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Primary non-necrotizing granulomatous hypophysitis mimicking pituitary adenomas.

September 12, 2015 By Manish Butte

Primary non-necrotizing granulomatous hypophysitis mimicking pituitary adenomas.

Turk Neurosurg. 2014;24(5):688-94

Authors: Yildirim AE, Divanlioglu D, Cetinalp NE, Sahin S, Kulacoglu S, Belen AD

Abstract
AIM: The authors review their experience in the endoscopic endonasal transsphenoidal treatment of 5 patients, finally diagnosed as primary hypophysitis but initially assumed to be pituitary adenomas.
MATERIAL AND METHODS: A retrospective study was undertaken to review 5 cases of primary non-necrotizing granulomatous hypophysitis (1.61%) through 310 endoscopic transsphenoidally operated cases with the diagnosis of pituitary adenoma between 2009 and 2013. All 5 cases were female without any background of autoimmunity or recent pregnancy. The initial presumptive diagnosis was pituitary adenoma for all patients. The endocrinological diagnoses of the patients were suspected Cushing’s Disease, anterior pituitary deficiency with hyponatremia, hyperprolactinemia, and acromegaly. One of the patients had normal hormonal levels. All patients had macroadenomas including one invasive adenoma with skull base involvement. One of the patients (20%) had visual field defects. All patients underwent endoscopic endonasal transsphenoidal surgery (EETS).
RESULTS: All patients had improvement of hormonal levels postoperatively except the one with anterior pituitary deficiency who required long term hormone replacement after the surgery. Mean follow-up duration was 14.8 months.
CONCLUSION: Primary granulomatous hypophysitis without any known etiological factors is very rare in the literature. It can mimic pituitary adenomas in radiological and endocrinological aspects. EETS is an effective and safe treatment especially for visual and compression symptoms.

PMID: 25269037 [PubMed – indexed for MEDLINE]

CVID Associated with Systemic Amyloidosis.

September 9, 2015 By Manish Butte

CVID Associated with Systemic Amyloidosis.

Case Reports Immunol. 2015;2015:879179

Authors: Esenboga S, Çagdas Ayvaz D, Saglam Ayhan A, Peynircioglu B, Sanal O, Tezcan I

Abstract
Common variable immunodeficiency (CVID) is a frequent primary immune deficiency (PID), which consists of a heterogeneous group of disorders and can present with recurrent infections, chronic diarrhea, autoimmunity, chronic pulmonary and gastrointestinal diseases, and malignancy. Secondary amyloidosis is an uncommon complication of CVID. We report an unusual case of a 27-year-old male patient who presented with recurrent sinopulmonary infections, chronic diarrhea, and hypogammaglobulinemia and was diagnosed with CVID. The patient was treated with intravenous immunoglobulin (IVIg) therapy once every 21 days and daily trimethoprim-sulfamethoxazole for prophylaxis. Two years after initial diagnosis, the patient was found to have progressive decline in IgG levels (as low as 200-300 mg/dL) despite regular Ig infusions. The laboratory tests revealed massive proteinuria and his kidney biopsy showed accumulation of AA type amyloid. We believe that the delay in the diagnosis of CVID and initiation of Ig replacement therapy caused chronic inflammation due to recurrent infections in our patient and this led to an uncommon and life-threatening complication, amyloidosis. Patients with CVID require regular follow-up for the control of infections and assessment of adequacy of Ig replacement therapy. Amyloidosis should be kept in the differential diagnosis when managing patients with CVID.

PMID: 26346511 [PubMed]

Patient-derived iPS cells as a tool for gene therapy research.

September 9, 2015 By Manish Butte

Patient-derived iPS cells as a tool for gene therapy research.

