Jean-David Bouaziz

IL‐10 produced by activated human B cells regulates CD4+ T‐cell activation in vitro

IL‐10‐producing regulatory B cells have been identified in mice and shown to downregulate inflammation, making them potentially important for maintenance of tolerance. In this study, we isolated B cells from human blood and spleen, and showed that after a short period of ex vivo stimulation a number of these cells produced IL‐10. The IL‐10‐producing B cells did not fall within a single clearly defined subpopulation, but were enriched in both the memory (CD27+) and the transitional (CD38high) B‐cell compartments. Combined CpG‐B+anti‐Ig stimulation was the most potent IL‐10 stimulus tested. B cells stimulated in this way inhibited CD4+CD25− T‐cell proliferation in vitro by a partially IL‐10‐dependent mechanism. These findings imply that manipulating IL‐10 production by human B cells could be a useful therapeutic strategy for modulating immune responses in humans.

CD24 hi CD27 + and plasmablast-like regulatory B cells in human chronic graft-versus-host disease

Interleukin 10 (IL-10)-producing B cells (regulatory B cells [Bregs]) regulate autoimmunity in mice and humans, and a regulatory role of IL-10-producing plasma cells has been described in mice. Dysfunction of B cells that maintain homeostasis may play a role in the pathogenesis of chronic graft-versus-host disease (cGVHD) after allogeneic stem cell transplantation. Here, we found a relation between decreased Breg frequencies and cGVHD severity. An impaired ability of B cells to produce IL-10, possibly linked to poor signal transducer and activator of transcription 3 and extracellular signal-regulated kinase phosphorylation, was found in patients with active cGVHD. IL-10 production was not confined to a single B-cell subset, but enriched in both the CD24(hi)CD27(+) and CD27(hi)CD38(hi) plasmablast B-cell compartments. In vitro plasmablast differentiation increased the frequency of IL-10-producing B cells. We confirmed that allogeneic transplant recipients had an impaired reconstitution of the memory B-cell pool. cGVHD patients had less CD24(hi)CD27(+) B cells and IL-10-producing CD24(hi)CD27(+) B cells. Patients with cGVHD had increased plasmablast frequencies but decreased IL-10-producing plasmablasts. These results suggest a role of CD24(hi)CD27(+) B-cell and plasmablast-derived IL-10 in the regulation of human cGVHD.

Neutrophilic dermatoses as systemic diseases

Neutrophilic dermatoses (ND) are inflammatory skin conditions characterized by a sterile infiltrate of normal polymorphonuclear leukocytes. The main clinical forms of ND include Sweet syndrome, pyoderma gangrenosum, erythema elevatum diutinum, subcorneal pustular dermatosis, and their atypical or transitional forms. ND are often idiopathic, but they may be associated with myeloid hematologic malignancies (Sweet syndrome), inflammatory bowel disease or rheumatoid arthritis (pyoderma gangrenosum), and monoclonal gammopathies (erythema elevatum diutinum, subcorneal pustular dermatosis). The possible infiltration of internal organs with neutrophils during the setting of ND underlies the concept of a neutrophilic systemic disease. ND may be seen as a polygenic autoinflammatory syndrome due to their frequent association with other autoinflammatory disorders (monogenic or polygenic) and the recent published efficacy of interleukin-1 blocking therapies in their management.

Long‐term efficacy and safety of alemtuzumab in advanced primary cutaneous T‐cell lymphomas

Alemtuzumab has been proposed as salvage therapy for refractory cutaneous T‐cell lymphomas (CTCLs). Long‐term follow‐up data are scarce.

Active Chronic Sarcoidosis is Characterized by Increased Transitional Blood B Cells, Increased IL-10-Producing Regulatory B Cells and High BAFF Levels

Background Sarcoidosis is a multisystemic disease of unknown etiology characterized by a disproportionate Th1 granulomatous immune response in the organs involved. Plasmatic hypergammaglobulinemia and B cell accumulation in granulomatous lesions suggest the possible role of humoral immune responses in the pathogenesis of sarcoidosis. The purpose of this study is to describe B cell peripheral compartment in sarcoidosis. Methodology/Principal Findings We analyzed blood B cell subsets and BAFF levels in 33 patients with chronic sarcoidosis (active sarcoidosis n = 18; inactive sarcoidosis n = 15) and 18 healthy donors. Active chronic sarcoidosis patients had significantly less circulating memory B cells (p<0.01), more transitional (p<0.01) and increased numbers of IL-10-producing regulatory B cells (p<0.05) compared with healthy donors and patients with inactive sarcoidosis. BAFF serum levels were significantly higher in patients with active sarcoidosis (p<0.01 versus healthy donors and inactive sarcoidosis patients) and strongly correlated with serum hypergammaglobulinemia (r = 0.53, p<0.01) and angiotensin converting enzyme levels (r = 0.61, p = <0.01). Conclusions/Significance These data show that there is an altered B cell homeostasis in active sarcoidosis and suggest BAFF antagonist drugs as potential new treatments of this disease.

