Background Recurrent bacterial and fungal infections, eczema and elevated serum IgE levels characterize patients with the hyper-IgE syndrome (HIES). Known genetic causes for HIES are mutations in STAT3 and DOCK8, involved in signal transduction pathways. However, glycosylation defects have not been described in HIES. One crucial enzyme in the glycosylation pathway is Phosphoglucomutase 3 (PGM3), which catalyzes a key step in the synthesis of UDP-GlcNAc which is required for the biosynthesis of N-glycans. Objective To elucidate the genetic cause in HIES patients who do not carry mutations in STAT3 or DOCK8. Methods After establishing a linkage interval by SNP-chip genotyping and homozygosity mapping in two HIES families from Tunisia, mutational analysis was performed with selector-based, high-throughput sequencing. Protein expression was analyzed by Western blotting and glycosylation was profiled by mass spectrometry. Results Mutational analysis of candidate genes in a 11.9 Mb linkage region on chromosome 6 shared by two multiplex families identified two homozygous mutations in PGM3 which segregated with the disease status and followed a recessive inheritance trait. The mutations predict amino acid changes in Phosphoglucomutase-3; PGM3 (p.Glu340del and p.Leu83Ser). A third homozygous mutation (p.Asp502Tyr) and the p.Leu83Ser variant were identified in two other affected families, respectively. These hypomorphic mutations have impact on the biosynthetic reactions involving UDP-GlcNAc. Glycomic analysis revealed an aberrant glycosylation pattern in leukocytes demonstrated by a reduced level of tri-/tetra-antennary N-glycans. T cell proliferation and differentiation was impaired in patients. Most patients showed developmental delay and many had psychomotor retardation. Conclusion Impairment of PGM3 function leads to a novel primary (inborn) error of development and immunity, as biallelic hypomorphic mutations are associated with impaired glycosylation and a hyper-IgE-like phenotype.

Summary Interleukin (IL)‐17 is a pro‐inflammatory cytokine produced by recently described T helper type 17 (Th17) cells, which have critical role in immunity to extracellular bacteria and the pathogenesis of several autoimmune disorders. IL‐6 and transforming growth factor (TGF)‐β are crucial for the generation of Th17 cells in mice, while the production of IL‐17 is supported by various cytokines, including IL‐23, IL‐1β, IL‐21, IL‐15 and tumour necrosis factor (TNF)‐α. In this study, the influence of a multifunctional cytokine, macrophage migration inhibitory factor (MIF), on IL‐17 production in mice was investigated. Treatment of lymph node cells (LNCs) with recombinant MIF up‐regulated mitogen‐stimulated IL‐17 expression and secretion. Additionally, LNCs from MIF knockout mice (mif−/−) had severely impaired production of IL‐17, as well as of IL‐1β, IL‐6, IL‐23 and TGF‐β. When stimulated with recombinant IL‐1β, IL‐23 or TNF‐α, mitogen‐triggered mif−/− LNCs were fully able to achieve the IL‐17 production seen in wild‐type (WT) LNCs, while the addition of IL‐6 and TGF‐β had no effect. Finally, after injection of mice with complete Freund’s adjuvant, secretion of IL‐17 as well as the number of IL‐17‐positive cells was significantly lower in the draining lymph nodes of mif−/− mice in comparison with WT mice. The effect of MIF on IL‐17 production was dependent on p38, extracellular signal‐regulated kinase (ERK), Jun N‐terminal kinase (JNK) and Janus kinase 2/signal transducer and activator of transcription 3 (Jak2/STAT3), and not on nuclear factor (NF)‐κB and nuclear factor of activated T cells (NFAT) signalling. Bearing in mind the contribution of MIF and IL‐17 to the pathology of inflammatory and autoimmune disorders, from the results presented here it seems plausible that targeting MIF biological activity could be a valid therapeutic approach for the treatment of such diseases.

Cytokines and nitric oxide (NO) stimulate rat mesangial cells to synthesize and secrete inflammatory mediators. To understand better the signaling pathways that contribute to this response, we exposed rat mesangial cells to the prototypic inflammatory cytokine IL-1␤ and analyzed the changes in the pattern of gene expression. IL-1␤ downregulated the gene encoding the matricellular glycoprotein secreted modular calcium-binding protein 1 (SMOC-1) in mesangial cells. Inflammatory cytokines attenuated SMOC-1 mRNA and protein expression through endogenous production of NO, which activated the soluble guanylyl cyclase. Silencing SMOC-1 expression with small interfering RNA decreased the formation of TGF-␤, reduced SMAD binding to DNA, and decreased mRNA expression of genes regulated by TGF-␤. In a rat model of anti-Thy-1 glomerulonephritis, glomerular SMOC-1 mRNA and protein decreased and inducible NO synthase expression increased simultaneously. Treatment of nephritic rats with the inducible NO synthase-specific inhibitor L-N 6 -(1-iminoethyl)-lysine prevented SMOC-1 downregulation. In summary, these data suggest that NO attenuates SMOC-1 expression in acute glomerular inflammation, thereby limiting TGF-␤-mediated profibrotic signaling.

Patients with hyperimmunoglobulin E syndrome (HIES) and chronic granulomatous disease (CGD) have prominently increased immunoglobulin (Ig) E levels. We present a 9-year-old boy with medical history revealing recurrent pneumonia, suppurative lymphadenitis, diarrhea, and otitis. The patient was hospitalized with severe pneumonia. The examination showed tachypnea, crackles at the right and left base of the lung, freckles on his face, red-hair, gingivitis, a high arched palate, and retained primary dentition. Serum IgE level was markedly increased. Nevertheless, patient did not have STAT3 or DOCK8 mutation, characteristic of HIES. Neutrophil function test with dihydrorhodamine (DHR) showed X linked-CGD pattern and molecular analysis of DNAshowed a splice site mutation (c.338-1G > A) in CYBB gene. Herein, we present a case of CGD with selective IgA deficiency. Laboratory findings and elevated IgE mimic the features seen in HIES. Thus, CGD must be considered as a differential diagnosis in patients with elevated Ig E.