Manish Butte

Correction to: Use of Genetic Testing for Primary Immunodeficiency Patients.

J Clin Immunol. 2018 May 21;:

Authors: Heimall JR, Hagin D, Hajjar J, Henrickson SE, Hernandez-Trujillo HS, Itan Y, Kobrynski L, Paris K, Torgerson TR, Verbsky JW, Wasserman RL, Hsieh EWY, Bleesing JJ, Chou JS, Lawrence MG, Marsh RA, Rosenzweig SD, Orange JS, Abraham RS

Abstract
The original version of this article unfortunately contained mistakes in some of the author names and affiliations. The correct list of author names and affiliations is below, with the corrections in bold.

PMID: 29781065 [PubMed – as supplied by publisher]

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A Novel de Novo Mutation in the CD40 Ligand Gene in a Patient With a Mild X-Linked Hyper-IgM Phenotype Initially Diagnosed as CVID: New Aspects of Old Diseases.

Front Pediatr. 2018;6:130

Authors: França TT, Leite LFB, Maximo TA, Lambert CG, Zurro NB, Forte WCN, Condino-Neto A

Abstract
Mutations in the CD40 ligand (CD40L) gene (CD40LG) lead to X-linked hyper-IgM syndrome (X-HIGM), which is a primary immunodeficiency (PID) characterized by decreased serum levels of IgG and IgA and normal or elevated IgM levels. Although most X-HIGM patients become symptomatic during the first or second year of life, during which they exhibit recurrent infections, some patients exhibit mild phenotypes, which are usually associated with hypomorphic mutations that do not abrogate protein expression or function. Here, we describe a 28-year-old man who initially presented with recurrent infections since the age of 7 years, when he exhibited meningitis caused by Cryptococcus neoformans. The patient had no family history of immunodeficiency, and based on clinical and laboratory presentation, he was initially diagnosed with common variable immunodeficiency (CVID). In subsequent years, he displayed several sporadic episodes of infection, including pneumonia, pharyngotonsillitis, acute otitis media, rhinosinusitis, fungal dermatosis, and intestinal helminthiasis. The evaluation of CD40L expression on the surface of activated CD3+CD4+ T cells from the patient showed decreased expression of CD40L. Genetic analysis revealed a novel de novo mutation consisting of a 6-nucleotide insertion in exon 1 of CD40LG, which confirmed the diagnosis of X-HIGM. In this report, we describe a novel mutation in the CD40L gene and highlight the complexities of PID diagnosis in light of atypical phenotypes and hypomorphic mutations as well as the importance of the differential diagnosis of PIDs.

PMID: 29780795 [PubMed]

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An Exponential Regression Model Reveals the Continuous Development of B Cell Subpopulations Used as Reference Values in Children.

Front Pediatr. 2018;6:121

Authors: Königs C, Schultze-Strasser S, Quaiser A, Bochennek K, Schwabe D, Klingebiel TE, Koehl U, Cappel C, Rolle U, Bader P, Bremm M, Huenecke S, Bakhtiar S

Abstract
B lymphocytes are key players in humoral immunity, expressing diverse surface immunoglobulin receptors directed against specific antigenic epitopes. The development and profile of distinct subpopulations have gained awareness in the setting of primary immunodeficiency disorders, primary or secondary autoimmunity and as therapeutic targets of specific antibodies in various diseases. The major B cell subpopulations in peripheral blood include naïve (CD19+ or CD20+IgD+CD27-), non-switched memory (CD19+ or CD20+IgD+CD27+) and switched memory B cells (CD19+ or CD20+IgD-CD27+). Furthermore, less common B cell subpopulations have also been described as having a role in the suppressive capacity of B cells to maintain self-tolerance. Data on reference values for B cell subpopulations are limited and only available for older age groups, neglecting the continuous process of human B cell development in children and adolescents. This study was designed to establish an exponential regression model to produce continuous reference values for main B cell subpopulations to reflect the dynamic maturation of the human immune system in healthy children.

PMID: 29780793 [PubMed]

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Hematopoietic Stem Cell Transplantation for Progressive Combined Immunodeficiency and Lymphoproliferation in Activated PI3K Syndrome Type 1.

