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Manish Butte

The Role of Anti-Neutrophil Antibodies in the Etiological Classification of Childhood Neutropenia: A Cross-Sectional Study in a Tertiary Center.

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The Role of Anti-Neutrophil Antibodies in the Etiological Classification of Childhood Neutropenia: A Cross-Sectional Study in a Tertiary Center.

J Pediatr Hematol Oncol. 2019 Dec 27;:

Authors: Karakilic-Ozturan E, Karaman S, Soguksu P, Mese S, Agacfidan A, Mutlu UD, Karakas Z, Tugcu D, Karagenc-Ozkan A, Devecioglu O

Abstract
Infections, drugs, malignancies, immunodeficiency, and autoimmunity may cause neutropenia. In primary autoimmune neutropenia, anti-neutrophil antibodies (ANeuA) bind to membrane antigens of neutrophils, which give rise to peripheral destruction of neutrophils. However, it is not always easy to detect these antibodies. This study aims to investigate the etiology of neutropenia, and at the same time to evaluate the immune mechanisms by ANeuA testing using granulocyte indirect immunofluorescence test. In our study, 310 neutropenic patients who were between 3 months and 18 years of age were evaluated. ANeuA screening tests were performed in 108 neutropenic patients (group 1), and these patients were divided into 2 subgroups as persistent neutropenia (group 1P, n=12) and recovered neutropenia (group 1R, n=96). Besides, a control group in the same age range was formed, consisting of 39 non-neutropenic children (group 2). ANeuA serum levels were also checked in these groups, and no statistically significant difference could be found between groups 1 and 2, or between groups 1P and 1R, regarding ANeuA levels. As a conclusion, our study was the first comprehensive research in Turkey investigating the large-scale etiology of neutropenia. Moreover, while ANeuA screening tests did not provide sufficient insight for immune neutropenia, we argue that it is not necessary for routine use and that further research in the etiology of neutropenia is required.

PMID: 31895216 [PubMed – as supplied by publisher]

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A novel ATM mutation associated with elevated atypical lymphocyte populations, hyper-IgM, and cutaneous granulomas.

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A novel ATM mutation associated with elevated atypical lymphocyte populations, hyper-IgM, and cutaneous granulomas.

Clin Immunol. 2019 03;200:55-63

Authors: Minto H, Mensah KA, Reynolds PR, Meffre E, Rubtsova K, Gelfand EW

Abstract
Ataxia-Telangiectasia (AT) is an immunodeficiency most often associated with T cell abnormalities. We describe a patient with a hyper-IgM phenotype and immune cell abnormalities that suggest a distinct clinical phenotype. Significant B cell abnormalities with increased unswitched memory B cells, decreased naive transitional B cells, and an elevated frequency of CD19+CD38loCD27-CD10-CD21-/low B cells expressing high levels of T-bet and Fas were demonstrated. The B cells were hyporesponsive to in vitro stimulation through the B cell receptor, Toll like receptors (TLR) 7 and 9, and CD40. T cell homeostasis was also disturbed with a significant increase in γδ T cells, circulating T follicular helper cells (Tfh), and decreased numbers of T regulatory cells. The ATM mutations in this patient are posited to have resulted in the perturbations in the frequencies and distributions of B and T cell subsets, resulting in the phenotype in this patient. KEY MESSAGES: A novel mutation creating a premature stop codon and a nonsense mutation in the ATM gene are postulated to have resulted in the unique clinical picture characterized by abnormal B and T cell populations, lymphocyte subset dysfunction, granuloma formation, and a hyper-IgM phenotype. CAPSULE SUMMARY: A patient presented with ataxia-telangiectasia, cutaneous granulomas, and a hyper-IgM phenotype; a novel combination of mutations in the ATM gene was associated with abnormal distributions, frequencies, and function of T and B lymphocyte subsets.

PMID: 30639167 [PubMed – indexed for MEDLINE]

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A novel monoallelic gain of function mutation in p110δ causing atypical activated phosphoinositide 3-kinase δ syndrome (APDS-1).

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A novel monoallelic gain of function mutation in p110δ causing atypical activated phosphoinositide 3-kinase δ syndrome (APDS-1).

Clin Immunol. 2019 03;200:31-34

Authors: Lougaris V, Baronio M, Moratto D, Tampella G, Gazzurelli L, Facchetti M, Martire B, Cardinale F, Lanzarotto F, Bondioni MP, Villanacci V, Grimbacher B, Plebani A

Abstract
This study reports on a novel activating p110δ mutation causing adult-onset hypogammaglobulinemia with lymphopenia without the classical presentation of atypical Activated phosphoinositide 3-kinase δ syndrome (ADPS-1), underlining thus the heterogeneous clinical and immunological presentation of p110δ mutated individuals and offers additional data on the role of p110δ in early and late B cell development in humans.

PMID: 30639166 [PubMed – indexed for MEDLINE]

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Severe combined immunodeficiency (SCID) presenting in childhood, with agammaglobulinemia, associated with novel compound heterozygous mutations in DCLRE1C.

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Severe combined immunodeficiency (SCID) presenting in childhood, with agammaglobulinemia, associated with novel compound heterozygous mutations in DCLRE1C.

