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Gain-of-Function STAT1 Mutation With Familial Lymphadenopathy and Hodgkin Lymphoma.

Front Pediatr. 2019;7:160

Authors: Henrickson SE, Dolan JG, Forbes LR, Vargas-Hernández A, Nishimura S, Okada S, Kersun LS, Brodeur GM, Heimall JR

Abstract
In this report, we describe a novel T437N STAT1 mutation found in a mother and 3 of her 4 children which we demonstrate yields gain-of-function. All of the four patients with the T437N STAT1 mutation experienced lymphadenopathy. However, two of the children developed Nodular Lymphocyte Predominant Hodgkin Lymphoma (NHLPL) and have responded to chemotherapeutic regimens. The fourth sibling had neither the STAT1 variant nor lymphadenopathy or malignancy. To our knowledge this is the first description of a potential association between STAT1 GOF mutations and lymphoma development.

PMID: 31114772 [PubMed]

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TRAIL-R1 and TRAIL-R2 Mediate TRAIL-Dependent Apoptosis in Activated Primary Human B Lymphocytes.

Front Immunol. 2019;10:951

Authors: Staniek J, Lorenzetti R, Heller B, Janowska I, Schneider P, Unger S, Warnatz K, Seidl M, Venhoff N, Thiel J, Smulski CR, Rizzi M

Abstract
The maintenance of B cell homeostasis requires a tight control of B cell generation, survival, activation, and maturation. In lymphocytes upon activation, increased sensitivity to apoptotic signals helps controlling differentiation and proliferation. The death receptor Fas is important in this context because genetic Fas mutations in humans lead to an autoimmune lymphoproliferative syndrome that is similar to lymphoproliferation observed in Fas-deficient mice. In contrast, the physiological role of TNF-related apoptosis-inducing ligand receptors (TRAIL-Rs) in humans has been poorly studied so far. Indeed, most studies have focused on tumor cell lines and on mouse models whose results are difficult to transpose to primary human B cells. In the present work, the expression of apoptosis-inducing TRAIL-R1 and TRAIL-R2 and of the decoy receptors TRAIL-R3 and TRAIL-R4 was systematically studied in all developmental stages of peripheral B cells isolated from the blood and secondary lymphoid organs. Expression of TRAIL-Rs is modulated along development, with highest levels observed in germinal center B cells. In addition, T-dependent and T-independent signals elicited induction of TRAIL-Rs with distinct kinetics, which differed among B cell subpopulations: switched memory cells rapidly upregulated TRAIL-R1 and -2 upon activation while naïve B cells only reached similar expression levels at later time points in culture. Increased expression of TRAIL-R1 and -2 coincided with a caspase-3-dependent sensitivity to TRAIL-induced apoptosis in activated B cells but not in freshly isolated resting B cells. Finally, both TRAIL-R1 and TRAIL-R2 could signal actively and both contributed to TRAIL-induced apoptosis. In conclusion, this study provides a systematic analysis of the expression of TRAIL-Rs in human primary B cells and of their capacity to signal and induce apoptosis. This dataset forms a basis to further study and understand the dysregulation of TRAIL-Rs and TRAIL expression observed in autoimmune diseases. Additionally, it will be important to foresee potential bystander immunomodulation when TRAIL-R agonists are used in cancer treatment.

PMID: 31114586 [PubMed – in process]

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Autoantibodies in patients with IL12 β1 receptor deficiency.

J Dig Dis. 2019 May 21;:

Authors: Ronca V, Chen Q, Lygoura V, Ben-Mustapha I, Shums Z, Trifa M, Carbone M, Mancuso C, Milani C, Bernuzzi F, Xiong M, Agrebi N, Norman GL, Chang C, Gershwin ME, Barbouche MR, Invernizzi P

Abstract
INTRODUCTION: IL-12Rβ1 deficiency is a primary immunodeficiency, which exposes affected individuals to an augmented risk of intracellular pathogen-mediated infections. The lacking of the subunit β1 of the interleukin (IL) 12 receptor reduces the responsiveness to the IL-12 and reduces IFN-γ levels. The paradoxical presence of autoimmune manifestations in immune-deficient subjects is recognized, but the basis of such phenomena is unclear, with the role of frequent infections as a possible trigger to break tolerance. The association of IL-12Rβ1 deficiency particularly with Sjögren syndrome, systemic lupus erythematosus and hemolytic anemia has been reported. The aim of our study was to extensively analyze a profile of autoantibodies in a clinically well-defined case series of patients affected by IL-12Rβ1 deficiency.
METHODS: Eight patients with IL-12Rβ1 deficiency referred to Children’s Medical Center in Tunis, Tunisia, during 1995-2012 were enrolled in the study. Sixteen age and gender-matched blood donors served as controls. Serum, liver-related autoantibodies IgG, IgM, IgA were tested by ELISA and by standard indirect immunofluorescence on HEp-2 cells.
RESULTS: Our results showed a significant prevalence of liver autoantibodies in the study group. Regarding primary biliary cholangitis (PBC), two of eight patients were positive for MIT3 autoantibodies and both positivity were confirmed by immunofluorescence; one patient was positive for PBC-specific ANA, sp100. Moreover, two patients had significantly increased GGT and one had IgM levels 2 times upper limit of normal. Intriguingly two patients were positive for anti-actin antibodies, a typical feature of autoimmune hepatitis type I, along with a significant increase in IgG levels.
CONCLUSIONS: This is the first report of a serological analysis in patients with IL-12Rβ1 deficiency. Despite the difficult interpretation of its role, the evidence of liver-specific autoantibodies confirms the importance of IL-12 pathway in the liver autoimmunity. This article is protected by copyright. All rights reserved.

