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

BACKGROUND: Monogenic autoinflammatory diseases (AID) are caused by mutations in innate immune genes. The effects of these mutations on allergic inflammation are unknown. OBJECTIVES: We 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). METHODS: In 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. RESULTS: Clinical 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. CONCLUSIONS: CAPS 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.

Atypical B cells in chronic infectious diseases and systemic autoimmunity: puzzles with many missing pieces.

The world's struggle to contain the SARS-CoV-2 epidemic, primarily through vaccination, has highlighted the importance of better understanding the biology of B cells that participate in defense against infectious diseases, both acute and chronic. Here, we focus on a population of human B cells, termed atypical B cells (ABCs), that comprise a distinct B-cell lineage that differentiates from naive B cells in an interferon-γ-driven process, and are infrequent in healthy individuals but significantly expanded in chronic infectious diseases, including malaria, as well as in systemic autoimmune diseases such as systemic lupus erythematosus (SLE). Recent comparisons of ABCs by single-cell RNAseq provided evidence that ABCs in diverse chronic infectious diseases and in systemic autoimmune diseases are highly related and share common drivers of differentiation and expansion. However, ABCs in different diseases are not identical and also show discrete disease-specific features. Here, we compare and contrast key features of two ABC populations, namely those that are expanded in individuals living in malaria-endemic areas of the world versus those in SLE patients. This comparison is of interest as it appears that unique features of these two diseases result in participation of autoreactive ABCs in parasite-specific responses in malaria but in pathogenic autoimmune responses in SLE. A better understanding of the commonality and differences in the ABC responses in these two diseases may provide critical insights into the development of vaccines that drive pathogen-specific antibody responses and avoid autoimmunity.