Manish Butte

[Late diagnosis of WHIM sydrome].

Medicina (B Aires). 2018;78(2):123-126

Authors: Paolini MV, Danielian S, Prieto E, Tami MF, Oleastro MM, Fernández Romero DS

Abstract
WHIM syndrome is a primary autosomal dominant immuno deficiency due to CXCR4 mutations characterized by mucocutaneous warts, hypogammaglobulinemia, recurrent bacterial infections and myelokathesis. Treatment consists in prophylactic antibiotics, immunoglobulin replacement and granulocyte or granulocyte/monocyte colony stimulating factors. We present the case of a 21 year old woman who showed leukopenia at 10 months of age and one year later multiple infections with hypogammaglobulinemia requiring intravenous immunoglobulin. During follow up she developed chronic neutropenia. A bone marrow aspiration showed increased myeloid series with predominance of immature elements. On the basis of infections, low levels of IgG, IgA, IgM and lymphopenia with absent memory B cells, a diagnosis of common variable immunodeficiency was made. She started intravenous immunoglobulin replacement and prophylactic antibiotics. At age 20, small warts in hands that progressed to forearms, knees, abdomen and face were recorded. CXCR4 gene sequencing was done detecting a heterozygous p.Arg334STOP mutation, confirming WHIM syndrome. This disease is infrequent and difficult to diagnose.

PMID: 29659363 [PubMed – in process]

Powered by WPeMatico

[Clinical features and gene mutations of primary immunodeficiency disease: an analysis of 7 cases].

Zhongguo Dang Dai Er Ke Za Zhi. 2018 Apr;20(4):285-289

Authors: Wang JC, Liu XX

Abstract
This research investigated the clinical features of immunodeficiency disease and the features of the mutation of its pathogenic genes. All 7 patients were boys aged 5 months to 4 years and 6 months and had a history of recurrent respiratory infection and pneumonia, low levels of IgM and IgG, and abnormal absolute values or percentages of lymphocyte subsets. High-throughput sequencing showed c.1684C>T mutations in the BTK gene in patient 1 and IVS8+2T>C splice site mutations in the BTK gene in patient 2. Both of these mutations came from their mothers. Patients 3, 4, and 5 had mutations in the IL2RG gene, i.e., c.298C>T, IVS3-2A>G, and c.164T>A, among which c.164T>A mutations had not been reported. Patient 6 had c.204C>G mutations in the RAG2 gene. Patient 7 had complex heterozygous mutations of c.913C>T and c.824G>A in the RAG2 gene, which came from his father and mother, respectively. Patients with immunodeficiency disease have abnormal immunological indices, and high-throughput sequencing helps to make a definite diagnosis.

PMID: 29658452 [PubMed – in process]

Powered by WPeMatico

Establishment and Development of the First Biobank of Inflammatory Bowel Disease, Suspected to Primary Immunodeficiency Diseases in Iran.

Adv Biomed Res. 2018;7:45

Authors: Sherkat R, Rostami S, Yaran M, Emami MH, Saneian H, Tavakoli H, Adibi P, Behnam M, Sheykhbahaei S, Bagherpour B, Khoshnevisan R, Najafi S

Abstract
Background: Inflammatory bowel disease (IBD) might be an immunodeficiency rather than an excessive inflammatory reaction. IBD, suspected to primary immunodeficiency diseases biobank (IBDSPIDB) as a resource for researches can help improve the prevention, diagnosis, and illness treatment and the health promotion throughout the society. Therefore, we launched the biobank of IBDSPID for the first time in Iran.
Materials and Methods: This study was designed to provide the IBDSPIDB to have a high-quality DNA, RNA, and cDNA. Among of 365 patients, 39 have inclusion criteria that were as below: (1) IBD diagnosis before 5 years of age. (2) Resistance to conventional therapy of IBD. (3) Severe IBD. (4) Signs of SPID (including ear infections or pneumonia or recurrent sinus within the 1-year period; failure to thrive; poor response to the prolonged use of antibiotics; persistent thrush or skin abscesses; or a family history of PID).
Results: Out of 39 patients, 51.3% were males. The mean age was 32.92 ± 15.90 years old. Ulcerative colitis (79.5%) was more than Crohn’s disease. The majority of patients (50.0%) had severe IBDSPID. Resistance to drugs and consanguinity was 12.9% and 47.4%, respectively. Age at onset in 65.8% of patients was after 17 years old. Patients with autoimmune, allergy, and immunodeficiency disease history were 33.3%, 33.3%, and 10.36%, respectively. RNA and cDNA yields large quantities of high-quality DNA obtained and stored.
Conclusion: Our biobank would be valuable for future genetic and molecular study to be more about the relation between IBD and PID.

