Manish Butte

Long Term Outcome and Immune Function After Hematopoietic Stem Cell Transplantation for Primary Immunodeficiency.

Front Pediatr. 2019;7:381

Authors: Gennery AR, Lankester A, Inborn Errors Working Party (IEWP) of the European Society for Blood and Marrow Transplantation (EBMT)

Abstract
Transplantation techniques for patients with primary immunodeficiencies have improved so that survival from the procedure in many cases is >80%. However, long term complications may arise due to the use or not of conditioning agents. This may result in variable immune reconstitution, the long term effects of chemotherapy, particularly on fertility, and complications relating to the genetic disorder, unresolved by transplantation. For patients with severe combined immunodeficiency (SCID), long term T- and B-lymphocyte immune reconstitution is best achieved after pre-transplant chemotherapy. For patients who receive an unconditioned infusion of donor stem cells, the quality of immune reconstitution depends on the SCID genotype. Long term effects include chemotherapy-induced impaired fertility, and sequelae specific to the genotype. For patients with other primary immunodeficiencies, conditioning is required-sequelae related to direct effects of chemotherapy may be observed. Additional long term effects may be observed due to partial donor chimerism resulting in incomplete eradication of disease, and other geno-specific effects.

PMID: 31616648 [PubMed]

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Differential immunomodulation of T-cells by immunoglobulin replacement therapy in primary and secondary antibody deficiency.

PLoS One. 2019;14(10):e0223861

Authors: Dinh T, Oh J, Cameron DW, Lee SH, Cowan J

Abstract
Patients with primary or secondary antibody deficiency (PAD or SAD) are at increased risk of recurrent infections that can be alleviated by immunoglobulin replacement therapy (IRT). In addition to replenishing antibody levels, IRT has been suggested to modulate immune response in patients with antibody deficiency. Although both commonly treated with IRT, the underlying causes of PAD and SAD vary greatly, suggesting differential modulation of T-cell function that may lead to different responses to IRT. To explore this, peripheral blood mononuclear cells (PBMCs) were sampled from 17 PAD and 14 SAD patients before and 2-10 months after initiation of IRT, and analyzed for changes in T-cell phenotype and function. Proportions of CD4, CD8, Treg, or memory T-cells did not significantly change post-IRT compared to pre-IRT. However, we report distinct modulation in T-cell function between PAD and SAD patients post-IRT. Upon α-CD3/CD28 stimulation, proportion of IFN-γ+ CD4 and CD8 T-cells increased in SAD (p = 0.005) but not PAD patients post-IRT compared to baseline. Interestingly, total T-cell proliferation was reduced post-IRT in both PAD and SAD patients, although the reduction in proliferation was primarily due to reduced CD4 T-cell proliferation in PAD (p = 0.025) in contrast to CD8 T-cells in SAD (p = 0.042). In summary, even though IRT provides patients with passive humoral immunity-mediated protection in PAD and SAD, our findings suggest that IRT immunomodulation of T-cells is different in T-cell subsets depending on underlying immunodeficiency.

PMID: 31613907 [PubMed – in process]

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Antioxidant Defense, Redox Homeostasis, and Oxidative Damage in Children With Ataxia Telangiectasia and Nijmegen Breakage Syndrome.

Front Immunol. 2019;10:2322

Authors: Maciejczyk M, Heropolitanska-Pliszka E, Pietrucha B, Sawicka-Powierza J, Bernatowska E, Wolska-Kusnierz B, Pac M, Car H, Zalewska A, Mikoluc B

Abstract
Ataxia-telangiectasia (AT) and Nijmegen breakage syndrome (NBS) belong to a group of primary immunodeficiency diseases (PI) characterized by premature aging, cerebral degeneration, immunoglobulin deficiency and higher cancer susceptibility. Despite the fact that oxidative stress has been demonstrated in vitro and in animal models of AT and NBS, the involvement of redox homeostasis disorders is still unclear in the in vivo phenotype of AT and NBS patients. Our study is the first to compare both enzymatic and non-enzymatic antioxidants as well as oxidative damage between AT and NBS subjects. Twenty two Caucasian children with AT and twelve patients with NBS were studied. Enzymatic and non-enzymatic antioxidants – glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase-1 (SOD) and uric acid (UA); redox status-total antioxidant capacity (TAC) and ferric reducing ability of plasma (FRAP); and oxidative damage products-8-hydroxy-2′-deoxyguanosine (8-OHdG), advanced glycation end products (AGE), advanced oxidation protein products (AOPP), 4-hydroxynonenal (4-HNE) protein adducts, and 8-isoprostanes (8-isop) were evaluated in serum or plasma samples. We showed that CAT, SOD and UA were significantly increased, while TAC and FRAP levels were statistically lower in the plasma of AT patients compared to controls. In NBS patients, only CAT activity was significantly elevated, while TAC was significantly decreased as compared to healthy children. We also showed higher oxidative damage to DNA (↑8-OHdG), proteins (↑AGE, ↑AOPP), and lipids (↑4-HNE, ↑8-isop) in both AT and NBS patients. Interestingly, we did not demonstrate any significant differences in the antioxidant defense and oxidative damage between AT and NBS patients. However, in AT children, we showed a positive correlation between 8-OHdG and the α-fetoprotein level as well as a negative correlation between 8-OHdG and IgA. In NBS, AGE was positively correlated with IgM and negatively with the IgG level. Summarizing, we demonstrated an imbalance in cellular redox homeostasis and higher oxidative damage in AT and NBS patients. Despite an increase in the activity/concentration of some antioxidants, the total antioxidant capacity is overwhelmed in children with AT and NBS and predisposes them to more considerable oxidative damage. Oxidative stress may play a major role in AT and NBS phenotype.