Rinsho Ketsueki. 2015;56(8):1016-24

Authors: Otsu M

Abstract
Gene therapy targeting hematopoietic stem cells (HSC) can now be recognized as a curative treatment option for patients with genetic disorders, including primary immunodeficiency (PID) diseases. Despite an increasing number of successfully treated cases, the therapeutic benefits still vary considerably among trials. To further optimize HSC gene therapy, it is hoped that a research model system capable of faithful recapitulation of the disease phenotypes can be established. Recently, a new model system that may meet this goal has become a reality; that is, patient-derived induced pluripotent stem cells (iPSCs). iPSCs are useful for modeling genetic disorders, because of their potential to differentiate into various types of somatic cells while retaining the specific genetic mutations. They are also susceptible to genetic manipulation in vitro, thus enabling pre-clinical assessment of candidate treatment strategies for their performance. This article introduces a proof that patient-derived iPSCs represent an invaluable tool for modelling genetic diseases such as PIDs, and also provide an indispensable research model usable for the development of ideal therapeutic modalities.

PMID: 26345561 [PubMed – in process]

Proven and novel strategies for efficient editing of the human genome.

September 8, 2015 By Manish Butte

Proven and novel strategies for efficient editing of the human genome.

Curr Opin Pharmacol. 2015 Sep 3;24:105-112

Authors: Mussolino C, Mlambo T, Cathomen T

Abstract
Targeted gene editing with designer nucleases has become increasingly popular. The most commonly used designer nuclease platforms are engineered meganucleases, zinc-finger nucleases, transcription activator-like effector nucleases and the clustered regularly interspaced short palindromic repeat/Cas9 system. These powerful tools have greatly facilitated the generation of plant and animal models for basic research, and harbor an enormous potential for applications in biotechnology and gene therapy. This review recapitulates proven concepts of targeted genome engineering in primary human cells and elaborates on novel concepts that became possible with the dawn of RNA-guided nucleases and RNA-guided transcription factors.

PMID: 26342909 [PubMed – as supplied by publisher]

Altered B-cell subsets and functional B-cell defects in selective IgM deficiency.

September 8, 2015 By Manish Butte

Altered B-cell subsets and functional B-cell defects in selective IgM deficiency.

Clin Immunol. 2015 Sep 2;

Authors: Mensen A, Krause T, Hanitsch LG, Meisel C, Kleint ME, Volk HD, Na IK, Scheibenbogen C

PMID: 26342539 [PubMed – as supplied by publisher]

BTK Signaling in B Cell Differentiation and Autoimmunity.

September 6, 2015 By Manish Butte

BTK Signaling in B Cell Differentiation and Autoimmunity.

Curr Top Microbiol Immunol. 2015 Sep 5;

Authors: Corneth OB, Klein Wolterink RG, Hendriks RW

Abstract
Since the original identification of Bruton’s tyrosine kinase (BTK) as the gene defective in the primary immunodeficiency X-linked agammaglobulinemia (XLA) in 1993, our knowledge on the physiological function of BTK has expanded impressively. In this review, we focus on the role of BTK during B cell differentiation in vivo, both in the regulation of expansion and in the developmental progression of pre-B cells in the bone marrow and as a crucial signal transducer of signals downstream of the IgM or IgG B cell antigen receptor (BCR) in mature B cells governing proliferation, survival, and differentiation. In particular, we highlight BTK function in B cells in the context of host defense and autoimmunity. Small-molecule inhibitors of BTK have very recently shown impressive anti-tumor activity in clinical studies in patients with various B cell malignancies. Since promising effects of BTK inhibition were also seen in experimental animal models for lupus and rheumatoid arthritis, BTK may be a good target for controlling autoreactive B cells in patients with systemic autoimmune disease.

PMID: 26341110 [PubMed – as supplied by publisher]

Subcutaneous Immunoglobulin Replacement Therapy with Hizentra® is Safe and Effective in Children Less Than 5 Years of Age.

September 5, 2015 By Manish Butte

Subcutaneous Immunoglobulin Replacement Therapy with Hizentra® is Safe and Effective in Children Less Than 5 Years of Age.

