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Diagnostic and therapeutic challenges in a child with complete interferon-γ receptor 1 deficiency.

July 16, 2015 By Manish Butte

Diagnostic and therapeutic challenges in a child with complete interferon-γ receptor 1 deficiency.

Pediatr Blood Cancer. 2015 Jul 14;

Authors: Olbrich P, Martínez-Saavedra MT, Perez-Hurtado JM, Sanchez C, Sanchez B, Deswarte C, Obando I, Casanova JL, Speckmann C, Bustamante J, Rodriguez-Gallego C, Neth O

Abstract
Autosomal recessive (AR) complete Interferon-γ Receptor1 (IFN-γR1) deficiency is a rare variant of Mendelian susceptibility to mycobacterial disease (MSMD). Although hematopoietic stem cell transplantation (HSCT) remains the only curative treatment, outcomes are heterogeneous; delayed engraftment and/or graft rejection being commonly observed. This case report and literature review expands the knowledge about this rare but potentially fatal pathology, providing details regarding diagnosis, antimicrobial treatment, transplant performance, and outcome that may help to guide physicians caring for patients with AR complete IFN-γR1 or IFN-γR2 deficiency. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.

PMID: 26173802 [PubMed – as supplied by publisher]

Primary CNS Immunomodulatory Therapy-Induced Lymphoproliferative Disorder in a Patient with Ulcerative Colitis: a Case Report and Review of the Literature.

July 15, 2015 By Manish Butte

Primary CNS Immunomodulatory Therapy-Induced Lymphoproliferative Disorder in a Patient with Ulcerative Colitis: a Case Report and Review of the Literature.

World Neurosurg. 2015 Jul 11;

Authors: Alobaid A, Torlakovic E, Kongkham P

Abstract
BACKGROUND: Immunosuppression and immunomodulatory therapy-induced lymphoproliferative disorders (ILPD) represent a heterogeneous group of lymphoid cell disorders that occur secondary to iatrogenic immune dysfunction, best described in the post-transplant setting.
CASE DESCRIPTION: We describe, to the best of our knowledge, the first reported case of a primary central nervous system (CNS) ILPD in a patient with ulcerative colitis (UC) treated chronically with the immunomodulatory agents infliximab and azathioprine. This 52-year old female presented with a one-month history of left sided weakness and paresthesias. Neuroimaging identified multiple heterogeneously-enhancing lesions in her cerebrum. Extensive systemic infectious and malignancy-related investigations were negative, prompting neurosurgical referral to obtain a tissue diagnosis. Pathologic assessment of her open excisional biopsy specimen confirmed the diagnosis of a polymorphic lymphoproliferative disorder. She was treated by withdrawal of infliximab and azathioprine, along with a prolonged course of prednisone. At early 6-month follow up she demonstrated both clinical and radiologic improvement.
CONCLUSION: ILPD should be considered in the differential diagnosis in patients with iatrogenic immunodeficiency presenting with neurological symptoms and intra-axial mass lesions on neuroimaging investigations. A standard treatment regimen for ILPD remains to be determined, however withholding the immunomodulatory agents and trial of corticosteroids may be tried as one first-line option prior to the use of more aggressive chemotherapy and/or radiotherapy.

PMID: 26171889 [PubMed – as supplied by publisher]

Diagnostic Criteria and Evaluation of Severe Combined Immunodeficiency in the Neonate.

July 15, 2015 By Manish Butte

Diagnostic Criteria and Evaluation of Severe Combined Immunodeficiency in the Neonate.

