Mutations in the perforin gene can be linked to macrophage activation syndrome in patients with systemic onset juvenile idiopathic arthritis.

OBJECTIVE: Macrophage activation syndrome (MAS) in systemic onset juvenile idiopathic arthritis (SoJIA) is considered to be an acquired form of familial haemophagocytic lymphohistiocytosis (fHLH). FHLH is an autosomal recessive disorder, characterized by diminished NK cell function and caused by mutations in the perforin gene (PRF1) in 20-50% of patients. Interestingly, SoJIA patients display decreased levels of perforin in NK cells and diminished NK cell function as well. Here, we analysed PRF1 and its putative promoter in SoJIA patients with or without a history of MAS. METHODS: DNA of 56 SoJIA patients (41 Italian and 15 Dutch) was isolated. Of these, 15 (27%) had a confirmed history of MAS. We sequenced PRF1 and 1.5 kb of the 5'-upstream region. DNA sequence variations in the promoter region were functionally tested in transfection experiments using a human NK cell line. RESULTS: We detected a previously undescribed sequence variation (-499 C > T) in the promoter of PRF1 in 18% of the SoJIA patients. However, transfection experiments did not show functional implications of this variation. Secondly, we found that 11 of 56 (20%) SoJIA patients were heterozygous for missense mutations in PRF1. In particular, we found a high prevalence of the Ala91Val mutation, a variant known to result in defective function of perforin. Interestingly, the prevalence of Ala91Val in SoJIA patients with a history of MAS (20%) was increased compared with SoJIA patients without MAS (9.8%). One SoJIA patient, heterozygous for Ala91Val, showed profound decreased perforin levels at the time of MAS. CONCLUSIONS: These findings suggest that PRF1 mutations play a role in the development of MAS in SoJIA patients.

Severe reaction in a child with asymptomatic codfish allergy: food challenge reactivating recurrent pancreatitis.

An 8-year-old child during the first year of life manifested severe atopic dermatitis and chronic diarrhea with mucorrhea and rectal bleeding; a fish-free diet was started based on weakly positive skin-prick tests to codfish extract. At the age of 4 years the child began to suffer of recurrent pancreatitis. When he came to our attention for the evaluation of his fish allergy, he was asymptomatic; a weak reactivity to codfish was observed (SPTs: cod, 4 mm, sIgE ImmunoCAP: cod, 1.30 kU/l). The food challenge test with cod was negative. When the child ate cod again, within 5 minutes, developed anaphylactic reaction and complained of abdominal pain compatible with pancreatitis (enzyme serum levels risen and parenchymal oedema at ultrasonography), that resolved within 7 days after specific therapy. This case raises two issues: the elimination diet in asymptomatic food allergy on the basis only of SPT and the ethicality of food challenge in gastrointestinal chronic disease.

Association of the macrophage migration inhibitory factor -173*C allele with childhood nephrotic syndrome.

Macrophage migration inflammatory factor (MIF) is a proinflammatory cytokine with a unique role as the physiologic counterregulator of the immunosuppressive effects of glucocorticoids. MIF has been implicated in the pathogenesis of glomerular inflammation. The MIF promoter contains a G/C polymorphism that is functionally relevant, with the C allele being associated with higher MIF production and linked to susceptibility to inflammatory diseases. We genotyped the MIF -173 polymorphism in 257 children with idiopathic nephrotic syndrome (INS) and 355 controls. Frequency of carriers of the high-producer MIF -173*C allele was higher in patients with INS (31.7%) than in controls (22.0%) [odds ratio (OR) 1.67, p = 0.006] The MIF -173 C allele was more frequent in steroid-resistant patients (43.5%) compared with steroid responders (22.8%) (OR 2.61, p = 0.0005). This difference was particularly evident in focal segmental glomerulosclerosis patients (OR 14.0, p = 0.002). No association with response to cyclosporin A was found. Carriers of the MIF -173*C allele had a significantly higher probability of end-stage renal disease (ESRD) compared with G/G homozygous patients within 5 years from onset (log rank 5.11 p = 0.024). These results underscore the role of MIF in INS disease progression and in the response to glucocorticoid treatment and suggest that screening of MIF genotype at disease onset may identify patients requiring a more aggressive therapeutic approach.

Low serum levels of mannose binding lectin are a risk factor for neonatal sepsis.

Mannose binding lectin (MBL) is a soluble pattern recognition receptor of innate immunity that binds a wide range of pathogens and exerts opsonic effects. We investigated the association between serum MBL levels and development of sepsis in infants admitted to neonatal intensive care units (NICUs). Serum MBL levels on admission were measured by enzyme-linked immunosorbent assay (ELISA) in 206 neonates consecutively admitted to an NICU of whom 138 did not develop hospital-acquired sepsis and 68 did. Of these 68, 40 had confirmed sepsis with positive blood cultures, 19 clinically suspected sepsis, with negative blood cultures, and nine had clinically suspected sepsis with blood culture yielding coagulase-negative staphylococci (CoNS). Serum MBL levels on admission were significantly lower in infants with sepsis [0.45 microg/mL; interquartile range (IQR) 0.09-1.68], particularly in those with confirmed sepsis (0.17 microg/mL; IQR 0.05-0.96), compared with infants without sepsis (1.45 microg/mL; IQR 0.43-3.52), and infants with CoNS-positive blood culture (1.70 microg/mL: IQR 0.85-3.60). After adjusting for duration of exposure gestational age (GA) and birth weight (BW), the association of low MBL levels with development of sepsis was maintained [odds ratio (OR) = 0.52; 95% confidence interval (CI): 0.36-0.75]. The measurement of serum MBL levels on admission in NICU may help to identify neonates at higher risk of developing sepsis.

Abnormal production of tumor necrosis factor (TNF) -- alpha and clinical efficacy of the TNF inhibitor etanercept in a patient with PAPA syndrome [corrected].

We report a family with pyogenic sterile arthritis, pyoderna and acne syndrome (PAPA). The proband presented several episodes of sterile pyogenic arthritis and became unresponsive to glucocorticoids. After treatment with the tumor necrosis factor inhibitor etanercept, the disease underwent rapid and sustained clinical remission. Production of tumor necrosis factor-alpha by mononuclear cells of the proband and of the affected relatives was abnormally elevated.