Human IgE(+) B cells are derived from T cell-dependent and T cell-independent pathways.

BACKGROUND: The prevalence of IgE-mediated diseases has been increasing worldwide, yet IgE-expressing B cells are poorly characterized, mainly because of their scarcity and low membrane IgE levels. OBJECTIVE: We sought to study the immunobiology of human IgE-expressing B cells in healthy subjects and patients with allergic disease. METHODS: We used a stepwise approach for flow cytometric detection and purification of human IgE-expressing B cells in control subjects, CD40 ligand-deficient patients, and patients with atopic dermatitis. Molecular analysis of replication histories, somatic hypermutation (SHM), and immunoglobulin class-switching was performed. RESULTS: Using multicolor flow cytometry, we reliably detected IgE-expressing plasma cells and 2 IgE-expressing memory B-cell subsets. These IgE-expressing cells showed molecular and phenotypic signs of antigen responses. The replication history and SHM levels of IgE(+) plasma cells and CD27(+)IgE(+) memory B cells fitted with a germinal center (GC)-dependent pathway, often through an IgG intermediate, as evidenced from Sγ remnants in Sµ-Sε switch regions. CD27(-)IgE(+) cells showed limited proliferation and SHM and were present in CD40 ligand-deficient patients, indicating a GC-independent origin. Patients with atopic dermatitis had normal numbers of blood IgE(+) plasma cells and CD27(+)IgE(+) memory B cells but increased numbers of CD27(-)IgE(+) memory B cells with high SHM loads compared with those seen in healthy control subjects and patients with psoriasis. CONCLUSIONS: We delineated GC-dependent and GC-independent IgE(+) B-cell responses in healthy subjects and indicated involvement of the GC-independent pathway in a human IgE-mediated disease. These findings provide new insights into the pathogenesis of IgE-mediated diseases and might contribute to accurate monitoring of IgE(+) B cells in patients with severe disease undergoing anti-IgE treatment.

The microbiome and psoriatic arthritis.

Psoriatic arthritis is a chronic inflammatory joint disease, seen in combination with the chronic inflammatory skin disease psoriasis and belonging to the family of spondylarthritides (SpA). A link is recognized between psoriatic arthritis and inflammatory bowel disease (IBD). Environmental factors seem to induce inflammatory disease in individuals with underlying genetic susceptibility. The microbiome is a subject of increasing interest in the etiology of these inflammatory immune-mediated diseases. The intestinal microbiome is able to affect extra-intestinal distant sites, including the joints, through immunomodulation. At this point, evidence regarding a relationship between the microbiome and psoriatic arthritis is scarce. However, we hypothesize that common immune-mediated inflammatory pathways seen in the "skin-joint-gut axis" in psoriatic arthritis are induced or at least mediated by the microbiome. Th17 has a crucial function in this mechanism. Further establishment of this connection may lead to novel therapeutic approaches for psoriatic arthritis.

Perigranuloma localization and abnormal maturation of B cells: emerging key players in sarcoidosis?

RATIONALE: Recent observations of abnormal immunoglobulin responses and case reports describing successful B-cell ablative therapy suggest involvement of B cells in the pathogenesis of sarcoidosis. OBJECTIVES: To investigate how abnormal B-cell maturation and function in patients with sarcoidosis contribute to disease. METHODS: Patients with sarcoidosis (n = 32) were included for detailed analysis by immunohistochemistry of tissue, flow cytometry of blood B-cell subsets, and serum immunoglobulin levels. Vaccination responses in patients with sarcoidosis to influenza virus and encapsulated bacteria and molecular analysis of immunoglobulin heavy chain transcripts were studied for functional analysis of immunoglobulin responses. MEASUREMENTS AND MAIN RESULTS: Perigranuloma localization of IgA-producing plasma cells and numerous B cells were found in affected tissues. Total blood B-cell numbers were normal, CD27(+) memory B cells were significantly reduced, and CD27(-)IgA(+) B cells were significantly increased; the results are normalized in patients treated with TNF-α blockers. Despite this, patients had normal serum immunoglobulin levels and normal antigen-specific immunoglobulin responses. IgA and IgG transcripts, however, showed high frequencies of somatic hypermutations and increased usage of downstream IgG subclasses, suggestive for prolonged or repetitive responses. CONCLUSIONS: The large B-cell infiltrates in granulomatous tissue and increased molecular signs of antibody maturation are indicative of direct involvement of B cells in local inflammatory processes in patients with sarcoidosis. Moreover, CD27(-)IgA(+) B cells could be a marker for treatment with TNF-α blockers. These findings of B cells as emerging key players provide a rationale for a systematic study on B-cell ablative therapy in patients with sarcoidosis.