Pediatr Ann. 2015 Jul 1;44(7):e181-e187

Authors: Diamond CE, Sanchez MJ, LaBelle JL

Abstract
Severe combined immunodeficiency disorders (SCID) are a group of primary immunodeficiencies resulting from any one of a diverse group of mutations impacting T-cell development. SCID is diagnosed and classified through assessment of the lymphocyte subset(s) affected and by the mechanisms responsible for the primary immune defect. Regardless of the genetics involved, patients invariably succumb to an early death without medical intervention. In the past, patients were primarily identified either by previous family history, physical manifestations, or after the onset of symptoms. However, the introduction of newborn screening for SCID has allowed the pediatrician to identify these patients at a much earlier age, greatly improving their survival. Currently, 23 states include SCID testing for T-cell deficiencies in their newborn screening platform. Protocols for confirmatory testing and medical intervention after a positive screen vary slightly from state-to-state. However, the standard curative treatment remains stem cell transplantation, although depending on the genetic cause of the disease, enzyme replacement and gene therapy may also be considered. [Pediatr Ann. 2015;44(7):e181-e187.].

PMID: 26171708 [PubMed – as supplied by publisher]

5-Methoxytryptophan-dependent inhibition of oral squamous cell carcinoma metastasis.

July 15, 2015 By Manish Butte

5-Methoxytryptophan-dependent inhibition of oral squamous cell carcinoma metastasis.

Electrophoresis. 2015 Jul 14;

Authors: Wang SH, Chang CW, Chou HC

Abstract
The metastatic status of oral cancer is highly associated with the overall survival rate of patients. Previous studies have revealed that the endogenous tryptophan metabolite 5-methoxytryptophan (5-MTP) can downregulate cyclooxygenase-2 expression; suppress tumor proliferation, migration, and invasion; and reduce the tumor size. To improve the understanding of the molecular mechanisms involved in the regulation of 5-MTP in the tumorigenesis of oral cancer, we conducted a comparative wound healing and transwell invasion assays. Our results revealed that 5-MTP reduce oral cancer cell migration and invasion ability. In addition, the results of an in vivo assay demonstrated that the growth of primary tumors was significantly inhibited by 5-MTP in OC3 oral cancer cells and in invasive OC3-I5 oral cancer cells. Moreover, enlarged spleens were observed in OC3-I5-implanted severe combined immunodeficiency mice although 5-MTP can inhibit spleen enlargement. Through comparative proteomics, we identified 32 differentially regulated protein spots by using 2D-DIGE/MALDI-TOF MS analyses. Some of the differentially regulated proteins such as amadillo-repeat-containing X-linked protein 1, phosphoglycerate kinase 1, tropomyosin alpha-1, and tropomyosin alpha-4 may be associated with the 5-MTP-dependent inhibition of oral cancer growth and metastasis. We conclude that 5-MTP plays a crucial role in inhibiting in vitro and in vivo cancer invasion and metastasis.

PMID: 26171676 [PubMed – as supplied by publisher]

TACI deficiency leads to alternatively activated macrophage phenotype and susceptibility to Leishmania infection.

July 15, 2015 By Manish Butte

TACI deficiency leads to alternatively activated macrophage phenotype and susceptibility to Leishmania infection.

Proc Natl Acad Sci U S A. 2015 Jul 13;

Authors: Allman WR, Dey R, Liu L, Siddiqui S, Coleman AS, Bhattacharya P, Yano M, Uslu K, Takeda K, Nakhasi HL, Akkoyunlu M

Abstract
The TNF family member, transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), is a key molecule for plasma cell maintenance and is required in infections where protection depends on antibody response. Here, we report that compared with WT mouse, TACI KO Μϕs expressed lower levels of Toll-like receptors (TLRs), CD14, myeloid differentiation primary response protein 88, and adaptor protein Toll/IL-1 receptor domain-containing adapter-inducing IFN-β and responded poorly to TLR agonists. Analysis of Μϕ phenotype revealed that, in the absence of TACI, Μϕs adapt the alternatively activated (M2) phenotype. Steady-state expression levels for M2 markers IL-4Rα, CD206, CCL22, IL-10, Arg1, IL1RN, and FIZZ1 were significantly higher in TACI KO Μϕ than in WT cells. Confirming their M2 phenotype, TACI-KO Mϕs were unable to control Leishmania major infection in vitro, and intradermal inoculation of Leishmania resulted in a more severe manifestation of disease than in the resistant C57BL/6 strain. Transfer of WT Μϕs to TACI KO mice was sufficient to significantly reduce disease severity. TACI is likely to influence Mϕ phenotype by mediating B cell-activating factor belonging to the TNF family (BAFF) and a proliferation inducing ligand (APRIL) signals because both these ligands down-regulated M2 markers in WT but not in TACI-deficient Μϕs. Moreover, treatment of Μϕs with BAFF or APRIL enhanced the clearance of Leishmania from cells only when TACI is expressed. These findings may have implications for understanding the shortcomings of host response in newborns where TACI expression is reduced and in combined variable immunodeficiency patients where TACI signaling is ablated.

