Research

An 18-Year-Old Male With X-linked Lymphoproliferative Syndrome Type 1 Who Developed Primary Central Nervous System Lymphoma 6 Months After Primary Epstein-Barr Virus Infection.

January 25, 2019 By Manish Butte

An 18-Year-Old Male With X-linked Lymphoproliferative Syndrome Type 1 Who Developed Primary Central Nervous System Lymphoma 6 Months After Primary Epstein-Barr Virus Infection.

J Pediatr Hematol Oncol. 2019 Jan 22;:

Authors: Kusano N, Sakata N, Sugimoto K, Miyazawa T, Ueda S, Okano M, Imadome KI, Hoshino A, Kanegane H, Kimura M, Sato T, Okada M, Takemura T

Abstract
X-linked lymphoproliferative syndrome type 1 (XLP1) is a rare congenital immunodeficiency disease. We report the case of an 18-year-old male who developed hemophagocytic lymphohistiocytosis (HLH) with neurological complications after primary Epstein-Barr virus (EBV) infection and subsequently developed EBV-related central nervous system lymphoma (CNSL). Given the vulnerability to EBV, he was finally diagnosed with XLP1 and treated with whole-brain irradiation along with chemotherapy and subsequent allogeneic hematopoietic stem cell transplantation from a SH2D1A wild-type sibling donor. Although the prognosis for CNSL is generally dismal, reconstitution of the immune system from a normal donor contributed to the patient remaining in remission for 30 months.

PMID: 30676439 [PubMed – as supplied by publisher]

Antibiotic Prophylaxis for Dental Treatment in Patients with Immunodeficiency.

January 25, 2019 By Manish Butte

Antibiotic Prophylaxis for Dental Treatment in Patients with Immunodeficiency.

J Allergy Clin Immunol Pract. 2019 Jan 21;:

Authors: Squire J, Gardner PJ, Moutsopoulos NM, Leiding JW

Abstract
Routine antibacterial prophylaxis is recommended prior to dental procedures in select patient populations. Currently no guidelines are in place for routine prophylaxis prior to dental procedures in patients with primary immunodeficiency diseases (PIDD). We review risk factors and provide recommendations on routine dental care and antibacterial prophylaxis in patients with PIDD.

PMID: 30677537 [PubMed – as supplied by publisher]

[Establishment of A Patient-derived Xenotransplantation Animal Model for Small Cell Lung Cancer and Drug Resistance Model].

January 25, 2019 By Manish Butte

[Establishment of A Patient-derived Xenotransplantation Animal Model for Small Cell Lung Cancer and Drug Resistance Model].

Zhongguo Fei Ai Za Zhi. 2019 Jan 20;22(1):6-14

Authors: Zhu Y, Huang W, Wu Y, Jia L, Li Y, Chen R, Guo L, Chen Q

Abstract
BACKGROUND: Small cell lung cancer (SCLC) is characterized by poor differentiation, high malignancy and rapid growth fast, short double time, early and extensive metastatic malignancy. In clinical, chemotherapy is the main treatment method, while resistance to multiple chemotherapy drugs in six to nine months has been a major clinical challenge in SCLC treatment. Therefore, It has important clinical value to building SCLC aninimal model which is similar to patients with SCLC. Animal model of xenotransplantation (PDX) from the patients with small cell lung cancer can well retain the characteristics of primary tumor and is an ideal preclinical animal model. The study is aimed to establish SCLC PDX animal model and induce the chemoresistance model to help to study the mechanism of chemoresistance and individual treatment.
METHODS: Fresh surgical excision or puncture specimens from SCLC patients were transplanted into B-NSGTM mice subcutaneous tissues with severe immunodeficiency in one hour after operation the B-NSGTM mice subcutaneous in 1 hour, and inject chemotherapy drugs intraperitoneally after its tumor growed to 400 mm³ with EP which is cisplatin 8 mg/kg eight days and etoposide 5 mg/kg every two days until 8 cycles. Measure the tumor volum and mice weights regularly, then re-engrafted the largest tumor and continue chemotherapy.
RESULTS: Nine cases were conducted for B-NSG mice modeling. Three of nine cases could be engrafted to new B-NSG mice at least two generation. The SCLC PDX animal models have been established successfully. After adopting chemotherapy drugs, the chemoresistance PDX models have been established. High homogeneity was found between xenograft tumor and patient’s tumor in histopathology, immunohistochemical phenotype (Syn, CD56, Ki67).
CONCLUSIONS: The SCLC PDX animal model and the chemoresistance PDX animal model have been successfully constructed, the success rate is 33%, which provides a platform for the clinical research, seeking for biological markers and choosing individual treatment methods of SCLC.

PMID: 30674387 [PubMed – in process]

Neurological Involvement in Childhood Evans Syndrome.

