Research

Patients with common variable immunodeficiency paradoxically have increased rates of autoimmune disorders.

BMJ Case Rep. 2017 Oct 13;2017:

Authors: Susheela AT, Hale A

Abstract
Common variable immunodeficiency (CVID), characterised by disordered B cell function, is one of the most common primary immunodeficiency disorders. Patients with CVID are at lifelong risk of recurrent infections, particularly of the respiratory and gastrointestinal tracts. Paradoxically, given their immunocompromised state, patients with CVID are also at significantly increased risk of autoimmune disorders, which are seen in almost 25% of cases. The authors report a 24-year-old female patient with CVID, manifested as severe hypogammaglobulinaemia with recurrent sinopulmonary infections and enterocolitis, who presented with transaminitis, chronic diarrhoea and haematemesis. No infectious aetiologies were identified. She was diagnosed with coeliac disease after a small bowel biopsy and positive response to gluten-free diet. Haematemesis was attributed to portal hypertension due to liver cirrhosis, which was confirmed via liver biopsy. Coeliac disease can be a cause of diarrhoea in patients with immunodeficiency disorders and is often underdiagnosed. It can also be the underlying source of liver disease and is an often under-recognised cause of cirrhosis. The case presented emphasises the paradoxical and challenging relationship that patients with CVID face between immunodeficiency and autoimmune disorders, and also highlights that coeliac disease is an under-recognised cause of liver disease.

PMID: 29030367 [PubMed – in process]

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Paracoccidioidomycosis associated with a heterozygous STAT4 mutation and impaired IFN-γ immunity.

J Infect Dis. 2017 Oct 05;:

Authors: Schimke LF, Hibbard J, Martinez-Barricarte R, Khan TA, de Souza Cavalcante R, Borges de Oliveira Junior E, Takahashi França T, Iqbal A, Yamamoto G, Arslanian C, Feriotti C, da Costa TA, Bustamante J, Boisson-Dupuis S, Casanova JL, Marzagao Barbuto JA, Zatz M, Poncio Mendes R, Garcia Calich VL, Ochs HD, Torgerson TR, Cabral-Marques O, Condino-Neto A

Abstract
Background: Mutations in genes affecting interferon (IFN)-γ immunity have contributed to understand the essential role of IFN-γ in the protection against intracellular pathogens. However, inborn errors in STAT4, which controls IL-12 responses, have not yet been reported.
Objective: To determine the underlying genetic defect in a family with a history of paracoccidioidomycosis (PCM) disease.
Methods: Genetic analysis was performed by whole-exome sequencing and sanger sequencing. STAT4 phosphorylation (pSTAT4) and translocation to the nucleus, IFN-γ release by patient lymphocytes and microbicidal activity of patient monocytes/macrophages were assessed. The effect on STAT4 function was evaluated by site-directed mutagenesis using a lymphoblastoid B cell line (B-LCL) and U3A cells.
Results: A heterozygous missense mutation, c.1952 A>T (p.E651V) in STAT4 was identified in the index patient and her father. Patient’s and father’s lymphocytes showed reduced pSTAT4, nuclear translocation and impaired IFN-γ production. Mutant B-LCL and U3A cells also displayed reduced pSTAT4. Patient´s and father´s PBMCs and macrophages demonstrated impaired fungicidal activity compared with those from healthy controls that improved in the presence of recombinant human IFN-γ, but not rhIL-12.
Conclusion: Our data suggest autosomal dominant STAT4 deficiency as a novel inborn error of IL-12-dependent IFN-γ immunity associated with susceptibility to PCM disease.

PMID: 29029192 [PubMed – as supplied by publisher]

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Inherited IL-12Rβ1 Deficiency in a Child With BCG Adenitis and Oral Candidiasis: A Case Report.

