A 38-year-old woman with necrotising cervical lymphadenitis due to Histoplasma capsulatum

Immunogenetics and cellular immunology of bacterial infectious disease

The Same IκBα Mutation in Two Related Individuals Leads to Completely Different Clinical Syndromes

Both innate and adaptive immune responses are dependent on activation of nuclear factor κB (NF-κB), induced upon binding of pathogen-associated molecular patterns to Toll-like receptors (TLRs). In murine models, defects in NF-κB pathway are often lethal and viable knockout mice have severe immune defects. Similarly, defects in the human NF-κB pathway described to date lead to severe clinical disease. Here, we describe a patient with a hyper immunoglobulin M–like immunodeficiency syndrome and ectodermal dysplasia. Monocytes did not produce interleukin 12p40 upon stimulation with various TLR stimuli and nuclear translocation of NF-κB was impaired. T cell receptor–mediated proliferation was also impaired. A heterozygous mutation was found at serine 32 in IκBα. Interestingly, his father has the same mutation but displays complex mosaicism. He does not display features of ectodermal dysplasia and did not suffer from serious infections with the exception of a relapsing Salmonella typhimurium infection. His monocyte function was impaired, whereas T cell function was relatively normal. Consistent with this, his T cells almost exclusively displayed the wild-type allele, whereas both alleles were present in his monocytes. We propose that the T and B cell compartment of the mosaic father arose as a result of selection of wild-type cells and that this underlies the widely different clinical phenotype

IFN-alpha cannot substitute lack of IFN-gamma responsiveness in cells of an IFN-gamma R1 deficient patient

Patients with complete IFN-gamma R deficiency are unable to respond to IFN-gamma and have impaired Th1-immunity and recurrent, severe infections with weakly virulent Mycobacteria. Since IFN-alpha and IFN-gamma share signalling pathways, treatment with IFN-alpha has been proposed in complete IFN-gamma R deficiency. We stimulated cells from healthy controls and from a patient lacking IFN-gamma R1 with IFN-alpha and IFN-gamma, to establish whether IFN-alpha would substitute for IFN-gamma effects. IFN-alpha induced STAT1 phosphorylation in monocytes of the IFN-gamma R1(-/-) patient, but did not prime for LPS-induced IL-12p70, IL-12p40, IL-23 or TNF production. In control cells, IFN-alpha inhibited the priming effect of IFN-gamma on LPS-induced pro-inflammatory cytokine release. Finally, IFN-gamma but not IFN-alpha induced killing of M. smegmatis in cultured macrophages. In conclusion, no evidence was found to support the use of IFN-alpha in IFN-gamma R-deficient patients as intervention against mycobacterial infection; on the contrary, treatment of individuals with IFN-alpha may even adversely affect host defence against Mycobacteria. (C) 2010 Elsevier Inc. All rights reserved.Immunogenetics and cellular immunology of bacterial infectious disease

Severe disseminated mycobacterial infection in a boy with a novel mutation leading to IFN-gamma R2 deficiency

Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare syndrome characterized by predisposition to severe, sometimes lethal, disease caused by otherwise poorly virulent mycobacteria. We report here a boy with a recurrent mycobacterial infection from the age of five months. Immunological analyses revealed an inability to respond to IFN-gamma, subsequent genetic analyses revealed a novel homozygous mutation, r.679G > A in the IFNGR2 gene, resulting in a G227R substitution, that caused IFN-gamma R2 deficiency. This is only the 8th mutation in IFN-gamma R2 known so far. The boy eventually died of hepatic coma due to liver failure at the age of five

ANALYSIS OF IFN-gamma R1 GENE EXPRESSION AND FUNCTION CAN DISTINGUISH LANGERHANS CELL HISTIOCYTOSIS PATIENTS FROM PATIENTS WITH MENDELIAN SUSCEPTIBILITY TO MYCOBACTERIAL DISEASE

Immunogenetics and cellular immunology of bacterial infectious disease

Pulmonary Mycobacterium abscessus: A canary in the cystic fibrosis coalmine

Immunogenetics and cellular immunology of bacterial infectious disease

A novel mutation in NCF1 in an adult CGD patient with a liver abscess as first presentation

Chronic granulomatous disease (CGD) is an immunodeficiency caused by defects in the nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase complex and is usually diagnosed in early childhood. CGD patients suffer from severe, recurrent infections with bacteria, fungi and yeasts. We report a 25-year-old female with protracted fever because of a Staphylococcus aureus liver abscess, which did not resolve until breakthrough into the stomach. Despite her age, CGD was considered on diagnosis on the basis of the clinical symptoms. Analysis of the NADPH-oxidase activity confirmed CGD as the underlying condition. Western blotting revealed the absence of p47(phox) and subsequent sequencing of the p47(phox)-encoding gene, neutrophil cytosolic factor (NCF1), identified a deletion of 837C in the maternal NCF1 allele. The paternal allele contained a stopcodon because of a conversion between NCF1 and one of its Psi NCF1 pseudogenes. The patient had one novel mutation, c.837delC, and one conversion in NCF1, resulting in the complete absence of the p47(phox) component of the NADPH-oxidase complex. This p47(phox)-deficient CGD patient had the highest age at diagnosis reported thus far. Journal of Human Genetics (2009) 54, 313-316; doi:10.1038/jhg.2009.24; published online 27 March 200

IFN-a inhibits the type I immune response of human monocytes

Experimental cancer immunology and therap