Monogenic autoinflammatory diseases: disorders of amplified danger sensing and cytokine dysregulation

Abstract

The pathogenesis of monogenic autoinflammatory diseases converges on the presence of exaggerated immune responses that are triggered through activation of altered pattern recognition receptor (PRR) pathways and result in cytokine/chemokine amplification loops and the inflammatory clinical phenotype seen in autoinflammatory patients. The PRR response can be triggered by accumulation of metabolites, by mutations in sensors leading to their constitutive overactivation, or by mutations in mediator cytokine pathways that lead to amplification and/or inability to downregulate an inflammatory response in hematopoietic and/or nonhematopoietic cells. The study of the pathogenesis of sterile inflammation in patients with autoinflammatory syndromes continues to uncover novel inflammatory pathways.

Keywords: Autoinflammatory diseases; Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE); Cryopyrin-associated periodic syndrome (CAPS); Deficiency of the IL-1 receptor antagonist (DIRA); Inflammasome; Intracellular pattern recognition receptors (PRR); Neonatal-onset multisystem inflammatory disease (NOMID); Proteasome-associated autoinflammatory syndrome (PRAAS).

Figure 1. Components of an inflammatory response

An immune response is triggered by exogenous or endogenous triggers that are sensed by a molecular sensor, a pattern recognition receptor (PRR) that can be located on the cell surface or in the cytoplasm. A triggering event is linked to the activation of mediators that lead to the stimulation and secretion of cytokines and chemokines which lead to the recruitment of immune cells into the tissue and the coordination of an immune response. The immune response is often tissue specific and may explain the difference in organ manifestations in autoinflammatory diseases. Some mutations that lead to cytokine dysregulation also influence cell growth and differentiation and/or cell death often in a cell specific manner

Figure 2. Proposed mechanisms of activation of proinflammatory signaling pathways in autoinflammatory diseases