PMID: 31111679 [PubMed – as supplied by publisher]

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Role of Allogeneic Hematopoietic Stem Cell Transplant for Chronic Granulomatous Disease (CGD): a Report of the United States Immunodeficiency Network.

J Clin Immunol. 2019 May 20;:

Authors: Yonkof JR, Gupta A, Fu P, Garabedian E, Dalal J, and the United States Immunodeficiency Network Consortium

Abstract
PURPOSE: Chronic granulomatous disease (CGD) is a primary immunodeficiency for which allogeneic hematopoietic stem cell transplant (HSCT) offers potential cure. Direct comparison of HSCT to non-HSCT management in the North American population was performed to identify clinical factors associated with overall survival (OS) and transplant-related survival (TRS).
METHODS: Retrospective review of CGD subjects enrolled in the United States Immunodeficiency Network. Survival was estimated by the Kaplan-Meier method and modeled by proportional hazards regression.
RESULTS: We identified 507 patients (66% CYBB mutants) diagnosed in 1953-2016. Fifty underwent allogeneic HSCT. Median follow-up was 9.1 years after diagnosis (0-45.8 years). OS was negatively associated with CYBB mutation (HR = 6.25; p = 0.034) and not associated with HSCT (88% v. 85% ± HCT) (HR = 1.26; p = 0.65). Transplant at ≤ 14 years old was associated with improved TRS (93% v. 82% at T + 60 months) (HR = - 4.51; p = 0.035). Patients transplanted before 15 years old had fewer severe infections pre-HSCT (mean 0.95 v. 2.13; p = 0.047). No mortality was reported in patients receiving stem cells from matched siblings. Infection incidence declined post-HSCT in subjects with greater than or equal to four infections pre-HSCT (p = 0.0010). Compared to non-HSCT patients ≥ 15 years old, post-transplant survivors had higher mean performance score (93.2 v. 85.9; p = 0.0039) and lower frequency of disability (11% v. 52%; p = 0.014).
CONCLUSION: Allogeneic HSCT was associated with reduced infection incidence and improved functional performance, but not with a change in overall survival. Transplant-related survival was elevated in patients undergoing HSCT before 15 years old. Consider HSCT prior to late adolescence in patients with severely diminished reactive oxygen intermediate synthesis, particularly if a matched sibling is available.

PMID: 31111420 [PubMed – as supplied by publisher]

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Clinical, Immunological, and Genetic Features in Patients with Activated PI3Kδ Syndrome (APDS): a Systematic Review.

Clin Rev Allergy Immunol. 2019 May 21;:

Authors: Jamee M, Moniri S, Zaki-Dizaji M, Olbrich P, Yazdani R, Jadidi-Niaragh F, Aghamahdi F, Abolhassani H, Condliffe AM, Aghamohammadi A, Azizi G

Abstract
Activated phosphoinositide 3-kinase delta syndrome (APDS) is a novel primary immunodeficiency (PID) caused by heterozygous gain of function mutations in PI3Kδ catalytic p110δ (PIK3CD) or regulatory p85α (PIK3R1) subunits leading to APDS1 and APDS2, respectively. Patients with APDS present a spectrum of clinical manifestations, particularly recurrent respiratory infections and lymphoproliferation. We searched PubMed, Web of Science, and Scopus databases for APDS patients and screened for eligibility criteria. A total of 243 APDS patients were identified from 55 articles. For all patients, demographic, clinical, immunologic, and molecular data were collected. Overall, 179 APDS1 and 64 APDS2 patients were identified. The most common clinical manifestations were respiratory tract infections (pneumonia (43.6%), otitis media (28.8%), and sinusitis (25.9%)), lymphoproliferation (70.4%), autoimmunity (28%), enteropathy (26.7%), failure to thrive (20.6%), and malignancy (12.8%). The predominant immunologic phenotype was hyper-IgM syndrome (48.1%). Immunologic profiling showed decreased B cells in 74.8% and CD4+ T cells in 64.8% of APDS patients. The c.3061 G>A (p. E1021K) mutation in APDS1 with 85% frequency and c.1425+1 G> (A, C, T) (p.434-475del) mutation in APDS2 with 79% frequency were hotspot mutations. The majority of APDS patients were placed on long-term immunoglobulin replacement therapy. Immunosuppressive agents such as rituximab, tacrolimus, rapamycin, and leniolisib were also administered for autoimmunity and inflammatory complications. In addition, hematopoietic stem cell transplantation (HSCT) was used in 12.8% of patients. APDS has heterogynous clinical manifestations. It should be suspected in patients with history of recurrent respiratory infections, lymphoproliferation, and raised IgM levels. Moreover, HSCT should be considered in patients with severe and complicated clinical manifestations with no or insufficient response to the conventional therapies.