Pediatrics. 2017 Oct 12;:

Authors: Hatipoglu N, Güvenç BH, Deswarte C, Koksalan K, Boisson-Dupuis S, Casanova JL, Bustamante J

Abstract
Tuberculosis is a major worldwide problem, and protection from it is achieved mainly by live attenuated bacille Calmette-Guérin vaccine, which is capable of causing disease in immunocompromised host. Oral thrush is abnormal in healthy children, which suggests an underlying immunodeficiency. Mendelian susceptibility to mycobacterial disease is a rare primary immunodeficiency characterized by a selective predisposition to weakly virulent Mycobacteria and Salmonella and also predisposition to chronic mucocutaneous candidiasis. Interleukin 12 receptor β1 (IL-12Rβ1) deficiency is the most common disease of Mendelian susceptibility to mycobacterial disease, and to date only 50 IL-12Rβ1 deficient patients with clinical signs of chronic mucocutaneous candidiasis have been reported. We report a 2.5-year-old daughter of consanguineous parents with both regional bacille Calmette-Guérin lymphadenitis and recurrent oral candidiasis carrying biallelic R175W mutation in the IL12RB1 gene, resulting in complete loss of expression of IL-12Rβ1. To our knowledge, this is the first report of bacille Calmette-Guérin lymphadenitis with concurrent oral candidiasis displaying such a mutation. New mutations and wide clinical diversities are the indisputable fact of populations with a high rate of consanguineous marriages.

PMID: 29025965 [PubMed – as supplied by publisher]

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Establishment of a dog primary prostate cancer organoid using the urine cancer stem cells.

Cancer Sci. 2017 Oct 10;:

Authors: Usui T, Sakurai M, Nishikawa S, Umata K, Nemoto Y, Haraguchi T, Itamoto K, Mizuno T, Noguchi S, Mori T, Iwai S, Nakagawa T, Yamawaki H, Ohama T, Sato K

Abstract
Dog spontaneously develops prostate cancer (PC) like human. Since most dogs with PC have poor prognosis, they are expected to become a translational model for human advanced PC. Stem cell-derived 3D organoid culture could recapitulate organ structures and physiology. Using patient tissues, human PC organoid culture system was established. Recent study showed that urine cells also possess the characteristic of stem cells. However, the urine cell-derived PC organoids have never been produced. We therefore generated PC organoids using the dog urine samples. Urine organoids from each PC dog were successfully generated. Each organoid showed cystic structures and resembled the epithelial structures of original tissues. Expression of an epithelial cell marker, E-cadherin and a myofibloblast marker, α-SMA was observed in the urine organoids. The organoids also expressed a basal cell marker, CK5 and a luminal cell marker, CK8. CD49f-sorted basal cell organoids rapidly grew compared with CD24-sorted luminal cell ones. The population of CD44-positive cells was the highest in both organoids and the original urine cells. Injection of the organoids into immunodeficiency mice successfully formed tumor, which exhibited the features of the organoids. Treatment with a microtubule inhibitor, docetaxel but not a cyclooxygenase inhibitor, piroxicam and an mTOR inhibitor, rapamycin decreased the cell viability of organoids. Treatment with a Hedgehog signal inhibitor, GANT61 increased the radiosensitivity in the organoids. These findings revealed that PC organoids using urine might become a useful tool to investigate the mechanisms of pathogenesis and treatment of dog PC. This article is protected by copyright. All rights reserved.

PMID: 29024204 [PubMed – as supplied by publisher]

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Novel ZBTB24 Mutation Associated with Immunodeficiency, Centromere Instability, and Facial Anomalies Type-2 Syndrome Identified in a Patient with Very Early Onset Inflammatory Bowel Disease.

Inflamm Bowel Dis. 2017 Oct 11;:

Authors: Conrad MA, Dawany N, Sullivan KE, Devoto M, Kelsen JR

Abstract
BACKGROUND: Very early onset inflammatory bowel disease, diagnosed in children ≤5 years old, can be the initial presentation of some primary immunodeficiencies.
METHODS: In this study, we describe a 17-month-old boy with recurrent infections, growth failure, facial anomalies, and inflammatory bowel disease. Immune evaluation, whole-exome sequencing, karyotyping, and methylation array were performed to evaluate the child’s constellation of symptoms and examination findings.
RESULTS: Whole-exome sequencing revealed that the child was homozygous for a novel variant in ZBTB24, the gene associated with immunodeficiency, centromere instability, and facial anomalies type-2 syndrome.
CONCLUSION: This describes the first case of inflammatory bowel disease associated with immunodeficiency, centromere instability, and facial anomalies type-2 syndrome in a child with a novel disease-causing mutation in ZBTB24 found on whole-exome sequencing.

