Manish Butte

Isolation and characterization of adult mammary stem cells from breast cancer-adjacent tissues.

Oncol Lett. 2017 Sep;14(3):2894-2902

Authors: Shi AP, Fan ZM, Ma KW, Jiang YF, Wang L, Zhang KW, Fu SB, Xu N, Zhang ZR

Abstract
Normal adult mammary stem cells (AMSCs) are promising sources for breast reconstruction, particularly following the resection of breast tumors. However, carcinogenic events can potentially convert normal AMSCs to cancer stem cells, posing a safety concern for the use of AMSCs for clinical tissue regeneration. In the present study, AMSCs and autologous primary breast cancer cells were isolated and compared for their ability to differentiate, their gene expression profile, and their potential to form tumors in vivo. AMSCs were isolated from normal tissue surrounding primary breast tumors by immunomagnetic sorting. The pluripotency of these cells was investigated by differentiation analysis, and gene expression profiles were compared with microarrays. Differentially expressed candidate genes were confirmed by reverse transcription-polymerase chain reaction and western blot analyses. The in vivo tumorigenicity of these cells, compared with low-malignancy MCF-7 cells, was also investigated by xenograft tumor formation analysis. The results revealed that AMSCs isolated from normal tissues surrounding primary breast tumors were positive for the stem cell markers epithelial-specific antigen and keratin-19. When stimulated with basic fibroblast growth factor, a differentiation agent, these AMSCs formed lobuloalveolar structures with myoepithelia that were positive for common acute lymphoblastic leukemia antigen. The gene expression profiles revealed that, compared with cancer cells, AMSCs expressed low levels of oncogenes, including MYC, RAS and ErbB receptor tyrosine kinase 2, and high levels of tumor suppressor genes, including RB transcriptional corepressor 1, phosphatase and tensin homolog, and cyclin-dependent kinase inhibitor 2A. When injected into nude non-obese diabetic/severe combined immunodeficiency-type mice, the AMSCs did not form tumors, and regular mammary ductal structures were generated. The AMSCs isolated from normal tissue adjacent to primary breast tumors had the normal phenotype of mammary stem cells, and therefore may be promising candidates for mammary reconstruction subsequent to breast tumor resection.

PMID: 28927044 [PubMed]

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Spinal cord injury-induced immunodeficiency is mediated by a sympathetic-neuroendocrine adrenal reflex.

Nat Neurosci. 2017 Sep 18;:

Authors: Prüss H, Tedeschi A, Thiriot A, Lynch L, Loughhead SM, Stutte S, Mazo IB, Kopp MA, Brommer B, Blex C, Geurtz LC, Liebscher T, Niedeggen A, Dirnagl U, Bradke F, Volz MS, DeVivo MJ, Chen Y, von Andrian UH, Schwab JM

Abstract
Acute spinal cord injury (SCI) causes systemic immunosuppression and life-threatening infections, thought to result from noradrenergic overactivation and excess glucocorticoid release via hypothalamus-pituitary-adrenal axis stimulation. Instead of consecutive hypothalamus-pituitary-adrenal axis activation, we report that acute SCI in mice induced suppression of serum norepinephrine and concomitant increase in cortisol, despite suppressed adrenocorticotropic hormone, indicating primary (adrenal) hypercortisolism. This neurogenic effect was more pronounced after high-thoracic level (Th1) SCI disconnecting adrenal gland innervation, compared with low-thoracic level (Th9) SCI. Prophylactic adrenalectomy completely prevented SCI-induced glucocorticoid excess and lymphocyte depletion but did not prevent pneumonia. When adrenalectomized mice were transplanted with denervated adrenal glands to restore physiologic glucocorticoid levels, the animals were completely protected from pneumonia. These findings identify a maladaptive sympathetic-neuroendocrine adrenal reflex mediating immunosuppression after SCI, implying that therapeutic normalization of the glucocorticoid and catecholamine imbalance in SCI patients could be a strategy to prevent detrimental infections.

PMID: 28920935 [PubMed – as supplied by publisher]

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Mitochondrial Priming by CD28.