January 24, 2019 By Manish Butte

Neurological Involvement in Childhood Evans Syndrome.

J Clin Immunol. 2019 Jan 22;:

Authors: Pincez T, Neven B, Le Pointe HD, Varlet P, Fernandes H, Gareton A, Leverger G, Leblanc T, Chambost H, Michel G, Pasquet M, Millot F, Hermine O, Mathian A, Hully M, Zephir H, Hamidou M, Durand JM, Perel Y, Landman-Parker J, Rieux-Laucat F, Aladjidi N

Abstract
PURPOSE: Immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AIHA) are associated in the definition of Evans syndrome (ES). The occurrence of neurological involvement in this population is poorly described and suggests an underlying primary immunodeficiency (PID). We aimed to describe the clinical manifestations, evolution, and PID profiles of these patients.
METHODS: OBS’CEREVANCE is a French, nationwide prospective cohort that includes children with chronic ITP, AIHA, and ES. Patients with a neurological involvement were described. Centralized radiological and pathological reviews and genetic analyses were performed.
RESULTS: On October 2016, eight patients (7/181 ES, 1/371 AIHA, and 0/615 ITP) were identified, all male, with a median age (range) at cytopenia onset of 11.5 years (1.6-15.8). Neurological symptoms appeared with a median delay of 6 years (2.5-18) after cytopenia and were polymorphic: seizures (n = 4), cranial nerve palsy (n = 2), Brown-Sequard syndrome (n = 2), intracranial pressure (n = 2), vertigo (n = 1), and/or sensory neuropathy (n = 1). Magnetic resonance imaging (MRI) showed inflammatory lesions, confirmed by pathology for five patients with macrophagic or lymphoplasmocytic infiltrates. All patients had other relevant immunopathological manifestations: pulmonary nodules (n = 6), lymphoproliferation (n = 4), abnormal immunophenotype (n = 8), and hypogammaglobulinemia (n = 7). Treatment consisted of steroids that improved symptomatology and MRI. Five patients relapsed and three had an asymptomatic radiological progression. A PID was identified in 3/8 patients: 22q11.2 microdeletion (n = 1) and CTLA deficiency (n = 2).
CONCLUSION: Neurological involvement is a rare and severe late event in the course of childhood ES, which can reveal an underlying PID. Imaging and pathology examination highlight a causative immune dysregulation that may guide targeted therapeutic strategies.

PMID: 30671780 [PubMed – as supplied by publisher]

IRF and STAT Transcription Factors – From Basic Biology to Roles in Infection, Protective Immunity, and Primary Immunodeficiencies.

January 24, 2019 By Manish Butte

IRF and STAT Transcription Factors – From Basic Biology to Roles in Infection, Protective Immunity, and Primary Immunodeficiencies.

Front Immunol. 2018;9:3047

Authors: Mogensen TH

Abstract
The induction and action of type I interferon (IFN) is of fundamental importance in human immune defenses toward microbial pathogens, particularly viruses. Basic discoveries within the molecular and cellular signaling pathways regulating type I IFN induction and downstream actions have shown the essential role of the IFN regulatory factor (IRF) and the signal transducer and activator of transcription (STAT) families, respectively. However, the exact biological and immunological functions of these factors have been most clearly revealed through the study of inborn errors of immunity and the resultant infectious phenotypes in humans. The spectrum of human inborn errors of immunity caused by mutations in IRFs and STATs has proven very diverse. These diseases encompass herpes simplex encephalitis (HSE) and severe influenza in IRF3- and IRF7/IRF9 deficiency, respectively. They also include Mendelian susceptibility to mycobacterial infection (MSMD) in STAT1 deficiency, through disseminated measles infection associated with STAT2 deficiency, and finally staphylococcal abscesses and chronic mucocutaneous candidiasis (CMC) classically described with Hyper-IgE syndrome (HIES) in the case of STAT3 deficiency. More recently, increasing focus has been on aspects of autoimmunity and autoinflammation playing an important part in many primary immunodeficiency diseases (PID)s, as exemplified by STAT1 gain-of-function causing CMC and autoimmune thyroiditis, as well as a recently described autoinflammatory syndrome with hypogammaglobulinemia and lymphoproliferation as a result of STAT3 gain-of-function. Here I review the infectious, inflammatory, and autoimmune disorders arising from mutations in IRF and STAT transcription factors in humans, highlightning the underlying molecular mechanisms and immunopathogenesis as well as the clinical/therapeutic perspectives of these new insights.

PMID: 30671054 [PubMed – in process]

Lactobacillus acidophilus/Bifidobacterium infantis probiotics are associated with increased growth of VLBWI among those exposed to antibiotics.

January 24, 2019 By Manish Butte

Lactobacillus acidophilus/Bifidobacterium infantis probiotics are associated with increased growth of VLBWI among those exposed to antibiotics.