A. Cryopyrinopathies (CAPS). Unlike wild-type NLRP3, mutated NLRP3 (which causes CAPS) is constitutively activated and thought to oligomerize and bind to adapter molecules apoptotic speck protein (ASC) and CARDINAL to form an active catalytic complex with two pro–caspase-1 molecules. Via autocatalysis, this complex generates active caspase-1, which cleaves inactive pro–interleukin(IL)-1β into its active form, IL-1β. B. Familial Mediterranean fever (FMF). (b.1). Wild-type pyrin can inhibit inflammasome activation by direct binding to caspase-1. Mutated pyrin cannot exert its inhibitory effect on the inflammasome, leading to unopposed inflammasome activation. (b.2) Wild-type pyrin can also interact directly with ASC forming the “pyrin inflammasome”, which is activated in the presence of FMF-causing mutations. C. Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS). TNFR1 molecules are transported from endoplasmic reticulum (ER) to the Golgi and then to the cell surface. Wild type TNFR1 complexes are bound to extracellular TNF, leading to NF-κB activation. Receptor cleavage from the cell surface abrogates receptor signaling and the soluble receptor can buffer soluble TNF. Mutated TNFR1 (which causes TRAPS) is misfolded and cannot be transported to the cell surface. Misfolded TNFR1 is sequestered in the ER, where it may lead to abnormal signaling through increased mitochondrial reactive oxygen species (ROS) production. D. Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS). Mevalonate kinase, a critical enzyme in the biosynthesis of sterol and non-sterol isoprenoids, catalyzes the conversion of mevalonate to mevalonate phosphate. In HIDS, activity of this enzyme is reduced, resulting in a decreased concentration of mevalonate phosphate, geranylgeranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP), leading to decreased activity of geranylgeranyltransferase and impaired geranylgeranylation of a number of proteins. Through an unknown mechanism, the reduced geranylgeranylation would lead to an increased pro-caspase-1 activation and consequent caspase-1 activation with resulting overproduction of IL-1 β. E. Deficiency of the interleukin-1 receptor antagonist (DIRA). Deficiency of IL-1Ra leads to unopposed IL-1α and IL-1β signaling. F. Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE). Proteasomes are an ATP dependent protein degradation system that targets intracellular polyubiquitinated proteins derived from self structures or foreign structures for proteolytic destruction. Patients who are homozygous for PSMB8 mutations show various assembly defects, with impaired proteolytic activity which is proposed to lead to an increase in, i.e polyubliquitylation of defective ribosomal products (DRiPs) which might umulate in tissues from these patients and induce an increased inflammatory response. Serum cytokine analysis in CANDLE and gene expression profiling identified the IFN signaling pathway as the most differentially regulated cytokine pathway. G. CARD14 mediated psoriasis (CAMPS). Mutated CARD14 protein is mainly expressed in keratinocytes and leads to NF-κB activation and increased chemokine production. H. Deficiency of the interleukin-36 receptor antagonist (DITRA). Deficiency of IL-36Ra in the keratinocyte leads to unopposed IL-36 signaling. I. Pyogenic sterile arthritis, pyoderma gangrenosum and acne (PAPA). Wild-type PSTPIP1, a regulatory molecule of the NLRP3 inflammasome, binds to pyrin. Mutated PSTPIP1 is proposed to not dissociate from its binding to pyrin, leading to uninhibited inflammasome and “pyrin inflammasome” activities. ASC (apoptotic speck protein); BCL10 (B-cell lymphoma/leukemia 10); CARD14 (caspase recruitment domain-containing protein 14); DAMPs (damage associated molecular patterns); IFN (interferon); IL-1β (interleukin-1β); IL-1 α/β (interleukin-1α/β); IL-1Ra (interleukin-1 receptor antagonist); IL-6 (interleukin-6); IL-36 (interleukin-36); IL36Ra (interleukin-36 receptor antagonist); IFNγ- inducible protein 10 (IP-10); JAK1 (Janus kinase 1); JAK2 (Janus kinase 2); MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1); MAPK (mitogen-activated protein kinase); PAMPs (pathogen associated molecular patterns)p-JNK (phosphorylated-JNK); ROS (reactive oxygen species); STAT1 (signal transducer and activator of transcription 1); TNFR (tumor necrosis factor receptor); TNF (tumor necrosis factor); TYK2 (tyrosine kinase 2).

Figure 3

A. Urticarial rash in a patient with CAPS - Muckle-Wells syndrome B. Severe hydrocephalus and cerebral atrophy in neonatal-onset multisystem inflammatory disease (NOMID) C. Papilledema in NOMID D. Patellar overgrowth in NOMID E. Knee MRI showing cartilaginous proliferation and widening of the growth plate of the distal femur in a patient with CAPS-NOMID F. Pustulosis in deficiency of the interleukin-1 receptor antagonist (DIRA) G. Metaphyseal osteolytic lesions in distal and proximal tibia in a very young DIRA patient, periosteal elevation is also seen H. Bony overgrowth in a DIRA patient (rare) I. Widening of multiple ribs (asterisk) and clavicles (arrows) in DIRA osteomyelitis J. Chest deformities in DIRA K. Block vertebral formation following osteolytic vertebral lesions in DIRA L. Enhancement in the right post-central and pre-central gyrus in a patient with vasculitis in DIRA M. Generalized psoriasis in CARD14 mediated psoriasis (CAMPS) N. Anterior synechiae and cataract with chronic uveitis in a patient with Blau syndrome O. Sagittal image of a fat suppressed T2 weighted sequence showing synovial thickening and enhancement with moderate fluid in the right elbow joint in pyogenic arthritis P. Extensive pyoderma gangrenosum lesion in a patient with pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome. Q. Finger swelling in chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures (CANDLE) R. Erythematous annular and nodular rash in CANDLE syndrome S. Characteristic facial lipodystrophy (red arrows) in CANDLE syndrome T. Basal ganglia calcifications in CANDLE syndrome U. Myositis in CANDLE syndrome