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Review
. 2019 Jan 31;10:101.
doi: 10.3389/fimmu.2019.00101. eCollection 2019.

Biochemistry of Autoinflammatory Diseases: Catalyzing Monogenic Disease

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Free PMC article
Review

Biochemistry of Autoinflammatory Diseases: Catalyzing Monogenic Disease

David B Beck et al. Front Immunol. .
Free PMC article

Abstract

Monogenic autoinflammatory disorders are a group of conditions defined by systemic or localized inflammation without identifiable causes, such as infection. In contrast to classical primary immunodeficiencies that manifest with impaired immune responses, these disorders are due to defects in genes that regulate innate immunity leading to constitutive activation of pro-inflammatory signaling. Through studying patients with rare autoinflammatory conditions, novel mechanisms of inflammation have been identified that bare on our understanding not only of basic signaling in inflammatory cells, but also of the pathogenesis of more common inflammatory diseases and have guided treatment modalities. Autoinflammation has further been implicated as an important component of cardiovascular, neurodegenerative, and metabolic syndromes. In this review, we will focus on a subset of inherited enzymatic deficiencies that lead to constitutive inflammation, and how these rare diseases have provided insights into diverse areas of cell biology not restricted to immune cells. In this way, Mendelian disorders of the innate immune system, and in particular loss of catalytic activity of enzymes in distinct pathways, have expanded our understanding of the interplay between many seemingly disparate cellular processes. We also explore the overlap between autoinflammation, autoimmunity, and immunodeficiency, which has been increasingly recognized in patients with dysregulated immune responses.

Keywords: autoinflammation; enzyme deficiency; innate immunity; metabolic sensors; mutations; protein homeostasis; ubiquitination.

Figures

Figure 1
Figure 1
Autoinflammatory diseases due to dysregulation in proteostasis. SIFD (A) and CANDLE (B) syndromes.
Figure 2
Figure 2
Autoinflammatory diseases due to dysregulation in lipid-mediated signaling. LPIN2 (A), PLAID (B), and APLIAD (C) syndromes.
Figure 3
Figure 3
Autoinflammatory diseases due to impaired metabolic sensors. LACC1 (A) and MVK (B) syndromes.
Figure 4
Figure 4
Autoinflammatory diseases due to dysregulation in post-translational modification. HA20 (A), Otulipenia (B), and RIPK1 deficiency (C) syndromes.
Figure 5
Figure 5
Autoinflammatory diseases due to dysregulation in purine metabolism. DADA2.
Figure 6
Figure 6
Overlapping and unique features of autoinflammatory diseases. Outer pentagon shows pathways altered in autoinflammatory disease, central pentagon highlights genes in the corresponding node found mutated in monogenic disease (dark blue), and inner pentagon showing shared clinical features and treatment (light blue).

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