Systematic evaluation of nine monogenic autoinflammatory diseases reveals common and disease-specific correlations with allergy-associated features

Abstract

BackgroundMonogenic autoinflammatory diseases (AID) are caused by mutations in innate immune genes. The effects of these mutations on allergic inflammation are unknown.ObjectivesWe investigated allergic, immunological and clinical phenotypes in FMF (familial Mediterranean fever), CAPS (cryopyrin-associated periodic syndrome), TRAPS (tumour necrosis factor receptor-associated periodic syndrome), HIDS (hyper-IgD syndrome), PAPA (pyogenic arthritis, pyoderma gangrenosum and acne), DADA2 (deficiency of adenosine deaminase 2), HA20 (haploinsufficiency of A20), CANDLE (chronic atypical neutrophilic dermatosis, lipodystrophy, elevated temperature) and SAVI (STING-associated vasculopathy of infancy).MethodsIn this cross-sectional study, clinical data were assessed in 425 patients with AID using questionnaires and chart reviews. Comparator data were obtained from public databases. Peripheral blood mononuclear cells obtained from 55 patients were stimulated and CD4+ cytokine production assessed.ResultsClinical laboratory features of Type 2 immunity were elevated in CAPS but reduced in most AID, particularly DADA2. Physician-diagnosed allergic diseases were prevalent in multiple AID, including CAPS and DADA2. T helper 2 (Th2) cells were expanded in CAPS, TRAPS and HIDS; Th9 cells were expanded in HA20.ConclusionsCAPS is characterised by an enhanced Type 2 signature, whereas FMF and CANDLE are associated with reduced Type 2 responses. DADA2 is associated with reduced Type 2 responses but a high rate of physician-diagnosed allergy. Therefore, NLRP3-driven autoinflammation may promote Type 2 immunity, whereas AID like DADA2 may manifest clinical phenotypes that masquerade as allergic disorders. Further investigations are needed to determine the contribution of autoinflammation to allergic clinical and immunological phenotypes, to improve the treatment of patients with AID.

The Interactions Between Autoinflammation and Type 2 Immunity: From Mechanistic Studies to Epidemiologic Associations

“…Several studies have suggested that FMF protected against asthma and atopy, potentially due to protective linkage of MEFV with asthma associated genes like IL4RA (199)(200)(201). Although one study suggested that Turkish FMF patients may have elevated total serum IgE relative to healthy volunteers, this result was not seen in other cohorts, where there was a trend towards reduced serum IgE (199,201,202). Taken together, these results suggest that activation of the pyrin inflammasome attenuates human type 2 immune responses.…”

“…One way to investigate the interaction between autoinflammatory pathways and type 2 immunity is to investigate the prevalence of allergic clinical and immunological phenotypes in subjects with monogenic autoinflammatory diseases ( Table 1 ). Because single gene mutations promote activation of discrete innate pathways, this approach can assess the in vivo roles of dysregulated autoinflammatory pathways in regulating human type 2 immune responses ( 199 ). This question has been most extensively studied in FMF, perhaps because it was the first autoinflammatory disease to be linked to a causative gene ( 16 ) ( Table 1 ).…”

“…This question has been most extensively studied in FMF, perhaps because it was the first autoinflammatory disease to be linked to a causative gene ( 16 ) ( Table 1 ). Several studies have suggested that FMF protected against asthma and atopy, potentially due to protective linkage of MEFV with asthma associated genes like IL4RA ( 199 – 201 ). Although one study suggested that Turkish FMF patients may have elevated total serum IgE relative to healthy volunteers, this result was not seen in other cohorts, where there was a trend towards reduced serum IgE ( 199 , 201 , 202 ).…”

“…By contrast, the autoinflammatory disease CAPS, caused by NLRP3 mutations, is associated with peripheral eosinophilia and eosinophilic skin infiltration ( 199 , 203 ) ( Table 1 ). Eosinophilia correlates with CAPS disease activity, suggesting that NLRP3 activation promotes eosinophilia ( 199 ).…”

Allergic Aspects of IgG4-Related Disease: Implications for Pathogenesis and Therapy

“…Indeed, non-type 2 factors such as IgG1 immunocomplexes and complement activation system have also a role in both allergy and IgG4-RD ( 113 – 115 ) ( Table 1 ). For example, asthma and chronic rhinitis can be caused by neutrophil- driven inflammation ( 116 , 117 ), which may underlie the high prevalence of rhinosinusitis in patients with certain autoinflammatory diseases ( 118 , 119 ). Another example is the association of inflammasome activation with eczema ( 120 ).…”