Hematopoietic Stem Cell Transplantation for XIAP Deficiency in Japan

Background

X-linked inhibitor of apoptosis protein (XIAP) deficiency is a rare immunodeficiency that is characterized by recurrent hemophagocytic lymphohistiocytosis (HLH) and splenomegaly and sometimes associated with refractory inflammatory bowel disease (IBD). Although hematopoietic stem cell transplantation (HSCT) is the only curative therapy, the outcomes of HSCT for XIAP deficiency remain unsatisfactory compared with those for SLAM-associated protein deficiency and familial HLH.

Aim

To investigate the outcomes and adverse events of HSCT for patients with XIAP deficiency, a national survey was conducted.

Methods

A spreadsheet questionnaire was sent to physicians who had provided HSCT treatment for patients with XIAP deficiency in Japan.

Results

Up to the end of September 2016, 10 patients with XIAP deficiency had undergone HSCT in Japan, 9 of whom (90%) had survived. All surviving patients had received a fludarabine-based reduced intensity conditioning (RIC) regimen. Although 5 patients developed post-HSCT HLH, 4 of them survived after etoposide administration. In addition, the IBD associated with XIAP deficiency improved remarkably after HSCT in all affected cases.

Conclusion

The RIC regimen and HLH control might be important factors for successful HSCT outcomes, with improved IBD, in patients with XIAP deficiency.

     

Clinical and Host Genetic Characteristics of Mendelian Susceptibility to Mycobacterial Diseases in Japan

Purpose  

The aim of this study is to investigate clinical characteristics and genetic backgrounds of Mendelian susceptibility to mycobacterial diseases (MSMD) in Japan.     

Late-Onset Progressive Multifocal Leukoencephalopathy (PML) and Lymphoma in a 65-Year-Old Patient with XIAP Deficiency

Journal of Clinical Immunology -     

Reduced-Intensity/Reduced-Toxicity Conditioning Approaches Are Tolerated in XIAP Deficiency but Patients Fare Poorly with Acute GVHD

X-linked inhibitor of apoptosis (XIAP) deficiency is an inherited primary immunodeficiency characterized by chronic inflammasome overactivity and associated with hemophagocytic lymphohistiocytosis (HLH) and inflammatory bowel disease (IBD). Allogeneic hematopoietic cell transplantation (HCT) with fully myeloablative conditioning may be curative but has been associated with poor outcomes. Reports of reduced-intensity conditioning (RIC) and reduced-toxicity conditioning (RTC) regimens suggest these approaches are well tolerated, but outcomes are not well established. Retrospective data were collected from an international cohort of 40 patients with XIAP deficiency who underwent HCT with RIC or RTC. Thirty-three (83%) patients had a history of HLH, and thirteen (33%) patients had IBD. Median age at HCT was 6.5 years. Grafts were from HLA-matched (n?=?30, 75%) and HLA-mismatched (n?=?10, 25%) donors. There were no cases of primary graft failure. Two (5%) patients experienced secondary graft failure, and three (8%) patients ultimately received a second HCT. Nine (23%) patients developed grade II–IV acute GVHD, and 3 (8%) developed extensive chronic GVHD. The estimated 2-year overall and event-free survival rates were 74% (CI 55–86%) and 64% (CI 46–77%), respectively. Recipient and donor HLA mismatch and grade II–IV acute GVHD were negatively associated with survival on multivariate analysis with hazard ratios of 5.8 (CI 1.5–23.3, p?=?0.01) and 8.2 (CI 2.1–32.7, p?<?0.01), respectively. These data suggest that XIAP patients tolerate RIC and RTC with survival rates similar to HCT of other genetic HLH disorders. Every effort should be made to prevent acute GVHD in XIAP-deficient patients who undergo allogeneic HCT.

     

Clinical, Immunological and Genetic Findings of a Large Tunisian Series of Major Histocompatibility Complex Class II Deficiency Patients

Introduction

Major histocompatibility complex class II (MHC-II) expression deficiency is a combined primary immunodeficiency leading to the impairment of the cellular and humoral immune responses. A majority of affected patients belong to consanguineous families particularly from the Maghreb, where a founder effect for a highly frequent mutation (named c.338-25_338del26) in the RFXANK gene was reported. Herein, we report the largest single Maghrebian country series of MHC-II deficient patients.

Patients and Methods

In Tunisia, among 551 PIDs diagnosed from 1993 to 2011, 54 had an MHC-II deficiency. The clinical features and immunological investigations were retrospectively analyzed in 34 children of them belonging to 28 kindred. The genetic study included the c.338-25_338del26 screening by the amplification of the affected region using polymerase chain reaction (PCR) followed by direct sequencing.

