP60 is primarily, though not exclusively, occurring in patients with a remitting course of disease, i.e., the subgroup of HLA-B27 negative JCA patients with an oligoarticular onset. Immunohistochemical analysis of HSP expression in synovial membranes showed a significantly higher intensity of staining in JCA patients than in non-JCA controls. The results suggest that, in accordance with the earlier observation made in experimental models, T lymphocyte reactivity to human HSP60 in this subgroup of JCA patients may be part of T cell regulatory mechanisms that control the development of arthritis.

Successful treatment of allergic bronchopulmonary aspergillosis with recombinant anti-IgE antibody

Allergic bronchopulmonary aspergillosis (ABPA) can cause severe worsening of the respiratory condition in patients with cystic fibrosis. Treatment can result in steroid dependency and serious adverse events. A dramatic and rapid improvement of respiratory symptoms and lung function after a single dose of anti-IgE antibody (omalizumab) in a 12-year-old girl with cystic fibrosis and ABPA is described. This is the first report of this experimental treatment. It suggests an important role for IgE in the pathogenesis of ABPA and offers new therapeutic possibilities.

The Immune Response in Adenoids and Tonsils

The adenoid and tonsils are lymphoid tissues located in the pharynx that play an important role in host defense against invading antigens of the upper respiratory tract. Histologically, these structures consist of four well-defined microcompartments which all participate in the immune response: the cryptepithelium, the follicular germinal center with the mantle zone and interfollicular area. With the uptake of antigen by M-cells present in the cryptepithelium a process is initiated which ultimately results in the generation and dissemination of antigen-specific memory and mainly dimeric IgA-producing effector B-lymphocytes. This process requires successful cognate interactions between antigen-presenting cells and lymphocytes and mutually between lymphocytes, which depend not only on antigen-specific signals but also on the expression of various complementary adhesion and costimulatory molecules.