PMID: 26170307 [PubMed – as supplied by publisher]

Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies.

July 15, 2015 By Manish Butte

Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies.

J Allergy Clin Immunol. 2015 Jul 7;

Authors: Ma CS, Wong N, Rao G, Avery DT, Torpy J, Hambridge T, Bustamante J, Okada S, Stoddard JL, Deenick EK, Pelham SJ, Payne K, Boisson-Dupuis S, Puel A, Kobayashi M, Arkwright PD, Kilic SS, El Baghdadi J, Nonoyama S, Minegishi Y, Mahdaviani SA, Mansouri D, Bousfiha A, Blincoe AK, French MA, Hsu P, Campbell DE, Stormon MO, Wong M, Adelstein S, Smart JM, Fulcher DA, Cook MC, Phan TG, Stepensky P, Boztug K, Kansu A, İkincioğullari A, Baumann U, Beier R, Roscioli T, Ziegler JB, Gray P, Picard C, Grimbacher B, Warnatz K, Holland SM, Casanova JL, Uzel G, Tangye SG

Abstract
BACKGROUND: Follicular helper T (TFH) cells underpin T cell-dependent humoral immunity and the success of most vaccines. TFH cells also contribute to human immune disorders, such as autoimmunity, immunodeficiency, and malignancy. Understanding the molecular requirements for the generation and function of TFH cells will provide strategies for targeting these cells to modulate their behavior in the setting of these immunologic abnormalities.
OBJECTIVE: We sought to determine the signaling pathways and cellular interactions required for the development and function of TFH cells in human subjects.
METHODS: Human primary immunodeficiencies (PIDs) resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Circulating follicular helper T (cTFH) cell subsets, memory B cells, and serum immunoglobulin levels were quantified and functionally assessed in healthy control subjects, as well as in patients with PIDs resulting from mutations in STAT3, STAT1, TYK2, IL21, IL21R, IL10R, IFNGR1/2, IL12RB1, CD40LG, NEMO, ICOS, or BTK.
RESULTS: Loss-of-function (LOF) mutations in STAT3, IL10R, CD40LG, NEMO, ICOS, or BTK reduced cTFH cell frequencies. STAT3 and IL21/R LOF and STAT1 gain-of-function mutations skewed cTFH cell differentiation toward a phenotype characterized by overexpression of IFN-γ and programmed death 1. IFN-γ inhibited cTFH cell function in vitro and in vivo, as corroborated by hypergammaglobulinemia in patients with IFNGR1/2, STAT1, and IL12RB1 LOF mutations.
CONCLUSION: Specific mutations affect the quantity and quality of cTFH cells, highlighting the need to assess TFH cells in patients by using multiple criteria, including phenotype and function. Furthermore, IFN-γ functions in vivo to restrain TFH cell-induced B-cell differentiation. These findings shed new light on TFH cell biology and the integrated signaling pathways required for their generation, maintenance, and effector function and explain the compromised humoral immunity seen in patients with some PIDs.

PMID: 26162572 [PubMed – as supplied by publisher]

Current and emerging treatment options for Wiskott-Aldrich syndrome.

July 11, 2015 By Manish Butte

Current and emerging treatment options for Wiskott-Aldrich syndrome.