PMID: 29657930 [PubMed]

Powered by WPeMatico

Defective immuno- and thymoproteasome assembly causes severe immunodeficiency.

Sci Rep. 2018 Apr 13;8(1):5975

Authors: Treise I, Huber EM, Klein-Rodewald T, Heinemeyer W, Grassmann SA, Basler M, Adler T, Rathkolb B, Helming L, Andres C, Klaften M, Landbrecht C, Wieland T, Strom TM, McCoy KD, Macpherson AJ, Wolf E, Groettrup M, Ollert M, Neff F, Gailus-Durner V, Fuchs H, Hrabě de Angelis M, Groll M, Busch DH

Abstract
By N-ethyl-N-nitrosourea (ENU) mutagenesis, we generated the mutant mouse line TUB6 that is characterised by severe combined immunodeficiency (SCID) and systemic sterile autoinflammation in homozygotes, and a selective T cell defect in heterozygotes. The causative missense point mutation results in the single amino acid exchange G170W in multicatalytic endopeptidase complex subunit-1 (MECL-1), the β2i-subunit of the immuno- and thymoproteasome. Yeast mutagenesis and crystallographic data suggest that the severe TUB6-phenotype compared to the MECL-1 knockout mouse is caused by structural changes in the C-terminal appendage of β2i that prevent the biogenesis of immuno- and thymoproteasomes. Proteasomes are essential for cell survival, and defective proteasome assembly causes selective death of cells expressing the mutant MECL-1, leading to the severe immunological phenotype. In contrast to the immunosubunits β1i (LMP2) and β5i (LMP7), mutations in the gene encoding MECL-1 have not yet been assigned to human disorders. The TUB6 mutant mouse line exemplifies the involvement of MECL-1 in immunopathogenesis and provides the first mouse model for primary immuno- and thymoproteasome-associated immunodeficiency that may also be relevant in humans.

PMID: 29654304 [PubMed – in process]

Powered by WPeMatico

The clinical and immunological features of patients with primary antibody deficiencies.

Endocr Metab Immune Disord Drug Targets. 2018 Apr 12;:

Authors: Azizi G, Bagheri Y, Tavakol M, Askarimoghaddam F, Poorrostami K, Rafiemanesh H, Yazdani R, Kiaee F, Habibi S, Abouhamzeh K, Mohammadi H, Qorbani M, Abolhassani H, Aghamohammadi A

Abstract
BACKGROUND: Primary antibody deficiency (PAD) comprises a range of diseases from early to late terminal B cells defects and is associated with the various clinical complications.
METHODS: A total of 461 patients (311 males and 150 females) with PADs enrolled in the retrospective cohort study and for all patients’ demographic information, clinical records and laboratory data were collected to investigate clinical complications.
RESULTS: The most prevalent first presentations of immunodeficiency were respiratory tract infections in 63.5% and chronic diarrhea in 17.2%. Common variable immune deficiency (CVID) patients had a higher diagnostic delay than class switching defect (CSD), and agammaglobulinemia. Among the non-infectious complications, autoimmunity (26.2%), and splenomegaly (23.4%) were the most common. Lymphadenopathy was higher in CSD patients than other PADs, while splenomegaly, hepatomegaly, autoimmunity and bronchiectasis were more common in CVID patients than others. Atopic manifestations were mostly recorded in patients with selective IgA deficiency. Malignancy was only reported in 5.8% of patients with CVID. There was a higher prevalence of autoimmune manifestations in CVID comparing to other PADs.
CONCLUSION: PADs are relatively rare diseases and these patients have a variety of first clinical manifestations, such as diverse infections, autoimmunity, lymphoproliferation, allergy, enteropathy and malignancy. Practitioner’s awareness about the heterogeneous presentations of PAD disorders is poor, therefore patients often are lately diagnosed, and they are complicated with several clinical complications before the certain diagnosis.

