Blog

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

August 22, 2015 By Manish Butte

[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]

Successful Treatment of ANCA-Associated Vasculitis in the Setting of Common Variable Immunodeficiency Using Rituximab.

August 21, 2015 By Manish Butte

Successful Treatment of ANCA-Associated Vasculitis in the Setting of Common Variable Immunodeficiency Using Rituximab.

Am J Ther. 2015 Aug 18;

Authors: Hill F, Yonkof J, Chaitanya Arudra SK, Thomas J, Altorok N

Abstract
Autoimmune diseases such as idiopathic thrombocytopenic purpura and autoimmune hemolytic anemia have a high reported prevalence in patients with common variable immunodeficiency (CVID). We describe the case of a 36-year-old Hispanic man with CVID treated with intravenous immunoglobulin, who developed antineutrophilic cytoplasmic antibodies (ANCA)-associated vasculitis 15 years after immunodeficiency diagnosis. After failing first-line immunosuppressive therapy, the patient was successfully treated with rituximab. Although autoimmunity in the setting of CVID is well documented, this is the first report to describe a case of ANCA-associated vasculitis associated with CVID. Moreover, we report effective and safe use of rituximab in a patient with primary immunodeficiency.

PMID: 26291596 [PubMed – as supplied by publisher]

A non-healing lesion in a 14-year old boy with primary immunodeficiency: a rare case of actinic keratosis affecting a child.

August 21, 2015 By Manish Butte

A non-healing lesion in a 14-year old boy with primary immunodeficiency: a rare case of actinic keratosis affecting a child.

J Eur Acad Dermatol Venereol. 2015 Aug 20;

Authors: Balakirski G, Dueckers G, Niehues T, Megahed M

PMID: 26290047 [PubMed – as supplied by publisher]

Facilitated Subcutaneous Immunoglobulin (fSCIg) Therapy – Practical Considerations.

August 20, 2015 By Manish Butte

Facilitated Subcutaneous Immunoglobulin (fSCIg) Therapy – Practical Considerations.

Clin Exp Immunol. 2015 Aug 19;

Authors: Ponsford M, Carne E, Kingdon C, Joyce C, Price C, Williams C, El-Shanawany T, Williams P, Jolles S

Abstract
There is an increasing range of therapeutic options for primary antibody deficient patients who require replacement immunoglobulin. These include intravenous immunoglobulin (IVIg), subcutaneous immunoglobulin (SCIg), rapid push SCIg and most recently recombinant human hyaluronidase facilitated SCIg (fSCIg). Advantages of fSCIg include fewer needle punctures, longer infusion intervals, and an improved adverse effect profile relative to IVIg. Limited real life experience exists concerning the practical aspects of switching or starting patients on fSCIg. We describe the first 14 patients who have been treated with fSCIg at the Immunodeficiency Centre for Wales (ICW), representing over 6 patient-years of experience. The regime was well tolerated with high levels of satisfaction and no increase in training requirement – including for a treatment-naive patient. Two patients discontinued fSCIg due to pain and swelling at the infusion site, and one paused therapy following post-infusion migraines. Ultrasound imaging of paired conventional and facilitated SCIg demonstrated clear differences in subcutaneous space distribution associated with a ten-fold increase in rate and volume delivery with fSCIg. Patient profiles for those choosing fSCIg fell into two main categories: those experiencing clinical problems with their current treatment and those seeking greater convenience and flexibility. When introducing fSCIg, consideration of the type and programming of infusion pump, needle gauge and length, infusion site, up-dosing schedule, home training and patient information are important as these may differ from conventional SCIg. This paper provides guidance on practical aspects of the administration, training and outcomes to help inform decision making for this new treatment modality. This article is protected by copyright. All rights reserved.

PMID: 26288095 [PubMed – as supplied by publisher]

Targeted Disruption of the β2-Microglobulin Gene Minimizes the Immunogenicity of Human Embryonic Stem Cells.

August 20, 2015 By Manish Butte

Targeted Disruption of the β2-Microglobulin Gene Minimizes the Immunogenicity of Human Embryonic Stem Cells.

