Protection from inflammatory organ damage in a murine model of hemophagocytic lymphohistiocytosis using treatment with IL-18 binding protein

Hemophagocytic lymphohistiocytosis (HLH) is a life threatening condition due to the association of an infectious agent with lymphocyte cytotoxicity defects, either of congenital genetic origin in children or presumably acquired in adults. In HLH patients, an excess of lymphocyte or macrophage cytokines, such as IFN-gamma and TN Fu is present in serum. In animal models of the disease, IFN-gamma and INF-alpha have been shown to play a central pathogenic role. In humans, unusually high concentrations of IL-18, an inducer of IFN-gamma, and INF-alpha have been reported, and are associated with an imbalance between IL-18 and its natural inhibitor IL18 binding protein (IL18BP) resulting in an excess of free IL18 Here we studied whether IL-18B P could reduce disease severity in an animal model of HLH. Mouse cytomegalovirus infection in perforin-1 knock out mice induced a lethal condition similar to human HLH characterized by cytopenia with marked inflammatory lesions in the liver and spleen as well as the presence of hemophagocytosis in bone marrow. IL-18B P treatment decreased hemophagocytosis and reversed liver as well as spleen damage. IL-18BP treatment also reduced both IFN-gamma and TNF-alpha production by CD8+ T and NK cells, as well as Fas ligand expression on NK cell surface. These data suggest that IL-18B P is beneficial in an animal model of HLH and in combination with anti infectious therapy may be a promising strategy to treat HLH patients

Natural Killer Cells Exhibit a Peculiar Phenotypic Profile in Systemic Sclerosis and Are Potent Inducers of Endothelial Microparticles Release

The pathophysiology of systemic sclerosis (SSc) involves early endothelial and immune activation, both preceding the onset of fibrosis. We previously identified soluble fractalkine and circulating endothelial microparticles (EMPs) as biomarkers of endothelial inflammatory activation in SSc. Fractalkine plays a dual role as a membrane-bound adhesion molecule expressed in inflamed endothelial cells (ECs) and as a chemokine involved in the recruitment, transmigration, and cytotoxic activation of immune cells that express CX3CR1, the receptor of fractalkine, namely CD8 and γδ T cells and natural killer (NK) cells. We aimed to quantify circulating cytotoxic immune cells and their expression of CX3CR1. We further investigated the expression profile of NK cells chemokine receptors and activation markers and the potential of NK cells to induce EC activation in SSc. We performed a monocentric study (NCT 02636127) enrolling 15 SSc patients [15 females, median age of 55 years (39–63), 11 limited cutaneous form and 4 diffuse] and 15 healthy controls. Serum fractalkine levels were significantly increased in SSc patients. Circulating CD8 T cells numbers were decreased in SSc patients with no difference in their CX3CR1 expression. Circulating γδ T cells and NK cells numbers were preserved. CX3CR1 expression in CD8 and γδ T cells did not differ between SSc patients and controls. The percentage and level of CX3CR1 expression in NK cells were significantly lowered in SSc patients. Percentages of CXCR4, NKG2D, CD69-expressing NK cells, and their expression levels were decreased in NK cells. Conversely, CD16 level expression and percentages of CD16+ NK cells were preserved. The exposure of human microvascular dermic EC line (HMVEC-d) to peripheral blood mononuclear cells resulted in similar NK cells degranulation activity in SSc patients and controls. We further showed that NK cells purified from the blood of SSc patients induced enhanced release of EMPs than NK cells from controls. This study evidenced a peculiar NK cells phenotype in SSc characterized by decreased chemokine and activation receptors expression, that might reflect NK cells involvement in the pathogenic process. It also highlighted the role of NK cells as a potent mechanism inducing endothelial activation through enhanced EMPs release

Rôle de l'interleukine-18 dans la physiopathologie du syndrome d'activation macrophagique de l'adulte

AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Successful treatment of systemic lupus erythematosus-related refractory autoimmune hemolytic anemia with ofatumumab

International audienc

Axial articular manifestations in primary Sjögren‘s syndrome: Association with spondyloarthritis

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Anti-NuMA antibodies: clinical associations and significance in patients with primary Sjögren’s syndrome or systemic lupus erythematosus