Cutaneous adverse events associated with disease-modifying treatment in multiple sclerosis: a systematic review.

Glatiramer acetate and interferon-beta are approved first-line disease-modifying treatments (DMTs) for multiple sclerosis (MS). DMTs can be associated with cutaneous adverse events, which may influence treatment adherence and patient quality of life. In this systematic review, we aimed to provide an overview of the clinical spectrum and the incidence of skin reactions associated with DMTs. A systematic literature search was performed up to May 2011 in Medline, Embase, and Cochrane databases without applying restrictions in study design, language, or publishing date. Eligible for inclusion were articles describing any skin reaction related to DMTs in MS patients. Selection of articles and data extraction were performed by two authors independently. One hundred and six articles were included, of which 41 (39%) were randomized controlled trials or cohort studies reporting incidences of mainly local injection-site reactions. A large number of patients had experienced some form of localized injection-site reaction: up to 90% for those using subcutaneous formulations and up to 33% for those using an intramuscular formulation. Sixty-five case-reports involving 106 MS patients described a wide spectrum of cutaneous adverse events, the most frequently reported being lipoatrophy, cutaneous necrosis and ulcers, and various immune-mediated inflammatory skin diseases. DMTs for MS are frequently associated with local injection-site reactions and a wide spectrum of generalized cutaneous adverse events, in particular, the subcutaneous formulations. Although some of the skin reactions may be severe and persistent, most of them are mild and do not require cessation of DMT.

The potent bile acid sequestrant colesevelam is not effective in cholestatic pruritus: results of a double-blind, randomized, placebo-controlled trial.

UNLABELLED: Colesevelam is an anion-exchange resin with a 7-fold higher bile acid-binding capacity and fewer side effects than cholestyramine, the current first-line treatment option for cholestatic pruritus. The aim of this trial was to compare the effects of colesevelam and a placebo in patients with cholestatic pruritus. In a randomized, double-blind, investigator-initiated, multicenter trial, patients with cholestatic pruritus, both treatment-naive and previously treated, received 1875 mg of colesevelam or an identical placebo twice daily for 3 weeks. The effect on pruritus was assessed with daily visual analogue scales, quality-of-life scores, and evaluations of cutaneous scratch lesions. The predefined primary endpoint was the proportion of patients with at least a 40% reduction in pruritus visual analogue scale scores. Thirty-eight patients were included, and 35 were evaluable: 17 took colesevelam, 18 took the placebo, 22 were female, 8 were treatment-naive, 14 had primary biliary cirrhosis, and 14 had primary sclerosing cholangitis. The mean serum bile acid levels were comparable between the groups before treatment (P = 0.74), but they were significantly different after treatment (P = 0.01) in favor of patients treated with colesevelam. Thirty-six percent of patients in the colesevelam group reached the primary endpoint versus 35% in the placebo group (P = 1.0). There were no significant differences between the groups with respect to pruritus scores, quality-of-life scores, and severity of cutaneous scratch lesions. Mild side effects occurred in one colesevelam-treated patient and four placebo-treated patients. CONCLUSION: Although colesevelam significantly decreased serum bile acid levels, this trial was unable to demonstrate that it was more effective than a placebo in alleviating the severity of pruritus of cholestasis.

Just a penile nodule...

In this paper we present a case history of a homosexual HIV-positive male with a painless nodule on the penis. Screening for sexually transmitted diseases did not detect any infection until the node perforated spontaneously. A diagnosis of lymphogranuloma venereum was made when chlamydia trachomatis type L2 DNA was extracted from the lesion. This case illustrates that standard screening may not be sufficient for making the diagnosis of lymphogranuloma venereum.

Rescue of progeria in trichothiodystrophy by homozygous lethal Xpd alleles.