PMID: 31611883 [PubMed – in process]

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WASp Is Essential for Effector-to-Memory conversion and for Maintenance of CD8+T Cell Memory.

Front Immunol. 2019;10:2262

Authors: Liu Q, Zhang L, Shu Z, Yu T, Zhou L, Song W, Zhao X

Abstract
Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency characterized by recurrent infections, micro thrombocytopenia, eczema, and a high incidence of autoimmunity and malignancy. A defect in the T cell compartment is thought to be a major cause of immunodeficiency in patients with WAS; However, whether the antigen specific T memory cell is altered has not been extensively studied. Here, we examined the expansion/contraction kinetics of CD8+ memory T cells and their maintenance in WASp-/- mice. The results showed that WAS protein (WASp) is not required for differentiation of CD8+ effector T cells; however, CD8+ T cells from WASp-/- mice were hyperactive, resulting in increased cytokine production. The number of CD8+ T memory cells decreased as mice aged, and CD8+ T cell recall responses and protective immunity were impaired. WASp-deficient CD8+ T cells in bone marrow chimeric mice underwent clonal expansion, but the resulting effector cells failed to survive and differentiate into CD8+ memory T cells. Taken together, these findings indicate that WASp plays an intrinsic role in differentiation of CD8+ memory T cells.

PMID: 31608063 [PubMed – in process]

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Wiskott-Aldrich syndrome protein senses irradiation-induced DNA damage to coordinate the cell-protective Golgi dispersal response in human T and B lymphocytes.

J Allergy Clin Immunol. 2019 Oct 08;:

Authors: Wen KK, Han SS, Vyas YM

Abstract
BACKGROUND: Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency disorder resulting from WASp deficiency. WAS lymphocytes manifest increased DNA damage and lymphopenia from cell death, yet how WASp influences DNA damage-linked cell survival is unknown. A recently-described mechanism promoting cell survival following irradiation (IR)-induced DNA damage involves fragmentation and dispersal of Golgi, known as the Golgi-dispersal response (GDR), which utilizes the GOLPH3•DNA-PK•MYO18A•F-actin signaling pathway.
OBJECTIVE: To define WASp role in the DNA damage-induced GDR, and its disruption as a contributor to the development of radiosensitivity-linked immunodeficiency in WAS.
METHODS: In human T helper (Th) and B cell culture systems, DNA-damage-induced GDR elicited by ionizing-radiation or radiomimetic-chemotherapy was monitored in the presence or absence of WASp or GOLPH3 alone or both together.
RESULTS: WASp-deficiency completely prevents the development of IR-induced GDR in human Th and B cells, this despite high DNA damage load. Loss of WASp impedes nuclear translocation of GOLPH3 and its colocalization with DNA-PKcs. Surprisingly, however, depletion of GOLPH3 alone or depolymerization of F-actin in the WASp-sufficient Th cells still allows the development of robust GDR, suggesting that WASp, but not GOLPH3, is essential for GDR and cell survival following IR-induced DNA-damage in human lymphocytes.
CONCLUSION: The study identifies WASp as a novel effector of nucleus-to-Golgi, cell-survival pathway triggered by IR-induced DNA damage in the cells of the hematolymphoid lineage, and proposes impaired GDR as a new etiology in the development of a “radiosensitive” form of immune dysregulation in WAS.

PMID: 31604087 [PubMed – as supplied by publisher]

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Manufacturing process optimization of ADMA Biologics’ intravenous immunoglobulin products, BIVIGAM® and ASCENIV™.

