Abstract A host of clinical scenarios can be depicted in hereditary autoinflammatory diseases, and the cardiovascular system can also be involved especially in familial Mediterranean fever (FMF), ...caused by mutations in the MEFV gene, and tumour necrosis factor receptor-associated periodic syndrome (TRAPS), caused by mutations in the TNFRSF1A gene. Pericardial diseases are the most represented cardiovascular abnormalities, though the role of MEFV and TNFRSF1A in the initiation of heart involvement has not been demonstrated formally and will be discussed herein.
Monogenic autoinflammatory syndromes (MAISs) are caused by innate immune system dysregulation leading to aberrant inflammasome activation and episodes of fever and involvement of skin, serous ...membranes, eyes, joints, gastrointestinal tract, and nervous system, predominantly with a childhood onset. To date, there are twelve known MAISs: familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, familial cold urticaria syndrome, Muckle-Wells syndrome, CINCA syndrome, mevalonate kinase deficiency, NLRP12-associated autoinflammatory disorder, Blau syndrome, early-onset sarcoidosis, PAPA syndrome, Majeed syndrome, and deficiency of the interleukin-1 receptor antagonist. Each of these conditions may manifest itself with more or less severe inflammatory symptoms of variable duration and frequency, associated with findings of increased inflammatory parameters in laboratory investigation. The purpose of this paper is to describe the main genetic, clinical, and therapeutic aspects of MAISs and their most recent classification with the ultimate goal of increasing awareness of autoinflammation among various internal medicine specialists.
The innate immune system is involved in the pathophysiology of systemic autoinflammatory diseases (SAIDs), an enlarging group of disorders caused by dysregulated production of proinflammatory ...cytokines, such as interleukin-1β and tumor necrosis factor-α, in which autoreactive T-lymphocytes and autoantibodies are indeed absent. A widely deranged innate immunity leads to overactivity of proinflammatory cytokines and subsequent multisite inflammatory symptoms depicting various conditions, such as hereditary periodic fevers, granulomatous disorders, and pyogenic diseases, collectively described in this review. Further research should enhance our understanding of the genetics behind SAIDs, unearth triggers of inflammatory attacks, and result in improvement for their diagnosis and treatment.
Hereditary autoinflammatory disorders encompass manifold dysfunctions of innate immunity caused by mutations in genes coding for the main characters of the inflammatory scene: most of these ...conditions have an early onset, ranging from the first days of life to the first decades, and include hereditary periodic fevers, NLRP-related diseases, granulomatous and pyogenic syndromes, which are basically characterized by upturned inflammasome activity and overproduction of bioactive interleukin (IL)-1β and other proinflammatory cytokines. The discovery of a causative link between autoinflammation and IL-1β release has improved our understanding of the intimate mechanisms of innate immunity, and has likewise led to the identification of extraordinary treatments for many of these disorders.
Abstract Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is an autosomal dominant autoinflammatory disorder characterized by periodic fever episodes, arthralgia, myalgia, ...abdominal pain, serositis, and skin rash. TRAPS is caused by mutations in the gene encoding the TNF Receptor Super Family 1A (TNFRSF1A) on chromosome 12p13. The identification of TNFRSF1A mutations as the genetic cause of TRAPS coincided with the wider use of biological agents in medicine and raised the possibility that blocking TNF could potentially represent the primary therapeutic goal in TRAPS, thus disclosing new treatment choices for this complex disease. Anti-TNF therapy in TRAPS has been based on etanercept, a recombinant human TNFR (p75)-Fc fusion protein comprising two receptors linked by an IgG1 Fc fragment. However a decrease in responsiveness to etanercept over time has been described, and it may be due to a non-specific action of etanercept in TRAPS; its efficacy may reflect ‘generic’ anti-inflammatory properties. Long-term adherence to etanercept is poor and a significant number of patients need to switch to anti-interleukin (IL)-1β therapy. In fact, the IL-1 receptor antagonist anakinra has recently been shown to prevent disease relapses both in the short- and in the long-term, and to induce a prompt and stable disease remission.
T cell activation requires sustained signaling at the immune synapse, a specialized interface with the antigen-presenting cell (APC) that assembles following T cell antigen receptor (TCR) engagement ...by major histocompatibility complex (MHC)-bound peptide. Central to sustained signaling is the continuous recruitment of TCRs to the immune synapse. These TCRs are partly mobilized from an endosomal pool by polarized recycling. We have identified IFT20, a component of the intraflagellar transport (IFT) system that controls ciliogenesis, as a central regulator of TCR recycling to the immune synapse. Here, we have investigated the interplay of IFT20 with the Rab GTPase network that controls recycling. We found that IFT20 forms a complex with Rab5 and the TCR on early endosomes. IFT20 knockdown (IFT20KD) resulted in a block in the recycling pathway, leading to a build-up of recycling TCRs in Rab5(+) endosomes. Recycling of the transferrin receptor (TfR), but not of CXCR4, was disrupted by IFT20 deficiency. The IFT components IFT52 and IFT57 were found to act together with IFT20 to regulate TCR and TfR recycling. The results provide novel insights into the mechanisms that control TCR recycling and immune synapse assembly, and underscore the trafficking-related function of the IFT system beyond ciliogenesis.
Abstract The pathogenesis of recurrent pericarditis is still poorly understood and may be related either to viral infections or autoimmune and autoinflammatory disorders. The immune system plays a ...major role in the pathogenesis of the disease, modulating individual responses to different noxa and explaining the variable reported recurrence rate (ranging from 20% to 50% of patients) following an attack of acute or recurrent pericarditis. Increasing interest is currently being devoted to autoinflammatory disorders, a group of conditions characterized by spontaneously relapsing and remitting bouts of systemic inflammation without apparent involvement of antigen-specific T cells or significant production of auto-antibodies. Ongoing basic and clinical research is needed to provide further evidence for the understanding of this common and troublesome disease, and to develop targeted and more efficacious therapies.
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