PMID: 29023266 [PubMed – as supplied by publisher]

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Immune Reconstitution and Survival of 100 SCID Patients Post Hematopoietic Cell Transplant: A PIDTC Natural History Study.

Blood. 2017 Oct 11;:

Authors: Heimall J, Logan BR, Cowan MJ, Notarangelo LD, Griffith LM, Puck JM, Kohn DB, Pulsipher MA, Parikh S, Martinez C, Kapoor N, O’Reilly R, Boyer M, Pai SY, Goldman F, Burroughs L, Chandra S, Kletzel M, Thakar M, Connelly J, Cuvelier G, Davila B, Shereck E, Knutsen A, Sullivan KE, DeSantes K, Gillio A, Haddad E, Petrovic A, Quigg T, Smith AR, Stenger E, Yin Z, Shearer WT, Fleisher T, Buckley RH, Dvorak CC

Abstract
The Primary Immune Deficiency Treatment Consortium (PIDTC) is enrolling children with severe combined immunodeficiency (SCID) to a prospective natural history study. We analyzed patients treated with allogeneic hematopoietic cell transplantation (HCT) from 2010-2014, including 68 with typical SCID and 32 with leaky SCID, Omenn Syndrome or Reticular Dysgenesis. Most (59%) were diagnosed by newborn screening or family history. The 2-year overall survival (OS) was 90%but was 95% for those infection-free at HCT vs. 81% for those with active infection (p=0.009). Other factors, including the diagnosis of typical vs. leaky SCID/Omenn Syndrome, diagnosis via family history or newborn screening (FH/NBS), use of preparative chemotherapy, or the type of donor utilized did not impact survival. While 1-year post-HCT median CD4 counts and freedom from IVIG were improved after use of preparative chemotherapy, other immunologic reconstitution parameters were not affected and the potential for late sequelae in extremely young infants requires further evaluation. Following a T-cell-replete graft, landmark analysis at Day +100 post-HCT revealed that CD3 <300 cells/uL, CD8 <50 cells/uL, CD45RA <10%, or a restricted Vβ T cell receptor repertoire (<13 of 24 families) was associated with need for second HCT or death. In the modern era, active infection continues to pose the greatest threat to survival for SCID patients. Although NBS has been effective in diagnosing SCID patients early in life, there is an urgent need to identify validated approaches through prospective trials to ensure that patients proceed to HCT infection free. The trial is registered at www.clinicaltrials.gov as NCT01186913.

PMID: 29021228 [PubMed – as supplied by publisher]

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Autoimmunity in a cohort of 471 patients with primary antibody deficiencies.

Expert Rev Clin Immunol. 2017 Oct 11;:1-8

Authors: Azizi G, Tavakol M, Rafiemanesh H, Kiaee F, Yazdani R, Heydari A, Abouhamzeh K, Anvari P, Mohammadikhajehdehi S, Sharifia L, Bagheri Y, Mohammadi H, Abolhassani H, Aghamohammadi A

Abstract
OBJECTIVES: The aim of this study was to evaluate the frequency of autoimmunity in primary antibody deficiency (PAD).
METHODS: A total of 471 patients with PADs enrolled in this retrospective cohort study. For all patients’ demographic information, clinical records and laboratory data were collected to investigate autoimmune complications.
RESULTS: Autoimmune disorders as the first presentation of immunodeficiency were recorded in 11 patients (2.5%). History of autoimmunity was recorded in 125 patients during the course of the disease (26.5%). The frequency of autoimmunity in common variable immune deficiency (32.0%) was higher than other forms of PADs. The most common autoimmune manifestations were reported to be autoimmune gastrointestinal disease and autoimmune cytopenias. Among patients with autoimmunity, 87 patients (69.6%) had a history of one autoimmune disorder, while 38 patients (30.4%) had a history of multiple autoimmunities. The immune thrombocytopenic purpura and autoimmune hemolytic anemia were the most two concomitant autoimmune disorders in 16 (42.1%) of 38 patients with multiple autoimmunities. Comparing the frequency of Tregs in PAD patients with autoimmunity showed that, patients with multiple autoimmunities had lower Tregs than those with single autoimmunity (p = 0.017).
CONCLUSION: It is important that non-immunologist physicians be alert of the associated autoimmunity with PADs in order to reduce the diagnostic delay and establish timely immunoglobulin replacement therapy in these patients.