Immunotherapy. 2019 Oct 09;:

Authors: Wasserman RL, Greener BN, Garcia D, Mond J, Kestenberg K, Grossman A

Abstract
Humoral immunodeficiency patients require immunoglobulin replacement to prevent infection. Traditional intravenous immunoglobulin manufacturing methods have had the potential for containing impurities caused by physical, chemical and thermal stressors that alter proteins. Two intravenous immunoglobulin products, BIVIGAM® and ASCENIV™, are manufactured by a modified Cohn-Oncley fractionation method followed by chromatographic purification. These products have undergone a systematic quality by design optimization to identify critical manufacturing processes to produce the highest quality product. This data driven, small-scale approach has led to manufacturing enhancements that have yielded consistent product improvements. The systematic approach to optimizing manufacturing has guided process changes, in-process, procedural and engineering controls that have reduced protein shearing and aggregation, and improved purity resulting in products with lot-to-lot consistency.

PMID: 31596642 [PubMed – as supplied by publisher]

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The evaluation of neutropenia in common variable immune deficiency patients.

Expert Rev Clin Immunol. 2019 Oct 08;:

Authors: Ghorbani M, Fekrvand S, Shahkarami S, Yazdani R, Sohani M, Shaghaghi M, Hassanpour G, Mohammadi J, Negahdari B, Abolhassani H, Aghamohammadi A

Abstract
Objectives: Common variable immunodeficiency is a primary immunodeficiency disease characterized by hypogammaglobulinemia and heterogeneous clinical features. Neutropenia is a rare complication among CVID patients leading to a higher rate of infections and morbidity. Multiple factors (e.g. autoimmunity, infections, drugs and etc.) are found to underlie this complication. Methods: In the present study, demographic, clinical and laboratory data were compared between two groups of CVID patients with and without neutropenia. Results: Frequency of neutropenia was 8.1%. Infectious complications were the most prevalent clinical manifestations regardless of presence of neutropenia. However, candida infection and septicemia were significantly higher in neutropenic patients (p=0.001 and p=0.01, respectively). The most prominent clinical phenotypes of CVID patients with neutropenia were polyclonal lymphocytic infiltration and autoimmunity, both being considerably higher compared to the non-neutropenic group (p=0.04 and p=0.009, respectively). The mortality rate in neutropenic patients was higher than in patients without neutropenia (61.1 vs. 25.2 %, p=0.004). Conclusion: Although neutropenia is a rare complication among CVID patients, it is associated with frequent and severe clinical complications, including autoimmunity and lymphoproliferative conditions. Also, its accompaniment with higher mortality frequency in CVID patients indicates a need for more precise attention and consideration regarding specific treatment in neutropenic patients.

PMID: 31592698 [PubMed – as supplied by publisher]

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Genetic Mutations and Immunological Features of Severe Combined Immunodeficiency Patients in Iran.

Immunol Lett. 2019 Oct 04;:

Authors: Shahbazi Z, Yazdani R, Shahkarami S, Shahbazi S, Hamid M, Sadeghi-Shabestari M, Momen T, Aleyasin S, Esmaeilzadeh H, Darougar S, Delavari S, Mahdaviani SA, Ahanchian H, Behmanesh F, Kiaee F, Shariat M, Keramatipour M, Rezaei N, Abolhassani H, Parvaneh N, Mahdian R, Aghamohammadi A

Abstract
BACKGROUND: Severe combined immunodeficiency (SCID) is the most severe form of primary immunodeficiency disorders that is characterized by impaired early T lymphocyte differentiation and is variably associated with abnormal development of other lymphocyte lineages. SCID can be caused by mutations in more than 20 different genes. Molecular diagnosis in SCID patients contributes to genetic counseling, prenatal diagnosis, treatment modalities, and overall prognosis. In this cohort, the clinical, laboratory and genetic data related to Iranian SCID patients were comprehensively evaluated and efficiency of stepwise sequencing methods approach based on immunophenotype grouping was investigated METHODS: Clinical and laboratory data from 242 patients with SCID phenotype were evaluated. Molecular genetic analysis methods including Sanger sequencing, targeted gene panel and whole exome sequencing were performed on 62 patients.
RESULTS: Mortality rate was 78.9% in the cohort with a median follow-up of four months. The majority of the patients had a phenotype of T-NK-B+ (34.3%) and the most severe clinical manifestation and highest mortality rate were observed in T-NK-B- SCID cases. Genetic mutations were confirmed in 50 patients (80.6%), of which defects in recombination-activating genes (RAG1 and RAG2) were found in 16 patients (32.0%). The lowest level of CD4+ and CD8+ cells were observed in patients with ADA deficiency (p = 0.026) and IL2RG deficiency (p = 0.019), respectively.
CONCLUSION: Current findings suggest that candidate gene approach based on patient’s immunophenotype might accelerate molecular diagnosis of SCID patients. Candidate gene selection should be done according to the frequency of disease-causing genes in different populations. Targeted gene panel, WES and WGS methods can be used for the cases which are not diagnosed using this method.

PMID: 31589898 [PubMed – as supplied by publisher]

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