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.

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.

[Sarcoidosis: changing insights in therapy]. / Sarcoïdose: verandering in therapeutische inzichten.

Sarcoidosis is a granulomatous disease of unknown etiology. Standard treatment with immune suppressants such as glucocorticoids is started when vital organ function is threatened. Biotechnology has resulted in new treatments ('biologicals'), in particular monoclonal antibodies, that may be effective in the treatment of sarcoidosis. In patients with sarcoidosis, only the use of monoclonal antibodies that block tumour necrosis factor (TNF) has been studied scientifically, other biologicals hardly at all. TNF-blockers are used at present in patients with therapy refractory sarcoidosis.

[Melanomas more serious in the elderly]. / Melanomen bij ouderen ernstiger.

Two patients, a 96-year-old woman and a 94-year-old man, were diagnosed with metastatic cutaneous melanoma. The first patient had undergone radical excision of the primary tumour 18 months before. The second patient presented with neurological symptoms caused by a metastatic melanoma; the primary tumour had recently been resected. Both patients died within three weeks of the diagnosis. Cutaneous melanomas have a high metastatic rate. Treatment options are limited for metastatic disease. The incidence of melanoma increases with age. Old age is an independent risk factor, which is also associated with a poor prognosis. Older patients more often present with more serious histological characteristics and more aggressive types of melanoma. The Breslow thickness is also higher in patients aged 65 or over. Nodular melanoma, lentigo maligna or acral lentiginous melanoma are observed more frequently in this group of patients. Moreover, elderly people more frequently present with liver or cerebral metastases. Early diagnosis improves the prognosis, also in the elderly.

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.

Pharmacokinetics of oral fumarates in healthy subjects.

AIMS: To characterize the pharmacokinetics of fumarates in healthy subjects. METHODS: Ten subjects received a single fumarate tablet (containing 120 mg of dimethylfumarate and 95 mg of calcium-monoethylfumarate) in the fasted state and after a standardized breakfast in randomized order. Prior to and at fixed intervals after the dose, blood samples were drawn and the concentrations of monomethylfumarate, the biologically active metabolite, as well as dimethylfumarate and fumaric acid were measured using high-performance liquid chromatography. RESULTS: After a lag time, a transient increase in serum monomethylfumarate concentrations in the blood was observed, whereas dimethylfumarate and fumaric acid concentrations remained below the detection limit. The tlag was 240 min [range 60-603 min; 95% confidence interval (CI) 139, 471] shorter when the tablet was taken after an overnight fast (90 min; range 60-120 min; 95% CI 66, 107) than when taken with breakfast (300 min; range 180-723 min; 95% CI 0, 1002). The tmax was 241 min (range 60-1189 min, 95% CI 53, 781) shorter when the tablet was taken after an overnight fast (182 min; range 120-240 min; 95% CI 146, 211) than when taken with breakfast (361 min; range 240-1429 min; 95% CI 0, 1062). The mean Cmax for monomethylfumarate in the blood of fasting subjects was to 0.84 mg l(-1) (range 0.37-1.29 mg l(-1); 95% CI 0.52, 1.07) and did not differ from that in fed subjects (0.48 mg l(-1); range 0-1.22 mg l(-1); 95% CI 0, 5.55). CONCLUSIONS: The pharmacokinetics of monomethylfumarate in healthy subjects after a single tablet of fumarate are highly variable, particularly after food intake. Further experiments exploring the pharmacokinetics of oral fumarates are warranted in order to elucidate the mechanisms underlying variability in response in patients.