Yongqing Chen

Recombinant human acid α-glucosidase: Major clinical benefits in infantile-onset Pompe disease

Background: Pompe disease is a progressive metabolic neuromuscular disorder resulting from deficiency of lysosomal acid α-glucosidase (GAA). Infantile-onset Pompe disease is characterized by cardiomyopathy, respiratory and skeletal muscle weakness, and early death. The safety and efficacy of recombinant human (rh) GAA were evaluated in 18 patients with rapidly progressing infantile-onset Pompe disease. Methods: Patients were diagnosed at 6 months of age and younger and exhibited severe GAA deficiency and cardiomyopathy. Patients received IV infusions of rhGAA at 20 mg/kg (n = 9) or 40 mg/kg (n = 9) every other week. Analyses were performed 52 weeks after the last patient was randomized to treatment. Results: All patients (100%) survived to 18 months of age. A Cox proportional hazards analysis demonstrated that treatment reduced the risk of death by 99%, reduced the risk of death or invasive ventilation by 92%, and reduced the risk of death or any type of ventilation by 88%, as compared to an untreated historical control group. There was no clear advantage of the 40-mg/kg dose with regard to efficacy. Eleven of the 18 patients experienced 164 infusion-associated reactions; all were mild or moderate in intensity. Conclusions: Recombinant human acid α-glucosidase is safe and effective for treatment of infantile-onset Pompe disease. Eleven patients experienced adverse events related to treatment, but none discontinued. The young age at which these patients initiated therapy may have contributed to their improved response compared to previous trials with recombinant human acid α-glucosidase in which patients were older.

PSORS2 Is Due to Mutations in CARD14

Psoriasis is a common, immune-mediated genetic disorder of the skin and is associated with arthritis in approximately 30% of cases. Previously, we localized PSORS2 (psoriasis susceptibility locus 2) to chromosomal region 17q25.3-qter after a genome-wide linkage scan in a family of European ancestry with multiple cases of psoriasis and psoriatic arthritis. Linkage to PSORS2 was also observed in a Taiwanese family with multiple psoriasis-affected members. In caspase recruitment domain family, member 14 (CARD14), we identified unique gain-of-function mutations that segregated with psoriasis by using genomic capture and DNA sequencing. The mutations c.349G>A (p.Gly117Ser) (in the family of European descent) and c.349+5G>A (in the Taiwanese family) altered splicing between CARD14 exons 3 and 4. A de novo CARD14 mutation, c.413A>C (p.Glu138Ala), was detected in a child with sporadic, early-onset, generalized pustular psoriasis. CARD14 activates nuclear factor kappa B (NF-kB), and compared with wild-type CARD14, the p.Gly117Ser and p.Glu138Ala substitutions were shown to lead to enhanced NF-kB activation and upregulation of a subset of psoriasis-associated genes in keratinocytes. These genes included chemokine (C-C motif) ligand 20 (CCL20) and interleukin 8 (IL8). CARD14 is localized mainly in the basal and suprabasal layers of healthy skin epidermis, whereas in lesional psoriatic skin, it is reduced in the basal layer and more diffusely upregulated in the suprabasal layers of the epidermis. We propose that, after a triggering event that can include epidermal injury, rare gain-of-function mutations in CARD14 initiate a process that includes inflammatory cell recruitment by keratinocytes. This perpetuates a vicious cycle of epidermal inflammation and regeneration, a cycle which is the hallmark of psoriasis.

Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production

Autosomal recessive mutations in proteasome subunit β 8 (PSMB8), which encodes the inducible proteasome subunit β5i, cause the immune-dysregulatory disease chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE), which is classified as a proteasome-associated autoinflammatory syndrome (PRAAS). Here, we identified 8 mutations in 4 proteasome genes, PSMA3 (encodes α7), PSMB4 (encodes β7), PSMB9 (encodes β1i), and proteasome maturation protein (POMP), that have not been previously associated with disease and 1 mutation in PSMB8 that has not been previously reported. One patient was compound heterozygous for PSMB4 mutations, 6 patients from 4 families were heterozygous for a missense mutation in 1 inducible proteasome subunit and a mutation in a constitutive proteasome subunit, and 1 patient was heterozygous for a POMP mutation, thus establishing a digenic and autosomal dominant inheritance pattern of PRAAS. Function evaluation revealed that these mutations variably affect transcription, protein expression, protein folding, proteasome assembly, and, ultimately, proteasome activity. Moreover, defects in proteasome formation and function were recapitulated by siRNA-mediated knockdown of the respective subunits in primary fibroblasts from healthy individuals. Patient-isolated hematopoietic and nonhematopoietic cells exhibited a strong IFN gene-expression signature, irrespective of genotype. Additionally, chemical proteasome inhibition or progressive depletion of proteasome subunit gene transcription with siRNA induced transcription of type I IFN genes in healthy control cells. Our results provide further insight into CANDLE genetics and link global proteasome dysfunction to increased type I IFN production.