J Clin Immunol. 2015 Sep 4;

Authors: Patel NC, Gallagher JL, Ochs HD, Prescott Atkinson T, Wahlstrom J, Dorsey M, Bonilla FA, Heimall J, Kobrynski L, Morris D, Haddad E

Abstract
BACKGROUND: Hizentra® (IGSC 20 %) is a 20 % liquid IgG product approved for subcutaneous administration in adults and children 2 years of age and older who have primary immunodeficiency disease (PIDD). There is limited information about the use of IGSC 20 % in very young children including those less than 5 years of age.
METHODS: A retrospective chart review involved 88 PIDD infants and children less than 5 years of age who received Hizentra®.
RESULTS: The mean age at the start of Hizentra® was 34 months (range 2 to 59 months). IGSC 20 % was administered weekly to 86 infants (two additional infants received twice weekly and three times weekly infusions, respectively) and included an average of 63 infusions (range 6-182) for an observation period up to 45.5 months. Infusion by manual delivery occurred in 15 patients. The mean dose was 674 mg/kg/4 weeks. The mean IgG level was 942 mg/dL while on IGSC 20 %, compared to a mean trough IgG level of 794 mg/dL (p < 0.0001) during intravenous or subcutaneous IgG administration prior to IGSC 20 %. Average infusion time was 47 (range 5-120) minutes, and the median number of infusion sites was 2 (range 1-4). Local reactions were mostly mild and observed in 36/88 (41 %) children. No serious adverse events were reported. A significant increase in weight percentile (7 % ± 19.2, p = 0.0012) among subjects was observed during IGSC 20 % administration. The rate of serious bacterial infections was 0.067 per patient-year while receiving IGSC 20 %, similar to previously reported efficacy studies.
CONCLUSIONS: Hizentra® is effective in preventing infections, and is well tolerated in children less than age 5 years.

PMID: 26336818 [PubMed – as supplied by publisher]

Decreased activation-induced cell death by EBV-transformed B cells from a patient with autoimmune lymphoproliferative syndrome caused by a novel FASLG mutation.

September 4, 2015 By Manish Butte

Decreased activation-induced cell death by EBV-transformed B cells from a patient with autoimmune lymphoproliferative syndrome caused by a novel FASLG mutation.

Pediatr Res. 2015 Sep 3;

Authors: Ruiz-García R, Mora S, Lozano-Sánchez G, Martínez-Lostao L, Paz-Artal E, Ruiz-Contreras J, Anel A, González-Granado LI, Moreno D, Allende LM

Abstract
BACKGROUND: Autoimmune lymphoproliferative syndrome (ALPS) is a primary immunodeficiency characterized by chronic lymphoproliferation, autoimmune manifestations, expansion of double-negative T-cells and susceptibility to malignancies. Most cases of ALPS are caused by germline or somatic FAS mutations. We report the case of an ALPS patient due to a novel homozygous Fasligand gene mutation (ALPS-FASLG).
METHODS: ALPS biomarkers were measured and FASLG mutation was identified. Functional characterization was carried out based on activation-induced cell death (AICD) and cytotoxicity assays.
RESULTS: This report describes the cases of a patient who presented a severe form of ALPSFASLG, and his brother who had died due to complications related to ALPS. Moreover, in another family, we present the first case of lymphoma in a patient with ALPS-FASLG. Functional studies showed defective Fasligand-mediated apoptosis, cytotoxicity and AICD in Tcell blasts. Otherwise, expression of the FASLG gene and corresponding protein was normal, but the shedding of the Fasligand was impaired in T-cells. Additionally, analyzing EBV-transformed B-cells, our results indicate impaired AICD in ALPS-FASLG patients.
CONCLUSION: Patients with autosomal recessive inheritance of ALPS-FASLG have a severe phenotype and a partial defect in AICD in T- and B-cell lines. The Fasligand could play a key role in immune surveillance preventing malignancy.Pediatric Research (2015); doi:10.1038/pr.2015.170.

