Limits...
Monogenic autoinflammatory syndromes: state of the art on genetic, clinical, and therapeutic issues.

Caso F, Rigante D, Vitale A, Lucherini OM, Costa L, Atteno M, Compagnone A, Caso P, Frediani B, Galeazzi M, Punzi L, Cantarini L - Int J Rheumatol (2013)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Padua, Padova, Italy.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Schematic sketch showing the main pathophysiologic mechanisms of the monogenic autoinflammatory syndromes. Familial Mediterranean fever (FMF), cryopyrin-associated periodic syndromes (CAPS), mevalonate kinase deficiency (MKD), and PAPA syndrome (PAPAs) are due to mutations on pyrin (mtPYRIN), cryopyrin (mtNLRP3), mevalonate kinase enzyme (mtMK), and PSTPIP1 (mtPSTPIP1) proteins, respectively, and are associated with enhanced procaspase-1 activation, leading to increased IL-1β processing and secretion. Mutations in TNF receptors (TNFRSF1A) are responsible for tumor necrosis factor receptor-associated periodic syndrome (TRAPS). Indeed, it is known that intracellular accumulation of mutated TNFRSF1A (mtTNFRSF1A) in the endoplasmic reticulum (ER) enhances inflammatory responses. This condition leads to the activation of ER-stress response and mitochondria (MT) release of reactive oxygen species (ROS), which in turn promotes upregulation of proinflammatory cytokines, including IL-1β, TNF-α, and IL-6. NLRP12-associated autoinflammatory disorder (NLRP12AD) and Blau syndrome (BS) are related to mutated NLRP12 protein (mtNLRP12) and mutated NOD2 protein (mtNOD2), respectively, and they bring about nuclear factor-κB (NF-κB) deregulation. Deficiency of the interleukin-1 (IL-1) receptor antagonist (DIRA) is due to mutations on the gene coding for IL-1 receptor antagonist (IL-1Ra), which lead to loss of IL-1β inhibition and unopposed inflammatory burst. TLR4: toll-like receptor-4; ASC: apoptosis-associated speck-like protein containing a caspase recruitment domain; TNF-α: tumor necrosis factor-alpha;   IL-1β: interleukin-1β; IL-1Ra: interleukin-1 receptor antagonist; IL-1RI: IL-1 receptor type I; mtIL-1Ra: mutated IL-1Ra; IL-6: interleukin-6.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3824558&req=5

fig1: Schematic sketch showing the main pathophysiologic mechanisms of the monogenic autoinflammatory syndromes. Familial Mediterranean fever (FMF), cryopyrin-associated periodic syndromes (CAPS), mevalonate kinase deficiency (MKD), and PAPA syndrome (PAPAs) are due to mutations on pyrin (mtPYRIN), cryopyrin (mtNLRP3), mevalonate kinase enzyme (mtMK), and PSTPIP1 (mtPSTPIP1) proteins, respectively, and are associated with enhanced procaspase-1 activation, leading to increased IL-1β processing and secretion. Mutations in TNF receptors (TNFRSF1A) are responsible for tumor necrosis factor receptor-associated periodic syndrome (TRAPS). Indeed, it is known that intracellular accumulation of mutated TNFRSF1A (mtTNFRSF1A) in the endoplasmic reticulum (ER) enhances inflammatory responses. This condition leads to the activation of ER-stress response and mitochondria (MT) release of reactive oxygen species (ROS), which in turn promotes upregulation of proinflammatory cytokines, including IL-1β, TNF-α, and IL-6. NLRP12-associated autoinflammatory disorder (NLRP12AD) and Blau syndrome (BS) are related to mutated NLRP12 protein (mtNLRP12) and mutated NOD2 protein (mtNOD2), respectively, and they bring about nuclear factor-κB (NF-κB) deregulation. Deficiency of the interleukin-1 (IL-1) receptor antagonist (DIRA) is due to mutations on the gene coding for IL-1 receptor antagonist (IL-1Ra), which lead to loss of IL-1β inhibition and unopposed inflammatory burst. TLR4: toll-like receptor-4; ASC: apoptosis-associated speck-like protein containing a caspase recruitment domain; TNF-α: tumor necrosis factor-alpha;   IL-1β: interleukin-1β; IL-1Ra: interleukin-1 receptor antagonist; IL-1RI: IL-1 receptor type I; mtIL-1Ra: mutated IL-1Ra; IL-6: interleukin-6.

Mentions: Thus, in conclusion, the elucidation of the molecular basis of MAISs has helped us recognize the consequences of excessive IL-1 signaling, proinflammatory isoprenoid production, or aberrant NK-κB activation (Figure 1). Future studies will hopefully also evaluate the clinical benefit of different highly selective biologicals for each of the MAISs: the availability of these new therapeutic options for patients who have previously failed to respond to conventional treatments (NSAIDS, corticosteroids, colchicines, or immunomodulating agents) and the promise of patient-centered treatment strategies are doubtlessly the start of a new era in the management of these rare complex disorders.


