Research

Malaysia’s First Transplanted Case of Chronic Granulomatous Disease: The Journey of Overcoming Obstacles.

Children (Basel). 2016;3(2)

Authors: Ismail IH, Jamli FM, Othman IS, Noh LM, Abdul Latiff AH

Abstract
The awareness of primary immunodeficiency (PID) in Malaysia is still not forthcoming. Certain practical issues such as lack of clinical immunologists and specialized laboratory diagnostic facilities remain to be addressed. However, great efforts taken by passionate clinicians and scientists in the immunology networking have ascertained some prevalence. Despite the limitation, all suspected cases of PID are being properly investigated and competently managed. In this case report we highlighted the obstacles we faced in managing PID patients, particularly preparing for bone marrow transplant. This is the first transplanted case of chronic granulomatous disease in Malaysia, which emphasizes the importance of collaborative work to ensure further morbidities or mortalities are prevented.

PMID: 27417247 [PubMed]

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Pleural empyema caused by Salmonella enteritidis in a patient with non-Hodgkin lymphoma.

Vojnosanit Pregl. 2016 Mar;73(3):280-3

Authors: Kojić M, Nozić D, Tarabar O, Perisić N

Abstract
INTRODUCTION: Extraintestinal manifestations of nontyphoidal salmonellosis are usually seen in patients with cellular immunodeficiency. Pleural empyema caused by nontyphoidal Salmonella is very rare clinical presentation of salmonellosis and there are just a few cases described in a literature. We presented a very rare case of pleural empyema caused by Salmonella enteritidis in a patient with non-Hodgkin limphoma.
CASE REPORT: A 60-year-old male with low grade B-cell lymphoma, mucosa associated lymphoid tissue (MALT) type in IV clinical degree, manifested with infiltration of stomach, bronchus, pleura and peritoneum was admitted to the hospital. Initially the patient was presented with non-specific symptoms and signs, suggesting poor general condition. During the hospitalization his pleural fluid became purulent and changes in blood counts were registered with the increase of leukocytes, especially neutrophils. A large number of leukocytes was found by microscopic evaluation of pleural fluid and Salmonella enteritidis was isolated by its culture. There were no pathogenic bacteria in stool culture and hemoculture remained sterile. Toxins A and B of Clostridium difficile were not detected in stool. The patient was treated by ciprofloxacin and cefrtiaxone for 14 days with drainage of the purulent content, what was followed by the resolution and organization of the pleural fluid. After the stabilization of his general condition, chemotherapy with cyclophosphamide, vincristine, prednisone (COP) was introduced, with complete response.
CONCLUSION: Although rare, pleural empyema caused by nontyphoidal Salmonella should be considered in patients with severe immunosuppression, because appropriate antimicrobial therapy with surgical measures are very important for the outcome in these patients.

PMID: 27295915 [PubMed – indexed for MEDLINE]

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Zoledronate as effective treatment for minimal trauma fractures in a child with STAT3 deficiency and osteonecrosis of the hip.

Pediatr Blood Cancer. 2016 Jul 14;

Authors: Staines Boone AT, Alcántara-Montiel JC, Sánchez-Sánchez LM, Arce-Cano M, García-Campos J, Lugo Reyes SO

Abstract
Signal transducer and activator of transcription 3 (STAT3) deficiency is a primary immunodeficiency characterized by eczema, complicated recurrent infections, elevated serum immunoglobulin E (IgE), osteopenia, and minimal trauma fractures. Zoledronic acid (ZA) is a long-acting bisphosphonate that has been successfully used in children with secondary osteoporosis and osteogenesis imperfecta. We describe the case of a 7-year-old male with STAT3 deficiency and minimal trauma fractures, who also developed osteonecrosis of the hip. He responded well to intravenous ZA every 6 months for 18 months. Three years later, he walks independently and unaided, and has not suffered any other fractures. Although more studies are needed, ZA might help reduce minimal trauma fractures in patients with STAT3 deficiency.

PMID: 27416072 [PubMed – as supplied by publisher]

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How genetic testing can lead to targeted management of XIAP deficiency-related inflammatory bowel disease.