Cell. 2017 Sep 01;:

Authors: Klein Geltink RI, O’Sullivan D, Corrado M, Bremser A, Buck MD, Buescher JM, Firat E, Zhu X, Niedermann G, Caputa G, Kelly B, Warthorst U, Rensing-Ehl A, Kyle RL, Vandersarren L, Curtis JD, Patterson AE, Lawless S, Grzes K, Qiu J, Sanin DE, Kretz O, Huber TB, Janssens S, Lambrecht BN, Rambold AS, Pearce EJ, Pearce EL

Abstract
T cell receptor (TCR) signaling without CD28 can elicit primary effector T cells, but memory T cells generated during this process are anergic, failing to respond to secondary antigen exposure. We show that, upon T cell activation, CD28 transiently promotes expression of carnitine palmitoyltransferase 1a (Cpt1a), an enzyme that facilitates mitochondrial fatty acid oxidation (FAO), before the first cell division, coinciding with mitochondrial elongation and enhanced spare respiratory capacity (SRC). microRNA-33 (miR33), a target of thioredoxin-interacting protein (TXNIP), attenuates Cpt1a expression in the absence of CD28, resulting in cells that thereafter are metabolically compromised during reactivation or periods of increased bioenergetic demand. Early CD28-dependent mitochondrial engagement is needed for T cells to remodel cristae, develop SRC, and rapidly produce cytokines upon restimulation-cardinal features of protective memory T cells. Our data show that initial CD28 signals during T cell activation prime mitochondria with latent metabolic capacity that is essential for future T cell responses.

PMID: 28919076 [PubMed – as supplied by publisher]

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Clinical, Immunological and Genetic Spectrum of 696 Patients with Combined Immunodeficiency.

J Allergy Clin Immunol. 2017 Sep 12;:

Authors: Abolhassani H, Chou J, Bainter W, Platt C, Tavassoli M, Momen T, Tavakol M, Eslamian MH, Gharagozlou M, Movahedi M, Ghadami M, Hamidieh AA, Azizi G, Yazdani R, Afarideh M, Ghajar A, Havaei A, Chavoushzadeh Z, Mahdaviani SA, Cheraghi T, Behniafard N, Amin R, Aleyasin S, Faridhosseini R, Jabbari-Azad F, Nabavi M, Bemanian MH, Arshi S, Molatefi R, Sherkat R, Mansouri M, Mesdaghi M, Babaie D, Mohammadzadeh I, Ghaffari J, Shafiei A, Kalantari N, Ahanchian H, Khoshkhui M, Soheili H, Dabbaghzadeh A, Shirkani A, Kalmarzi RN, Mortazavi SH, Tafaroji J, Khalili A, Mohammadi J, Negahdari B, Joghataei MT, Al-Ramadi BK, Picard C, Parvaneh N, Rezaei N, Chatila T, Massaad MJ, Keles S, Hammarström L, Geha RS, Aghamohammadi A

Abstract
BACKGROUND: Combined immunodeficiencies (CIDs) are diseases of defective adaptive immunity with diverse clinical phenotypes. Although CIDs are more prevalent in the Middle East than Western countries, the resources for genetic diagnosis are limited.
OBJECTIVES: This study aims to characterize the categories of CID patients in Iran clinically and genetically.
METHODS: Clinical and laboratory data were obtained from 696 patients with CIDs. Patients were subdivided into those with syndromic (344 patients) and non-syndromic CIDs (352 patients). Targeted DNA sequencing was performed on 243 patients (34.9%).
RESULTS: The overall diagnostic yield of the 243 sequenced patients was 77.8% (189 patients). The clinical diagnosis of HIES (p<0.001), onset of disease > 5y (p=0.02), and the absence of multiple affected family members (p=0.04), were significantly more frequent in the patients without a genetic diagnosis. An autosomal recessive disease was found in 62.9% of patients, reflecting the high rate of consanguinity in this cohort. Mutations impairing VDJ recombination and DNA repair were the most common underlying causes of CIDs. However, in patients with syndromic CIDs, autosomal recessive mutations in ATM, autosomal dominant mutations in STAT3 and microdeletions in 22q11.21 were the most commonly affected genomic loci. Patients with syndromic CIDs had a significantly lower five-year survival rate rather than those with non-syndromic CIDs.
CONCLUSIONS: This study provides proof of principle for the application of targeted next-generation sequencing panels in countries with limited diagnostic resources. The impact of genetic diagnosis on clinical care requires continued improvements in therapeutic resources for these patients.

PMID: 28916186 [PubMed – as supplied by publisher]

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Signal transducer and activator of transcription gain-of-function primary immunodeficiency/immunodysregulation disorders.

