Research

Genotyping an immunodeficiency causing c.1624-11G>A ZAP70 mutation in Canadian Mennonites.

BMC Med Genet. 2016;17(1):50

Authors: Schroeder ML, Triggs-Raine B, Zelinski T

Abstract
BACKGROUND: Primary immunodeficiency is a life-threatening genetic disease that appeared to have an increased incidence in Manitoba Mennonites. Determining the genetic basis of this immunodeficiency was an essential step for providing early and appropriate medical intervention.
METHODS: Initially, DNA from probands affected with primary immunodeficiency and their family members was assessed for linkage to genes previously associated with immunodeficiency. Candidate genes were sequenced to identify the causative mutation. The frequency of the mutation among first and second degree relatives, as well as apparently unrelated community members was analyzed using a PCR-based assay.
RESULTS: A previously described c.1624-11G>A mutation in ZAP70 was identified as the causative mutation in all affected probands that were analyzed. Among 125 study participants of Mennonite descent, 79 genotyped as normal, 39 were carriers and seven were affected. None of 115 non-Mennonite random individuals carried the mutation, whereas one of ten random DNA samples from individuals who self-identified as Mennonite was a carrier.
CONCLUSIONS: In collaboration with the target community, we have developed a robust screening test for determining ZAP70 genotype. Early identification of affected individuals has provided an opportunity for timely clinical intervention, while carrier identification has allowed for genetic counselling of at risk couples.

PMID: 27448562 [PubMed – in process]

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Mycophenolate mofetil for the treatment of children with immune thrombocytopenia and Evans syndrome. A retrospective data review from the Italian association of paediatric haematology/oncology.

Br J Haematol. 2016 Jul 22;

Authors: Miano M, Ramenghi U, Russo G, Rubert L, Barone A, Tucci F, Farruggia P, Petrone A, Mondino A, Lo Valvo L, Crescenzio N, Bellia F, Olivieri I, Palmisani E, Caviglia I, Dufour C, Fioredda F

Abstract
Mycophenolate mofetil (MMF) has been shown to be effective in children with immune thrombocytopenia (ITP) and Evans syndrome (ES), but data from larger series and details on the timing of the response are lacking. We evaluated 56 children treated with MMF for ITP (n = 40) or ES (n = 16), which was primary or secondary to autoimmune lymphoproliferative syndrome -related syndrome (ARS). Thirty-five of the 54 evaluable patients (65%) achieved a partial (18%) or complete (46%) response after a median (range) of 20 (7-137) and 37 (7-192) d, respectively. ITP and ES patients responded in 58% and 81% of cases (P = not significant, ns), with complete response in 32% and 81% (P = 0·01), respectively. 60% and 73% of children with primary disease and ARS responded (P = ns) with complete response in 34% and 68% of cases (P = 0·01), respectively. Six of 35 (17%) children relapsed after a median of 283 d (range 189-1036). Limited toxicity was observed in four patients. The median durations of treatment and follow-up were seven and 12·7 months, respectively. This is the largest reported cohort of patients treated with MMF for ITP/ES. The results show that MMF is effective and safe and provides a relatively quick response, suggesting that it has a potential role as an alternative to more aggressive and expensive second/further-line treatments.

PMID: 27447678 [PubMed – as supplied by publisher]

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Pulmonary Aspergillosis in a Previously Healthy 13-Year-Old Boy.

Can Respir J. 2016;2016:4575942

Authors: Rayment JH, Narang I

Abstract
Chronic granulomatous disease (CGD) is a rare, polygenic primary immunodeficiency. In this case report, we describe a previously healthy 13-year-old boy who presented with multifocal pulmonary aspergillosis and was subsequently diagnosed with an autosomal recessive form of chronic granulomatous disease. CGD has a variable natural history and age of presentation and should be considered when investigating a patient with recurrent or severe infections with catalase-positive organisms.

PMID: 27445540 [PubMed – in process]

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Long-Term Outcomes of Hematopoietic Stem Cell Transplantation for ZAP70 Deficiency.

J Clin Immunol. 2016 Jul 20;