Genet Med. 2016 Jul 14;

Authors: Nielsen OH, LaCasse EC

Abstract
X-linked lymphoproliferative disease type 2 (XLP-2, OMIM 300635) is a primary immunodeficiency caused by the loss of X chromosome-linked inhibitor of apoptosis (XIAP), the X-linked inhibitor of apoptosis gene at Xq25. XLP-2 individuals are susceptible to several specific and potentially fatal infections, such as Epstein-Barr virus (EBV). Children with XIAP-related XLP-2 may present with either familial hemophagocytic lymphohistiocytosis, often triggered in response to EBV infection, or with a treatment-refractory severe pediatric form of inflammatory bowel disease (IBD) that might be diagnosed as Crohn disease. However, this monogenic cause of IBD is distinct from adult Crohn disease (a polygenic and multifactorial disease) in its etiology and responsiveness to therapy. XLP-2 and the associated IBD symptoms are managed by a reduced-intensity conditioning regimen with an allogeneic hematopoietic stem cell transplantation that causes resolution of gastrointestinal symptoms. Exome sequencing has enabled identification of XIAP-deficient diseased individuals and has altered their morbidity by providing potentially lifesaving strategies in a timely and effective manner. Here, we summarize XLP-2 IBD treatment history and patient morbidity/mortality since its original identification in 2006. Since XLP-2 is rare, cases are probably undergiagnosed or misdiagnosed. Consideration of XLP-2 in children with severe symptoms of IBD can prevent serious morbidities and mortality, avoid unnecessary procedures, and expedite specific targeted therapy.Genet Med advance online publication 14 July 2016Genetics in Medicine (2016); doi:10.1038/gim.2016.82.

PMID: 27416006 [PubMed – as supplied by publisher]

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Prophylactic immunoglobulin therapy in secondary immune deficiency – an expert opinion.

Expert Rev Clin Immunol. 2016 Jul 14;:1-6

Authors: Agostini C, Blau IW, Kimby E, Plesner T

Abstract
INTRODUCTION: In primary immunodeficiency (PID), immunoglobulin replacement therapy (IgRT) for infection prevention is well-established and supported by a wealth of clinical data. On the contrary, very little evidence-based data is available on the challenges surrounding the use of IgRT in secondary immune deficiencies (SID), and most published guidelines are mere extrapolations from the experience in PID.
AREAS COVERED: In this article, four European experts provide their consolidated opinion on open questions surrounding the prophylactic use of IgRT in SID, based on their clinical experience. The main topics are IgRT initiation, route of administration, dose optimization, and therapy discontinuation. The authors hope this discussion will be of assistance to practicing physicians in their daily decision-making. Expert commentary: Although growing experience indicates that IgRT could play an important role in the management of SID, very little robust evidence is available to guide clinical practice. The authors stress the urgent need for new studies in the field and discuss points they find of importance to design them adequately.

PMID: 27415820 [PubMed – as supplied by publisher]

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Extracoporeal photopheresis treatment of acute graft-versus-host disease following allogeneic haematopoietic stem cell transplantation.

F1000Res. 2016;5

Authors: Flinn AM, Gennery AR

Abstract
Acute graft-versus-host disease (aGvHD) continues to be a major obstacle to allogeneic haematopoietic stem cell transplantation. Thymic damage secondary to aGvHD along with corticosteroids and other non-selective T lymphocyte-suppressive agents used in the treatment of aGvHD concurrently impair thymopoiesis and negatively impact on immunoreconstitution of the adaptive immune compartment and ultimately adversely affect clinical outcome. Extracorporeal photopheresis (ECP) is an alternative therapeutic strategy that appears to act in an immunomodulatory fashion, potentially involving regulatory T lymphocytes and dendritic cells. By promoting immune tolerance and simultaneously avoiding systemic immunosuppression, ECP could reduce aGvHD and enable a reduction in other immunosuppression, allowing thymic recovery, restoration of normal T lymphopoiesis, and complete immunoreconstitution with improved clinical outcome. Although the safety and efficacy of ECP has been demonstrated, further randomised controlled studies are needed as well as elucidation of the underlying mechanisms responsible and the effect of ECP on thymic recovery.

PMID: 27408705 [PubMed]

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Abnormal TREC-Based Newborn Screening Test in a Premature Neonate with Massive Perivillous Fibrin Deposition of the Placenta.

Case Reports Immunol. 2016;2016:5083274

Authors: Kostadinov S, Robbins KA, Hayward A

Abstract
Severe combined immunodeficiency (SCID), a primary immunodeficiency arising from variable defects in lymphocyte development and survival, is characterized by significant deficiency of thymus derived (T-) lymphocytes and variable defects in the B-lymphocyte population. Newborn screening for SCID is based on detection of low numbers of T-cell receptor excision circles (TRECs) by real time quantitative PCR (RT-qPCR). This screening allows for early identification of individuals with SCID and other disorders characterized by T-lymphopenia. Higher rates of abnormal screens are commonly seen in premature and critically ill neonates, often representing false positives. It is possible that many abnormal screens seen in these populations are result of conditions that are characterized by systemic inflammation or stress, possibly in the context of stress-induced thymic involution. We present a case of a male infant delivered at 27 weeks, 6 days of gestation, with severe intrauterine growth restriction who had an abnormal TREC screen and a massive perivillous fibrin deposition (MPFD) of the placenta. This association has not been reported previously. We are raising the awareness to the fact that conditions, such as MPFD, that can create adverse intrauterine environment are capable of causing severe stress-induced thymic involution of the fetus which can present with abnormal TREC results on newborn screening.