PMID: 26334989 [PubMed – as supplied by publisher]

Suppression of a Natural Killer Cell Response by Simian Immunodeficiency Virus Peptides.

September 4, 2015 By Manish Butte

Suppression of a Natural Killer Cell Response by Simian Immunodeficiency Virus Peptides.

PLoS Pathog. 2015 Sep;11(9):e1005145

Authors: Schafer JL, Ries M, Guha N, Connole M, Colantonio AD, Wiertz EJ, Wilson NA, Kaur A, Evans DT

Abstract
Natural killer (NK) cell responses in primates are regulated in part through interactions between two highly polymorphic molecules, the killer-cell immunoglobulin-like receptors (KIRs) on NK cells and their major histocompatibility complex (MHC) class I ligands on target cells. We previously reported that the binding of a common MHC class I molecule in the rhesus macaque, Mamu-A1*002, to the inhibitory receptor Mamu-KIR3DL05 is stabilized by certain simian immunodeficiency virus (SIV) peptides, but not by others. Here we investigated the functional implications of these interactions by testing SIV peptides bound by Mamu-A1*002 for the ability to modulate Mamu-KIR3DL05+ NK cell responses. Twenty-eight of 75 SIV peptides bound by Mamu-A1*002 suppressed the cytolytic activity of primary Mamu-KIR3DL05+ NK cells, including three immunodominant CD8+ T cell epitopes previously shown to stabilize Mamu-A1*002 tetramer binding to Mamu-KIR3DL05. Substitutions at C-terminal positions changed inhibitory peptides into disinhibitory peptides, and vice versa, without altering binding to Mamu-A1*002. The functional effects of these peptide variants on NK cell responses also corresponded to their effects on Mamu-A1*002 tetramer binding to Mamu-KIR3DL05. In assays with mixtures of inhibitory and disinhibitory peptides, low concentrations of inhibitory peptides dominated to suppress NK cell responses. Consistent with the inhibition of Mamu-KIR3DL05+ NK cells by viral epitopes presented by Mamu-A1*002, SIV replication was significantly higher in Mamu-A1*002+ CD4+ lymphocytes co-cultured with Mamu-KIR3DL05+ NK cells than with Mamu-KIR3DL05- NK cells. These results demonstrate that viral peptides can differentially affect NK cell responses by modulating MHC class I interactions with inhibitory KIRs, and provide a mechanism by which immunodeficiency viruses may evade NK cell responses.

PMID: 26333068 [PubMed – in process]

The WASP-WIP complex in the molecular pathogenesis of Wiskott-Aldrich syndrome.

September 4, 2015 By Manish Butte

The WASP-WIP complex in the molecular pathogenesis of Wiskott-Aldrich syndrome.

Pediatr Int. 2015 Sep 2;

Authors: Sasahara Y

Abstract
Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency disease that is characterized by recurrent infections, thrombocytopenia, and eczema. The gene responsible for X-linked WAS encodes the Wiskott-Aldrich syndrome protein (WASP), which is expressed in hematopoietic cells and which regulates T cell activation and cytoskeletal reorganization in T cell receptor (TCR) signaling. Here, I review our recent research on WASP and the WASP-interacting protein (WIP) complex in T cells. We first established a diagnostic screening method using flow cytometry and genetic analysis, and elucidated the molecular pathogenesis in WAS patients with unique clinical manifestations. We investigated the mechanisms by which WASP is recruited to lipid rafts following TCR stimulation and to immunological synapses between antigen-presenting cells and T cells. Subsequently, we revealed the molecular mechanisms by which WASP is degraded by calpain and ubiquitinated by Cbl-family proteins, which terminate WASP activation. More importantly, we found that WIP plays a critical role in WASP stability in T cells. These results provided new insights into the molecular pathogenesis of X-linked WAS and facilitated the discovery of WIP deficiency as an autosomal recessive form of WAS. This article is protected by copyright. All rights reserved.

PMID: 26331277 [PubMed – as supplied by publisher]