ABSTRACT

SummaryLipid metabolism and receptor-mediated signaling are highly intertwined processes that cooperate to fulfill cellular functions and safeguard cellular homeostasis. Activation of Toll-like receptors (TLRs) leads to a complex cellular response, orchestrating a diverse range of inflammatory events that need to be tightly controlled. Here, we identified the GPI-anchored Sphingomyelin Phosphodiesterase, Acid-Like 3B (SMPDL3B) in a mass spectrometry screening campaign for membrane proteins co-purifying with TLRs. Deficiency of Smpdl3b in macrophages enhanced responsiveness to TLR stimulation and profoundly changed the cellular lipid composition and membrane fluidity. Increased cellular responses could be reverted by re-introducing affected ceramides, functionally linking membrane lipid composition and innate immune signaling. Finally, Smpdl3b-deficient mice displayed an intensified inflammatory response in TLR-dependent peritonitis models, establishing its negative regulatory role in vivo. Taken together, our results identify the membrane-modulating enzyme SMPDL3B as a negative regulator of TLR signaling that functions at the interface of membrane biology and innate immunity.

Conclusion. In addition to supporting the role of IFNs in SLE immunopathogenesis in general, the findings of the present study support a role of IFN␥ in this disease.Type I interferons (e.g., IFN␣) and type II IFN (IFN␥) have both been implicated in the immunopathogenesis of systemic lupus erythematosus (SLE). IFN␣ and IFN␥ serum levels are increased (1-5), and IFN messenger RNA (mRNA) signatures are expressed in the peripheral blood cells of SLE patients (6-8). IFN␣ and IFN␥ are known to induce SLE flares and druginduced lupus (9-11). In murine models of the disease, both IFN␣ and IFN␥ may be pathogenetically important (12-15), and, especially, a deficiency in either IFN␥ or the IFN␥ receptor (IFN␥R) totally abates the disease process (16)(17)(18)(19).IFNs act on a variety of cells, including lymphocytes and monocytes (20,21). The biologic effects of IFN␣ and IFN␥ are mediated via the phosphorylation, and thus the activation, of members of the STAT family

Objective. To determine the prevalence, clinical picture, and disease burden of arthritis in patients with hereditary hemochromatosis.Methods. In this cross-sectional observational study of 199 patients with hemochromatosis and iron overload, demographic and disease-specific variables, genotype, and organ involvement were recorded. The prevalence, intensity, and localization of joint pain were assessed, and a complete rheumatologic investigation was performed. Radiographs of the hands, knees, and ankles were scored for joint space narrowing, erosions, osteophytes, and chondrocalcinosis. In addition, the number and type of joint replacement surgeries were recorded.Results. Joint pain was reported by 72.4% of the patients. Their mean ؎ SD age at the time of the initial joint symptoms was 45.8 ؎ 13.2 years. If joint pain was present, it preceded the diagnosis of hemochromatosis by a mean ؎ SD of 9.0 ؎ 10.7 years. Bony enlargement was observed in 65.8% of the patients, whereas synovitis was less common (13.6%). Joint space narrowing and osteophytes as well as chondrocalcinosis of the wrist and knee joints were frequent radiographic features of hemochromatosis. Joint replacement surgery was common, with 32 patients (16.1%) undergoing total joint replacement surgery due to severe OA. The mean ؎ SD age of these patients was 58.3 ؎ 10.4 years at time of joint replacement surgery. Female sex, metacarpophalangeal joint involvement, and the presence of chondrocalcinosis were associated with a higher risk of early joint failure (i.e., the need for joint replacement surgery).Conclusion. Arthritis is a frequent, early, and severe symptom of hemochromatosis. Disease is not confined to involvement of the metacarpophalangeal joints and often leads to severe damage requiring the replacement of joints.