Results

Consanguinity was present in 22 out of 28 families. Mean age at the first infection was 6.1 months. Chronic diarrhea with failure to thrive and pulmonary infections were the most common manifestations occurring in 26 and 28 patients respectively. The most specific laboratory findings were the defect of MHC-II (HLA-DR) expression in all patients. The c.338-25_338del26 mutation was identified in 25 of them.

Conclusion

In Maghrebian settings, pediatricians should definitely consider this diagnosis in the presence of an early onset of severe and recurrent infections of the respiratory and intestinal tracts, particularly protracted diarrhea with a failure to thrive. The founder effect for the c.338-25_338del26 mutation in the RFXANK gene is also confirmed, facilitating prenatal diagnosis as a preventive approach in the Tunisian affected families with severe forms, particularly in the context of limited access to bone marrow transplantation.     

Clinical pharmacology and clinical trials in Japan

Clinical pharmacology is the pursuit of rational therapeutics by following the scientific principles of medicine and pharmacology. In Japan the roles for clinical pharmacology and clinical pharmacologists have been evolving since the discipline appeared in the 1950s. Clinical pharmacology and clinical trials for drug development depend on each other, and clinical pharmacologists play an important role in drug development in Japan. As the discipline becomes more important and complicated, many issues regarding drug therapeutics and clinical trials in Japan have been raised, and several points of view have been expressed. The following suggestions have been made to improve clinical pharmacology in Japan: (a) Medical education in the field of clinical pharmacology must be improved by creating or improving clinical pharmacology programs in medical schools. (b) The appropriate infrastructure for clinical trials must be established so that the physicians' workload is reduced, and patients' participation in clinical trials becomes much easier. (c) Scientific and ethical standards of the pharmaceutical industry must be improved, and the effort should be made to produce drugs with new mechanisms of action or with significant expected benefits. (d) The regulatory agency must provide stronger support, encompassing all the various points of view of academic institutes and the pharmaceutical industry. In light of the enthusiasm demonstrated by the government, physicians, and pharmaceutical industry in Japan for continued progress in clinical pharmacology, it seems likely that all its challenges will be overcome in the near future. Hence, despite the various problems discussed here the future seems promising for the continued development of clinical pharmacology.Abbreviations GCP Good clinical practice - JSCPT Japanese Society of Clinical Pharmacology and Therapeutics     

Expanding the Clinical and Genetic Spectrum of Human CD40L Deficiency: The Occurrence of Paracoccidioidomycosis and Other Unusual Infections in Brazilian Patients

CD40 ligand (CD40L) deficiency or X-linked hyper-IgM syndrome (X-HIGM) is a well-described primary immunodeficiency in which Pneumocystis jiroveci pneumonia is a common clinical feature. We have identified an unusual high incidence of fungal infections and other not yet described infections in a cohort of 11 X-HIGM patients from nine unrelated Brazilian families. Among these, we describe the first case of paracoccidioidomycosis (PCM) in X-HIGM. The molecular genetic analysis of CD40L was performed by gene sequencing and evaluation of CD40L protein expression. Nine of these 11 patients (82%) had fungal infections. These included fungal species common to CD40L deficiency (P. jiroveci and Candida albicans) as well as Paracoccidioides brasiliensis. One patient presented with PCM at age 11 years and is now doing well at 18 years of age. Additionally, one patient presented with a simultaneous infection with Klebsiella and Acinetobacter, and one with condyloma caused by human papilloma virus. Molecular analysis revealed four previously described CD40L mutations, two novel missense mutations (c.433 T?>?G and c.476 G?>?C) resulting in the absence of CD40L protein expression by activated CD4(+) cells and one novel insertion (c.484_485insAA) within the TNFH domain leading to a frame shift and premature stop codon. These observations demonstrated that the susceptibility to fungal infections in X-HIGM extends beyond those typically associated with X-HIGM (P. jiroveci and C. albicans) and that these patients need to be monitored for those pathogens.     

Clinical and Immunological Characterization of ICF Syndrome in Japan

Objective

Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare autosomal recessive primary immunodeficiency. Hypogammaglobulinemia is a major manifestation of ICF syndrome, but immunoglobulin replacement therapy does not seem to be effective for some ICF patients. Therefore, we aimed to reassess the immunological characteristics of this syndrome.

Methods

Eleven Japanese patients with ICF syndrome were enrolled. We performed whole-exome sequencing in four cases and homozygosity mapping using SNP analysis in two. We evaluated their clinical manifestations and immunological status.