PMID: 29651973 [PubMed – as supplied by publisher]

Powered by WPeMatico

CEBPE-Mutant Specific Granule Deficiency Correlates With Aberrant Granule Organization and Substantial Proteome Alterations in Neutrophils.

Front Immunol. 2018;9:588

Authors: Serwas NK, Huemer J, Dieckmann R, Mejstrikova E, Garncarz W, Litzman J, Hoeger B, Zapletal O, Janda A, Bennett KL, Kain R, Kerjaschky D, Boztug K

Abstract
Specific granule deficiency (SGD) is a rare disorder characterized by abnormal neutrophils evidenced by reduced granules, absence of granule proteins, and atypical bilobed nuclei. Mutations in CCAAT/enhancer-binding protein-ε (CEBPE) are one molecular etiology of the disease. Although C/EBPε has been studied extensively, the impact of CEBPE mutations on neutrophil biology remains elusive. Here, we identified two SGD patients bearing a previously described heterozygous mutation (p.Val218Ala) in CEBPE. We took this rare opportunity to characterize SGD neutrophils in terms of granule distribution and protein content. Granules of patient neutrophils were clustered and polarized, suggesting that not only absence of specific granules but also defects affecting other granules contribute to the phenotype. Our analysis showed that remaining granules displayed mixed protein content and lacked several glycoepitopes. To further elucidate the impact of mutant CEBPE, we performed detailed proteomic analysis of SGD neutrophils. Beside an absence of several granule proteins in patient cells, we observed increased expression of members of the linker of nucleoskeleton and cytoskeleton complex (nesprin-2, vimentin, and lamin-B2), which control nuclear shape. This suggests that absence of these proteins in healthy individuals might be responsible for segmented shapes of neutrophilic nuclei. We further show that the heterozygous mutation p.Val218Ala in CEBPE causes SGD through prevention of nuclear localization of the protein product. In conclusion, we uncover that absence of nuclear C/EBPε impacts on spatiotemporal expression and subsequent distribution of several granule proteins and further on expression of proteins controlling nuclear shape.

PMID: 29651288 [PubMed]

Powered by WPeMatico

Neutralizing Anti-Cytokine Autoantibodies Against Interferon-α in Immunodysregulation Polyendocrinopathy Enteropathy X-Linked.

Front Immunol. 2018;9:544

Authors: Rosenberg JM, Maccari ME, Barzaghi F, Allenspach EJ, Pignata C, Weber G, Torgerson TR, Utz PJ, Bacchetta R

Abstract
Anti-cytokine autoantibodies (ACAAs) have been described in a growing number of primary immunodeficiencies with autoimmune features, including autoimmune polyendocrine syndrome type I (APS-1), a prototypical disease of defective T cell-mediated central tolerance. Whether defects in peripheral tolerance lead to similar ACAAs is unknown. Immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) is caused by mutations in FOXP3, a master regulator of T regulatory cells (Treg), and consequently results in defective T cell-mediated peripheral tolerance. Unique autoantibodies have previously been described in IPEX. To test the hypothesis that ACAAs are present in IPEX, we designed and fabricated antigen microarrays. We discovered elevated levels of IgG ACAAs against interferon-α (IFN-α) in a cohort of IPEX patients. Serum from IPEX patients blocked IFN-α signaling in vitro and blocking activity was tightly correlated with ACAA titer. To show that blocking activity was mediated by IgG and not other serum factors, we purified IgG and showed that blocking activity was contained entirely in the immunoglobulin fraction. We also screened for ACAAs against IFN-α in a second geographically distinct cohort. In these samples, ACAAs against IFN-α were elevated in a post hoc analysis. In summary, we report the discovery of ACAAs against IFN-α in IPEX, an experiment of nature demonstrating the important role of peripheral T cell tolerance.

