Genetics, Pathophysiology, and Treatment of Dominant Autoinflammatory Diseases

National Human Genome Research Institute

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Abstract

During the current reporting period we focused on three areas of investigation: 1) Studies of pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome For the last two decades, we have followed a cohort of patients with pyogenic arthritis, pyoderma gangrenosum, and acne in our clinic. Most of these patients have mutations in the PSTPIP1 gene, which encodes a protein known to bind to pyrin, the protein mutated in familial Mediterranean fever (FMF). However, about one third of these patients have no demonstrable PSTPIP1 mutations. PSTPIP1 mutation-positive patients' clinical findings overlapped with mutation-negative PAPA-like patients, but mutation-positive patients had earlier onset and more arthritis. In collaboration with Scott Canna at the Childrens Hospital of Philadelphia, we found uniform elevation of total serum IL-18 in treated PAPA patients at levels nearly as high as NLRC4-associated autoinflammation with infantile enterocolitis (AIFEC) patients and well above levels in most FMF patients. IL-18 elevation in PAPA patients' serum persisted despite fluctuations in disease activity. The soluble IL-18 antagonist IL-18BP was modestly elevated, and PAPA patients had detectable free IL-18. PAPA syndrome was rarely associated with elevation of CXCL9, an indicator of interferon-gamma activity, but no PAPA patients had histories of macrophage activation syndrome. These findings suggest a link between pyrin inflammasome activation, IL-18, and autoinflammation without susceptibility to macrophage activation syndrome. This work is in press in Arthritis and Rheumatology. 2) A collaborative study of allergy-associated features in autoinflammatory disease Dr. Daniella Schwartz, an Assistant Clinical Investigator in the NIAID, collaborated with our group to study allergic manifestations in autoinflammatory disease. Dr. Schwartz studied 425 patients with autoinflammatory disease with questionnaires and chart reviews. These included patients with FMF, cryopyrin-associated periodic syndrome (CAPS), TNF receptor-associated periodic syndrome (TRAPS), hyper-IgD syndrome (HIDS), PAPA syndrome, deficiency of ADA2 (DADA2), haploinsufficiency of A20 (HA20), chronic atypical neutrophilic dermatosis, lipodystrophy, and elevated temperature (CANDLE), and STING-associated vasculopathy of infancy (SAVI). Peripheral blood mononuclear cells from 55 patients were stimulated and CD4 cytokine production assessed. In particular, T helper type 2 responses, which are typical of allergic inflammation, were assessed. FMF and CANDLE were associated with reduced T helper Type 2 responses and a low prevalence of clinical allergy. CAPS is associated with eosinophilia, clinical allergy, and Th2 expansion. Several autoinflammatory diseases, including DADA2, are associated with reduced Th2 responses but a high prevalence of physician-diagnosed allergy, suggesting that autoinflammation can masquerade as allergic disease. The data indicate that physicians should consider Type 2 immunity as a factor in CAPS but should be cautious in attributing allergic symptoms in other autoinflammatory diseases to type 2 immune activation, as these features could be due to untreated autoinflammation. Understanding how innate immune genes modulate allergic phenotypes will provide new insights into the role of innate immunity in allergy-associated diseases and may identify novel targets in patients refractory to treatments targeting type 2 immunomodulators. This work is in press in the Annals of the Rheumatic Diseases. 3) A collaborative study examining signaling in the mechanoactivation of human mast cells through mutant ADGRE2 In an earlier reporting period, we discovered a dominantly inherited p.C492Y mutation in the G-protein coupled receptor ADGRE2 (EMR2) in patients with familial vibratory urticaria. In these patients, friction of the skin induces mast cell hyper-degranulation through p.C492Y-ADGRE2, causing localized hives, flushing, and hypotension. ADGRE2 is expressed in neutrophils, monocytes, and mast cells. In this collaborative study, Drs. Andrea Naranjo, Dean Metcalfe, and Anna Olivera examined the intracellular signals elicited by mechanical activation in human mast cells expressing p.C492Y-ADGRE2 and attached to dermatan sulfate, a ligand for ADGRE2. They found that the presence of mutant ADGRE2 reduced the threshold to activation and increased the extent of degranulation along with the percentage of mast cells responding. Vibration caused phospholipase C activation, transient increases in cytosolic calcium, and downstream activation of phosphoinositide 3-kinase and extracellular signal-regulated kinases 1 and 2. Degranulation induced by vibration was dependent on phospholipase C pathways, including calcium, protein kinase C, and phosphoinositide 3-kinase but not extracellular signal-related kinases 1/2 pathways, along with pertussis toxin-sensitive signals. In addition, mechanoactivation of mast cells stimulated the synthesis and release of prostaglandin D2, a previously unreported mediator in vibratory urticaria, and extracellular signal-related kinases 1/2 activation was required for this response together with calcium, protein kinase C, and to some extent phosphoinositide 3-kinase. These studies thus identified critical molecular events initiated by mechanical forces and potential therapeutic targets for patients with vibratory urticaria. This work was published in November in the Journal of Investigative Dermatology.