PMID: 29019451 [PubMed – as supplied by publisher]

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Recurrent and Prolonged Infections in a Child with a Homozygous IFIH1 Nonsense Mutation.

Front Genet. 2017;8:130

Authors: Zaki M, Thoenes M, Kawalia A, Nürnberg P, Kaiser R, Heller R, Bolz HJ

Abstract
In an Egyptian girl born to consanguineous parents, whole-exome sequencing (WES) identified a homozygous mutation in PHGDH, c.1273G>A (p.Val425Met), indicating 3-phosphoglycerate dehydrogenase deficiency. This diagnosis was compatible with the patient’s microcephaly, severe psychomotor retardation, seizures and cataracts. However, she additionally suffered from recurrent (at least monthly) episodes of prolonged and severe chest infections requiring hospitalization, suggesting a secondary, predisposing and potentially Mendelian, condition. A local reactivation of an EBV infection in the respiratory tract was detected after a recent chest infection, likely representing an opportunistic infection based on a compromised immune system. Further inspection of WES data revealed a homozygous nonsense mutation, c.2665A>T (p.Lys889(∗)), in IFIH1, encoding MDA5. MDA5 detects long viral double-stranded RNA that is generated during replication of picorna viruses, and thereby activates the type I interferon signaling pathway. The results of Western blot analysis of protein from cultured fibroblasts of the patient indicates absence of wild type MDA5/IFIH1, compatible with NMD. We propose that, analogous to the severe course of primary influenza infection due to biallelic deficiency of a downstream effector, IRF7, homozygous loss of IFIH1 defines a novel Mendelian immunodeficiency disorder that increases susceptibility to severe viral infections. This is contrasted to heterozygous gain-of-function IFIH1 mutations in autoimmune diseases. Our findings highlight the potential of comprehensive genomic investigations in patients from consanguineous families to identify monogenic predispositions to severe infections.

PMID: 29018476 [PubMed]

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Prolonged Excretion of Poliovirus among Individuals with Primary Immunodeficiency Disorder: An Analysis of the World Health Organization Registry.

Front Immunol. 2017;8:1103

Authors: Macklin G, Liao Y, Takane M, Dooling K, Gilmour S, Mach O, Kew OM, Sutter RW, iVDPV Working Group

Abstract
Individuals with primary immunodeficiency disorder may excrete poliovirus for extended periods and will constitute the only remaining reservoir of virus after eradication and withdrawal of oral poliovirus vaccine. Here, we analyzed the epidemiology of prolonged and chronic immunodeficiency-related vaccine-derived poliovirus cases in a registry maintained by the World Health Organization, to identify risk factors and determine the length of excretion. Between 1962 and 2016, there were 101 cases, with 94/101 (93%) prolonged excretors and 7/101 (7%) chronic excretors. We documented an increase in incidence in recent decades, with a shift toward middle-income countries, and a predominance of poliovirus type 2 in 73/101 (72%) cases. The median length of excretion was 1.3 years (95% confidence interval: 1.0, 1.4) and 90% of individuals stopped excreting after 3.7 years. Common variable immunodeficiency syndrome and residence in high-income countries were risk factors for long-term excretion. The changing epidemiology of cases, manifested by the greater incidence in recent decades and a shift to from high- to middle-income countries, highlights the expanding risk of poliovirus transmission after oral poliovirus vaccine cessation. To better quantify and reduce this risk, more sensitive surveillance and effective antiviral therapies are needed.

PMID: 28993765 [PubMed]

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