Expert Rev Clin Immunol. 2015 Jul 9;:1-18

Authors: Worth AJ, Thrasher AJ

Abstract
Wiskott-Aldrich syndrome is a life-threatening primary immunodeficiency associated with a bleeding tendency, eczema and a high incidence of autoimmunity and malignancy. Stem cell transplantation offers the opportunity of cure for all these complications, and over the past 35 years there has been a remarkable improvement in survival following this treatment. Here, we review advances in management of clinical complications pre- and post-transplant, as well as discuss the morbidity Wiskott-Aldrich syndrome patients experience following treatment. For patients with a poorly matched stem cell donor, recent gene therapy trials demonstrate encouraging results and the potential of low-toxicity therapy for all patients.

PMID: 26159751 [PubMed – as supplied by publisher]

Thrombocytopenia in common variable immunodeficiency patients – clinical course, management, and effect of immunoglobulins.

July 11, 2015 By Manish Butte

Thrombocytopenia in common variable immunodeficiency patients – clinical course, management, and effect of immunoglobulins.

Cent Eur J Immunol. 2015;40(1):83-90

Authors: Pituch-Noworolska A, Siedlar M, Kowalczyk D, Szaflarska A, Błaut-Szlósarczyk A, Zwonarz K

Abstract
Common variable immunodeficiency (CVID) is a primary immunodeficiency of humoral immunity with heterogeneous clinical features. Diagnosis of CVID is based on hypogammaglobulinaemia, low production of specific antibodies, and disorders of cellular immunity. The standard therapy includes replacement of specific antibodies with human immunoglobulin, prophylaxis, and symptomatic therapy of infections. High prevalence of autoimmunity is characteristic for CVID, most commonly: thrombocytopaenia and neutropaenia, celiac disease, and systemic autoimmune diseases. The study included seven children diagnosed with CVID and treated with immunoglobulin substitution from 2 to 12 years. Thrombocytopenia was diagnosed prior to CVID in four children, developed during immunoglobulin substitution in three children. In one boy with CVID and thrombocytopaenia, haemolytic anaemia occurred, so a diagnosis of Evans syndrome was established. Therapy of thrombocytopaenia previous to CVID included steroids and/or immunoglobulins in high dose, and azathioprine. In children with CVID on regular immunoglobulin substitution, episodes of acute thrombocytopaenia were associated with infections and were treated with high doses of immunoglobulins and steroids. In two patients only chronic thrombocytopaenia was noted. Splenectomy was necessary in one patient because of severe course of thrombocytopaenia. The results of the study indicated a supportive role of regular immunoglobulin substitution in patients with CVID and chronic thrombocytopaenia. However, regular substitution of immunoglobulins in CVID patients did not prevent the occurrence of autoimmune thrombocytopaenia episodes or exacerbations of chronic form. In episodes of acute thrombocytopaenia or exacerbations of chronic thrombocytopaenia, infusions of immunoglobulins in high dose are effective, despite previous regular substitution in the replacing dose.

PMID: 26155188 [PubMed]

In vitro interferon γ improves the oxidative burst activity of neutrophils in patients with chronic granulomatous disease with a subtype of gp91phox deficiency.

July 11, 2015 By Manish Butte

In vitro interferon γ improves the oxidative burst activity of neutrophils in patients with chronic granulomatous disease with a subtype of gp91phox deficiency.