Stem Cells Transl Med. 2015 Aug 18;

Authors: Wang D, Quan Y, Yan Q, Morales JE, Wetsel RA

Abstract
: Human embryonic stem cells (hESCs) are a promising source of cells for tissue regeneration, yet histoincompatibility remains a major challenge to their clinical application. Because the human leukocyte antigen class I (HLA-I) molecules are the primary mediators of immune rejection, we hypothesized that cells derived from a hESC line lacking HLA-I expression could be transplanted without evoking a robust immune response from allogeneic recipients. In the present study, we used the replacement targeting strategy to delete exons 2 and 3 of β2-microglobulin on both gene alleles in hESCs. Because β2-microglobulin serves as the HLA-I light chain, disruption of the β2-microglobulin gene led to complete HLA-I deficiency on the cell surface of hESCs and their derivatives. Therefore, these cells were resistant to CD8(+) T-cell-mediated destruction. Although interferon-γ (IFN-γ) treatment significantly induced β2-microglobulin expression, promoting CD8(+) T cell-mediated killing of control hESCs and their derivatives, CD8(+) T-cell-mediated cytotoxicity was barely observed with β2-microglobulin-null hESCs and their derivatives treated with IFN-γ. This genetic manipulation to disrupt HLA-I expression did not affect the self-renewal capacity, genomic stability, or pluripotency of hESCs. Despite being relatively sensitive to natural killer (NK) cell-mediated killing due to the lack of HLA-I expression, when transplanted into NK cell-depleted immunocompetent mice, β2-microglobulin-null hESCs developed into tumors resembling those derived from control hESCs in severe combined immunodeficiency mice. These results demonstrate that β2-microglobulin-null hESCs significantly reduce immunogenicity to CD8(+) T cells and might provide a renewable source of cells for tissue regeneration without the need for HLA matching in the future.
SIGNIFICANCE: This study reports the generation of a novel β2-microglobulin (B2M)(-/-) human embryonic stem cell (hESC) line. Differentiated mature cells from this line do not express cell surface human leukocyte antigen molecules even after interferon-γ stimulation and are resistant to alloreactive CD8(+) T cells. Moreover, this B2M(-/-) hESC line contains no off-target integration or cleavage events, is devoid of stable B2M mRNA, exhibits a normal karyotype, and retains its self-renewal capacity, genomic stability, and pluripotency. Although B2M(-/-) hESC-derived cells are more susceptible to natural killer (NK) cells, murine transplantation studies have indicated that they are, overall, much less immunogenic than normal hESCs. Thus, these data show for the first time that, in vivo, the advantages provided by B2M(-/-) hESC-derived cells in avoiding CD8(+) T-cell killing appear significantly greater than any disadvantage caused by increased susceptibility to NK cells.

PMID: 26285657 [PubMed – as supplied by publisher]

Primary central nervous system lymphoma in Miyazaki, southwestern Japan, a human T-lymphotropic virus Type-1 (HTLV-1)-endemic area: clinicopathological review of 31 cases.

August 20, 2015 By Manish Butte

Primary central nervous system lymphoma in Miyazaki, southwestern Japan, a human T-lymphotropic virus Type-1 (HTLV-1)-endemic area: clinicopathological review of 31 cases.

J Clin Exp Hematop. 2014;54(3):179-85

Authors: Maekawa K, Moriguchi-Goto S, Kamiunten A, Kubuki Y, Shimoda K, Takeshima H, Asada Y, Marutsuka K

Abstract
Primary central nervous system lymphoma (PCNSL) is a rare and aggressive brain tumor. The aim of this study was to clarify the prevalence of T-cell-type PCNSL (T-PCNSL) in a human T-lymphotropic virus type-1 (HTLV-1)-endemic area of Southwestern Japan. We retrospectively investigated 31 PCNSL cases diagnosed between 1996 and 2013 at the University of Miyazaki Hospital. These cases accounted for 4.4% of all nodal or extranodal malignant lymphomas. Histologically, most of these cases were diagnosed as diffuse large B-cell lymphoma, while only two cases were considered to be low-grade and high-grade B-cell lymphoma (not otherwise specified). No T-PCNSL was found in this series. In addition, Epstein-Barr virus-encoded RNAs were not detected by in situ hybridization in any of the cases. Overall, no T-PCNSL cases were found in 18 years in a region with a high frequency of HTLV-1 seropositivity, namely, Southwestern Japan. This suggests that PCNSL and lymphomas of other anatomical sites are biologically distinct.

PMID: 25501108 [PubMed – indexed for MEDLINE]

Characteristics relating to the interiorization of acquired immunodeficiency syndrome in Brazil: a cross-sectional study.

August 19, 2015 By Manish Butte

Characteristics relating to the interiorization of acquired immunodeficiency syndrome in Brazil: a cross-sectional study.