Absolute CD3+ CD158k+ lymphocyte count is reliable and more sensitive than cytomorphology to evaluate blood tumour burden in Sézary syndrome

Background  CD158k/KIR3DL2 is a specific marker for Sézary cells which can be used to diagnose Sézary syndrome (SS) in erythrodermic patients with abnormal circulating T cells.

Cutaneous lesions of the digits in systemic lupus erythematosus: 50 cases

The objective of this study was to observe the clinical and pathologic features of digital lesions in a cohort of 50 patients with systemic lupus erythematosus (SLE). Biopsy and pictures of digital lesions were performed in 50 consecutive patients with SLE and digital lesions. A clinical diagnosis of vasculitis was previously suggested in 36% of cases. Pictures were reviewed by three dermatologists and all the tissue sections were analysed by the same pathologist. Files of patients were reviewed retrospectively. Activity of SLE was established according to the lupus activity index (LAI). Digital lesions in SLE were frequently painful (60%) with a finger-pulp inflammation (70%). According to clinical and pathological correlation, five patients had acute cutaneous lupus, five subacute cutaneous lupus, 21 discoid lupus and 15 chilblain lupus. Two patients presented vasculitis: one had an urticarial vasculitis concomitantly to a lupus flare, the other had an erythema elevatum diutinum, independent of SLE evolution. Thrombosis of dermal vessels was present in two patients with SLE-associated antiphospholipid syndrome and in two patients with chilblain lupus. LAI was > 1.5 in only seven patients. These results highlight the tendency to clinically overestimate the prevalence of cutaneous vasculitis of the fingers in patients without active SLE. Clinical features of cutaneous lupus of the digits are polymorphous. So, a pathological examination of the lesions is often necessary for diagnosis and proper management.

Posaconazole Treatment of Extensive Skin and Nail Dermatophytosis Due to Autosomal Recessive Deficiency of CARD9

IMPORTANCE Deep dermatophytosis is a disease that involves dermatophytic infection of the dermis and/or lymph nodes and sometimes the central nervous system. Autosomal recessive deficiency of the CARD9 (caspase recruitment domain 9) protein has been described in 17 patients with deep dermatophytosis from Algeria, Tunisia, and Morocco. OBSERVATIONS We report a case of extensive dermatophytosis due to autosomal recessive CARD9 deficiency in a patient of Egyptian origin. This patient had extensive superficial Trichophyton rubrum infection of the skin and nails without significant visceral involvement. Treatment with posaconazole was well tolerated and induced a complete clinical remission within 3 months that continued for 8 months of follow-up. CONCLUSIONS AND RELEVANCE This case report underlines the phenotypic variability of dermatophytic infection in patients with CARD9 deficiency and the potential efficacy of posaconazole for this indication.

Limited efficacy and tolerance of imatinib mesylate in steroid-refractory sclerodermatous chronic GVHD

To the editor: Imatinib mesylate (IM), a tyrosine kinase inhibitor, has shown efficacy for the treatment of chronic GVHD (cGVHD),[1][1][⇓][2]–[3][3] with overall response rates of fibrotic skin symptoms evaluated in 2 open-label studies ranging from 50%[1][1] to 79%.[2][2] To assess the global

Allogeneic stem cell transplantation for advanced cutaneous T-cell lymphomas: a study from the French Society of Bone Marrow Transplantation and French Study Group on Cutaneous Lymphomas

The treatment of advanced stage primary cutaneous T-cell lymphomas remains challenging. In particular, large-cell transformation of mycosis fungoides is associated with a median overall survival of two years for all stages taken together. Little is known regarding allogeneic hematopoietic stem cell transplantation in this context. We performed a multicenter retrospective analysis of 37 cases of advanced stage primary cutaneous T-cell lymphomas treated with allogeneic stem cell transplantation, including 20 (54%) transformed mycosis fungoides. Twenty-four patients (65%) had stage IV disease (for mycosis fungoides and Sézary syndrome) or disseminated nodal or visceral involvement (for non-epidermotropic primary cutaneous T-cell lymphomas). After a median follow up of 29 months, 19 patients experienced a relapse, leading to a 2-year cumulative incidence of relapse of 56% (95%CI: 0.38–0.74). Estimated 2-year overall survival was 57% (95%CI: 0.41–0.77) and progression-free survival 31% (95%CI: 0.19–0.53). Six of 19 patients with a post-transplant relapse achieved a subsequent complete remission after salvage therapy, with a median duration of 41 months. A weak residual tumor burden before transplantation was associated with increased progression-free survival (HR=0.3, 95%CI: 0.1–0.8; P=0.01). The use of antithymocyte globulin significantly reduced progression-free survival (HR=2.9, 95%CI: 1.3–6.2; P=0.01) but also transplant-related mortality (HR=10−7, 95%CI: 4.10−8−2.10−7; P<0.001) in univariate analysis. In multivariate analysis, the use of antithymocyte globulin was the only factor significantly associated with decreased progression-free survival (P=0.04). Allogeneic stem cell transplantation should be considered in advanced stage primary cutaneous T-cell lymphomas, including transformed mycosis fungoides.