Research

Dose and outcomes in primary immunodeficiency disorders.

Clin Exp Immunol. 2014 Dec;178 Suppl S1:7-9

Authors: Bonagura VR

PMID: 25546743 [PubMed – as supplied by publisher]

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Fetal-onset IPEX: Report of two families and review of literature.

Clin Immunol. 2014 Dec 26;

Authors: Xavier-da-Silva MM, Moreira-Filho CA, Suzuki E, Patricio F, Coutinho A, Carneiro-Sampaio M

Abstract
Early-life autoimmunity is an IPEX characteristic, however intrauterine forms had not yet been described. Here, two unrelated families with clear evidence of fetal-onset IPEX are reported. One had 5 miscarriages of males in two generations, and a newborn presenting type-1 diabetes mellitus immediately after birth, diarrhea, thrombocytopenia, eczematous dermatitis, eosinophilia, high IgE levels and autoantibodies to pancreatic islet antigens at 4-days-old. Maternal serology was negative. He presented a FOXP3 mutation, c.1189C>T, p.Arg397Trp, previously described only in another family with IPEX at birth. The second family had several miscarriages of males in three consecutive generations and a novel FOXP3 c.319_320delTC mutation was observed in two miscarried monochorionic twin male fetuses. These twins died at 21weeks of gestation due to hydrops, and CD3+ infiltrating lymphocytes were found in their pancreas. We demonstrate that: i) IPEX may develop in fetal life; ii) c.1189C>T and c.319_320delTC mutations are associated with early-onset phenotype.

PMID: 25546394 [PubMed – as supplied by publisher]

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Lag-times between lympho-proliferative disorder and clinical diagnosis of chronic lymphocytic leukemia (CLL): a prospective analysis using plasma soluble CD23.

Cancer Epidemiol Biomarkers Prev. 2014 Dec 26;

Authors: Kaaks R, Sookthai D, Luczynska A, Oakes CC, Becker S, Johnson T, Johansson AS, Melin B, Sjöberg K, Trichopoulos D, Trichopoulou A, Lagiou P, Mattiello A, Tumino R, Masala G, Agnoli C, Boeing H, Aleksandrova K, Brennan P, Franceschi S, Roulland S, Casabonne D, de Sanjose S, Sanchez M, Huerta J, Ardanaz E, Sala N, Overvad K, Tjonneland A, Halkjær J, Weiderpass E, Bueno-de-Mesquita HB, Vermeulen R, Peeters PH, Vineis P, Kelly RS, Khaw K, Travis RC, Key TJ, Riboli E, Nieters A

Abstract
Background:CLL is a chronic disease that often progresses slowly from a precursor stage, monoclonal B-cell lymphocytosis (MBL), and that can remain undiagnosed for a long time. Methods:Within the European EPIC cohort, we measured pre-diagnostic plasma sCD23 for 179 individuals who eventually were diagnosed with CLL and an equal number of matched control subjects who remained free of cancer. Results: In a very large proportion of CLL patients plasma sCD23 was clearly elevated 7 or more years before diagnosis. Considering sCD23 as a disease predictor, the area under the ROC curve (AUROC) was 0.95 [95% CI (0.90, 1.00)] for CLL diagnosed within 0.1-2.7 years after blood measurement, 0.90 [0.86-0.95] for diagnosis within 2.8-7.3 years, and 0.76 [0.65-0.86] for CLL diagnosed between 7.4 and 12.5 years. Even at a 7.4-year and longer time interval, elevated plasma sCD23 could predict a later clinical diagnosis of CLL with 100% specificity at >45% sensitivity. Conclusions:Our findings provide unique documentation for the very long latency times during which measurable B-cell lympho-proliferative disorder exists prior to the clinical manifestation of CLL. Impact:Our findings have relevance for the interpretation of prospective epidemiologic studies on the causes of CLL in terms of reverse causation bias. The lag-times indicate a time frame within which an early detection of CLL would be theoretically possible.