Infect Dis Poverty. 2015;4(1):31

Authors: Vieira GD, Dos Reis AR, Augusto FO, Martins KR, Kern PR, de Souza TF, Basano SA, Camargo LM, de Sousa CM

Abstract
BACKGROUND: In recent years there has been changes in the social and geographic profile of acquired immunodeficiency syndrome (AIDS). The aim of this study was to evaluate the internalization of AIDS in the state of Rondônia, Brazil.
FINDINGS: In Rondônia, 1473 AIDS cases were reported, with an average annual incidence of 15.8/100,000 persons (42.7 % women). The most common mode of viral transmission was sexual (96.5 %), and the majority of the individuals had not completed their primary education (64.8 %). There was heterogeneity in relation to case distribution, involving almost all of the municipalities in the state. The average annual mortality rate was 2.5/100,000 persons.
CONCLUSION: Rondônia has a higher incidence of AIDS than the national average and the northern region. Efforts to provide access to treatment and follow-up of these individuals should be implemented, prioritizing areas where the incidence is higher and decentralizing the treatment of patients with AIDS in the state.

PMID: 26284512 [PubMed – as supplied by publisher]

The Antipancreatic Cancer Activity of OSI-027, a Potent and Selective Inhibitor of mTORC1 and mTORC2.

August 19, 2015 By Manish Butte

The Antipancreatic Cancer Activity of OSI-027, a Potent and Selective Inhibitor of mTORC1 and mTORC2.

DNA Cell Biol. 2015 Aug 18;

Authors: Chen B, Xu M, Zhang H, Xu MZ, Wang XJ, Tang QH, Tang JY

Abstract
In the present study, we investigated the potential activity of OSI-027, a potent and selective mammalian target of rapamycin (mTOR) complex 1/2 (mTORC1/2) dual inhibitor, against pancreatic cancer cells both in vitro and in vivo. We demonstrated that OSI-027 inhibited survival and growth of both primary and transformed (PANC-1 and MIA PaCa-2 lines) human pancreatic cancer cells. Meanwhile, OSI-027 induced caspase-dependent apoptotic death of the pancreatic cancer cells. On the other hand, caspase inhibitors alleviated cytotoxicity by OSI-027. At the molecular level, OSI-027 treatment blocked mTORC1 and mTORC2 activation simultaneously, without affecting ERK-mitogen-activated protein kinase activation. Importantly, OSI-027 activated cytoprotective autophagy in the above cancer cells. Whereas pharmacological blockage of autophagy or siRNA knockdown of Beclin-1 significantly enhanced the OSI-027-induced activity against pancreatic cancer cells. Specifically, a relatively low dose of OSI-027 sensitized gemcitabine-induced pancreatic cancer cell death in vitro. Further, administration of OSI-027 or together with gemcitabine dramatically inhibited PANC-1 xenograft growth in severe combined immunodeficiency mice, leading to significant mice survival improvement. In summary, the preclinical results of this study suggest that targeting mTORC1/2 synchronously by OSI-027 could be further investigated as a valuable treatment for pancreatic cancer.

PMID: 26284306 [PubMed – as supplied by publisher]

Primary immunodeficiency update: Part II. Syndromes associated with mucocutaneous candidiasis and noninfectious cutaneous manifestations.

August 19, 2015 By Manish Butte

Primary immunodeficiency update: Part II. Syndromes associated with mucocutaneous candidiasis and noninfectious cutaneous manifestations.

J Am Acad Dermatol. 2015 Sep;73(3):367-81

Authors: Pichard DC, Freeman AF, Cowen EW

Abstract
Several primary immunodeficiencies (PIDs) have recently been described that confer an elevated risk of fungal infections and noninfectious cutaneous manifestations. In addition, immunologic advances have provided new insights into our understanding of the pathophysiology of fungal infections in established PIDs. We reviewed PIDs that present with an eczematous dermatitis in part I. In part II of this continuing medical education article we discuss updates on PIDs associated with fungal infections, their biologic basis in PIDs, and noninfectious cutaneous manifestations.

PMID: 26282795 [PubMed – in process]

Primary immunodeficiency update: Part I. Syndromes associated with eczematous dermatitis.

August 19, 2015 By Manish Butte

Primary immunodeficiency update: Part I. Syndromes associated with eczematous dermatitis.

J Am Acad Dermatol. 2015 Sep;73(3):355-64

Authors: Pichard DC, Freeman AF, Cowen EW

Abstract
In the past decade, the availability of powerful molecular techniques has accelerated the pace of discovery of several new primary immunodeficiencies (PIDs) and revealed the biologic basis of other established PIDs. These genetic advances, in turn, have facilitated more precise phenotyping of associated skin and systemic manifestations and provide a unique opportunity to better understand the complex human immunologic response. These continuing medical education articles will provide an update of recent advances in PIDs that may be encountered by dermatologists through their association with eczematous dermatitis, infectious, and non-infectious cutaneous manifestations. Part I will discuss new primary immunodeficiencies that have an eczematous dermatitis. Part II will focus on primary immunodeficiencies that greatly increase susceptibility to fungal infection and the noninfectious presentations of PIDs.

PMID: 26282794 [PubMed – in process]