J Allergy Clin Immunol. 2018 May 17;:

Authors: Okano T, Imai K, Tsujita Y, Mitsuiki N, Yoshida K, Kamae C, Honma K, Mitsui-Sekinaka K, Sekinaka Y, Kato T, Hanabusa K, Endo E, Takashima T, Hiroki H, Yeh TW, Tanaka K, Nagahori M, Tsuge I, Bando Y, Iwasaki F, Shikama Y, Inoue M, Kimoto T, Moriguchi N, Yuza Y, Kaneko T, Suzuki K, Matsubara T, Maruo Y, Kunitsu T, Waragai T, Sano H, Hashimoto Y, Tasaki K, Suzuki O, Shirakawa T, Kato M, Uchiyama T, Ishimura M, Tauchi T, Yagasaki H, Jou ST, Yu HH, Kanegane H, Kracker S, Durandy A, Kojima D, Muramatsu H, Wada T, Inoue Y, Takada H, Kojima S, Ogawa S, Ohara O, Nonoyama S, Morio T

Abstract
BACKGROUND: Activated phosphatidylinositol-3-OH kinase-delta (PI3Kδ) syndrome type 1 (APDS1) is a recently described primary immunodeficiency syndrome characterized by recurrent respiratory infections, lymphoid hyperplasia, and herpesviridae infections due to germline gain-of-function mutations of PIK3CD. Hematopoietic stem cell transplantation (HSCT) may be considered to ameliorate progressive immunodeficiency and associated malignancy, but appropriate indications, method, and outcomes of HSCT for APDS1 remain undefined.
OBJECTIVE: Our objective was to analyze the clinical manifestations, laboratory findings, prognosis, and treatment of APDS1 and explore appropriate indications and methods of HSCT.
METHODS: We retrospectively reviewed the medical records of cohorts undergoing HSCT at collaborating facilities.
RESULTS: Thirty-year overall survival was 86.1%, but event-free survival was 39.6%. Life-threatening events, such as severe infections or lymphoproliferation, were frequent in childhood and adolescence, and were common indications for HSCT. Nine patients underwent HSCT with fludarabine-based reduced intensity conditioning (RIC). Seven patients survived after frequent adverse complications and engraftment failure. Most symptoms improved after HSCT.
CONCLUSION: Patients with APDS1 showed variable clinical manifestations. Life-threatening progressive combined immunodeficiency and massive lymphoproliferation were common indications for HSCT. Fludarabine-based RIC-HSCT ameliorated clinical symptoms, but transplant-related complications were frequent, including graft failure.

PMID: 29778502 [PubMed – as supplied by publisher]

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Respiratory manifestations in LPS-responsive beige-like anchor (LRBA) protein-deficient patients.

Eur J Pediatr. 2018 May 18;:

Authors: Shamriz O, Shadur B, NaserEddin A, Zaidman I, Simanovsky N, Elpeleg O, Kerem E, Reiter J, Stepensky P

Abstract
Lipopolysaccharide (LPS)-responsive beige-like anchor (LRBA) protein deficiency is a rare syndrome of primary immune deficiency and immune dysregulation. In this study, we sought to summarize our experience with respiratory manifestations in LRBA-deficient patients. We conducted a retrospective analysis of the medical records of LRBA-deficient patients treated at Hadassah-Hebrew University Medical Center, Jerusalem, Israel. Data retrieved included pulmonary workup, disease course, treatment, and outcome. Ten patients were included. Mean age at presentation of LRBA deficiency-related symptoms was 4.65 years (range 3 months-14 years). Respiratory symptoms were noted in six patients and consisted of chronic cough. Computed tomography revealed consolidation in five patients, atelectasis and bronchiectasis in two patients each, and diffuse interstitial lung disease in two additional patients. Respiratory tract cultures yielded a bacterial pathogen in five patients. Seven patients required active therapy: intravenous immunoglobulins (six patients), immunosuppressive drugs (five patients), and one was successfully treated with abatacept. Two patients underwent successful bone marrow transplantation. Mean follow-up period was 4.5 (range 0.4-14.4) years. On their latest examination, seven patients had no respiratory symptoms.
CONCLUSION: Pulmonary manifestations are common in LRBA deficiency. Respiratory characteristics in LRBA-deficient patients should be investigated, monitored, and treated from the time of diagnosis. What is Known: • Lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency is a syndrome of primary immune deficiency and immune dysregulation. • Studies concerning the pulmonary characteristics of LRBA-deficient patients are lacking. What is New: • Respiratory manifestations include infections, bronchiectasis, interstitial lung disease, thoracic lymphadenopathy, and clubbing. • Awareness to pulmonary morbidity in LRBA-deficient patients and involvement of a pulmonologist in the workup and clinical decision-making is important. • Respiratory characteristics in LRBA-deficient patients should be investigated, monitored, and treated from a young age.

PMID: 29777306 [PubMed – as supplied by publisher]

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Epithelial proliferation in inflammatory skin disease is regulated by Ttc7 in fibroblasts and lymphocytes.

