The differences between patients from the Turkish and US cohorts may be due to epigenetic or environmental factors. In addition, the Eurofever FMF criteria may perform better in certain areas, if the weight of ethnic origin parameter or cutoff values were modified.
Hemophagocytic Lymphohistiocytosis (HLH) and Macrophage Activation Syndrome (MAS) are life-threatening hyperinflammatory syndromes typically associated with underlying hematologic and rheumatic diseases, respectively. Familial HLH is associated with genetic cytotoxic impairment, and thereby to excessive antigen presentation. Extreme elevation of serum Interleukin (IL)-18 has been observed specifically in patients with MAS, making it a promising therapeutic target, but how IL-18 promotes hyperinflammation remains unknown. In an adjuvant-induced MAS model, excess IL-18 promoted immunopathology whereas perforin-deficiency had no effect. To determine the effects of excess IL-18 on virus-induced immunopathology, we infected Il18-transgenic (Il18tg) mice with Lymphocytic Choriomeningitis Virus (LCMV, Armstrong). LCMV infection is self-limited in wild-type (WT) mice, but Prf1-/- mice develop prolonged viremia and fatal HLH. LCMV-infected Il18-transgenic (Il18tg) mice developed cachexia and hyperinflammation comparable to Prf1-/- mice, albeit with minimal mortality. Like Prf1-/- mice, immunopathology was largely rescued by CD8 depletion or Interferon-gamma (IFNg) blockade. Unlike Prf1-/- mice, they showed normal target cell killing and normal clearance of viral RNA and antigens. Rather than impairing cytotoxicity, excess IL-18 acted on T lymphocytes to amplify their inflammatory responses. Surprisingly, combined perforin-deficiency and transgenic IL-18 production caused spontaneous hyperinflammation specifically characterized by CD8 T-cell expansion and improved by IFNg blockade. Even Il18tg;Prf1-haplosufficient mice demonstrated hyperinflammatory features. Thus, excess IL-18 promotes hyperinflammation via an autoinflammatory mechanism distinct from, and synergistic with, cytotoxic impairment. These data establish IL-18 as a potent, independent, and modifiable driver of life-threatening innate and adaptive hyperinflammation, and support the rationale for an IL-18-driven subclass of hyperinflammation.
Autoinflammatory diseases have emerged as a group of disorders that have significant morbidity, and even mortality. Since their onset predominately occurs during childhood, it is important that paediatricians are aware of what these diseases are, how they present, when to include them in differential diagnoses, and when to refer to a specialist. This review will focus on the clinical indicators suggestive of autoinflammatory disease, how the presence of an autoinflammatory disease may influence routine care, indications for immediate referral, and both their acute and chronic complications.
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