Although compound heterozygosity, or the presence of two different mutant alleles of the same gene, is common in human recessive disease, its potential to impact disease outcome has not been well documented. This is most likely because of the inherent difficulty in distinguishing specific biallelic effects from differences in environment or genetic background. We addressed the potential of different recessive alleles to contribute to the enigmatic pleiotropy associated with XPD recessive disorders in compound heterozygous mouse models. Alterations in this essential helicase, with functions in both DNA repair and basal transcription, result in diverse pathologies ranging from elevated UV sensitivity and cancer predisposition to accelerated segmental progeria. We report a variety of biallelic effects on organismal phenotype attributable to combinations of recessive Xpd alleles, including the following: (i) the ability of homozygous lethal Xpd alleles to ameliorate a variety of disease symptoms when their essential basal transcription function is supplied by a different disease-causing allele, (ii) differential developmental and tissue-specific functions of distinct Xpd allele products, and (iii) interallelic complementation, a phenomenon rarely reported at clinically relevant loci in mammals. Our data suggest a re-evaluation of the contribution of "null" alleles to XPD disorders and highlight the potential of combinations of recessive alleles to affect both normal and pathological phenotypic plasticity in mammals.

[The next step in the treatment of immune diseases: jakinibs, inhibitors of the intracellular Janus kinase]. / Nieuwe stap in behandeling van immuunziekten.

The next step in the treatment of immune diseases: jakinibs, inhibitors of the intracellular Janus kinase The intracellular Janus kinase (JAK) and the signal transduction and activator of transcription (STAT) proteins are involved in the whole spectrum of immune-mediated diseases. Currently, agents are developed that influence the JAK-STAT mechanism. JAK inhibitors (jakinibs) have only recently made their way into clinical practice. These agents exhibit both similarities and differences in terms of effectiveness and safety. In the coming years, results from basic and clinical research will improve our knowledge of these agents. For patients who suffer from immune-mediated diseases, their introduction appears to be a breakthrough that will offer new treatment options. One advantage over biologicals is that jakinibs can be taken orally. As with all new innovative medicines, with jakinibs one cannot escape a discussion over costs as well. The balance between the added value of jakinibs compared to biologicals, and the actual purchase prices for each of these treatment modalities, will influence the eventual positioning of jakinibs.

Skin manifestations of diabetes.

Diabetes mellitus can be complicated by a variety of cutaneous manifestations. Good metabolic control may prevent some of these manifestations and may support cure. Unfortunately, most glucose-lowering drugs also have cutaneous side effects. It is important to be able to recognize these signs and symptoms and to either treat them appropriately or refer the patient to a dermatologist or diabetologist.

Drug evaluation: BG-12, an immunomodulatory dimethylfumarate.

Biogen Idec Inc, following its acquisition of Fumapharm AG, is developing BG-12 (Panaclar, BG-00012, FAG-201), an oral second-generation fumarate derivative, for the potential treatment of multiple sclerosis (MS). In January 2007, a phase III program for relapsing-remitting MS patients was initiated. The company was also developing the drug for psoriasis and, in October 2003, Biogen Idec expected to commence phase III trials for psoriasis in the US in the following year. In April 2005, the drug met its European phase III psoriasis trial endpoint, with the data expected to be used to support a market authorization filing in Germany in 2005. It was later disclosed that while an application had been filed, this was subsequently withdrawn based on a joint decision by Fumapharm and Biogen Idec. No further development has been reported on BG-12 for psoriasis in the US and it was not listed as a pursued indication on Biogen Idec's April 2007 pipeline.

Depletion of Saccharomyces cerevisiae in psoriasis patients, restored by Dimethylfumarate therapy (DMF).

BACKGROUND: Psoriasis and inflammatory bowel disease (IBD) are chronic inflammatory diseases sharing similar pathogenic pathways. Intestinal microbial changes such as a decrease of bakers' yeast Saccharomyces cerevisiae have been reported in IBD, suggesting the presence of a gut-skin axis. OBJECTIVE: To investigate whether the S. cerevisiae abundance was altered in psoriasis patients versus healthy controls, and whether dimethylfumarate (DMF) interacted with this yeast. METHODS: Using qPCR, faecal samples were compared between psoriasis patients without DMF (n = 30), psoriasis patients with DMF (n = 28), and healthy controls (n = 32). RESULTS: Faecal S. cerevisiae abundance was decreased in psoriasis compared to healthy controls (p<0.001). Interestingly, DMF use raised S. cerevisiae levels (p<0.001). Gastrointestinal adverse-effects of DMF were correlated with a higher S. cerevisiae abundance (p = 0.010). In vitro, a direct effect of DMF on S. cerevisiae growth was observed. In addition, anti-Saccharomyces cerevisiae antibodies were not elevated in psoriasis. CONCLUSION: The abundance of baker's yeast S. cerevisiae is decreased in psoriasis patients, but appears to be restored upon DMF use. S. cerevisiae is generally classified as a yeast with beneficial immunomodulatory properties, but may also be involved in the occurrence of DMF's gastrointestinal adverse-effects. Potentially, DMF might be a new therapy for IBD.

