IL-10 and IL-10 receptor defects in humans Glocker, Erik-Oliver; Kotlarz, Daniel; Klein, Christoph ...
Annals of the New York Academy of Sciences,
December 2011, Letnik:
1246, Številka:
1
Journal Article
Recenzirano
Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is chronic in nature and is characterized by abdominal pain, diarrhea, bleeding, and malabsorption. ...It is considered a complex multigenic and multifactorial disorder that results from disturbed interactions between the immune system and commensal bacteria of the gut. Recent work has demonstrated that IBD with an early‐onset within the first months of life can be monogenic: mutations in IL‐10 or its receptor lead to a loss of IL‐10 function and cause severe intractable enterocolitis in infants and small children. Both IL‐10 and IL‐10 receptor deficiency can be successfully treated by hematopoietic stem cell transplantation.
Background
Antimicrobial susceptibility of Helicobacter (H.) pylori is usually determined by phenotypic methods. When H. pylori cannot be grown owing to contaminations or delay in transport of ...gastric tissue samples to the microbiological laboratory, molecular genetic testing is a reasonable alternative. The aim of this retrospective study was to assess the outcome of salvage eradication treatments based on molecular genetic susceptibility testing.
Methods
Data on 144 H. pylori PCR‐positive gastric tissue samples of patients primarily with prior unsuccessful eradication treatments were retrospectively analyzed. Eradication treatments were recommended based on genotypic clarithromycin and/or levofloxacin susceptibility as tested by real‐time PCR or reverse hybridization. Treatment success was assessed by attending physicians using urea breath test; stool‐antigen ELISA; and microbiology/histopathology.
Results
Overall success rate of molecular genetic testing‐guided salvage treatments was low (68%); none of the regimens chosen was significantly better than another. Multivariable logistic regression analysis did not reveal any factors that may predict treatment failure.
Conclusions
Eradication success was poor despite susceptibility testing. Gastroenterologists are advised to prescribe recommended salvage treatments, considering recommended dosages and prolonged treatment duration.
Genetic analyses showed that mutations affecting the interleukin-10 receptor are associated with early-onset colitis. Further molecular analyses showed that the mutations abrogated interleukin-10 ...signaling. Treatment of one of the affected children by means of allogeneic hematopoietic stem-cell transplantation was successful.
Genetic analyses showed that mutations affecting the interleukin-10 receptor are associated with early-onset colitis. Treatment of an affected child by means of allogeneic hematopoietic stem-cell transplantation was successful.
Inflammatory bowel disease is a heterogeneous group of disorders, classified as Crohn's disease, ulcerative colitis, and indeterminate colitis.
1
,
2
In most patients, these disorders are manifested in adolescence or adulthood; however, they may present in infancy and may be inherited as an autosomal recessive trait.
3
–
6
The genetic causes of inflammatory bowel disease are only partly understood. Studies in transgenic murine models
7
and genomewide genetic-linkage and association studies have provided insights into the genetic complexity underlying these inflammatory conditions.
8
Investigators using these approaches have implicated several genes in the pathogenesis of inflammatory bowel disease; the identity of these genes suggests . . .
Background
Antimicrobial therapy is recommended to eradicate Helicobacter (H.) pylori in infected individuals. As first‐line treatments are empiric, knowledge of antimicrobial resistance is key to ...successful eradication.
Aims
We investigated primary resistance in an eastern German region to derive recommendations for eradication treatment.
Methods
We used molecular genetic methods to examine Helicobacter rapid urease test (RUT) positive gastric specimens of 533 patients from Berlin and the federal state of Brandenburg with allegedly no prior eradication treatment. Tissue samples were removed from RUT and screened by real‐time PCR for mutations conferring resistance to clarithromycin. In addition, 182 samples out of 533 were tested for resistance to levofloxacin and tetracycline.
Results
Primary resistances were 10.9% (58 out of 533) to clarithromycin; 13.7% (25/182) to levofloxacin; and 2.2% to tetracycline (4/182). Combined resistance to clarithromycin/levofloxacin was low (2.2%, 4/182). Female sex was significantly associated with clarithromycin resistance.
Conclusion
Clarithromycin may be a suitable first‐line antibiotic for about 90% of outpatients. A simple molecular test may help physicians avoid prescription of an ineffective first‐line regimen.
Infant colitis—it's in the genes Glocker, Erik-Oliver, MD; Frede, Natalie; Perro, Mario, MSc ...
The Lancet (British edition),
10/2010, Letnik:
376, Številka:
9748
Journal Article
Recenzirano
The online tool Polymorphism Phenotyping (Polyphen) predicted that the mutation might be damaging, and molecular modelling with Swiss PDB viewer indicated changes in the formation of hydrogen bonds ...that might affect the tertiary structure of interleukin-10 and its dimerisation (see webappendix figure 2). Despite the importance of interleukin-10 for intestinal immunity, in patients with Crohn's disease recombinant human interleukin-10 did not induce significant remission.3 The use of genetically modified bacteria (eg, Lactococcus spp) that secrete the human protein could be an attractive therapy option, but its efficacy in patients with interleukin-10 mutations remains unproven.4 Our clinical cases underline the importance of molecular diagnostics in modern clinical medicine.
