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Stephen Jolles

Publications and source records attributed to Stephen Jolles.

8 recordsLinked to original sources
PubMed2020

Human NK cell deficiency as a result of biallelic mutations in MCM10.

Human natural killer cell deficiency (NKD) arises from inborn errors of immunity that lead to impaired NK cell development, function, or both. Through the understanding of the biological perturbations in individuals with NKD, requirements for the generation of terminally mature functional innate effector cells can be elucidated. Here, we report a cause of NKD resulting from compound heterozygous mutations in minichromosomal maintenance complex member 10 (MCM10) that impaired NK cell maturation in a child with fatal susceptibility to CMV. MCM10 has not been previously associated with monogenic disease and plays a critical role in the activation and function of the eukaryotic DNA replisome. Through evaluation of patient primary fibroblasts, modeling patient mutations in fibroblast cell lines, and MCM10 knockdown in human NK cell lines, we have shown that loss of MCM10 function leads to impaired cell cycle progression and induction of DNA damage-response pathways. By modeling MCM10 deficiency in primary NK cell precursors, including patient-derived induced pluripotent stem cells, we further demonstrated that MCM10 is required for NK cell terminal maturation and acquisition of immunological system function. Together, these data define MCM10 as an NKD gene and provide biological insight into the requirement for the DNA replisome in human NK cell maturation and function.

Alleles↗
PubMed2006

Chronic granulomatous disease caused by mutations other than the common GT deletion in NCF1, the gene encoding the p47phox component of the phagocyte NADPH oxidase.

Chronic granulomatous disease (CGD) is an inherited immunodeficiency caused by defects in any of four genes encoding components of the leukocyte nicotinamide dinucleotide phosphate, reduced (NADPH) oxidase. One of these is the autosomal neutrophil cytosolic factor 1 (NCF1) gene encoding the p47phox protein. Most (>97%) CGD patients without p47phox (A47 degrees CGD) are homozygotes for one particular mutation in NCF1, a GT deletion in exon 2. This is due to recombination events between NCF1 and its two pseudogenes (psiNCF1) that contain this GT deletion. We have previously set up a gene-scan method to establish the ratio of NCF1 genes and pseudogenes. With this method we now found, in three CGD families patients with the normal number of two intact NCF1 genes (and four psiNCF1 genes) and in six CGD families, patients with one intact NCF1 gene (and five psiNCF1 genes). All patients lacked p47phox protein expression. These results indicate that other mutations were present in their NCF1 gene than the GT deletion. To identify these mutations, we designed PCR primers to specifically amplify the cDNA or parts of the genomic DNA from NCF1 but not from the psiNCF1 genes. We found point mutations in NCF1 in eight families. In another family, we found a 2,860-bp deletion starting in intron 2 and ending in intron 5. In six families the patients were compound heterozygotes for the GT deletion and one of these other mutations; in two families the patients had a homozygous missense mutation; and in one family the patient was a compound heterozygote for a splice defect and a nonsense mutation. Family members with either the GT deletion or one of these other mutations were identified as carriers. This knowledge was used in one of the families for prenatal diagnosis.

Adolescent↗
PubMed2005

Use of IGIV in the treatment of atopic dermatitis, urticaria, scleromyxedema, pyoderma gangrenosum, psoriasis, and pretibial myxedema.

There has been a rapid expansion in the use of IGIV for an ever-growing number of conditions. It is a product with an excellent safety record without the side effects of steroids or other immunosuppressive agents. There have been numerous recent advances in our understanding of the mechanisms of action of IGIV in many of the conditions for which it is being used, but there is still much to be learned. IGIV has had a major impact in neurology, haematology, immunology, rheumatology and dermatology. The limitations for IGIV are cost of the preparation itself and the logistical problems associated with its administration. Here we describe the published evidence for the use of high-dose IGIV in the dermatological conditions atopic dermatitis, urticaria, scleromyxedema, pyoderma gangrenosum, psoriasis and pretibial myxedema. These conditions have an emerging evidence base for hdIGIV which is relatively small consisting mainly of case reports and small case series. The outcomes in a number of these conditions appear encouraging, but as the reports are likely to reflect a bias for positive results, one must be cautious about drawing firm conclusions.