Similar Depletion of Protective Faecalibacterium prausnitzii in Psoriasis and Inflammatory Bowel Disease, but not in Hidradenitis Suppurativa.

BACKGROUND AND AIMS: Psoriasis and hidradenitis suppurativa [HS] co-occur more often with inflammatory bowel disease [IBD] than expected, due to shared pathogenic and genetic features. It is known that IBD patients harbour an altered intestinal microbiome characterised by a depletion of Faecalibacterium prausnitzii and increase of Escherichia coli. At present, it is unclear whether a similar intestinal microbiome trend can be identified in IBD-associated skin disorders. We therefore investigated the F. prausnitzii and E. coli abundance in psoriasis and HS, with and without concomitant IBD. METHODS: Using quantitative polymerase chain reaction , we compared the F. prausnitzii and E. coli abundances in faecal samples from healthy controls [n = 33] with samples from patients with psoriasis [n = 29], IBD [n = 31], and concomitant IBD and psoriasis [n = 13]. Likewise, we analysed samples from patients with HS [n = 17], and concomitant IBD and HS [n = 17]. RESULTS: Psoriasis patients harboured a significantly lower abundance of F. prausnitzii in their stool than healthy controls [p < 0.001], which was similar to IBD patients. Together with the reduced F. prausnitzii levels, the psoriasis patients had a significantly higher abundance of E. coli [p < 0.001]. No significant difference in F. prausnitzii or E. coli abundance was found in HS. It was apparent that patients with concomitant IBD and associated skin disorder had the greatest decrease of F. prausnitzii and increase of E. coli. CONCLUSIONS: The study demonstrates, for the first time, an IBD-like decrease of F. prausnitzii together with an increase of E.coli in psoriasis, supporting the presence of a gut-microbiome-skin axis in psoriasis and IBD.

A cluster of acute hepatitis C virus infection among men who have sex with men--results from contact tracing and public health implications.

OBJECTIVE: An acute hepatitis C virus (HCV) infection in an HIV-positive man who had sex with men (MSM) was notified. In the period of his seroconversion he was also diagnosed with a rectal lymphogranuloma venereum (LGV) infection, and was part of a cluster of 15 LGV cases in 2003. Our aim was to investigate HCV transmission and to search for potential spread among sexual contacts and known LGV patients. METHODS: Our case series included the index, two recent contacts, and 14 LGV cases. They were interviewed about parenteral exposure for HCV, history of sexually transmitted diseases(STDs), sexual behaviour and drug use. Laboratory investigations included anti-HCV antibodies, HCV-polymerase chain reaction, and HCV genotyping. RESULTS: Seven out of 17 MSM recently seroconverted for HCV (41%). Three genotypes were found. Parenteral risk factors were excluded. Six out of seven had LGV proctitis coinciding with HCV seroconversion, six (86%) were HIV infected. Unprotected anal contact was practised by both HCV uninfected and infected cases. Unprotected active and passive fisting was reported by all seven HCV infected men, compared with two of nine uninfected men (P = 0.003). Non-intravenous drug use during sexual activities was common among all MSM. Numerous, often anonymous, sexual contacts in various European countries were reported. CONCLUSIONS: A cluster of acute HCV infection is reported among mostly HIV-positive MSM, with multiple partners throughout Europe. Sexual techniques potentially leading to mucosal damage (fisting), concomitant STDs such as LGV and drug use seem facilitating factors for spread. Extensive case finding and partner tracing is advocated as well as targeted prevention messages.

Psoriasis is not associated with IL-12p70/IL-12p40 production and IL12B promoter polymorphism.

Psoriasis is a type-1 T cell-mediated, chronic inflammatory disease. Since interleukin (IL)-12p70 promotes the development of type-1 T cells, we investigated whether psoriasis is associated with an increased production of this cyctokine by blood cells. Results revealed that the production of IL-12p70 by cells of psoriasis patients stimulated by 1 and 10 ng per mL, but not 100 ng per mL of lipopolysaccharide (LPS) was higher (p=0.03) than that by cells of healthy volunteers. The production of IL-12p40 by patients cells upon stimulation with 0.1 ng per mL LPS, but not higher concentrations, was higher (p=0.02) than that by cells of healthy volunteers. No association between IL-12p70 production by blood cells and the severity of psoriasis was observed, nor was there a difference in the LPS-stimulated production of this cytokine between cells of the early and late onset type of patients. The frequencies of the various genotypes for the promoter region of the gene encoding IL-12p40 (IL12B) did not differ between psoriasis patients and controls. No association was observed between the various IL12B promoter genotypes and the LPS-stimulated production of IL-12p70 or IL-12p40 by blood cells. Together, psoriasis is not associated with a promoter polymorphism in the IL12B gene nor with the production of IL-12p70 by LPS-stimulated blood cells.