Authors: Cuvelier GD, Rubin TS, Wall DA, Schroeder ML

Abstract
ZAP70 deficiency is a rare T + B + NK+ combined immunodeficiency with limited outcome data to help guide decisions around hematopoietic stem cell transplant (HSCT). We sought to understand the long-term clinical and immunologic outcomes of both conditioned and unconditioned HSCT for ZAP70 deficiency following transplant from a variety of graft sources. We performed a retrospective, single center review of all cases of HSCT for genetically confirmed ZAP70 deficiency since 1992. At a median of 13.5-year post-HSCT, 8/8 (100 %) patients are alive. Three received unconditioned bone marrow transplants from human leukocyte antigen (HLA)-matched siblings and achieved stable mixed donor-recipient T cell chimerism but low B cell (4-9 %) and absent to near-absent myeloid donor engraftment. Despite this, all three have normal immunoglobulin levels, have developed specific protective antibody responses to post-HSCT vaccinations, and have discontinued immunoglobulin replacement. Five patients received myeloablative conditioning (three T cell-depleted haploidentical and two unrelated cord blood) and have full donor chimerism for T and B cells and myeloid lineages. One patient experienced primary graft failure after serotherapy only. CD8 T cell count is normal in 5/8, high in 1/8, and low in 2/8. Infectious complications in 5/5 and autoimmune thrombocytopenia in one patient resolved post-HSCT. Mitogen proliferation to phytohemagglutinin was normal after HSCT in 8/8 patients. In total, seven have discontinued immunoglobulin replacement. In conclusion, HSCT using a variety of graft sources and approaches, including unconditioned matched sibling donor transplant, is a life-saving therapy for ZAP70 deficiency, providing excellent long-term immune function and resolution of clinical problems.

PMID: 27438785 [PubMed – as supplied by publisher]

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Chronic Recurrent Multifocal Osteomyelitis and Thalidomide in Chronic Granulomatous Disease.

Pediatrics. 2016 Jul 19;

Authors: Martín-Nalda A, Roca I, Fontecha CG, Fernández-Polo A, Barber I, Martinez-Gallo M, Soler-Palacin P

Abstract
Chronic granulomatous disease (CGD) is a primary immunodeficiency that leads to severe recurrent infection and inflammatory complications that are usually difficult to diagnose and treat. Several hyperinflammation mechanisms, such as decreased neutrophil apoptosis, toll-like receptor activation imbalance, Th17 cell induction, Nrf2 activity deficiency, and inflammasome activation, have been described in CGD patients However, there have been no reports of chronic recurrent multifocal osteomyelitis as an inflammatory complication in CGD, and the differential diagnosis of this condition with infectious osteomyelitis is challenging. Thalidomide has been used to treat several inflammatory manifestations in CGD patients with good clinical results. Here, we report the case of a previously asymptomatic 11-year-old boy who consulted for difficulty walking and pain at the back of the right thigh, with increased inflammatory markers. Multifocal bone involvement was seen on bone scintigraphy, and acute-phase reactants were elevated. On the basis of a suspected diagnosis of infectious osteomyelitis, broad-spectrum antibiotic therapy was started, with no clinical response. Bone biopsy and microbiological tests yielded negative results; at that point, chronic recurrent multifocal osteomyelitis was suspected. The patient was unresponsive to nonsteroidal antiinflammatory drugs and corticosteroids. Thalidomide was started, and within 6 months, clinical and radiologic resolution of the condition was achieved with no adverse effects. More than 1 year after stopping thalidomide, the patient remained free of symptoms and inflammatory parameters are within normal levels. Thalidomide has a favorable safety profile compared with other alternatives and could be considered a feasible therapeutic option for this type of condition in selected patients.

PMID: 27436506 [PubMed – as supplied by publisher]

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Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3-kinase δ syndrome-like immunodeficiency.

J Allergy Clin Immunol. 2016 Jun 29;

Authors: Tsujita Y, Mitsui-Sekinaka K, Imai K, Yeh TW, Mitsuiki N, Asano T, Ohnishi H, Kato Z, Sekinaka Y, Zaha K, Kato T, Okano T, Takashima T, Kobayashi K, Kimura M, Kunitsu T, Maruo Y, Kanegane H, Takagi M, Yoshida K, Okuno Y, Muramatsu H, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Kojima S, Ogawa S, Ohara O, Okada S, Kobayashi M, Morio T, Nonoyama S

Abstract
BACKGROUND: Activated phosphatidylinositol 3-kinase δ syndrome (APDS) is a recently discovered primary immunodeficiency disease (PID). Excess phosphatidylinositol 3-kinase (PI3K) activity linked to mutations in 2 PI3K genes, PIK3CD and PIK3R1, causes APDS through hyperphosphorylation of AKT, mammalian target of rapamycin (mTOR), and S6.
OBJECTIVE: This study aimed to identify novel genes responsible for APDS.
METHODS: Whole-exome sequencing was performed in Japanese patients with PIDs. Immunophenotype was assessed through flow cytometry. Hyperphosphorylation of AKT, mTOR, and S6 in lymphocytes was examined through immunoblotting, flow cytometry, and multiplex assays.
RESULTS: We identified heterozygous mutations of phosphatase and tensin homolog (PTEN) in patients with PIDs. Immunoblotting and quantitative PCR analyses indicated that PTEN expression was decreased in these patients. Patients with PTEN mutations and those with PIK3CD mutations, including a novel E525A mutation, were further analyzed. The clinical symptoms and immunologic defects of patients with PTEN mutations, including lymphocytic AKT, mTOR, and S6 hyperphosphorylation, resemble those of patients with APDS. Because PTEN is known to suppress the PI3K pathway, it is likely that defective PTEN results in activation of the PI3K pathway.
CONCLUSION: PTEN loss-of-function mutations can cause APDS-like immunodeficiency because of aberrant PI3K pathway activation in lymphocytes.