PMID: 25542829 [PubMed – as supplied by publisher]

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Hyper-IgE syndrome with a novel STAT3 mutation-a single center study from India.

Asian Pac J Allergy Immunol. 2014 Dec;32(4):321-7

Authors: Saikia B, Suri D, Goel S, Rawat A, Minz RW, Gupta A, Sharma S, Ohara O, Imai K, Nonoyama S, Sehgal S, Singh S

Abstract
BACKGROUND: Hyper IgE syndrome (HIES) is a rare primary immunodeficiency disorder characterized by the triad of elevated IgE and eosinophilia, eczema and recurrent skin and pulmonary infections. Mutation in the STAT3 gene accounts for majority of the autosomal dominant and sporadic forms of HIES.
OBJECTIVE: To report clinical and molecular analyses of patients with Hyper IgE syndrome from a single tertiary care center in India.
METHODS: Four patients with suspected HIES were studied. Flowcytometry for TH17 cell numbers and phosphoSTAT3, and STAT3 gene sequencing were performed.
RESULTS: TH17 cells were significantly reduced. Mutations were found in the DNA-binding domain in three and a mutation in the transactivation domain in one patient. One of the mutations detected was a novel mutation (g54792 c.1018A> C p.K340Q) in the DNA binding domain. Mycobacterial infection, which is usually not commonly associated with HIES was found in two of our cases, one with a cutaneous abscess in the shoulder, and the other with BCG site reactivation.
CONCLUSIONS: A novel mutation in the STAT3 is reported. Mycobacterial infections can be seen in the spectrum of HIES related infections.

PMID: 25543043 [PubMed – in process]

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Linear growth and endocrine function in children with ataxia telangiectasia.

Indian J Endocrinol Metab. 2014 Nov;18(Suppl 1):S93-6

Authors: Ehlayel M, Soliman A, De Sanctis V

Abstract
INTRODUCTION: Ataxia telangiectasia (AT) is a rare, genetic, primary immune deficiency disease characterized by immunodeficiency and neurological manifestations, with an increased tendency to infection, malignancy, and autoimmune diseases. Both growth delay and endocrine abnormalities are occasionally reported in these patients.
PATIENTS AND METHODS: We studied growth parameters height (Ht), weight, body mass index (BMI) and calculated the Ht standard deviation scores (HtSDS) of 13 patients (age 7.7 ± 3.5 years-age range: 3-14.5 years) with AT in relation to their mid-parental Ht SDS (MPHtSDS). We measured their serum calcium (Ca), phosphorus (PO4), alkaline phosphatase, alanine transferase (ALT), serum ferritin, creatinine and albumin concentrations. Endocrine investigations included the assessment of serum free thyroxine (FT4), thyrotropin (TSH), insulin-like growth factor-I (IGF-I) and morning cortisol. Complete blood count and serum immunoglobulins (IgG, IgM and IgA antibodies) were also measured. Growth data were correlated to hormonal and immune data.
RESULTS: About 31% of patients with AT had short stature (HtSDS <-2). However, their MPHtSDS denoted that their short stature was familial because four out of 13 had MPHtSDS <-2. They had low BMI, and two of them had low serum albumin and IGF-I, denoting malnutrition or disturbed growth hormone secretion. Elevated serum ALT and ferritin in some patients suggest immune-related inflammation in the liver. 30% of patients had high TSH, two of them had low FT4 diagnosing overt (15%) and sub-clinical (15%) hypothyroidism. Anti-thyroid peroxidase antibodies were high in two out of 13 patients denoting immune-related thyroid aggression. Eight out of 13 patients had Vitamin D deficiency (<20 ng/ml) however, their serum Ca and PO4 levels were in the normal range. One adolescent girl (14.5 years) had hyper-gonadotropic hypogonadism (low estradiol and high follicle stimulating hormone). All patients had normal 8 AM cortisol and renal function. None of the growth parameters were correlated with the IgG, IgM or IgA levels.
IN SUMMARY: Patients with AT had a high prevalence of growth retardation and endocrine dysfunction in the form of low IGF-I, overt and subclinical hypothyroidism and hypogonadism. Physicians should be aware of these possible endocrinopathies for an early diagnosis and proper treatment.