Cent Eur J Immunol. 2015;40(1):54-60

Authors: Filiz S, Uygun DF, Köksoy S, Şahin E, Yeğin O

Abstract
AIM OF THIS STUDY: Chronic granulomatous disease (CGD) is a genetically heterogeneous primary immunodeficiency caused by a defect in phagocyte production of oxygen metabolites, and resulting in infections produced by catalase-positive microorganisms and fungi. Interferon γ (IFN-γ) has a multitude of effects on the immune system. Although preliminary studies with CGD patients on treatment with IFN-γ showed that it enhanced phagocytosis and superoxide production, ongoing studies did not reveal a significant increase of this function. Here we investigated the oxidative capacity of phagocytes in different subtypes of CGD patients on treatment with IFN-γ in vitro.
MATERIAL AND METHODS: Fifty-seven patients with CGD from 14 immunology centres were enrolled to our multi-centre study. Twenty-one patients were studied as controls. Oxidative burst assay with dihydrorhodamine 123 (DHR) was used and the stimulation index (SI) was calculated with respect to CGD subtypes in both neutrophils and monocytes before, and then one and 24 hours after adding IFN-γ.
RESULTS: Upon comparison of the SIs of the patients’ neutrophils before in vitro IFN-γ at hour 0, and after adding IFN-γ at hour 1 and 24 were compared, and the differences were determined between hours 0-24 and hours 1-24. This difference was especially apparent between hours 1-24. In CGD subtypes, particularly in gp91phox subtype, it was seen that, following in vitro IFN-γ, SIs of neutrophils began to increase after hour 1, and that increase became more apparent at hour 24.
CONCLUSIONS: Our study showed that IFN-γ treatment may increase the oxidative bursting activity by increasing the superoxide production in neutrophils, particularly in gp91phox subtype.

PMID: 26155184 [PubMed]

Leukocyte telomere length in relation to pancreatic cancer risk: a prospective study.

July 11, 2015 By Manish Butte

Leukocyte telomere length in relation to pancreatic cancer risk: a prospective study.

Cancer Epidemiol Biomarkers Prev. 2014 Nov;23(11):2447-54

Authors: Campa D, Mergarten B, De Vivo I, Boutron-Ruault MC, Racine A, Severi G, Nieters A, Katzke VA, Trichopoulou A, Yiannakouris N, Trichopoulos D, Boeing H, Quirós JR, Duell EJ, Molina-Montes E, Huerta JM, Ardanaz E, Dorronsoro M, Khaw KT, Wareham N, Travis RC, Palli D, Pala V, Tumino R, Naccarati A, Panico S, Vineis P, Riboli E, Siddiq A, Bueno-de-Mesquita HB, Peeters PH, Nilsson PM, Sund M, Ye W, Lund E, Jareid M, Weiderpass E, Duarte-Salles T, Kong SY, Stepien M, Canzian F, Kaaks R

Abstract
BACKGROUND: Several studies have examined leukocyte telomere length (LTL) as a possible predictor for cancer at various organ sites. The hypothesis originally motivating many of these studies was that shorter telomeres would be associated with an increase in cancer risk; the results of epidemiologic studies have been inconsistent, however, and suggested positive, negative, or null associations. Two studies have addressed the association of LTL in relation to pancreatic cancer risk and the results are contrasting.
METHODS: We measured LTL in a prospective study of 331 pancreatic cancer cases and 331 controls in the context of the European Prospective Investigation into Cancer and Nutrition (EPIC).
RESULTS: We observed that the mean LTL was higher in cases (0.59 ± 0.20) than in controls (0.57 ± 0.17), although this difference was not statistically significant (P = 0.07), and a basic logistic regression model showed no association of LTL with pancreas cancer risk. When adjusting for levels of HbA1c and C-peptide, however, there was a weakly positive association between longer LTL and pancreatic cancer risk [OR, 1.13; 95% confidence interval (CI), 1.01-1.27]. Additional analyses by cubic spline regression suggested a possible nonlinear relationship between LTL and pancreatic cancer risk (P = 0.022), with a statistically nonsignificant increase in risk at very low LTL, as well as a significant increase at high LTL.
CONCLUSION: Taken together, the results from our study do not support LTL as a uniform and strong predictor of pancreatic cancer.
IMPACT: The results of this article can provide insights into telomere dynamics and highlight the complex relationship between LTL and pancreatic cancer risk.

PMID: 25103821 [PubMed – indexed for MEDLINE]