Manish Butte

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IMMUNODEFICIENCIES. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations.

Science. 2015 Aug 7;349(6248):606-13

Authors: Okada S, Markle JG, Deenick EK, Mele F, Averbuch D, Lagos M, Alzahrani M, Al-Muhsen S, Halwani R, Ma CS, Wong N, Soudais C, Henderson LA, Marzouqa H, Shamma J, Gonzalez M, Martinez-Barricarte R, Okada C, Avery DT, Latorre D, Deswarte C, Jabot-Hanin F, Torrado E, Fountain J, Belkadi A, Itan Y, Boisson B, Migaud M, Arlehamn CS, Sette A, Breton S, McCluskey J, Rossjohn J, de Villartay JP, Moshous D, Hambleton S, Latour S, Arkwright PD, Picard C, Lantz O, Engelhard D, Kobayashi M, Abel L, Cooper AM, Notarangelo LD, Boisson-Dupuis S, Puel A, Sallusto F, Bustamante J, Tangye SG, Casanova JL

Abstract
Human inborn errors of immunity mediated by the cytokines interleukin-17A and interleukin-17F (IL-17A/F) underlie mucocutaneous candidiasis, whereas inborn errors of interferon-γ (IFN-γ) immunity underlie mycobacterial disease. We report the discovery of bi-allelic RORC loss-of-function mutations in seven individuals from three kindreds of different ethnic origins with both candidiasis and mycobacteriosis. The lack of functional RORγ and RORγT isoforms resulted in the absence of IL-17A/F-producing T cells in these individuals, probably accounting for their chronic candidiasis. Unexpectedly, leukocytes from RORγ- and RORγT-deficient individuals also displayed an impaired IFN-γ response to Mycobacterium. This principally reflected profoundly defective IFN-γ production by circulating γδ T cells and CD4(+)CCR6(+)CXCR3(+) αβ T cells. In humans, both mucocutaneous immunity to Candida and systemic immunity to Mycobacterium require RORγ, RORγT, or both.

PMID: 26160376 [PubMed – indexed for MEDLINE]

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IgH sequences in common variable immune deficiency reveal altered B cell development and selection.

Sci Transl Med. 2015 Aug 26;7(302):302ra135

Authors: Roskin KM, Simchoni N, Liu Y, Lee JY, Seo K, Hoh RA, Pham T, Park JH, Furman D, Dekker CL, Davis MM, James JA, Nadeau KC, Cunningham-Rundles C, Boyd SD

Abstract
Common variable immune deficiency (CVID) is the most common symptomatic primary immune deficiency, affecting ~1 in 25,000 persons. These patients suffer from impaired antibody responses, autoimmunity, and susceptibility to lymphoid cancers. To explore the cellular basis for these clinical phenotypes, we conducted high-throughput DNA sequencing of immunoglobulin heavy chain gene rearrangements from 93 CVID patients and 105 control subjects and sorted naïve and memory B cells from 13 of the CVID patients and 10 of the control subjects. The CVID patients showed abnormal VDJ rearrangement and abnormal formation of complementarity-determining region 3 (CDR3). We observed a decreased selection against antibodies with long CDR3s in memory repertoires and decreased variable gene replacement, offering possible mechanisms for increased patient autoreactivity. Our data indicate that patient immunodeficiency might derive from both decreased diversity of the naïve B cell pool and decreased somatic hypermutation in memory repertoires. The CVID patients also exhibited an abnormal clonal expansion of unmutated B cells relative to the controls. Although impaired B cell germinal center activation is commonly viewed as causative in CVID, these data indicate that CVID B cells diverge from controls as early as the pro-B stage, cell and suggest possible explanations for the increased incidence of autoimmunity, immunodeficiency, and lymphoma CVID patients.

PMID: 26311730 [PubMed – as supplied by publisher]

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Retrospective study of cytomegalovirus retinitis complicated with acquired immunodeficiency syndrome.