PMID: 25538885 [PubMed]

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Related Articles

The pleiotropic movement disorders phenotype of adult ataxia-telangiectasia.

Neurology. 2014 Sep 16;83(12):1087-95

Authors: Méneret A, Ahmar-Beaugendre Y, Rieunier G, Mahlaoui N, Gaymard B, Apartis E, Tranchant C, Rivaud-Péchoux S, Degos B, Benyahia B, Suarez F, Maisonobe T, Koenig M, Durr A, Stern MH, Dubois d’Enghien C, Fischer A, Vidailhet M, Stoppa-Lyonnet D, Grabli D, Anheim M

Abstract
OBJECTIVE: To assess the clinical spectrum of ataxia-telangiectasia (A-T) in adults, with a focus on movement disorders.
METHODS: A total of 14 consecutive adults with A-T were included at 2 tertiary adult movement disorders centers and compared to 53 typical patients with A-T. Clinical evaluation, neurophysiologic and video-oculographic recording, imaging, laboratory investigations, and ATM analysis were performed.
RESULTS: In comparison with typical A-T cases, our patients demonstrated later mean age at onset (6.1 vs 2.5 years, p < 0.0001), later loss of walking ability (p = 0.003), and longer survival (p = 0.0039). The presenting feature was ataxia in 71% and dysarthria and dystonia in 14% each. All patients displayed movement disorders, among which dystonia and subcortical myoclonus were the most common (86%), followed by tremor (43%). Video-oculographic recordings revealed mostly dysmetric saccades and 46% of patients had normal latencies (i.e., no oculomotor apraxia) and velocities. The α-fetoprotein (AFP) level was normal in 7%, chromosomal instability was found in 29% (vs 100% of typical patients, p = 0.0006), and immunoglobulin deficiency was found in 29% (vs 69%, p = 0.057). All patients exhibited 2 ATM mutations, including at least 1 missense mutation in 79% of them (vs 36%, p = 0.0067).
CONCLUSION: There is great variability of phenotype and severity in A-T, including a wide spectrum of movement disorders. Karyotype and repeated AFP level assessments should be performed in adults with unexplained movement disorders as valuable clues towards the diagnosis. In case of a compatible phenotype, A-T should be considered even if age at onset is late and progression is slow.

PMID: 25122203 [PubMed – indexed for MEDLINE]

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Diagnosing Primary Immunodeficiency: A Practical Approach for the Non-immunologist.

Curr Med Res Opin. 2014 Dec 22;:1-23

Authors: Lehman H, Hernandez-Trujillo V, Ballow M

Abstract
Abstract Objective: This review will provide an overview of the most common clinical presentations of primary immunodeficiency (PI), navigating through various affected organ systems. The goal is to accurately portray the high variability of this disease and provide a resource that helps to raise the index of suspicion of PI among physicians, aid in recognition of various PI disorders, and trigger more frequent screenings with appropriate referrals to immunologists for further evaluation and treatment. Summary: Patients with PI comprise more than 200 defined genetic abnormalities. Patients have an array of clinical manifestations, ranging from the most widely-associated recurrent and chronic bacterial infections to other associated comorbid conditions involving many organ systems. There is still considerable delay between the onset of symptoms and the time of diagnosis of PI. This review will present an overview of the clinical manifestations that will enhance a physician’s recognition of a possible PI. Particular emphasis is placed on the pathogens associated with the specific arm of the immune system that is related to each particular type of PI. The initial immune evaluation is described, which together with the history and physical exam can help focus the physician on the immune compartment most likely associated with a PI. Conclusions: Understanding the types of PI and the related clinical manifestations can help physicians see beyond the presenting symptoms and lead to improved recognition and diagnosis of PI. Timely diagnosis is of utmost importance in PI, as recent advances in bone transplantation and immunoglobulin replacement therapy, as well as future gene therapies, provide effective ways to prevent significant mortality and morbidity.