PMID: 29651287 [PubMed]

Powered by WPeMatico

Germline deletion of CIN85 in humans with X chromosome-linked antibody deficiency.

J Exp Med. 2018 Apr 10;:

Authors: Keller B, Shoukier M, Schulz K, Bhatt A, Heine I, Strohmeier V, Speckmann C, Engels N, Warnatz K, Wienands J

Abstract
Ubiquitously expressed Cbl-interacting protein of 85 kD (CIN85) is a multifunctional adapter molecule supposed to regulate numerous cellular processes that are critical for housekeeping as well as cell type-specific functions. However, limited information exists about the in vivo roles of CIN85, because only conditional mouse mutants with cell type-specific ablation of distinct CIN85 isoforms in brain and B lymphocytes have been generated so far. No information is available about the roles of CIN85 in humans. Here, we report on primary antibody deficiency in patients harboring a germline deletion within the CIN85 gene on the X chromosome. In the absence of CIN85, all immune cell compartments developed normally, but B lymphocytes showed intrinsic defects in distinct effector pathways of the B cell antigen receptor, most notably NF-κB activation and up-regulation of CD86 expression on the cell surface. These results reveal nonredundant functions of CIN85 for humoral immune responses.

PMID: 29636373 [PubMed – as supplied by publisher]

Powered by WPeMatico

Genetic and mechanistic diversity in pediatric hemophagocytic lymphohistiocytosis.

Blood. 2018 Apr 09;:

Authors: Chinn IK, Eckstein OS, Peckham-Gregory EC, Goldberg BR, Forbes LR, Nicholas SK, Mace EM, Vogel TP, Abhyankar HA, Diaz MI, Heslop HE, Krance RA, Martinez CA, Nguyen TC, Bashir DA, Goldman JR, Stray-Pedersen A, Pedroza LA, Poli MC, Aldave Becerra JC, McGhee SA, Al-Herz W, Chamdin A, Coban-Akdemir ZH, Jhangiani SN, Muzny DM, Cao TN, Hong DN, Gibbs RA, Lupski JR, Orange JS, McClain KL, Allen CE

Abstract
The HLH-2004 criteria are used to diagnose hemophagocytic lymphohistiocytosis (HLH), yet concern exists for their misapplication, resulting in suboptimal treatment of some patients. We sought to define the genomic spectrum and associated outcomes of a diverse cohort of children who met the HLH-2004 criteria. Genetic testing was performed clinically or through research-based whole exome sequencing. Clinical metrics were analyzed with respect to genomic results. Of 122 subjects enrolled over 17 years, 101 subjects received genetic testing. Biallelic familial HLH (fHLH) gene defects were identified in only 19 (19%) and correlated with presentation below 1 year of age (p < 0.0001). "Digenic" fHLH variants were observed but lacked statistical support for disease association. In 28 of 48 subjects (58%), research whole exome sequencing analyses successfully identified likely molecular explanations, including underlying primary immunodeficiency diseases, dysregulated immune activation and proliferation disorders, and potentially novel genetic conditions. Two-thirds of patients identified by the HLH-2004 criteria had underlying etiologies for HLH, including genetic defects, autoimmunity, and malignancy. Overall survival was 45%; increased mortality correlated with HLH triggered by infection or malignancy (p < 0.05). Differences in survival did not correlate with genetic profile or extent of therapy. "HLH" should be conceptualized as a phenotype of critical illness characterized by toxic activation of immune cells from different underlying mechanisms. In most HLH patients, targeted sequencing of fHLH genes remains insufficient for identifying pathogenic mechanisms. Whole exome sequencing, however, may identify specific therapeutic opportunities and impact hematopoietic stem cell transplantation options for these patients.

PMID: 29632024 [PubMed – as supplied by publisher]

Powered by WPeMatico