Autoinflammatory diseases are a group of clinical syndromes characterized by constitutive overactivation of innate immune pathways. This results in increased production of or responses to monocyte- and neutrophil-derived cytokines such as interleukin-1β (IL-1β), Tumor Necrosis Factor-α (TNF-α), and Type 1 interferon (IFN). By contrast, clinical allergy is caused by dysregulated type 2 immunity, which is characterized by expansion of T helper 2 (Th2) cells and eosinophils, as well as overproduction of the associated cytokines IL-4, IL-5, IL-9, and IL-13. Traditionally, type 2 immune cells and autoinflammatory effectors were thought to counter-regulate each other. However, an expanding body of evidence suggests that, in some contexts, autoinflammatory pathways and cytokines may potentiate type 2 immune responses. Conversely, type 2 immune cells and cytokines can regulate autoinflammatory responses in complex and context-dependent manners. Here, we introduce the concepts of autoinflammation and type 2 immunity. We proceed to review the mechanisms by which autoinflammatory and type 2 immune responses can modulate each other. Finally, we discuss the epidemiology of type 2 immunity and clinical allergy in several monogenic and complex autoinflammatory diseases. In the future, these interactions between type 2 immunity and autoinflammation may help to expand the spectrum of autoinflammation and to guide the management of patients with various autoinflammatory and allergic diseases.

Background and ObjectivesPsoriasis is a heterogeneous inflammatory disease that involves the skin, joints, liver, heart, and other organs. Psoriatic arthritis (PsA) is associated with cardiovascular disease (CVD), but the relative contributions of inflammatory and metabolic dysregulation to CVD are incompletely understood. We set out to discover novel potential contributors to CVD in PsA patients by comprehensively phenotyping a cohort of PsA patients using these advanced technologies.MethodsIn this cross-sectional analysis of a cohort study, we investigated associations of systemic inflammation and metabolic dysregulation with Coronary CT angiography (CCTA)-proven coronary artery disease (CAD) in 39 subjects with PsA. We measured traditional CVD risk factors [blood pressure, Body Mass Index (BMI), diabetes, age, sex, smoking], serum markers of systemic inflammation (hsCRP, GlycA) and metabolic dysfunction (cholesterol efflux capacity), and inflammatory cytokines (IL-1β, IL-6, IL-12/IL-23, IL-17A, TNF-α, IFN-γ). We also incorporated radiographic measures of metabolic dysfunction (visceral and subcutaneous adipose volume) and tissue-specific inflammation (positron emission tomography-computed tomography, PET-CT). To quantify relative contributions of FDG (fluorodeoxyglucose) uptake and adiposity to coronary plaque, we performed multiple linear regression, controlling for Framingham risk score (FRS) and FRS + visceral adiposity.ResultsCompared with non-psoriatic volunteers, subjects with PsA had elevated markers of metabolic and inflammatory disease, which was more pronounced in subjects with moderate-to-severe skin disease. This included visceral (p = 0.005) and subcutaneous (p = 0.004) adiposity, BMI (p = 0.001), hemoglobin A1C (p = 0.037), high sensitivity C-reactive protein (p = 0.005), IL-6 (p = 0.003), IFN-γ (p = 0.006), and liver FDG uptake (p = 0.03). In subjects with PsA, visceral adiposity correlated significantly with subclinical CAD (standardized β = 0.681, p = 0.002), as did FDG uptake in bone marrow (standardized β = 0.488, p = 0.008), liver (standardized β = 0.619, p < 0.001), spleen (standardized β = 0.523, p = 0.004), and subcutaneous adipose (standardized β = 0.524, p = 0.003).InterpretationTogether, these findings reveal inflammatory and metabolic potential contributors to subclinical CAD in PsA, including adipose inflammation, and suggesting novel targets for CVD prevention and treatment in PsA.

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