Erratum: Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type i IFN production (Journal of Clinical Investigation (2015) 125:11 (4196-4211) DOI: 10.1172/JCI81260)

Autosomal recessive mutations in proteasome subunit b 8 (PSMB8), which encodes the inducible proteasome subunit b5i, cause the immune-dysregulatory disease chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE), which is classified as a proteasome-associated autoinflammatory syndrome (PRAAS). Here, we identified 8 mutations in 4 proteasome genes, PSMA3 (encodes a7), PSMB4 (encodes b7), PSMB9 (encodes b1i), and proteasome maturation protein (POMP), that have not been previously associated with disease and 1 mutation in PSMB8 that has not been previously reported. One patient was compound heterozygous for PSMB4 mutations, 6 patients from 4 families were heterozygous for a missense mutation in 1 inducible proteasome subunit and a mutation in a constitutive proteasome subunit, and 1 patient was heterozygous for a POMP mutation, thus establishing a digenic and autosomal dominant inheritance pattern of PRAAS. Function evaluation revealed that these mutations variably affect transcription, protein expression, protein folding, proteasome assembly, and, ultimately, proteasome activity. Moreover, defects in proteasome formation and function were recapitulated by siRNA-mediated knockdown of the respective subunits in primary fibroblasts from healthy individuals. Patient-isolated hematopoietic and nonhematopoietic cells exhibited a strong IFN gene-expression signature, irrespective of genotype. Additionally, chemical [...] Research Article Immunology

Comparative cytokine analysis across a spectrum of genetically and/or clinically defined auto-inflammatory syndromes

Background/purpose Auto-inflammatory diseases constitute a group of disorders that manifest systemic inflammation in the absence of infection, auto-antibodies or auto-reactive T cells. A specific genetic mutation is identified in some of them, such as in neonatal onset multisystem inflammatory disease (NOMID) or chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome, while in others such as Chronic Recurrent Multifocal Osteomyelitis (CRMO), and Adult onset Stills Disease (AOSD) a specific cause is yet to be elucidated. The rapid response to targeted cytokine blocking therapies suggests that these disorders are mediated by specific cytokines. Herein, the authors investigate whether each disease is characterised by a specific cytokine signature. Method Serum samples, on visits when patients had clinically active disease, were collected and assayed by Luminex for the presence of 43 inflammatory cytokines at 9 timepoints. Disease groups (mutation positive and negative NOMID; CANDLE syndrome; CRMO; adult and pediatric Stills disease; rheumatoid arthritis, including juvenile idiopathic arthritis were compared to normal controls whose assays were run at the same time. Ratios of patient values divided by the average of corresponding set of healthy control values were statistically tested for whether they significantly differed from 1 and also among the various disease groups. Result A distinct cytokine profile is found in different auto-inflammatory diseases. Specifically, AOSD is characterised by markedly increased levels of Interleukin-18 (p=0.005, mean=3.068) and IL-1a (p=0.032, mean=1.5687) compared to controls. NOMID mutation positive patients had increased levels of IL-1a (p=0.00078, mean=1.7819), IL-6 (p=0.001, mean=1.5376) and IL-18 (p=0.001, mean=1.4924) compared to controls and NOMID mutation negative patients. Il-18 levels in AOSD patients were actually significantly higher than in patients with mutation positive and negative NOMID. CANDLE patients have highly increased IFNg inducing protein 10 (IP-10) levels (p=0.00053, mean=3.9872) compared to controls and the other autoinflammatory diseases. CRMO patients had low levels of IL-8 (p=0.005, mean=0.1697), GM-CSF (p=0.00684, mean=0.0969) and MCP-1 (p2=0.002, mean=0.0687) compared to controls and other diseases. These differences in cytokine profiles disappeared when patients were on effective therapies. Conclusion During active disease specific cytokine profiles may allow us to detect dysregulated cytokine pathways that discriminate between clinically different autoinflammatory syndromes. A comprehensive approach of cytokine profiling may be useful to develop a therapeutic plan. Further studies are needed to determine it this approach can be used to monitor therapy and help in the definition of inflammatory disease.