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Review
, 37 (4), 387-94

New Monogenic Autoinflammatory Diseases--A Clinical Overview

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Review

New Monogenic Autoinflammatory Diseases--A Clinical Overview

Scott W Canna et al. Semin Immunopathol.

Abstract

Translating pathogenic insights gained from monogenic defects that cause autoinflammatory diseases into novel therapies has dramatically improved the lives of patients with these syndromes. The last 15 years have focused on the central role of IL-1 in driving autoinflammatory phenotypes and on therapies blocking IL-1 signaling. Recent discoveries from patients unresponsive to IL-1 blockade have highlighted other key inflammatory mediators and pathways. New genetic discoveries have confirmed unifying mechanisms of autoinflammation, including dysregulation of danger sensing, cell stress, and immune-receptor signaling. Recent gene discovery in novel diseases has demonstrated new concepts. First, several complex clinical syndromes, caused by mutations leading to chronic type I interferon (IFN) production present with organ manifestations different from IL-1 mediated diseases including cerebral calcifications, myositis, and interstitial lung disease and the frequent occurrence of autoantibodies. These disorders introduce type I IFN's as inflammatory mediators that cause autoinflammatory phenotypes. Second, conditions associated with high IL-18 production may provide a direct link between autoinflammation and macrophage activation syndrome. Third, dysregulation of inflammatory and cell differentiation pathways in nonhematopoietic cells, such as aberrant calcium signaling and impaired endothelial or keratinocyte development, provide an understanding of organ specificity in autoinflammatory disorders. Many of these discoveries highlight the intricate interconnections between autoinflammation, autoimmunity, immunodeficiency, and lymphoproliferation and suggest ways in which we may better diagnose and treat autoinflammatory diseases.

Conflict of interest statement

Conflict of interest None.

Figures

Fig. 1
Fig. 1. Mechanisms to macrophage activation syndrome
loss-of-function mutations that impair perforin/granzyme-mediated cytotoxicity lead to FHL. FHL patients are well until infected dendritic cells presenting viral antigens and expressing Th1-cytokines cannot be killed by NK and cytotoxic T cells. This unchecked dendritic cell activity causes massive lymphocyte proliferation, interferon gamma secretion, and systemic macrophage activation. Cytotoxicity may also be important for limiting macrophage activation directly. In MAS, primary defects in macrophages or dendritic cells may promote the phenotype by several mechanisms: Spontaneous inflammasome activity or XIAP-deficiency may activate macrophages directly, while chronic IL-18 over-secretion may prime for exaggerated lymphocyte responses and/or impair cytotoxicity (as in FHL). Caused by loss-of-function mutations in PRF1, UNC13D, STX11, and STXBP2 (asterisk). FHL familial hemophagocytic lymphohistiocytosis, DC dendritic cell, MAS macrophage activation syndrome, sJIA systemic juvenile idiopathic arthritis, DAMPs damage associated molecular patterns
Fig. 2
Fig. 2. Schematic of pathogenesis of four novel autoinflammatory diseases
In CARD14-mediated psoriasis (CAMPS), excessive CARD14 activity promotes NF-kB signaling in keratinocytes, which release inflammatory and chemotactic molecules (a). Neutrophils and IL-17 and 23-secreting lymphocytes recruited to the area induce psoriasiform rash. In PLCy2-associated antibody deficiency and immune dysregulation (PLAID), abnormal activity of PLCy2 promotes increased basal and stimulated intracellular calcium, which apparently impairs B cell responses but promotes excessive mast cell degranulation (b). In deficiency of ADA2 (DADA2), the absence of adenosine deaminase 2 in immune cells promotes inflammatory macrophage differentiation (c). This inflammation, as well as a potential extrinsic defect in endothelial cell development, results in widespread vasculitis most critically affecting CNS vessels. Photo reproduced from reference 40. Sideroblastic anemia, immunodeficiency, fevers, developmental delay (SIFD) is a complex fever syndrome with disrupted erythroid and B cell development, innate immune activation, and CNS disease all caused by impairment of (largely) mitochondrial protein synthesis and resultant cellular stress (d). ER endoplasmic reticulum, IgG immunoglobulin gamma, CNS central nervous system

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