International audienceAbstract Objective To determine the clinical significance of anti-nuclear mitotic apparatus (NuMA) antibodies (AC-26 or AC-25) in patients with primary Sjögren’s syndrome (pSS) and SLE. Methods Between 2013 and 2018, clinical and immunological features of pSS and SLE patients with anti-NuMA antibodies were compared with anti-NuMA antibodies-negative pSS and SLE cohorts. Results Among 31 284 sera positive for antinuclear antibodies, 90 patients (0.29%) had anti-AC-26 (anti-NuMA1) and AC-25 (anti-HsEg5) antibodies (73.3% and 26.7%, respectively). Autoimmune diseases, mainly consisting in pSS (28.9%) and SLE (21.1%), were found in 67.8%. Anti-NuMA antibodies represented the unique ANA in 60% and 50% of patients with pSS and SLE patients, respectively. Compared with 137 anti-NuMA-negative pSS patients, 20 anti-NuMA-positive pSS presented with less frequent ocular sicca syndrome (70.0% vs 89.1%, P=0.031), dryness complications (15.0% vs 39.4%, P=0.045), or detectable anti-SSa and/or anti-SSb antibodies (40.0% vs 66.4%, P=0.027). Compared with 80 anti-NuMA-negative SLE patients, 14 anti-NuMA-positive SLE patients had no lupus nephritis (0.0% vs 28.8%, P=0.049), less frequent dsDNA antibodies (42.9% vs 75.0%, P=0.025) and complement consumption (21.4% vs 53.8%, P=0.040). Anti-NuMA-positive pSS and SLE patients less frequently required treatments compared with anti-NuMA-negative patients. Conclusion Although rare, anti-NuMA antibodies are mainly associated with pSS and SLE and may be useful for diagnosis when other auto-antibodies are negative. PSS and SLE patients with anti-NuMA antibodies have less severe clinical and biological profiles, suggesting that anti-NuMA antibodies may constitute a good prognosis marker in both autoimmune diseases

Bilateral Breast Ulcers: Granulomatosis with Polyangiitis

International audiencePRESENTATION An investigation into the patient's unusual dermatologic symptoms identified an underlying autoimmune disease. Fourteen days after breast-reduction surgery, the patient, a 25-year-old white woman, was completely recovered. But at 20 days after surgery, she had bilateral mammary ulcera-tive lesions and was admitted to another hospital. The lesions were painless, and she was afebrile. Negative pressure wound therapy failed to accomplish secondary intention healing. For 6 weeks, she was treated with oral prednisolone, 1 mg/kg/day, and hyperbaric oxygen therapy, but these had limited effect. She then underwent a biopsy of the right breast. The specimen showed perivascular inflammation of the superficial and deep dermis, as denoted by an infiltrate of numerous neutrophils, eosinophils, lymphocytes, and some giant cells. Areas of nonfibrinoid necrosis were evident in the superficial dermis. Bacterial cultures of the wound and blood were negative. A diagnosis of pyoderma gangreno-sum was suspected based on the necrotic ulceration and characteristic violaceous undermined borders of the patient's lesions, the high proportion of neutrophils in the biopsy specimen, and the appearance of lesions on the scar site after a complete recovery. Yet, though the biopsy findings suggested pyoderma gangrenosum, there was some atypia, such as the absence of a central necrotic zone. Treatment with prednisolone and hyperbaric oxygen was restarted 5 days after biopsy results returned. She was then referred to our internal medicine department for further work-up. ASSESSMENT On admission, the patient was afebrile. She had bilateral, painless , inframammary ulcerations with inflammatory borders (Figure 1A). These measured 5 cm in diameter and ran horizontally across the surgical scar line. She also had pain in the sinus region. She reported a 1-year history of rhinitis with crusting and bleeding in both nostrils. Treatment had consisted of several courses of corticosteroids and antibiotics, which offered transient relief from symptoms, and ultimately, she underwent nasal septum surgery. Interestingly, the patient's ear, nose, and throat symptoms improved while she was being treated with prednisolone for her mammary lesions. Laboratory tests revealed elevations in the plasma fibrin-ogen level (5.4 g/L) and the C-reactive protein levels Figure 1 On presentation, the patient had bilateral ulcera-tive mammary lesions

Severe imbalance of IL-18/IL-18BP in patients with secondary hemophagocytic syndrome

Hemophagocytic syndrome (HPS) is characterized by an uncontrolled and poorly understood activation of T-helper 1 (Th-1) lymphocytes and macrophages. We studied 20 patients with HPS secondary to infections, autoimmune disease, lymphoma, or cancer and observed that the concentrations of serum interleukin 18 (IL-18), a strong inducer of Th-1 responses, interferon γ (IFN-γ) production, and stimulation of macrophages and natural killer (NK) cells were highly increased in HPS but not in control patients. In contrast, concentrations of its natural inhibitor, the IL-18 binding protein (IL-18BP), were only moderately elevated, resulting in a high level of biologically active free IL-18 in HPS (4.6-fold increase compared with controls; P < .001). Free IL-18 but not IL-12 concentrations significantly correlated with clinical status and the biologic markers of HPS such as anemia (P < .001), hypertriglyceridemia, and hyperferritinemia (P < .01) and also with markers of Th-1 lymphocyte or macrophage activation, such as elevated concentrations of IFN-γ and soluble IL-2 and tumor necrosis factor α (TNF-α) receptor concentrations. Despite high IL-18 elevation, in vitro NK-cell cytotoxicity was severely impaired in HPS patients, in part due to NK-cell lymphopenia that was observed in a majority of patients but also secondary to an intrinsic NK-cell functional deficiency. We concluded that a severe IL-18/IL-18BP imbalance results in Th-1 lymphocyte and macrophage activation, which escapes control by NK-cell cytotoxicity and may allow for secondary HPS in patients with underlying diseases