Int J Clin Exp Med. 2015;8(6):9537-9542

Authors: Huang G, Jiang Q, Li M, Lu Y, Wang Z

Abstract
PURPOSE: This study was designed to explore the characteristics and therapy of cytomegalovirus retinitis (CR) in patients diagnosed with acquired immunodeficiency syndrome (AIDS).
METHODS: A total of 67 AIDS patients (78 eyes) with CR findings of were collected from January 2009 to January 2013. The correlation between CR, cellular immunity, risk factor, clinical characteristics, treatment and prognosis of CR was assessed. The incidence of CR in different CD4+T lymphocyte count groups was analyzed.
RESULTS: Among all participants, 58 were male and 9 females, aged from 18-60 years, (38±9) years on average. CD4+ T lymphocyte count of CR patients ranged from 0-141 cells/µl and < 50 cells/µl in 81.3% of cases. CR was the primary manifestation in 10.2%, retinal lesions in 25.1%, best corrected visual acuity (BCVA) < 0.3 in 54% of AIDS patients. Retinal necrosis was involved near the posterior pole in 62.5% of CR patients. The visual acuity of 60 (47.6%) eyes was improved after treatment and 94.1% cases were cured within 3 months. Anti-CMV treatments including induction and maintenance of ganciclovir or foscarnet were discontinued when CD4+T lymphocyte count was > 150 cells/µl for three consecutive months. Complicated cataract, retinal detachment and immune reconstitution uveitis were observed in 20.5%, 12.1% and 13.1% of cases, respectively.
CONCLUSION: Decreased CD4+T lymphocyte count is a risk factor for CR. HAART and anti-CMV therapy are efficacious treatment of CR. Conventional eye examinations should be conducted to early diagnose CR or other opportunistic infections in all AIDS patients.

PMID: 26309620 [PubMed – as supplied by publisher]

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Hematopoietic Stem Cell Transplantations for Primary Immune Deficiencies: 3 Decades of Experience From a Tertiary Medical Center.

J Pediatr Hematol Oncol. 2015 Jul;37(5):e295-300

Authors: Rousso SZ, Shamriz O, Zilkha A, Braun J, Averbuch D, Or R, Weintraub M, Revel-Vilk S, Stepensky P

Abstract
Hematopoietic stem cell transplantation (HSCT) remains the leading treatment for the majority of severe primary immune deficiency (PID). This study aims to analyze changes in outcome over time. We conducted a retrospective analysis of HSCT in children with PID in a tertiary medical center over the period of 1983 to 2012. We identified 93 children with PID with a median follow-up of 3.6 years (range, 29 d to 21.2 y) after HSCT. The 2-year survival rates after HSCT for children with severe combined immune deficiency, hemophagocytic lymphohistiocytosis/lymphoproliferative disease, Wiskott-Aldrich syndrome, granulocyte defect, and undefined PID were 65.7%±6.8%, 80%±10.3%, 83.3%±15.2%, 75%±12.5%, and 25%±21.7%, respectively. Survival was associated with year of HSCT and matching. The hazard ratio (HR) (95% CI) for HSCT done in 1983 to 1999 compared with 2000 to 2012 and for matched (related and unrelated) compared with mismatched donor were 2.14 (0.99 to 4.653) and 3.07 (1.46 to 6.4), respectively. Survival was not associated with age, sex of the recipient, underlying PID, conditioning regimen, and presence of acute graft-versus-host disease. After adjustment to the underlying PID, donor and use of fludarabine-based conditioning, the HR (95% CI) for HSCT from the year 2000 was 4.69 (range, 1.4 to 15.45). Advances in HSCT over time have improved the survival of children with PID.

PMID: 25985240 [PubMed – indexed for MEDLINE]

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Fatal autoimmunity in mice reconstituted with human hematopoietic stem cells encoding defective FOXP3.