Resurgence of lymphogranuloma venereum in Western Europe: an outbreak of Chlamydia trachomatis serovar l2 proctitis in The Netherlands among men who have sex with men.

BACKGROUND: Lymphogranuloma venereum (LGV) is a sexually transmitted disease (STD) and is rare in the Western world. Recently, 3 men who have sex with men presented with LGV proctitis at the Erasmus Medical Center, Rotterdam, The Netherlands. We investigated a possible outbreak in a sexual network of men who have sex with men (MSM). METHODS: After active case finding, a total of 15 men presented and were investigated. Serum antibody titers to Chlamydia trachomatis were determined. Urine and rectum specimens were analyzed by polymerase chain reaction (PCR) for the presence of C. trachomatis. C. trachomatis-positive specimens were genotyped to detect the specific C. trachomatis serovars. All subjects underwent routine STD screening. Sociodemographic, clinical, and endoscopic characteristics were evaluated. RESULTS: Thirteen subjects had high immunoglobulin (Ig) G and IgA titers to C. trachomatis, suggesting an invasive infection. Rectal specimens of 12 subjects were PCR-positive for C. trachomatis. All urine specimens were negative. Genotyping revealed serovars L(2) (n=8) and L(1) (n=1). An ulcerative proctitis was found in all subjects obtaining sigmoidoscopy (n=9). Eleven of 13 subjects with an LGV diagnosis were seropositive for human immunodeficiency virus (HIV), 6 had another concomitant STD, and 1 had recently acquired a hepatitis C virus infection. Further sexual contacts were reported from The Netherlands, Germany, Belgium, the United Kingdom, and France. CONCLUSIONS: We revealed an outbreak of LGV proctitis among MSM in The Netherlands. The ulcerous character favors transmission of HIV, other STDs, and blood-borne diseases. From a public health perspective, it seems important to increase the awareness of possible LGV in MSM with symptomatic proctitis.

In vitro pharmacokinetics of anti-psoriatic fumaric acid esters.

BACKGROUND: Psoriasis is a chronic inflammatory skin disease that can be successfully treated with a mixture of fumaric acid esters (FAE) formulated as enteric-coated tablets for oral use. These tablets consist of dimethylfumarate (DMF) and salts of monoethylfumarate (MEF) and its main bioactive metabolite is monomethylfumarate (MMF). Little is known about the pharmacokinetics of these FAE. The aim of the present study was to investigate the hydrolysis of DMF to MMF and the stability of MMF, DMF and MEF at in vitro conditions representing different body compartments. RESULTS: DMF is hydrolyzed to MMF in an alkaline environment (pH 8), but not in an acidic environment (pH 1). In these conditions MMF and MEF remained intact during the period of analysis (6 h). Interestingly, DMF was hardly hydrolyzed to MMF in a buffer of pH 7.4, but was rapidly hydrolyzed in human serum having the same pH. Moreover, in whole blood the half-life of DMF was dramatically reduced as compared to serum. The concentrations of MMF and MEF in serum and whole blood decreased with increasing time. These data indicate that the majority of the FAE in the circulation are metabolized by one or more types of blood cells. Additional experiments with purified blood cell fractions resuspended in phosphate buffered saline (pH 7.4) revealed that at concentrations present in whole blood monocytes/lymphocytes, but not granulocytes and erythrocytes, effectively hydrolyzed DMF to MMF. Furthermore, in agreement with the data obtained with the pure components of the tablet, the enteric-coated tablet remained intact at pH 1, but rapidly dissolved at pH 8. CONCLUSION: Together, these in vitro data indicate that hydrolysis of DMF to MMF rapidly occurs at pH 8, resembling that within the small intestines, but not at pH 1 resembling the pH in the stomach. At both pHs MMF and MEF remained intact. These data explain the observation that after oral FAE intake MMF and MEF, but not DMF, can be readily detected in the circulation of human healthy volunteers and psoriasis patients.