PMID: 27403355 [PubMed]

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Immune Gamma Globulin Therapeutic Indications in Immune Deficiency and Autoimmunity.

Curr Allergy Asthma Rep. 2016 Jul;16(8):55

Authors: Yang L, Wu EY, Tarrant TK

Abstract
Immune gamma globulin (IgG) has a long history in the treatment of both primary immune deficiency and autoimmune disorders. Disease indications continue to expand and new-generation products increase the versatility of delivery. This review encompasses a historical perspective as well as current and future implications of human immune globulin for the treatment of immune-mediated illness.

PMID: 27401913 [PubMed – in process]

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Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4+ T cells into distinct effector subsets.

J Exp Med. 2016 Jul 11;

Authors: Ma CS, Wong N, Rao G, Nguyen A, Avery DT, Payne K, Torpy J, O’Young P, Deenick E, Bustamante J, Puel A, Okada S, Kobayashi M, Martinez-Barricarte R, Elliott M, Sebnem Kilic S, El Baghdadi J, Minegishi Y, Bousfiha A, Robertson N, Hambleton S, Arkwright PD, French M, Blincoe AK, Hsu P, Campbell DE, Stormon MO, Wong M, Adelstein S, Fulcher DA, Cook MC, Stepensky P, Boztug K, Beier R, Ikincioğullari A, Ziegler JB, Gray P, Picard C, Boisson-Dupuis S, Phan TG, Grimbacher B, Warnatz K, Holland SM, Uzel G, Casanova JL, Tangye SG

Abstract
Naive CD4(+) T cells differentiate into specific effector subsets-Th1, Th2, Th17, and T follicular helper (Tfh)-that provide immunity against pathogen infection. The signaling pathways involved in generating these effector cells are partially known. However, the effects of mutations underlying human primary immunodeficiencies on these processes, and how they compromise specific immune responses, remain unresolved. By studying individuals with mutations in key signaling pathways, we identified nonredundant pathways regulating human CD4(+) T cell differentiation in vitro. IL12Rβ1/TYK2 and IFN-γR/STAT1 function in a feed-forward loop to induce Th1 cells, whereas IL-21/IL-21R/STAT3 signaling is required for Th17, Tfh, and IL-10-secreting cells. IL12Rβ1/TYK2 and NEMO are also required for Th17 induction. Strikingly, gain-of-function STAT1 mutations recapitulated the impact of dominant-negative STAT3 mutations on Tfh and Th17 cells, revealing a putative inhibitory effect of hypermorphic STAT1 over STAT3. These findings provide mechanistic insight into the requirements for human T cell effector function, and explain clinical manifestations of these immunodeficient conditions. Furthermore, they identify molecules that could be targeted to modulate CD4(+) T cell effector function in the settings of infection, vaccination, or immune dysregulation.

PMID: 27401342 [PubMed – as supplied by publisher]

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Gene Correction of iPSCs from a Wiskott-Aldrich Syndrome Patient Normalizes the Lymphoid Developmental and Functional Defects.

Stem Cell Reports. 2016 Jul 6;

Authors: Laskowski TJ, Van Caeneghem Y, Pourebrahim R, Ma C, Ni Z, Garate Z, Crane AM, Li XS, Liao W, Gonzalez-Garay M, Segovia JC, Paschon DE, Rebar EJ, Holmes MC, Kaufman D, Vandekerckhove B, Davis BR

Abstract
Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency disease caused by mutations in the gene encoding the WAS protein (WASp). Here, induced pluripotent stem cells (iPSCs) were derived from a WAS patient (WAS-iPSC) and the endogenous chromosomal WAS locus was targeted with a wtWAS-2A-eGFP transgene using zinc finger nucleases (ZFNs) to generate corrected WAS-iPSC (cWAS-iPSC). WASp and GFP were first expressed in the earliest CD34(+)CD43(+)CD45(-) hematopoietic precursor cells and later in all hematopoietic lineages examined. Whereas differentiation to non-lymphoid lineages was readily obtained from WAS-iPSCs, in vitro T lymphopoiesis from WAS-iPSC was deficient with few CD4(+)CD8(+) double-positive and mature CD3(+) T cells obtained. T cell differentiation was restored for cWAS-iPSCs. Similarly, defects in natural killer cell differentiation and function were restored on targeted correction of the WAS locus. These results demonstrate that the defects exhibited by WAS-iPSC-derived lymphoid cells were fully corrected and suggests the potential therapeutic use of gene-corrected WAS-iPSCs.

PMID: 27396937 [PubMed – as supplied by publisher]

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