Blood. 2015 Jun 18;125(25):3886-95

Authors: Goettel JA, Biswas S, Lexmond WS, Yeste A, Passerini L, Patel B, Yang S, Sun J, Ouahed J, Shouval DS, McCann KJ, Horwitz BH, Mathis D, Milford EL, Notarangelo LD, Roncarolo MG, Fiebiger E, Marasco WA, Bacchetta R, Quintana FJ, Pai SY, Klein C, Muise AM, Snapper SB

Abstract
Mice reconstituted with a human immune system provide a tractable in vivo model to assess human immune cell function. To date, reconstitution of murine strains with human hematopoietic stem cells (HSCs) from patients with monogenic immune disorders have not been reported. One obstacle precluding the development of immune-disease specific “humanized” mice is that optimal adaptive immune responses in current strains have required implantation of autologous human thymic tissue. To address this issue, we developed a mouse strain that lacks murine major histocompatibility complex class II (MHC II) and instead expresses human leukocyte antigen DR1 (HLA-DR1). These mice displayed improved adaptive immune responses when reconstituted with human HSCs including enhanced T-cell reconstitution, delayed-type hypersensitivity responses, and class-switch recombination. Following immune reconstitution of this novel strain with HSCs from a patient with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, associated with aberrant FOXP3 function, mice developed a lethal inflammatory disorder with multiorgan involvement and autoantibody production mimicking the pathology seen in affected humans. This humanized mouse model permits in vivo evaluation of immune responses associated with genetically altered HSCs, including primary immunodeficiencies, and should facilitate the study of human immune pathobiology and the development of targeted therapeutics.

PMID: 25833964 [PubMed – indexed for MEDLINE]

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A new subcutaneous immune globulin (HyQvia) for primary immunodeficiency.

Med Lett Drugs Ther. 2015 Aug 31;57(1476):121-122

Authors:

PMID: 26305523 [PubMed – as supplied by publisher]

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Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome.

J Exp Med. 2015 Aug 24;

Authors: Kreins AY, Ciancanelli MJ, Okada S, Kong XF, Ramírez-Alejo N, Kilic SS, El Baghdadi J, Nonoyama S, Mahdaviani SA, Ailal F, Bousfiha A, Mansouri D, Nievas E, Ma CS, Rao G, Bernasconi A, Sun Kuehn H, Niemela J, Stoddard J, Deveau P, Cobat A, El Azbaoui S, Sabri A, Lim CK, Sundin M, Avery DT, Halwani R, Grant AV, Boisson B, Bogunovic D, Itan Y, Moncada-Velez M, Martinez-Barricarte R, Migaud M, Deswarte C, Alsina L, Kotlarz D, Klein C, Muller-Fleckenstein I, Fleckenstein B, Cormier-Daire V, Rose-John S, Picard C, Hammarstrom L, Puel A, Al-Muhsen S, Abel L, Chaussabel D, Rosenzweig SD, Minegishi Y, Tangye SG, Bustamante J, Casanova JL, Boisson-Dupuis S

Abstract
Autosomal recessive, complete TYK2 deficiency was previously described in a patient (P1) with intracellular bacterial and viral infections and features of hyper-IgE syndrome (HIES), including atopic dermatitis, high serum IgE levels, and staphylococcal abscesses. We identified seven other TYK2-deficient patients from five families and four different ethnic groups. These patients were homozygous for one of five null mutations, different from that seen in P1. They displayed mycobacterial and/or viral infections, but no HIES. All eight TYK2-deficient patients displayed impaired but not abolished cellular responses to (a) IL-12 and IFN-α/β, accounting for mycobacterial and viral infections, respectively; (b) IL-23, with normal proportions of circulating IL-17(+) T cells, accounting for their apparent lack of mucocutaneous candidiasis; and (c) IL-10, with no overt clinical consequences, including a lack of inflammatory bowel disease. Cellular responses to IL-21, IL-27, IFN-γ, IL-28/29 (IFN-λ), and leukemia inhibitory factor (LIF) were normal. The leukocytes and fibroblasts of all seven newly identified TYK2-deficient patients, unlike those of P1, responded normally to IL-6, possibly accounting for the lack of HIES in these patients. The expression of exogenous wild-type TYK2 or the silencing of endogenous TYK2 did not rescue IL-6 hyporesponsiveness, suggesting that this phenotype was not a consequence of the TYK2 genotype. The core clinical phenotype of TYK2 deficiency is mycobacterial and/or viral infections, caused by impaired responses to IL-12 and IFN-α/β. Moreover, impaired IL-6 responses and HIES do not appear to be intrinsic features of TYK2 deficiency in humans.