J Allergy Clin Immunol. 2018 May 15;:

Authors: Nüesch U, Mauracher AA, Opitz L, Volkmer B, Michalak-Mićka K, Kamarachev J, Hartwig T, Reichmann E, Becher B, Vavassori S, Schmid JP

Abstract
BACKGROUND: Mutations in tetratricopeptide repeat domain 7A (TTC7A) and its mouse orthologue Ttc7 result in a multisystemic disease, mostly affecting epithelial barriers and the immune system. Despite successful hematopoietic stem cell transplantation, ongoing progression of gastrointestinal manifestations can be life-threatening in TTC7A-deficient patients.
OBJECTIVE: To identify whether TTC7A mutations dysregulate epithelial cells only, or whether a cell-intrinsic defect in lymphocytes or other cells contributes to disease manifestations.
METHODS: Ttc7-mutated (Ttc7fsn/fsn) mice were crossed to generate double mutant (Rag2-/-Ttc7fsn/fsn) and triple mutant (Rag2-/-IL2rg-/-Ttc7fsn/fsn) mice. These models together with bone marrow chimeras were used to explore the role of adaptive and innate lymphocytes in the flaky skin phenotype. The effect of Ttc7fsn/fsn mutation on stromal cells was tested in a xenograft model in conjunction with transcriptomic analysis of Ttc7fsn/fsn fibroblasts.
RESULTS: We observed that severity of epithelial hyper-proliferation was accentuated by lymphocytes, whereas the phenotype was not induced by the transfer of Ttc7-mutated hematopoietic cells. Furthermore, mice completely lacking the lymphocytic compartment were not protected from epithelial hyper-proliferation. Ttc7-mutated mouse fibroblasts expressed elevated transcript levels of insulin-like growth factor 1 (Igf1) and the antimicrobial protein regenerating islet-derived protein 3 gamma (Reg3γ). In a xenograft model, Ttc7-mutated fibroblasts markedly increased epithelial proliferation of keratinocytes. Thus, Ttc7-mutated fibroblasts were identified as potent instigators of epithelial hyper-proliferation.
CONCLUSION: Our results reveal a previously unsuspected, fundamental cell-extrinsic role of Ttc7. We have identified potential candidates for molecularly targeted treatment strategies that will need to be evaluated in future preclinical studies.

PMID: 29775636 [PubMed – as supplied by publisher]

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Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes.

N Engl J Med. 2018 May 17;378(20):1908-1919

Authors: De Benedetti F, Gattorno M, Anton J, Ben-Chetrit E, Frenkel J, Hoffman HM, Koné-Paut I, Lachmann HJ, Ozen S, Simon A, Zeft A, Calvo Penades I, Moutschen M, Quartier P, Kasapcopur O, Shcherbina A, Hofer M, Hashkes PJ, Van der Hilst J, Hara R, Bujan-Rivas S, Constantin T, Gul A, Livneh A, Brogan P, Cattalini M, Obici L, Lheritier K, Speziale A, Junge G

Abstract
Background Familial Mediterranean fever, mevalonate kinase deficiency (also known as the hyperimmunoglobulinemia D syndrome), and the tumor necrosis factor receptor-associated periodic syndrome (TRAPS) are monogenic autoinflammatory diseases characterized by recurrent fever flares. Methods We randomly assigned patients with genetically confirmed colchicine-resistant familial Mediterranean fever, mevalonate kinase deficiency, or TRAPS at the time of a flare to receive 150 mg of canakinumab subcutaneously or placebo every 4 weeks. Patients who did not have a resolution of their flare received an add-on injection of 150 mg of canakinumab. The primary outcome was complete response (resolution of flare and no flare until week 16). In the subsequent phase up to week 40, patients who had a complete response underwent a second randomization to receive canakinumab or placebo every 8 weeks. Patients who underwent a second randomization and had a subsequent flare and all other patients received open-label canakinumab. Results At week 16, significantly more patients receiving canakinumab had a complete response than those receiving placebo: 61% vs. 6% of patients with colchicine-resistant familial Mediterranean fever (P<0.001), 35% versus 6% of those with mevalonate kinase deficiency (P=0.003), and 45% versus 8% of those with TRAPS (P=0.006). The inclusion of patients whose dose was increased to 300 mg every 4 weeks yielded a complete response in 71% of those with colchicine-resistant familial Mediterranean fever, 57% of those with mevalonate kinase deficiency, and 73% of those with TRAPS. After week 16, an extended dosing regimen (every 8 weeks) maintained disease control in 46% of patients with colchicine-resistant familial Mediterranean fever, 23% of those with mevalonate kinase deficiency, and 53% of those with TRAPS. Among patients who received canakinumab, the most frequently reported adverse events were infections (173.3, 313.5, and 148.0 per 100 patient-years among patients with colchicine-resistant familial Mediterranean fever, those with mevalonate kinase deficiency, and those with TRAPS, respectively), with a few being serious infections (6.6, 13.7, and 0.0 per 100 patient-years). Conclusions In this trial, canakinumab was effective in controlling and preventing flares in patients with colchicine-resistant familial Mediterranean fever, mevalonate kinase deficiency, and TRAPS. (Funded by Novartis; CLUSTER ClinicalTrials.gov number, NCT02059291 .).