PMID: 31111319 [PubMed – as supplied by publisher]

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Impaired immune responses to herpesviruses and microbial ligands in patients with MonoMAC.

Br J Haematol. 2019 May 20;:

Authors: Mardahl M, Jørgensen SE, Schneider A, Raaschou-Jensen K, Holm M, Veirum J, Kristensen TK, Johansen IS, Christiansen M, Assing K, Mogensen TH

Abstract
MonoMAC is a complex primary immunodeficiency caused by mutations in the myeloid transcription factor GATA2, characterized by multilineage cytopenia with malignant complications and severe infections, including mycobacteria and herpesviruses. We describe the clinical presentation, genetics and antiviral inflammatory responses in a small case series. Two patients presented in childhood with mycobacterial infection and were diagnosed with MonoMAC germline GATA2 variants; their healthy fathers with the same mutations were also studied. Three patients were elderly individuals with acquired GATA2 mutations and malignant haematological conditions. Overall, this study demonstrates the heterogeneous clinical presentation and variation in immunodeficiency caused by GATA2 mutations.

PMID: 31106410 [PubMed – as supplied by publisher]

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Low percentages of regulatory T cells in common variable immunodeficiency (CVID) patients with autoimmune diseases and its association with increased numbers of CD4+CD45RO+ T and CD21low B cells.

Allergol Immunopathol (Madr). 2019 May 15;:

Authors: López-Herrera G, Segura-Méndez NH, O’Farril-Romanillos P, Nuñez-Nuñez ME, Zarate-Hernández MC, Mogica-Martínez D, Yamazaki-Nakashimada MA, Staines-Boone AT, Santos-Argumedo L, Berrón-Ruiz L

Abstract
BACKGROUND: Common variable immunodeficiency (CVID) is a heterogeneous group of primary antibody deficiencies defined by marked reductions in serum IgG, IgA and/or IgM levels and recurrent bacterial infections. Some patients are associated with defects in T cells and regulatory T cells (Tregs), resulting in recurrent viral infections and early-onset autoimmune disease.
METHODS: We analyzed whether there is an association between Tregs cells (CD4+CD25+CD127low and CD4+CD25+FoxP3+); memory T cells (CD4+CD45RO+); memory B cells (CD19+CD27-IgD-); and CD21low B cells (CD19+CD38lowCD21low); as well as autoimmune manifestations in 36 patients with CVID (25 women and 11 men, mean age 24 years), all by flow cytometry.
RESULTS: Fourteen patients presented with autoimmune diseases (AI) (39%), including 11 with autoimmune thrombocytopenia (ITP) (31%); two with vitiligo (6%); one with systemic lupus erythematosus (LES) (3%); and one with multiple sclerosis (MS) (3%). CVID patients with AI had a reduced proportion of Tregs (both CD4+CD25+CD127low and FoxP3+ cells) compared with healthy controls. CVID patients with AI had expanded CD21low B cell populations compared with patients who did not have AI. A correlation between increased CD4+CD45RO T cell populations and reduced Tregs was also observed.
CONCLUSIONS: Our results showed that 39% of patients with CVID had AI and reduced Tregs populations. Research in this area might provide noteworthy data to better understand immune dysfunction and dysregulation related to CVID.

PMID: 31103252 [PubMed – as supplied by publisher]

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Achromobacter xylosoxidans Sepsis Unveiling X-linked Agammaglobulinemia Masquerading as Systemic-onset Juvenile Idiopathic Arthritis.

Indian Pediatr. 2019 May 15;56(5):423-425

Authors: Janarthanan M, Gollapalli S, Sankaranarayanan S

Abstract
BACKGROUND: X-linked agammaglobulinemia, a primary immunodeficiency, can present with musculoskeletal manifestations.
CASE CHARACTERISTICS: A 4-year-old boy, diagnosed as systemic juvenile idiopathic arthritis at the age of 3 years and treated with biological agents, presented with fever, dyspnea and chest pain. Blood culture and pericardial fluid culture revealed Achromobacter xylosoxidans.
OUTCOME: Investigation revealed normal serum ferritin but low levels of serum immunoglobulins. Further immunological work-up revealed diagnosis of X-linked agammaglobulinemia. Child improved on antibiotic therapy; treatment with steroids and biological was discontinued.
MESSAGE: Underlying immunodeficiency disease must be looked for in children suspected to have juvenile arthritis, more so if they develop unusual serious infection in response to immunomodulatory therapy.

PMID: 31102385 [PubMed – in process]

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Successful Rituximab Treatment for Lymphoma, Secondary Immunodeficiency Causing Debilitating Sinusitis: Underlying Primary Immunodeficiency Disease, and Alternative Treatments to Improve the Quality of Life?

J Clin Immunol. 2019 May 17;:

Authors: Bonagura VR

PMID: 31102034 [PubMed – as supplied by publisher]

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