Sci Rep. 2017 07 17;7(1):5633

Authors: Härtel C, Pagel J, Spiegler J, Buma J, Henneke P, Zemlin M, Viemann D, Gille C, Gehring S, Frommhold D, Rupp J, Herting E, Göpel W

Abstract
We performed an observational study with very-low-birth weight infants (VLBWI) ≤33 weeks of gestation born in centers of the German Neonatal Network (GNN; (total n = 8534, n = 6229 received probiotics). The primary objectives of our study were (a) to assess the effect of Lactobacillus acidophilus/Bifidobacterium infantis probiotics on growth in VLBWI during primary stay in hospital and (b) to determine whether this effect is modified by antibiotic exposure. In linear regression models the administration of probiotics was independently associated with improved weight gain [g/d; effect size B = 0.62 (95% CI: 0.37-0.87), p < 0.001], and higher growth rates for body length [(mm/d; B = 0.06 (95% CI: 0.04-0.08), p < 0.001] and head circumference [mm/d; B = 0.03, 95% CI: 0.02-0.04, p < 0.001]. This effect was pronounced in infants with postnatal exposure to antibiotics; i.e. weight gain [g/d; B = 0.66 (95% CI: 0.32-1), p < 0.001], growth rate body length [(mm/d; B = 0.09 (95% CI: 0.06-0.12), p < 0.001] and head circumference [mm/d; B = 0.04, 95% CI: 0.02-0.06, p < 0.001]. In the small subgroup that was available for analysis at 5-year-follow-up (with probiotics: n = 120 vs. without probiotics: n = 54) we noted a sustained effect of probiotics in infants who received postnatal antibiotics. Probiotics may improve growth in antibiotic-treated infants which needs to be confirmed in randomized-controlled trials.

PMID: 28717131 [PubMed – indexed for MEDLINE]

PI3K Orchestrates T Follicular Helper Cell Differentiation in a Context Dependent Manner: Implications for Autoimmunity.

January 23, 2019 By Manish Butte

PI3K Orchestrates T Follicular Helper Cell Differentiation in a Context Dependent Manner: Implications for Autoimmunity.

Front Immunol. 2018;9:3079

Authors: Preite S, Huang B, Cannons JL, McGavern DB, Schwartzberg PL

Abstract
T follicular helper (Tfh) cells are a specialized population of CD4+ T cells that provide help to B cells for the formation and maintenance germinal centers, and the production of high affinity class-switched antibodies, long-lived plasma cells, and memory B cells. As such, Tfh cells are essential for the generation of successful long-term humoral immunity and memory responses to vaccination and infection. Conversely, overproduction of Tfh cells has been associated with the generation of autoantibodies and autoimmunity. Data from gene-targeted mice, pharmacological inhibitors, as well as studies of human and mice expressing activating mutants have revealed that PI3Kδ is a key regulator of Tfh cell differentiation, acting downstream of ICOS to facilitate inactivation of FOXO1, repression of Klf2 and induction of Bcl6. Nonetheless, here we show that after acute LCMV infection, WT and activated-PI3Kδ mice (Pik3cd E1020K/+) show comparable ratios of Tfh:Th1 viral specific CD4+ T cells, despite higher polyclonal Tfh cells in Pik3cd E1020K/+ mice. Thus, the idea that PI3K activity primarily drives Tfh cell differentiation may be an oversimplification and PI3K-mediated pathways are likely to integrate multiple signals to promote distinct effector T cell lineages. The consequences of dysregulated Tfh cell generation will be discussed in the context of the human primary immunodeficiency “Activated PI3K-delta Syndrome” (APDS), also known as “p110 delta-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency” (PASLI). Overall, these data underscore a major role for PI3K signaling in the orchestration of T lymphocyte responses.

PMID: 30666254 [PubMed – in process]

Extreme Phenotypes With Identical Mutations: Two Patients With Same Non-sense NHEJ1 Homozygous Mutation.

January 23, 2019 By Manish Butte

Extreme Phenotypes With Identical Mutations: Two Patients With Same Non-sense NHEJ1 Homozygous Mutation.

Front Immunol. 2018;9:2959

Authors: Recio MJ, Dominguez-Pinilla N, Perrig MS, Rodriguez Vigil-Iturrate C, Salmón-Rodriguez N, Martinez Faci C, Castro-Panete MJ, Blas-Espada J, López-Nevado M, Ruiz-Garcia R, Chaparro-García R, Allende LM, Gonzalez-Granado LI

Abstract
Cernunnos/XLF deficiency is a rare primary immunodeficiency classified within the DNA repair defects. Patients present with severe growth retardation, microcephaly, lymphopenia and increased cellular sensitivity to ionizing radiation. Here, we describe two unrelated cases with the same non-sense mutation in the NHEJ1 gene showing significant differences in clinical presentation and immunological profile but a similar DNA repair defect.