PMID: 26304966 [PubMed – as supplied by publisher]

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Cordycepin induced MA-10 mouse Leydig tumor cell apoptosis by regulating p38 MAPKs and PI3K/AKT signaling pathways.

Sci Rep. 2015;5:13372

Authors: Pan BS, Wang YK, Lai MS, Mu YF, Huang BM

Abstract
The p38 MAPKs play important roles in the regulation of balance between cell survival and cell death on the development of various cancers. However, the roles of p38 MAPKs regulating apoptotic effects on Leydig tumor cells remain unclear. In the present study, we showed that cordycepin (3′-deoxyadenosine) selectively induced apoptosis in MA-10 mouse Leydig tumor cells through regulating the p38 MAPK and PI3K/AKT signaling pathways. Cordycepin reduced viability in MA-10, TM4, and NT2/D1 cells, but not cause cell death of primary mouse Leydig cells on moderate concentration. Cordycepin increased reactive oxygen species (ROS) levels, which is associated with the induction of apoptosis as characterized by positive Annexin V binding, activation of caspase-3, and cleavage of PARP. Inhibition of p38 MAPKs activity by SB203580 significantly prevented cordycepin-induced apoptosis in MA-10 cells. Co-treatment with wortmannin or the autophagy inhibitor 3-methyladenine (3-MA) elevated levels of apoptosis in cordycepin-treated MA-10 cells. Moreover, cordycepin activated p53, p21 and TGFß; and downregulated CDK2. The antitumour activity of cordycepin-treated MA-10 cells was significantly distinct in severe combined immunodeficiency (SCID) mice in vivo. These results suggested that cordycein is a highly selective treatment to induce MA-10 cells apoptosis via p38 MAPKs signaling.

PMID: 26303320 [PubMed – in process]

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Therapeutic immunoglobulin should be dosed by clinical outcome rather than by body weight in obese patients.

Clin Exp Immunol. 2015 Jul;181(1):179-87

Authors: Hodkinson JP, Lucas M, Lee M, Harrison M, Lunn MP, Chapel H

Abstract
There are currently no data to support the suggestion that the dose of therapeutic immunoglobulin (Ig) should be capped in obese patients for pharmacokinetic (PK), safety and economic reasons. We compared IgG trough levels, increment and efficiency in matched pairs of obese and lean patients receiving either replacement or immunomodulatory immunoglobulin therapy. Thirty-one obese patients were matched with a clinically equivalent lean patient across a range of indications, including primary antibody deficiency or autoimmune peripheral neuropathy. Comprehensive matching was carried out using ongoing research databases at two centres in which the dose of Ig was based on clinical outcome, whether infection prevention or documented clinical neurological stability. The IgG trough or steady state levels, IgG increments and Ig efficiencies at times of clinical stability were compared between the obese and lean cohorts and within the matched pairs. This study shows that, at a population level, obese patients achieved a higher trough and increment (but not efficiency) for a given weight-adjusted dose compared with the lean patients. However at an individual patient level there were significant exceptions to this correlation, and upon sub-group analysis no significant difference was found between obese and lean patients receiving replacement therapy. Across all dose regimens a high body mass index (BMI) cannot be used to predict reliably the patients in whom dose restriction is clinically appropriate.

PMID: 25731216 [PubMed – indexed for MEDLINE]

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[Severe atopy and allergy–rare hyper-IgE syndrome caused by the DOCK8 mutation as underlying condition].

Duodecim. 2015;131(6):541-4

Authors: Koskenvuo M, Kainulainen L, Vanto T, Lukkarinen H, Lähteenmäki P, Ruuskanen O

Abstract
The DOCK8 hyperimmunoglobulin E syndrome is an autosomal recessive primary combined immunological deficiency. Severe atopic eczema having its onset in infancy, food allergies, chronic viral infections of the skin, and recurrent pneumonias are central symptoms. Serum IgE level is high and eosinophilia is found in the blood. In addition, abnormalities in the number and function of lymphocytes can be detected. The disease may be difficult to distinguish from severe allergic eczema and asthma. The diagnosis is made through a gene test. We describe a 13-year-old boy, whose disease was cured with allogenic stem cell transplantation.

PMID: 26237897 [PubMed – indexed for MEDLINE]

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