Curr Opin Pediatr. 2017 Sep 13;:

Authors: Consonni F, Dotta L, Todaro F, Vairo D, Badolato R

Abstract
PURPOSE OF REVIEW: To describe primary immunodeficiencies caused by gain-of-function (GOF) mutations of signal transducer and activator of transcription (STAT) genes, a group of genetically determined disorders characterized by susceptibility to infections and, in many cases, autoimmune manifestations.
RECENT FINDINGS: GOF mutations affecting STAT1 result in increased STAT tyrosine phosphorylation and secondarily increased response to STAT1-signaling cytokines, such as interferons. In contrast, STAT3 hyperactivity is not usually related to hyperphosphorylation but rather to increased STAT3-mediated transcriptional activity. In both cases, heterozygous STAT1 and STAT3 GOF mutations trigger a distinct set of genes in target cells that lead to abnormal functioning of antimicrobial response and/or autoimmunity and result in autosomal dominant diseases.
SUMMARY: Clinical manifestations of patients with STAT1 GOF are characterized by mucocutaneous candidiasis and recurrent lower tract respiratory infections. In addition, many patients have thyroiditis, type 1 diabetes mellitus, autoimmune cytopenias, cancer or aneurysms. Patients with germline STAT3 GOF mutations have an increased frequency of early-onset multiorgan autoimmunity (i.e. autoimmune enteropathy, type 1 diabetes mellitus, autoimmune interstitial lung disease and autoimmune cytopenias), lymphoproliferation, short stature and, less frequently, severe recurrent infections. Treatment options range from antimicrobial therapy, intravenous or subcutaneous immunoglobulin and immunosuppressive drugs. Some patients with STAT1 GOF disorder have undergone hematopoietic stem cell transplantation, although these have been difficult because of the underlying proinflammatory milieu from the mutation.

PMID: 28914637 [PubMed – as supplied by publisher]

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Effects of Immunoglobulin Replacement on Asthma Exacerbation in Adult Asthmatics with IgG Subclass Deficiency.

Allergy Asthma Immunol Res. 2017 Nov;9(6):526-533

Authors: Kim JH, Ye YM, Ban GY, Shin YS, Lee HY, Nam YH, Lee SK, Cho YS, Jang SH, Jung KS, Park HS

Abstract
PURPOSE: Recurrent respiratory tract infection is a common manifestation of primary immunodeficiency disease, and respiratory viruses or bacteria are important triggers of asthma exacerbations. Asthma often coexists with humoral immunodeficiency in adults, and some asthmatics with immunoglobulin (Ig) G subclass deficiency (IgGSCD) suffer from recurrent exacerbations. Although some studies suggest a benefit from Ig replacement, others have failed to support its use. This study aimed to assess the effect of Ig replacement on asthma exacerbation caused by respiratory infection as well as the asthma control status of adult asthmatics with IgGSCD.
METHODS: This is a multi-center, open-label study of adult asthmatics with IgGSCD. All patients received monthly intravenous immunoglobulin (IVIG) for 6 months and were evaluated regarding asthma exacerbation related to infection, asthma control status, quality of life, and lung function before and after IVIG infusion.
RESULTS: A total of 30 patients were enrolled, and 24 completed the study. Most of the patients had a moderate degree of asthma severity with partly (52%) or uncontrolled (41%) status at baseline. IVIG significantly reduced the proportion of patients with asthma exacerbations, lowered the number of respiratory infections, and improved asthma control status, compared to the baseline values (P<0.001). The mean asthma-specific quality of life and asthma control test scores were improved significantly (P=0.009 and P=0.053, respectively); however, there were no significant changes in lung function.
CONCLUSIONS: IVIG reduced the frequency of asthma exacerbations and improved asthma control status in adult asthmatics with IgGSCD, suggesting that IVIG could be an effective treatment option in this population.

PMID: 28913992 [PubMed]

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The Lung in Dysregulated States of Humoral Immunity.

Respiration. 2017 Sep 15;94(5):

Authors: Uzunhan Y, Jeny F, Kambouchner M, Didier M, Bouvry D, Nunes H, Bernaudin JF, Valeyre D

Abstract
In common variable immunodeficiency, lung manifestations are related to different mechanisms: recurrent pneumonias due to encapsulated bacteria responsible for diffuse bronchiectasis, diffuse infiltrative pneumonia with various patterns, and lymphomas, mostly B cell extranodal non-Hodgkin type. The diagnosis relies on significant serum Ig deficiency and the exclusion of any primary or secondary cause. Histopathology may be needed. Immunoglobulin (IgG) replacement is crucial to prevent infections and bronchiectasis. IgG4-related respiratory disease, often associated with extrapulmonary localizations, presents with solitary nodules or masses, diffuse interstitial lung diseases, bronchiolitis, lymphadenopathy, and pleural or pericardial involvement. Diagnosis relies on international criteria including serum IgG4 dosage and significantly increased IgG4/IgG plasma cells ratio in pathologically suggestive biopsy. Respiratory amyloidosis presents with tracheobronchial, nodular, and cystic or diffuse interstitial lung infiltration. Usually of AL (amyloid light chain) subtype, it may be localized or systemic, primary or secondary to a lymphoproliferative process. Very rare other diseases due to nonamyloid IgG deposits are described. Among the various lung manifestations of dysregulated states of humoral immunity, this article covers only those associated with the common variable immunodeficiency, IgG4-related disease, amyloidosis, and pulmonary light-chain deposition disease. Autoimmune connective-vascular tissue diseases or lymphoproliferative disorders are addressed in other chapters of this issue.