PMID: 27426521 [PubMed – as supplied by publisher]

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Secondary Sjogren’s Syndrome in 83 Patients With Rheumatoid Arthritis.

Acta Med Iran. 2016 Jul;54(7):448-453

Authors: Hajiabbasi A, Shenavar Masooleh I, Alizadeh Y, Banikarimi AS, Ghavidel Parsa P

Abstract
Sjogren syndrome (SS) can occur alone, primary Sjogren syndrome, or in association with other rheumatic diseases, secondary Sjogren syndrome (sSS), such as Rheumatoid arthritis (RA). The occurrence of Sjogren syndrome with RA makes it course worse and increases high morbidity and mortality of RA. In this exploratory study we aim to determine the prevalence of sSS (diagnosed based on the revised version of American-European consensus Group Classification Criteria: AUCG-criteria), sicca symptoms (dry eye, dry mouth), positive autoantibody tests (Anti RO or Anti-LA antibodies), UWSFR (Unstimulated Whole Salivary Flow Rate), Schirmer and Lissamine test. In this cross-sectional study, eighty three consecutive RA patients (according to American College of Rheumatology criteria 1987) who were visited at rheumatology clinic of Razi General Hospital located in the north of Iran entered into our study. Our exclusion criteria was a positive history of past head and neck radiation treatment, Hepatitis C infection, acquired immunodeficiency disease (AIDS), pre-existing lymphoma, sarcoidosis, graft versus host disease, use of anticholinergic drugs (including neuroleptics, antidepressants, antihypertensive and parasympatholytics). They examined with UWSFR by a rheumatologist and with Schirmer test and Lissamine test by an ophthalmologist. Participants were 90.4% female with the mean age 48.3±13 years. Duration of RA was in 36.1% less than 5 years, in 22.9% 5-10 years, in 12.1% 11-15 years and in 28.9% more than 15 years. Our results demonstrated that the prevalence of sSS was 5.9% (CI:0.6%-10.5%). Number of 27.7% of RA patients positively responded to at least one question about sicca symptoms. Among objective tests, only Positive UWSFR and Lissamine test were significantly more common in RA patients with sSS in comparison to ones without sSS (P<0.001, P=0.01 respectively). In RA patients, we found a linear trend between sicca symptoms and aging (P=0.02). In patients with sicca symptoms, among tests that used for assessing decrease in saliva or tear production, only USWFR significantly more common (P=0.01).
IN CONCLUSION: In RA population in North of Iran prevalence of sSS was less than 10%. In them, a significant linear trend existed between aging and sicca symptoms. Among objective tests of AUCG-criteria (except for lip biopsy that was not performed in the current study) only UWSFR and Lissamine test were significantly more common in patients with sSS in comparison ones without it.

PMID: 27424016 [PubMed – as supplied by publisher]

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EXPANDING THE INTERACTOME OF THE NON-CANONICAL NF-κB SIGNALING PATHWAY.

J Proteome Res. 2016 Jul 15;

Authors: Willmann KL, Sacco R, Martins R, Garncarz W, Krolo A, Knapp S, Bennett KL, Boztug K

Abstract
NF-κB signaling is a central pathway of immunity and integrates signal transduction upon a wide array of inflammatory stimuli. Non-canonical NF-κB signaling is activated by a small subset of TNF family receptors and characterized by NF-κB2/p52 transcriptional activity. The medical relevance of this pathway has recently re-emerged from the discovery of primary immunodeficiency patients that have loss-of-function mutations in the MAP3K14 gene encoding NIK. Nevertheless, knowledge of protein interactions that regulate non-canonical NF-κB signaling is sparse. Here, we report a detailed state-of-the-art mass spectrometry-based protein-protein interaction network including the non-canonical NF-κB signaling nodes TRAF2, TRAF3, IKKα, NIK and NF-κB2/p100. The value of the dataset was confirmed by the identification of interactions already known to regulate this pathway. In addition, a remarkable number of novel interactors were identified. We provide validation of the novel NIK and IKKα interactor FKBP8, which may regulate processes downstream of non-canonical NF-κB signaling. To understand perturbed non-canonical NF-κB signaling in the context of misregulated NIK in disease, we also provide a differential interactome of NIK mutants that cause immunodeficiency. Altogether, this data set not only provides critical insight into how protein-protein interactions can regulate immune signaling, but also offers a novel resource on non-canonical NF-κB signaling.

PMID: 27416764 [PubMed – as supplied by publisher]

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