Background Inherited deficiencies of IL-10 or IL-10 receptor (IL-10R) lead to immune dysregulation with life-threatening early-onset enterocolitis. Objectives We sought to gather clinical data of ...IL-10/IL-10R–deficient patients and devise guidelines for diagnosis and management, including hematopoietic stem cell transplantation (HSCT). Methods We enrolled 40 patients with early-onset enterocolitis and screened for mutations in IL10 / IL10R using genetic studies, functional studies, or both of the IL-10 signaling pathway. Medical records of IL-10/IL-10R–deficient patients were reviewed and compiled. Results Of 40 patients, we identified 7 with novel mutations, predominantly in consanguineous families with more than 1 affected member. IL-10/IL-10R–deficient patients had intractable enterocolitis, perianal disease, and fistula formation. HSCT was carried out in 2 patients with IL-10 deficiency and 1 patient with IL-10R α chain deficiency and proved to be an effective therapy, leading to rapid improvement of clinical symptoms and quality of life. Conclusion Because the defect in patients with IL-10/IL-10R deficiency resides in hematopoietic lineage cells and their colitis is resistant to standard immunosuppressive therapy, HSCT should be considered early as a potentially curative therapeutic option.
Homozygous mutations in the
CARD9
gene, with a premature termination codon, are associated with chronic mucocutaneous candidiasis in an Iranian family. Dysfunction of
CARD9
impairs the innate ...signaling of dectin-1, an antifungal pattern-recognition receptor.
Homozygous mutations in the
CARD9
gene are associated with chronic mucocutaneous candidiasis in an Iranian family. Dysfunction of
CARD9
impairs the innate signaling of dectin-1, an antifungal pattern-recognition receptor.
Chronic mucocutaneous candidiasis is characterized by impaired clearance of fungal infections and results in colonization and infections of the mucosa or skin, predominantly with
Candida albicans
.
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,
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A variety of clinical conditions, such as infection with the human immunodeficiency virus or the use of corticosteroids, favor the development of chronic mucocutaneous candidiasis, but the disease may also be a primary immunodeficiency arising from unknown genetic defects.
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,
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In chronic mucocutaneous candidiasis, the most common infections are due to
C. albicans;
however, patients may also have an increased susceptibility to dermatophytes.
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,
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Severe complications rarely develop in patients with chronic . . .
The aim of this study was to update data on levofloxacin/ciprofloxacin and triple resistance (resistance to metronidazole, clarithromycin and levofloxacin/ciprofloxacin) in Helicobacter pylori ...clinical isolates and to identify the impact of prior eradication therapies on their development.
We tested the antimicrobial susceptibility to amoxicillin, metronidazole, clarithromycin, levofloxacin/ciprofloxacin, tetracycline and rifampicin of 5296 clinical H. pylori strains isolated between 2006 and 2011. Information on prior eradication therapies was gathered and their impact on the development of antimicrobial resistance, in particular to levofloxacin/ciprofloxacin and triple resistance, was analysed.
From 2006 onwards, both levofloxacin/ciprofloxacin and triple resistance have steadily increased and peaked in 2011 with 29.1% and 18.6%, respectively. Unsuccessful prior eradication attempts proved a major risk factor for resistance development. Patients who had undergone unsuccessful eradication attempts harboured levofloxacin/ciprofloxacin- and triple-resistant isolates significantly more often than untreated individuals (26.7% and 18.1% versus 10.6% and 1.6%). Levofloxacin/ciprofloxacin and triple resistance occurred significantly more often in patients who had received quinolones when compared with patients who had not (44.5% versus 23.1% and 28.7% versus 15.6%). We did not observe any significant differences in resistance rates in the different German federal states.
Resistance to levofloxacin/ciprofloxacin and triple resistance have continuously risen and reached worrying numbers. Hence we strongly advise against the use of quinolones in empirical second-line therapies for H. pylori without prior susceptibility testing and/or a carefully taken patient medical history.
The ability of anti-cytokine antibodies to play a disease-causing role in the pathogenesis of immunodeficiencies is widely accepted. The aim of this study was to investigate whether autoantibodies ...against BAFF (important B cell survival signal), APRIL (important plasma cell survival signal), or Interleukin-21 (important cytokine for immunoglobulin class switch) present an alternative mechanism for the development of the following primary antibody deficiencies (PADs): common variable immune deficiency (CVID) or selective IgA deficiency (sIgAD).
Two hundred thirty-two sera from patients with PADs were screened for autoantibodies against cytokines by ELISA. Statistical data analysis yielded a significant difference (p < 0.01) between the healthy donor sera and both PAD cohorts. The analysis was deepened by subdividing the patient collective into groups with distinct B cell phenotypes but no significant differences were found. For selected sera with notable high ELISA-read outs functional analysis ensued. Anti-BAFF and anti-APRIL antibodies were further examined by a B cell survival assay, whilst the functional relevance of putative anti-IL-21 autoantibodies was investigated by means of a STAT3 phosphorylation assay. However, the results of these experiments revealed no discernible functional effect.
Whilst statistical analysis of ELISA results showed significant differences between patients and healthy controls, in our set of patients functional tests yielded no evidence for an involvement of autoantibodies against BAFF, APRIL, or IL-21 in the pathogenesis of CVID or sIgAD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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