Dermatitis, Atopic↗
PubMed2005

Asymptomatic choroidal granulomas in common variable immunodeficiency.

Common variable immunodeficiency disease represents the most common cause of significant antibody deficiency in adults. It is a heterogeneous group of disorders that can be sporadic or familial with various modes of inheritance with defects in B-cell function, regulatory T-cells and macrophage function all being reported. Herein a case of asymptomatic bilateral choroidal granulomatous disease in a 27-year-old man with common variable immunodeficiency disease is described.

Adult↗
PubMed2005

Therapeutic efficacy of high-dose intravenous immunoglobulin in Mycobacterium tuberculosis infection in mice.

Intravenous immunoglobulin (IVIg) is used to treat patients with primary antibody deficiencies and, at high doses, to treat a range of autoimmune and inflammatory disorders. With high-dose IVIg (hdIVIg), immunomodulatory mechanisms act on a range of cells, including T cells, B cells, and dendritic cells. Here, we demonstrate that the treatment of M. tuberculosis-infected mice with a single cycle of hdIVIg resulted in substantially reduced bacterial loads in the spleen and lungs when administered at either an early or late stage of infection. Titration of the IVIg showed a clear dose-response effect. There was no reduction in bacterial load when mice were given equimolar doses of another human protein, human serum albumin, or maltose, the stabilizing agent in the IVIg preparation. HdIVIg in vitro had no inhibitory effect on the growth of M. tuberculosis in murine bone marrow-derived macrophages. In addition, the effect of hdIVIg on bacterial loads was not observed in nude mice, suggesting the involvement of conventional T cells. Analysis of T cells infiltrating the lungs revealed only small increases in CD8(+) but not CD4(+) T-cell numbers in hdIVIg-treated mice. The mechanism of action of hdIVIg against tuberculosis in mice remains to be determined. Nevertheless, since hdIVIg is already widely used clinically, the magnitude and long duration of the therapeutic effect seen here suggest that IVIg, or components of it, may find ready application as an adjunct to therapy of human tuberculosis.

Animals↗
PubMed2005

Drug-induced aseptic meningitis.

Drug-induced aseptic meningitis (DIAM) is an important entity. This article reviews the literature on this rare idiosyncratic event which may occur after local or systemic drug administration. The data on this adverse reaction is predominantly collated from anecdotal case reports and case series.

Anti-Infective Agents↗
PubMed2003

Adjunctive high-dose intravenous immunoglobulin treatment for resistant atopic dermatitis: efficacy and effects on intracellular cytokine levels and CD4 counts.

Although atopic dermatitis generally responds to topical therapy, small numbers of patients have severe resistant disease despite second-line therapies. High-dose intravenous immunoglobulin has been suggested to be of benefit in a small number of reports. We have conducted an open, single-centre study of adjunctive high-dose intravenous immunoglobulin (Flebogamma 5%). Six patients received treatment at 2 g kg(-1) month(-1) for 6 cycles, with a 3-month follow-up period. Skin scores, lymphocyte phenotypes and intracellular cytokine analysis were performed. Four of six patients had major improvements in skin scores and the overall reduction was significant (p = 0.035). CD4+ T-cell numbers fell following high-dose intravenous immunoglobulin infusions, recovering by the next cycle. T-cell CD69 expression decreased to 60% of baseline values. Reductions in the proinflammatory cytokines IFN-gamma and TNF-alpha were non-significant. Adjunctive high-dose intravenous immunoglobulin may be a useful therapeutic approach in adults with severe treatment-resistant atopic dermatitis, but it will require further assessment in randomized controlled trials to establish this.

Adolescent↗