PMID: 29768139 [PubMed – in process]

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How i treat primary haemophagocytic lymphohistiocytosis.

Br J Haematol. 2018 May 16;:

Authors: Marsh RA, Haddad E

Abstract
Primary haemophagocytic lymphohistiocytosis (HLH) diseases are a collection of inherited genetic disorders that cause the syndrome of HLH. Great advances have been made in the last 20 years with regard to the discovery of many of the genetic aetiologies of disease. Several advances have also been made on the clinical stage. Accurate screening diagnostics for primary HLH diseases that are superior to traditional Natural Killer cell function testing have been developed and are now available in many countries. There is now grounded clinical experience on which to base routine treatment decisions for patients with HLH. Newer approaches to allogeneic haematopoietic cell transplantation have increased overall patient survival. Despite these advances, however, there is still much work to be done to further improve patient care. This ‘How I Treat’ article will focus on summarizing current diagnostic, treatment and transplant strategies for patients with primary HLH diseases.

PMID: 29767843 [PubMed – as supplied by publisher]

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Severe Combined Immunodeficiency: A Case Series and Review from a Tertiary Pediatric Hospital.

Iran J Allergy Asthma Immunol. 2018 Apr;17(2):201-207

Authors: Fallah S, Mesdaghi M, Mansouri M, Babaei D, Karimi A, Fahimzad SA, Armin S, Rafiei Tabatabaei S, Azma R, Khanbabaee G, Bashardoost B, Amirmoeini M, Sadr S, Jalilianhasanpour R, Ghanaei R, Rezaei N, Chavoshzadeh Z

Abstract
Severe combined immunodeficiency syndrome (SCID) is a life-threatening condition leading to early infant death as a result of severe infection, due to impaired cellular and humoral immune systems. Various forms of SCID are classified based on the presence or absence of T cells, B cells and natural killer cells. Patients usually present with recurrent infections and failure to thrive. Definitive treatment is hematopoietic stem cell transplantation. To achieve the best outcome, it should be performed prior to the development of severe infection. In This study, we described 10 patients (6 male and 4 female) with SCID who were admitted to Mofid Children Hospital, Tehran, Iran, from 2006 to 2013. We reviewed patients’ clinical manifestation, laboratory data, family history and outcome. The mean age at the time of diagnosis was 131.8 days. One patient had non-consanguineous parents. Seven patients received BCG vaccine before the diagnosis of SCID, three of them showed disseminated BCG infection. One patient presented with invasive pulmonary aspergillosis. Flow cytometric analysis showed T⁻B⁺NK⁻ in three patients, T⁻B⁻NK⁺ in five patients, T⁻B⁻NK⁻ in one patient, and T⁻B⁺NK⁺ in one patient. This study highlights the importance of early diagnosis and patient referral before the occurrence of serious infection.

PMID: 29757593 [PubMed – in process]

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The Profile of Toll-like Receptor 2 (TLR2), TLR4 and Their Cytosolic Downstream Signaling Pathway in Common Variable Immunodeficiency (CVID) Patients.

Iran J Allergy Asthma Immunol. 2018 Apr;17(2):188-200

Authors: Sharifi L, Aghamohammadi A, Rezaei N, Yazdani R, Mahmoudi M, Amiri MM, Masoumi F, Bokaie S, Tavasolian P, Sanaei R, Moshiri M, Tavakolinia N, Alinia T, Azizi G, Mirshafiey A

Abstract
Common variable immunodeficiency (CVID) is the most common clinical primary antibody deficiency, characterized by increased susceptibility to recurrent bacterial infections. Since Toll-like receptors (TLRs) play an important role in the maturation and differentiation of B-cells, TLRs’ defect can be involved in the pathogenesis of CVID. Therefore, we evaluated the expression of TLR2 and TLR4 and their signaling pathway; also their association with autoimmunity, B-cell subtypes and response to pneumovax-23 were assessed in CVID patients. Sixteen CVID patients were enrolled in the study. Flow cytometry was used for assessing the protein expression of TLR2 and TLR4, and real-time PCR was used for gene expression of myeloid differentiation primary response 88 (MyD88) and toll interacting protein (Tollip). We found a higher protein expression of TLR2 in CVID patients which was associated with lower number of end stage B-cells and hyporesponse to pneumovax-23 vaccination. We showed a lower mRNA expression of MyD88 and an almost equal Tollip mRNA expression in CVID patients compared with controls. There was a profound association between MyD88 gene expression and autoimmunity in CVID patients. According to the presence of the lower number of end stage B-cells and poor vaccine response in CVID patients and their correlation with the higher expression of TLR2, we hypothesized that there is a functional defect in this receptor and/or its downstream in the peripheral blood mononuclear cells (PBMCs) of CVID patients.

PMID: 29757592 [PubMed – in process]

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