Monogenic autoinflammatory syndromes: state of the art on genetic, clinical, and therapeutic issues.

Caso F, Rigante D, Vitale A, Lucherini OM, Costa L, Atteno M, Compagnone A, Caso P, Frediani B, Galeazzi M, Punzi L, Cantarini L - Int J Rheumatol (2013)

Schematic sketch showing the main pathophysiologic mechanisms of the monogenic autoinflammatory syndromes. Familial Mediterranean fever (FMF), cryopyrin-associated periodic syndromes (CAPS), mevalonate kinase deficiency (MKD), and PAPA syndrome (PAPAs) are due to mutations on pyrin (mtPYRIN), cryopyrin (mtNLRP3), mevalonate kinase enzyme (mtMK), and PSTPIP1 (mtPSTPIP1) proteins, respectively, and are associated with enhanced procaspase-1 activation, leading to increased IL-1β processing and secretion. Mutations in TNF receptors (TNFRSF1A) are responsible for tumor necrosis factor receptor-associated periodic syndrome (TRAPS). Indeed, it is known that intracellular accumulation of mutated TNFRSF1A (mtTNFRSF1A) in the endoplasmic reticulum (ER) enhances inflammatory responses. This condition leads to the activation of ER-stress response and mitochondria (MT) release of reactive oxygen species (ROS), which in turn promotes upregulation of proinflammatory cytokines, including IL-1β, TNF-α, and IL-6. NLRP12-associated autoinflammatory disorder (NLRP12AD) and Blau syndrome (BS) are related to mutated NLRP12 protein (mtNLRP12) and mutated NOD2 protein (mtNOD2), respectively, and they bring about nuclear factor-κB (NF-κB) deregulation. Deficiency of the interleukin-1 (IL-1) receptor antagonist (DIRA) is due to mutations on the gene coding for IL-1 receptor antagonist (IL-1Ra), which lead to loss of IL-1β inhibition and unopposed inflammatory burst. TLR4: toll-like receptor-4; ASC: apoptosis-associated speck-like protein containing a caspase recruitment domain; TNF-α: tumor necrosis factor-alpha;   IL-1β: interleukin-1β; IL-1Ra: interleukin-1 receptor antagonist; IL-1RI: IL-1 receptor type I; mtIL-1Ra: mutated IL-1Ra; IL-6: interleukin-6.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3824558&req=5

fig1: Schematic sketch showing the main pathophysiologic mechanisms of the monogenic autoinflammatory syndromes. Familial Mediterranean fever (FMF), cryopyrin-associated periodic syndromes (CAPS), mevalonate kinase deficiency (MKD), and PAPA syndrome (PAPAs) are due to mutations on pyrin (mtPYRIN), cryopyrin (mtNLRP3), mevalonate kinase enzyme (mtMK), and PSTPIP1 (mtPSTPIP1) proteins, respectively, and are associated with enhanced procaspase-1 activation, leading to increased IL-1β processing and secretion. Mutations in TNF receptors (TNFRSF1A) are responsible for tumor necrosis factor receptor-associated periodic syndrome (TRAPS). Indeed, it is known that intracellular accumulation of mutated TNFRSF1A (mtTNFRSF1A) in the endoplasmic reticulum (ER) enhances inflammatory responses. This condition leads to the activation of ER-stress response and mitochondria (MT) release of reactive oxygen species (ROS), which in turn promotes upregulation of proinflammatory cytokines, including IL-1β, TNF-α, and IL-6. NLRP12-associated autoinflammatory disorder (NLRP12AD) and Blau syndrome (BS) are related to mutated NLRP12 protein (mtNLRP12) and mutated NOD2 protein (mtNOD2), respectively, and they bring about nuclear factor-κB (NF-κB) deregulation. Deficiency of the interleukin-1 (IL-1) receptor antagonist (DIRA) is due to mutations on the gene coding for IL-1 receptor antagonist (IL-1Ra), which lead to loss of IL-1β inhibition and unopposed inflammatory burst. TLR4: toll-like receptor-4; ASC: apoptosis-associated speck-like protein containing a caspase recruitment domain; TNF-α: tumor necrosis factor-alpha;   IL-1β: interleukin-1β; IL-1Ra: interleukin-1 receptor antagonist; IL-1RI: IL-1 receptor type I; mtIL-1Ra: mutated IL-1Ra; IL-6: interleukin-6.
Mentions: Thus, in conclusion, the elucidation of the molecular basis of MAISs has helped us recognize the consequences of excessive IL-1 signaling, proinflammatory isoprenoid production, or aberrant NK-κB activation (Figure 1). Future studies will hopefully also evaluate the clinical benefit of different highly selective biologicals for each of the MAISs: the availability of these new therapeutic options for patients who have previously failed to respond to conventional treatments (NSAIDS, corticosteroids, colchicines, or immunomodulating agents) and the promise of patient-centered treatment strategies are doubtlessly the start of a new era in the management of these rare complex disorders.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Padua, Padova, Italy.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus