Research

Generation and characterization of four Chediak-Higashi Syndrome (CHS) induced pluripotent stem cell (iPSC) lines.

Stem Cell Res. 2020 Jun 22;47:101883

Authors: Serra-Vinardell J, Sandler MB, Pak E, Zheng W, Dutra A, Introne W, Gahl WA, Malicdan MC

Abstract
Chediak-Higashi Syndrome (CHS) is a lysosome-related organelle (LRO) disorder caused by biallelic mutations in the lysosomal trafficking regulator gene, LYST. The clinical features of CHS include oculocutaneous albinism, primary immunodeficiency, bleeding diathesis, risk for development of hemophagocyticlymphohistiocytosis,and progressive neurological problems. The pathophysiological mechanisms underlying this disease are unknown, so developing therapeutic options remains challenging. In this study,four induced pluripotent stem (iPSC) lines from unrelated CHS patients have been generated and successfully characterized for exploring the role of LYST in health and disease in diversecell types.

PMID: 32619719 [PubMed – as supplied by publisher]

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Clinical and Genetic Study of X-linked Agammaglobulinemia Patients (The Benefit of Early Diagnosis).

Iran J Allergy Asthma Immunol. 2020 Jun 23;19(3):305-309

Authors: Alizadeh Z, Dashti P, Mazinani M, Nourizadeh M, Shakerian L, Tajik S, Movahedi M, Mamishi S, Pourpak Z, Fazlollahi MR

Abstract
X-linked agammaglobulinemia (XLA) is a primary immunodeficiency caused by genetic defects in the Bruton tyrosine kinase (Btk) gene. XLA is characterized as an antibody deficiency by recurrent bacterial infections, the absence of peripheral B cells, and profound reductions in all immunoglobulin isotypes. This study aims to report the clinical and genetic features of five Iranian patients with XLA. Five male cases with recurrent bacterial infection entered this study based on clinical evaluation and Immunological screening tests. The levels of T-cell receptor excision circle (TREC) and kappa-deleting recombination excision circle (KREC) were also measured in dried blood spot (DBS) samples. Sanger sequencing was applied to PCR products of DNA samples of the patients for genetic studies. All patients were from unrelated families with a mean age of 6.7 years (2.5-11) at the time of diagnosis with 4.8 mean years of delay in diagnosis. The most frequent clinical manifestations were recurrent respiratory infections and arthritis. In these patients, five previously reported mutations were found including four mutations (p.Q496X, p.Q497X, p.R520X, and p.R641H) in the Kinase domain besides one mutation (p.L37P) in the pleckstrin homology (PH) domain. Evaluations of KREC and TREC level in patients’ DBS showed low-to-undetectable copies of KREC (0-2 copies/3.2mm DBS) with normal copies of TREC. As patients with XLA have complete immunoglobulin defects and develop severe and recurrent infections, early diagnosis would be beneficial for the improvement of their quality of life. The study results may provide valuable information for the diagnosis, genetic counseling and prenatal diagnosis for the patients and their family members and emphasize performing KREC as an early diagnostic test in patients with XLA.

PMID: 32615664 [PubMed – in process]

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Monogenic Primary Immunodeficiency Disorder Associated with Common Variable Immunodeficiency and Autoimmunity.

Int Arch Allergy Immunol. 2020 Jul 02;:1-9

Authors: Asgardoon MH, Azizi G, Yazdani R, Sohani M, Pashangzadeh S, Kalantari A, Shariat M, Shafiei A, Salami F, Jamee M, Rasouli SE, Mohammadi J, Hassanpour G, Tavakol M, Chavoshzadeh Z, Mahdaviani SA, Momen T, Behniafard N, Nabavi M, Bemanian MH, Arshi S, Molatefi R, Sherkat R, Shirkani A, Alyasin S, Jabbari-Azad F, Ghaffari J, Mesdaghi M, Ahanchian H, Khoshkhui M, Eslamian MH, Cheraghi T, Dabbaghzadeh A, Nasiri Kalmarzi R, Esmaeilzadeh H, Tafaroji J, Khalili A, Sadeghi-Shabestari M, Darougar S, Moghtaderi M, Ahmadiafshar A, Shakerian B, Heidarzadeh M, Ghalebaghi B, Fathi SM, Darabi B, Fallahpour M, Mohsenzadeh A, Ebrahimi S, Sharafian S, Vosughimotlagh A, Tafakoridelbari M, Rahimi Haji-Abadi M, Ashournia P, Razaghian A, Rezaei A, Delavari S, Shirmast P, Babaha F, Samavat A, Mamishi S, Khazaei HA, Negahdari B, Rezaei N, Abolhassani H, Aghamohammadi A

Abstract
BACKGROUND: Common variable immunodeficiency (CVID) is the most frequent primary immunodeficiency disorder mainly characterized by recurrent bacterial infections besides other immunological defects including loss of or dysfunction of B cells and decreased immunoglobulin levels. In this study, our aim is to evaluate clinical, immunological, and molecular data of patients with a primary clinical diagnosis of CVID and autoimmune phenotype with a confirmed genetic diagnosis.
METHODS: Among 297 patients with CVID, who were registered in the Iranian Primary Immunodeficiency Registry at Children’s Medical Center Hospital in Iran, 83 patients have been genetically examined and 27 patients with autoimmunity and confirmed genetic mutations were selected for analysis. Whole-exome sequencing and confirmatory Sanger sequencing methods were used for the study population. A questionnaire was retrospectively filled for all patients to evaluate demographic, laboratory, clinical, and genetic data.
RESULTS: In the 27 studied patients, 11 different genetic defects were identified, and the most common mutated gene was LRBA, reported in 17 (63.0%) patients. Two patients (7.7%) showed autoimmune complications as the first presentation of immunodeficiency. Eleven patients (40.7%) developed one type of autoimmunity, and 16 patients (59.3%) progressed to poly-autoimmunity. Most of the patients with mono-autoimmunity (n = 9, 90.0%) primarily developed infectious complications, while in patients with poly-autoimmunity, the most common first presentation was enteropathy (n = 6, 37.6%). In 13 patients (61.9%), the diagnosis of autoimmune disorders preceded the diagnosis of primary immunodeficiency. The most frequent autoimmune manifestations were hematologic (40.7%), gastrointestinal (48.1%), rheumatologic (25.9%), and dermatologic (22.2%) disorders. Patients with poly-autoimmunity had lower regulatory T cells than patients with mono-autoimmunity.
CONCLUSION: In our cohort, the diagnosis of autoimmune disorders preceded the diagnosis of primary immunodeficiency in most patients. This association highlights the fact that patients referring with autoimmune manifestations should be evaluated for humoral immunity.

PMID: 32615565 [PubMed – as supplied by publisher]

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Haematopoietic Cell Transplantation in Chronic Granulomatous Disease: a Study on 712 Children and Adults.

Blood. 2020 Jul 02;:

Authors: Chiesa R, Wang J, Blok HJ, Hazelaar S, Neven B, Moshous D, Schulz AS, Hoenig M, Hauck F, Al Seraihy A, Gozdzik J, Ljungman PT, Lindemans C, Fernandes J, Kalwak K, Strahm B, Schanz U, Sedlacek P, Sykora KW, Aksoylar S, Locatelli F, Stepensky P, Wynn RF, Lum SH, Zecca M, Porta F, Taskinen MH, Gibson BE, Matthes-Martin S, Karakukcu M, Hauri-Hohl MM, Veys P, Gennery AR, Lucchini G, Felber M, Albert MH, Balashov D, Lankester AC, Güngör T, Slatter M

Abstract
Chronic Granulomatous Disease (CGD) is a primary immunodeficiency resulting in life-threatening infections and inflammatory complications. Allogeneic hematopoietic cell transplantation (allo-HCT) can cure patients, but indication to transplant remains controversial. We performed a retrospective multicentre study on 712 patients with CGD undergoing allo-HCT transplanted in EBMT centres between 1993 and 2018. We studied 635 children (aged < 18 years) and 77 adults. Median follow-up was 45 months. Median age at transplant was 7 years (range: 0.1-48.6). Kaplan-Meier estimates of OS and EFS at 3 years were 85.7% (95% CI, 82.8-88.5) and 75.8% (95% CI, 72.3-79.3), respectively. On MVA, older age was associated with reduced survival (HR= 1.69, p= 0.0001) and increased chronic GVHD (HR 1.35, p=0.01). Nevertheless OS and EFS at 3 years for patients ≥ 18 years was 76% (95%CI, 66-86) and 69% (95%CI, 57-80), respectively. Use of one antigen-mismatched donors was associated with reduced OS (HR= 2.29, p= 0.01) and EFS (HR 2.37, p=0.001). No significant difference was found in OS, but a significantly reduced EFS (HR 3.69 p=0.001), in the small group who received a transplant from a donor with more than one antigen-mismatch. Choice of conditioning regimen did not influence OS or EFS. In conclusion we report an excellent outcome after allo-HCT in CGD, with low incidence of graft failure and mortality in all ages. Older patients and recipients of one antigen-mismatched grafts have a less favourable outcome. Transplant should be strongly considered at a younger age and particularly in the presence of a well-matched donor.

PMID: 32614953 [PubMed – as supplied by publisher]

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Whipple disease mimicking inflammatory bowel disease.

Intest Res. 2020 Jul 03;:

Authors: Tatsuki M, Ishige T, Igarashi Y, Hatori R, Hokama A, Hirato J, Muise A, Takizawa T, Arakawa H

Abstract
Whipple disease is a systemic chronic infection caused by Tropheryma whipplei. Although chronic diarrhea is a common gastrointestinal symptom, diagnosis is often difficult because there are no specific endoscopic findings, and the pathogen is not detectable by stool culture. We present a female patient with Whipple disease who developed chronic bloody diarrhea and growth retardation at the age of 4 years. Colonoscopy showed a mildly edematous terminal ileum and marked erythema without vascular patterns throughout the sigmoid colon and rectum. Subsequently, a primary diagnosis of ulcerative colitis was made. Histopathological analysis of the terminal ileum showed the presence of foamy macrophages filled with periodic acidSchiff-positive particles. Polymerase chain reaction using DNA from a terminal ileum biopsy sample amplified a fragment of 16S rRNA from T. whipplei. Antibiotic treatment relieved the patient’s symptoms. There was no evidence of immunodeficiency in the present case. Since Whipple disease worsens after anti-tumor necrosis factor inhibitor therapy, considering this infection in the differential diagnosis may be important in patients with inflammatory bowel disease, especially before initiation of immunotherapy.

PMID: 32610889 [PubMed – as supplied by publisher]

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A novel complete autosomal recessive STAT1 LOF variant causes immunodeficiency with hemophagocytic lymphohistiocytosis-like hyperinflammation.

J Allergy Clin Immunol Pract. 2020 Jun 27;:

Authors: Boehmer DFR, Koehler LM, Magg T, Metzger P, Rohlfs M, Ahlfeld J, Rack-Hoch A, Reiter K, Albert MH, Endres S, Rothenfusser S, Klein C, Koenig LM, Hauck F

Abstract
BACKGROUND: Complete STAT1 deficiency causes a rare primary immunodeficiency that is characterized by defective IFN-dependent gene expression leading to life-threatening viral and mycobacterial infections early in life.
OBJECTIVE: Characterization of a novel STAT1 loss-of-function (LOF) variant leading to pathological infection susceptibility and hyperinflammation.
METHODS: Clinical, immunological and genetic characterization of a patient with severe infections and hemophagocytic lymphohistiocytosis (HLH)-like hyperinflammation.
RESULTS: We report a child of consanguineous parents who presented with multiple severe viral infections that ultimately triggered HLH and liver failure. Despite intensified therapy with antivirals and CMV-specific donor cells the child died post-HSCT due to CMV reactivation with acute respiratory distress syndrome. Exome sequencing revealed a homozygous STAT1 variant (p.Val339ProfsTer18), leading to loss of STAT1 protein expression. Upon type-I and -II interferon stimulation, immune and non-immune cells showed defective upregulation of interferon-stimulated genes and increased susceptibility to viral infection in vitro. Increased viral infection rates were paralleled by hyperinflammatory ex vivo cytokine responses with increased production of TNF, IL-6 and IL-18.
CONCLUSION: Complete STAT1 deficiency is a devastating disorder characterized by severe viral infections and ensuing hyperinflammatory responses. Early diagnosis can be made by exome sequencing and variant validation by functional testing of STAT1-dependent PD-L1 surface expression on monocytes. Furthermore, high awareness for hyperinflammatory complications and potential targeted treatment strategies such as IL-18-binding protein could be considered. HSCT is the only definitive treatment strategy but remains challenging.

PMID: 32603902 [PubMed – as supplied by publisher]

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