Results

We newly diagnosed six ICF patients who had tentatively been diagnosed with common variable immunodeficiency. We identified two novel mutations in the DNMT3B gene and one novel mutation in the ZBTB24 gene. All patients showed low serum IgG and/or IgG₂ levels and were treated by periodic immunoglobulin replacement therapy. Three of the six patients showed worse results of the mitogen-induced lymphocyte proliferation test. Analyses of lymphocyte subpopulations revealed that CD19⁺CD27⁺ memory B cells were low in seven of nine patients, CD3⁺ T cells were low in three patients, CD4/8 ratio was inverted in five patients, CD31⁺ recent thymic emigrant cells were low in two patients, and CD19⁺ B cells were low in four patients compared with those in the normal controls. ICF2 patients showed lower proportions of CD19⁺ B cells and CD16⁺56⁺ NK cells and significantly higher proportions of CD3⁺ T cells than ICF1 patients. T cell receptor excision circles were undetectable in two patients. Despite being treated by immunoglobulin replacement therapy, three patients died of influenza virus, fatal viral infection with persistent Epstein–Barr virus infection, or JC virus infection. One of three dead patients showed normal intelligence with mild facial anomaly. Two patients presented with autoimmune or inflammatory manifestations. Infectious episodes decreased in three patients who were started on trimethoprim–sulfamethoxazole and/or antifungal drugs in addition to immunoglobulin replacement therapy. These patients might have suffered from T cell immunodeficiency.

Conclusion

These results indicate that patients with ICF syndrome have a phenotype of combined immunodeficiency. Thus, to achieve a better prognosis, these patients should be treated as having combined immunodeficiency in addition to receiving immunoglobulin replacement therapy.

     

Immunohistochemical detection of XIAP in mesothelium and mesothelial lesions

We examined benign and malignant mesothelial tissue samples for the presence of X-linked inhibitor of apoptosis protein (XIAP), a potent constituent of the inhibitor of apoptosis family of caspase inhibitors. We subjected 55 sections (31 malignant mesotheliomas, 2 well-differentiated peritoneal mesotheliomas, 13 pleural mesothelial hyperplasias, and 9 benign mesothelial tissues) from archival formalin-fixed, paraffin-embedded surgical tissue blocks to citrate-based antigen retrieval and then incubated them with monoclonal anti-XIAP (clone 48, dilution 1:250; BD Biosciences, San Jose, CA) at 4 degrees C for 72 hours and developed them using EnVision-Plus reagents (DAKO, Carpinteria, CA) and diaminobenzidine as the chromogen. Particulate or nonhomogeneous cytoplasmic staining was considered positive. All 9 normal mesothelial samples were negative for XIAP. Of 13 mesothelial hyperplasias, 1 (8%) was weakly positive in fewer than 10% of cells, as was 1 of 2 well-differentiated peritoneal mesotheliomas. Of 31 malignant mesotheliomas, 25 (81%) displayed XIAP positivity. XIAP immunostaining, when strong, allows for distinction of malignant from benign and hyperplastic mesothelial cell populations and is a potentially useful immunodiagnostic marker in small samples and morphologically controversial cases. Elevated expression of XIAP could contribute to tumorigenesis in mesothelioma.     

IgA Deficiency: Correlation Between Clinical and Immunological Phenotypes

Background  IgA deficiency (IGAD) is the most common primary antibody deficiency. Although many affected individuals have no apparent symptom, selected patients suffer from recurrent mucosal infections, allergies, and autoimmune diseases. We aimed to investigate the clinical features in relation to immune function of Iranian patients with symptomatic IGAD. Methods  Thirty-seven patients (21 male and 16 female), aged 4–32 years, were evaluated in this study. Patients were followed for a total of 131 patient years with a mean follow-up of 3.5 years per patient. Results  The most prevalent presentations were recurrent infections occurring in 27 subjects, followed by allergy in eight cases and autoimmunity in two patients. However, during the follow-up period, 35 patients developed infections in respiratory and gastrointestinal tracts, necessitating medical care. Apart from infections, allergy was the most frequent complaint (31 cases); the major features were asthma, atopic dermatitis, and allergic rhinoconjunctivitis. Autoimmune diseases were documented in ten cases; thyroiditis was the most common. In 31 patients who received unconjugated pneumococcal polyvalent vaccine, antibody response against polysaccharide antigen was measured before and 28 days after vaccination. One fourth of vaccinated patients were hyporesponsive to vaccine; four of these patients developed bronchiectasis. The patients with IGAD were classified into two groups: group 1 (14 cases) consisted of patients with IGAD and other associated immune defects, such as immunoglobulin G (IgG) subclass deficiency and defective specific antibody production. Group 2 (23 cases) had isolated IGAD without other immunological abnormalities. There was a significantly increased number of lower respiratory tract infections in group 1 compared with group 2 (P = 0.006). Moreover, four patients of group 1 had bronchiectasis whereas none of the patients in group 2 developed this complication (P = 0.015). Conclusion  Subclassification of IGAD regarding the existence of associated immune defects is useful in terms of morbidity and planning for medical care. IgA-deficient patients with concomitant immune defects such as defects in specific antibody production have higher rates of recurrent infections and bronchiectasis, which necessitates more effective monitoring.