== Increased expression of Hferritin in lymph node (LN) samples of adultonset Still’s disease (AOSD) patients. number of CD68+/Hferritin+cells in the same organs. Furthermore, a correlation among both the tissue Tianeptine Hferritin levels and the CD68+/Hferritin+cells and the clinical picture was noticed. Keywords: adultonset Still’s disease, Hferritin, hyperferritinaemic syndrome, macrophage == Intro == Adultonset Still’s disease (AOSD) is a rare systemic inflammatory disorder of unknown aetiology, characterized by quotidian high spiking fevers, arthritis and multiorgan involvement, requiring immunosuppressive therapies1, 2, 3. A large percentage of AOSD patients showed an evanescent salmonpink or erythematous maculopapular eruption which appears frequently during febrile attacks, and is found predominantly on the proximal limbs and trunk3, 4. Furthermore, both splenomegaly and mildsevere enlargement of cervical lymph nodes (LNs) are noticed frequently in AOSD patients and lymphoma should be always considered in the differential diagnosis of this clinical picture1, 2, 3, 4. Recently, it has been suggested that AOSD and other uncommon medical conditions such as macrophage activation syndrome (MAS), catastrophic antiphospholipid syndrome and septic shock, which share similar clinical and laboratory features, may be considered an intermediate phenotype of the same inflammatory process, affecting target cells killed by cytotoxic T cells and natural killer (NK) cells5. In this context the cytokine storm observed in these conditions, associated with hyperferritinaemia, may further trigger both NK and cytotoxic Tianeptine T cells with consequent release of uncontrolled granzyme system and perforin release, thus amplifying the cytokine storm and the production of proinflammatory cytokines6, 7. Ferritin is an intracellular iron storage protein including 24 subunits: weighty (H) subunits and light (L) subunits on the bases of their molecular weight8, 9. The H/Lsubunits ratio may change, depending on the specific tissue and the physiological status of the cell. In normal conditions, ferritin enriched in L subunits (Lferritin) continues Tianeptine to be found in the liver and in the spleen; on the contrary, the ferritin enriched in H subunits (Hferritin), may be noticed mainly in the heart and kidneys8, 9. Although the secretory pathway of serum ferritin has not been clarified fully, hepatocytes, macrophages ART4 and Kpffer cells may be involved in its secretion8, 9, 10, 11. For many years, ferritin continues to be considered as a potential immunosuppressant, inducing suppression of delayedtype hypersensitivity12, suppression of antibody production by B lymphocytes13, decreasing the phagocytosis by granulocytes14and regulating granulomonocytopoiesis. More recently, it has been suggested that Hferritin induces production from the antiinflammatory cytokine in lymphocytes15and may work as a negative regulator of the CXC chemokine receptor 4 (CXCR4), impairing the signalling leading to the activation of mitogenactivated protein kinase (MAPK), a kinase that is known to play an important role in cell proliferation, differentiation and migration16. Intriguingly, in recent years, a proinflammatory role of extracellular ferritin has been suggested for some specific cells, such as hepatic stellate cells17. Cells treated with ferritin trigger PI3 kinase phosphorylation, protein kinase C zeta activation and MAPK activation, culminating in nuclear factorkappa B (NFB) activation. This activation leads to the production of proinflammatory molecules, inducible nitric oxide synthase and others. Of note, this function is independent of the iron content of ferritin, suggesting that exogenous ferritin may play active roles independently of its main function17. In fact , ferritin synthesis may be regulated not only in response to iron availability, but also by different inflammatory cytokines such as interleukin (IL)1 and IL6, and by different Tianeptine biological stimuli such as oxidative stress, hypoxiaischaemia, hyperoxia and lipopolysaccharide (LPS) toxicity7, 9, 10, 11. Hferritin specifically binds a member from the T cell immunoglobulin and mucindomain (TIM) gene family, TIM27, which is.