PMID: 28910817 [PubMed – as supplied by publisher]

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Squamous Cell Carcinoma With Hyper-IgE Syndrome: A Case Report.

J Pediatr Hematol Oncol. 2017 Sep 08;:

Authors: Sasihuseyinoglu AS, Yilmaz M, Altintaş DU, Dogruel D, Serbes M, Uğuz AH, Kiroğlu M

Abstract
BACKGROUND: Hyper-immunoglobulin E syndrome (HIES) is a rare primary immunodeficiency disease characterized by recurrent infections and elevated levels of serum immunoglobulin E, usually over 2000 IU/mL. Recurrent and chronic infection of the epidermis and squamous epithelium may also be a cause of squamous cell carcinoma (SCC). SCC is rare with HIES.
CASE REPORT: A 17-year-old male patient who was diagnosed as HIES was admitted with purulent right ear discharge. The patient had a history of eczema starting from the age of 7 months and a history of recurrent middle ear infection starting from the age of 5. Biopsy specimens were taken from the lesion in the external auditory canal, and the lesion was reported as SCC.
CONSLUSION: Patients with autosomal recessive HIES are at an increased risk for infections and malignancies. SCC should be considered in the differential diagnosis of the patients presenting with recurrent middle ear infections and immunodeficiency.

PMID: 28902078 [PubMed – as supplied by publisher]

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Reduced-toxicity alternate-donor stem cell transplantation with posttransplant cyclophosphamide for primary immunodeficiency disorders.

Pediatr Blood Cancer. 2017 Sep 13;:

Authors: Rastogi N, Katewa S, Thakkar D, Kohli S, Nivargi S, Yadav SP

Abstract
We describe here the outcomes of reduced-toxicity alternate-donor stem cell transplant (SCT) with posttransplant cyclophosphamide (PTCy) for primary immunodeficiency disorders (PIDs) in eight children (haploidentical-seven and matched unrelated donor-one). The conditioning was with serotherapy (alemtuzumab-3/rabbit-anti-thymoglobulin-5); fludarabine, cyclophosphamide, and total body irradiation-5 (additional thiotepa-3); fludarabine and treosulfan-2; and fludarabine and busulfan-1. All received PTCy 50 mg/kg on days 3 and 4 as graft versus host disease prophylaxis along with tacrolimus and mycophenolate. Mean CD34 dose was 13.8 × 10(6) /kg. Two children died because of PIDs. Acute graft versus host disease up to grades I and II was seen in three children. All six survivors are fully donor and disease free at median follow-up of 753 days. Alternate donor SCT with PTCy is feasible in PID and has good outcomes.

PMID: 28901730 [PubMed – as supplied by publisher]

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Genetic Counseling in Primary Immunodeficiency Disorders: An Emerging Experience in Egypt.

Mol Diagn Ther. 2017 Sep 12;:

Authors: El Hawary RE, Meshaal SS, Abd Elaziz DS, Elsharkawy MA, Alkady RS, Lotfy S, El-Sheikhah A, Hassan A, Galal NM, Boutros JA, Elmarsafy AM

Abstract
BACKGROUND: Primary immunodeficiency disorders (PIDs) are a heterogeneous group of diseases of the immune system leading to life-threatening infections, and, unless urgently treated with immune reconstitution, patients do not usually survive. With the continuing progress in molecular diagnosis, many mutations have been described in more than 300 genes. Genetic counseling has recently been considered an essential part of the management of PIDs. This study presents the experience of genetic counseling services in the largest PID center in Egypt, and reports on our management plan and the impact of prenatal diagnosis (PND) on families.
METHODS: Based on the biochemical and molecular diagnosis of index cases, PND was offered for 10 families in 12 subsequent pregnancies. Five different genes were sequenced by Sanger sequencing in fetal samples.
RESULTS: Seven fetuses were either normal or were carriers, while five fetuses were affected and human leukocyte antigen typing was performed, seeking a suitably related donor for stem cell transplantation.
CONCLUSION: In spite of the genetic heterogeneity behind PIDs, genetic counseling should play a critical role in the management and future decisions of affected families.

PMID: 28900865 [PubMed – as supplied by publisher]

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