PMID: 30666249 [PubMed – in process]

Exogenous Stimulation of Type I Interferon Protects Mice with Chronic Granulomatous Disease from Aspergillosis through Early Recruitment of Host-Protective Neutrophils into the Lung.

January 23, 2019 By Manish Butte

Exogenous Stimulation of Type I Interferon Protects Mice with Chronic Granulomatous Disease from Aspergillosis through Early Recruitment of Host-Protective Neutrophils into the Lung.

MBio. 2018 03 27;9(2):

Authors: Seyedmousavi S, Davis MJ, Sugui JA, Pinkhasov T, Moyer S, Salazar AM, Chang YC, Kwon-Chung KJ

Abstract
Invasive aspergillosis (IA) remains the primary cause of morbidity and mortality in chronic granulomatous disease (CGD) patients, often due to infection by Aspergillus species refractory to antifungals. This motivates the search for alternative treatments, including immunotherapy. We investigated the effect of exogenous type I interferon (IFN) activation on the outcome of IA caused by three Aspergillus species, A. fumigatus, A. nidulans, and A. tanneri, in CGD mice. The animals were treated with poly(I):poly(C) carboxymethyl cellulose poly-l-lysine (PICLC), a mimetic of double-stranded RNA, 24 h preinfection and postinfection. The survival rates and lung fungal burdens were markedly improved by PICLC immunotherapy in animals infected with any one of the three Aspergillus species. While protection from IA was remarkable, PICLC induction of type I IFN in the lungs surged 24 h posttreatment and returned to baseline levels by 48 h, suggesting that PICLC altered early events in protection against IA. Immunophenotyping of recruited leukocytes and histopathological examination of tissue sections showed that PICLC induced similar cellular infiltrates as those in untreated-infected mice, in both cases dominated by monocytic cells and neutrophils. However, the PICLC immunotherapy resulted in a marked earlier recruitment of the leukocytes. Unlike with conidia, infection with A. nidulans germlings reduced the protective effect of PICLC immunotherapy. Additionally, antibody depletion of neutrophils totally reversed the protection, suggesting that neutrophils are crucial for PICLC-mediated protection. Together, these data show that prophylactic PICLC immunotherapy prerecruits these cells, enabling them to attack the conidia and thus resulting in a profound protection from IA.IMPORTANCE Patients with chronic granulomatous disease (CGD) are highly susceptible to invasive aspergillosis (IA). While Aspergillus fumigatus is the most-studied Aspergillus species, CGD patients often suffer IA caused by A. nidulans, A. tanneri, and other rare species. These non-fumigatus Aspergillus species are more resistant to antifungal drugs and cause higher fatality rates than A. fumigatus Therefore, alternative therapies are needed to protect CGD patients. We report an effective immunotherapy of mice infected with three Aspergillus species via PICLC dosing. While protection from IA was long lasting, PICLC induction of type I IFN surged but quickly returned to baseline levels, suggesting that PICLC was altering early events in IA. Interestingly, we found responding immune cells to be similar between PICLC-treated and untreated-infected mice. However, PICLC immunotherapy resulted in an earlier recruitment of the leukocytes and suppressed fungal growth. This study highlights the value of type I IFN induction in CGD patients.

PMID: 29588403 [PubMed – indexed for MEDLINE]

Application of induced pluripotent stem cells to primary immunodeficiency diseases.

January 22, 2019 By Manish Butte

Application of induced pluripotent stem cells to primary immunodeficiency diseases.

Exp Hematol. 2019 Jan 18;:

Authors: Karagiannis P, Yamanaka S, Saito MK

Abstract
Primary immunodeficiency diseases (PIDs) are a heterogeneous group of rare immune disorders with genetic causes. Effective treatments using hematopoietic stem cells or pharmaceutical agents have been around for decades. However, for many patients, these treatment options are ineffective, partly because the rarity of these PIDs complicates the diagnosis and therapy. Induced pluripotent stem cells (iPSCs) offer a potential solution to these problems. The proliferative capacity of iPSCs allows for the preparation of a large, stable supply of hematopoietic cells with the same genome as the patient, allowing for new human cell models that can trace cellular abnormalities during the pathogenesis and lead to new drug discovery. PID models using patient iPSCs have been instrumental in identifying deviations in the development or function of several types of immune cells, revealing new molecular targets for experimental therapies. These models are only in their early stages and for the most part have recapitulated results from existing models using animals or primary cells. However, iPSC-based models are now being used to study complex diseases of other organs including those with multigenic causes, suggesting advances in differentiation processes will expand iPSC-based models to complex PIDs as well.

PMID: 30664903 [PubMed – as supplied by publisher]