PMID: 25530045 [PubMed – as supplied by publisher]

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IgA deficiency in wolves from Canada and Scandinavia.

Dev Comp Immunol. 2014 Dec 18;

Authors: Frankowiack M, Olsson M, Cluff HD, Evans AL, Hellman L, Månsson J, Arnemo JM, Hammarström L

Abstract
Immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency in both humans and selected breeds of domestic dogs. In both species, IgAD is associated with recurrent infections and immune mediated diseases. Previous results imply that IgAD is also common in the wild ancestor of domestic dogs, the gray wolf. Here, we report that serum IgA concentrations are significantly different in Scandinavian and Canadian wolves (p=3.252e-15) with an increased prevalence for IgAD in Scandinavian wolves (60 %), which is as high as those found in high-risk dog breeds.

PMID: 25530092 [PubMed – as supplied by publisher]

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Dynamics of perinatal bovine leukemia virus infection.

BMC Vet Res. 2014;10:82

Authors: Gutiérrez G, Alvarez I, Merlini R, Rondelli F, Trono K

Abstract
BACKGROUND: Bovine leukemia virus (BLV) is highly endemic in many countries, including Argentina. As prevention of the spread from infected animals is of primary importance in breaking the cycle of BLV transmission, it is important to know the pathophysiology of BLV infection in young animals, as they are the main source of animal movement. In this work, we determined the proviral load and antibody titers of infected newborn calves from birth to first parturition (36 months).
RESULTS: All calves under study were born to infected dams with high proviral load (PVL) in blood and high antibody titers and detectable provirus in the colostrum. The PVL for five out of seven calves was low at birth. All animals reached PVLs of more than 1% infected peripheral blood mononuclear cells (PBMCs), three at 3 months, one at 6 months, and one at 12 months. High PVLs persisted until the end of the study, and, in two animals, exceeded one BLV copy per cell. Two other calves maintained a high PVL from birth until the end of the study. Antibody titers were 32 or higher in the first sample from six out of seven calves. These decayed at 3-6 months to 16 or lower, and then increased again after this point.
CONCLUSIONS: Calves infected during the first week of life could play an active role in early propagation of BLV to susceptible animals, since their PVL raised up during the first 12 months and persist as high for years. Early elimination could help to prevent transmission to young susceptible animals and to their own offspring. To our knowledge, this is the first study of the kinetics of BLV proviral load and antibody titers in newborn infected calves.

PMID: 24708791 [PubMed – indexed for MEDLINE]

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[Diagnostics of ataxia-telangiectasia by the express-test found on the method of indirect immunofluorescence].

Tsitologiia. 2013;55(8):560-5

Authors: Kuranova ML, Ledashcheva TA, Tulush EK, Beliaev DL, Zherebtsov SV, Pleskach NM, Prokof’eva VV, Mikhel’son VM, Spivak IM

Abstract
Ataxia-telangiectasia (AT) is a hereditary severe neurodegenerative disease developing, when mutations take place in both alleles of the atm gene, which encodes the key protein of the cellular response to DNA damage (DDR)–ATM proteinkinase. In response to the occurrence of double-strand DNA breaks, the ATM proteinkinase pass the autophosphorylation, and its active form–the phospho-ATM (P-ATM) appears in cells. In the nuclei of cells having the atm gene, P-ATM is revealed, being absent in cells with mutated forms of this gene, by means of the application of the modified method of indirect immunofluorescence. This peculiarity may be applied in the clinic, in order to confirm the diagnosis of AT.

PMID: 25486788 [PubMed – indexed for MEDLINE]

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