Clin Immunol. 2019 03;200:16-18

Authors: Sundin M, Marits P, Ramme K, Kolios AGA, Nilsson J

Abstract
Severe combined immunodeficiency (SCID) can be caused by deleterious mutations in DCLRE1C, leading to deficient non-homologous end joining by compromising the function of the Artemis protein. This impairs the process of V(D)J recombination of the T- and B-cell receptors and typically results in radiosensitive T-, B-, NK+ SCID presenting during the first months of life. We present a case of a 3-year-old girl with two novel compound heterozygous variants in DCLRE1C (c.58G>C and c.374A>C) that were associated with marked reduced numbers of peripheral T- and B-cells and undetectable total serum IgG. Despite the severe laboratory phenotype, the patient had a normal development, albeit failure to thrive (-2.5 to -3 SD), during her first years of life including day-care attendance at preschool for 1.5 years. After being diagnosed with pneumonia the clinical picture of SCID was recognized and the girl successfully underwent hematopoietic stem-cell transplantation.

PMID: 30630113 [PubMed – indexed for MEDLINE]

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Long-term outcome of LRBA deficiency in 76 patients after various treatment modalities as evaluated by the immune deficiency and dysregulation activity (IDDA) score.

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Long-term outcome of LRBA deficiency in 76 patients after various treatment modalities as evaluated by the immune deficiency and dysregulation activity (IDDA) score.

J Allergy Clin Immunol. 2019 Dec 27;:

Authors: Tesch VK, Abolhassani H, Shadur B, Zobel J, Mareika Y, Sharapova S, Karakoc-Aydiner E, Rivière JG, Garcia-Prat M, Moes N, Haerynck F, Gonzales-Granado LI, Santos Pérez JL, Mukhina A, Shcherbina A, Aghamohammadi A, Hammarström L, Dogu F, Haskologlu S, İkincioğulları AI, Bal SK, Baris S, Kilic SS, Karaca NE, Kutukculer N, Girschick H, Kolios A, Keles S, Uygun V, Stepensky P, Worth A, van Montfrans JM, Peters AMJ, Meyts I, Adeli M, Marzollo A, Padem N, Khojah AM, Chavoshzadeh Z, Stefanija MA, Bakhtiar S, Florkin B, Meeths M, Gamez L, Grimbacher B, Seppänen MR, Lankester A, Gennery AR, Seidel MG, Inborn Errors, Clinical, and Registry Working Parties of the European Society for Blood and Marrow Transplantation (EBMT) and the European Society of Immunodeficiencies (ESID)

Abstract
BACKGROUND: Recent findings strongly support hematopoietic stem cell transplantation (HSCT) in patients with severe presentations of lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency, but long-term follow-up and survival data for non-transplanted patients beyond previous patient reports or meta-reviews are scarce.
OBJECTIVE: This international, retrospective study was conducted to elucidate the longitudinal clinical course of transplanted and non-transplanted LRBA-deficient patients.
METHODS: We assessed disease burden and treatment responses with a specially developed immune deficiency and dysregulation activity (IDDA) score, reflecting the sum and severity of organ involvement and infections, days of hospitalization, supportive care requirements, and performance indices.
RESULTS: Twenty-four of 76 LRBA-deficient patients from 29 centers (10 years median follow-up, range: 1-52) underwent HSCT from 2005 to 2019. Overall survival after HSCT (median follow-up 20 months) was 70.8% (17/24 patients); all deaths were due to non-specific, early, transplant-related mortality. Currently, 82.7% (43/52) of non-transplanted patients (aged 3-69 years) are alive. Of 17 HSCT survivors, seven are in complete and five in good partial remission without treatment (12/17, 70.6%). Only five of 43 non-transplanted patients (11.6%) are without immunosuppression. IDDA scores were significantly lower in patients who survived HSCT than in those receiving conventional treatment (P=0.005) or in patients who received abatacept or sirolimus as compared to other therapies, and in patients with residual LRBA expression. Higher disease burden, longer duration before HSCT, and lung involvement were associated with poor outcome.
CONCLUSIONS: The life-long disease activity, implying a need for immunosuppression and risk of malignancy, must be weighed against the risks of HSCT.

PMID: 31887391 [PubMed – as supplied by publisher]

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Novel homozygous ataxia‑telangiectasia (A‑T) mutated gene mutation identified in a Chinese pedigree with A‑T.

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Novel homozygous ataxia‑telangiectasia (A‑T) mutated gene mutation identified in a Chinese pedigree with A‑T.

Mol Med Rep. 2019 Aug;20(2):1655-1662

Authors: Chen W, Liu S, Hu H, Chen G, Zhu S, Jia B, Sheng W, Huang G

Abstract
Ataxia‑telangiectasia (A‑T) syndrome is a rare autosomal recessive disorder mainly caused by mutations in the A‑T mutated (ATM) gene. However, the genomic abnormalities and their consequences associated with the pathogenesis of A‑T syndrome remain to be fully elucidated. In the present study, a whole‑exome sequencing analysis of a family with A‑T syndrome was performed, revealing a novel homozygous deletion mutation [namely, NM_000051.3:c.50_72+7del,p.Asp18_Lys24delins(23)] in ATM in three affected siblings, which was inherited from their carrier parents who exhibited a normal phenotype in this pedigree. The identified mutation spans the exon 2 and intron 2 regions of the ATM gene, causing a splicing aberration that resulted in a 30‑bp deletion in exon 2 and intron 2, as well as a 71‑bp insertion in intron 2 in the splicing process, which was confirmed by reverse transcription‑polymerase chain reaction and sequencing analysis. The change in the three‑dimensional structure of the protein caused by the mutation in ATM may affect the functions associated with telomere length maintenance and DNA damage repair. Taken together, the present study reported a novel homozygous deletion mutation in the ATM gene resulting in A‑T syndrome in a Chinese pedigree and expanded on the spectrum of known causative mutations of the ATM gene.

PMID: 31257506 [PubMed – indexed for MEDLINE]

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