The imbalance of circulating T helper subsets and regulatory T cells in patients with LRBA deficiency: Correlation with disease severity. Azizi Gholamreza,Mirshafiey Abbas,Abolhassani Hassan,Yazdani Reza,Ghanavatinejad Alireza,Noorbakhsh Farshid,Rezaei Nima,Aghamohammadi Asghar Journal of cellular physiology Patients with lipopolysaccharides responsive beige-like anchor protein (LRBA) deficiency suffer from a variety of immunological abnormalities. In the current study, we investigated the role of T helper (Th) cell subsets and regulatory T (Treg) cells and their related cytokines and transcription factors in the immune dysregulation of LRBA deficiency. The study population comprised of 13 LRBA-deficient patients and 13 age- and sex-matched healthy controls (HCs). Th subsets and Treg were examined by flow cytometry. The expression of determinant cytokines (interferon-γ [IFN-γ], interleukin [IL]-17, IL-22, and IL-10), and cell subset-specific transcription factors were evaluated before and after proliferation and activation stimuli. The frequencies of Th1, Th1-like Th17 and Th22 cells along with the expression of T-box transcription factor (TBET) and runt-related transcription factor 1 (RUNX1) were significantly increased in patients with LRBA. Moreover, IFN-γ and IL-22 production in LRBA-deficient CD4 T cells were elevated after lymphocyte stimulation, particularly in patients with enteropathy. However, CD4 CD25 FoxP3 CD127 cells were significantly decreased in LRBA-deficient patients compared with those of HCs, particularly in patients with autoimmunity. There was a negative correlation between the frequencies of CD4 CD25 FoxP3 CD127 cells and Th1-like Th17 cells in LRBA-deficient patients, and an overlapping phenotype of autoimmunity and enteropathy were observed in ~70% of patients. The frequency of Th17 cells was lower in patients with enteropathy, while Th1-like Th17 cells were higher than in those without enteropathy. Our findings demonstrated an imbalance in Th subsets, mainly in Th1-like Th17 and Treg cells and their corresponding cytokines in LRBA deficiency, which might be important in the immunopathogenesis of autoimmunity and enteropathy. 10.1002/jcp.26772
    Clinical Phenotypes and Immunological Characteristics of 18 Egyptian LRBA Deficiency Patients. Meshaal Safa,El Hawary Rabab,Adel Rana,Abd Elaziz Dalia,Erfan Aya,Lotfy Sohilla,Hafez Mona,Hassan Mona,Johnson Matthew,Rojas-Restrepo Jessica,Gamez-Diaz Laura,Grimbacher Bodo,Shoman Walaa,Abdelmeguid Yasmine,Boutros Jeannette,Galal Nermeen,El-Guindy Nancy,Elmarsafy Aisha Journal of clinical immunology LPS-responsive beige-like anchor (LRBA) deficiency is an autosomal recessive primary immunodeficiency disorder, OMIM (#614700). LRBA deficiency patients suffer from variable manifestations including recurrent infections, immune dysregulation, autoimmunity, cytopenias, and enteropathy. This study describes different clinical phenotypes and immunological characteristics of 18 LRBA deficiency patients diagnosed from Egypt. T and B lymphocyte subpopulations, LRBA, and cytotoxic T lymphocyte-associated protein 4 (CTLA4) expression were evaluated in resting and stimulated T cells using flow cytometry. Next-generation sequencing was used to identify mutations in the LRBA gene. LRBA deficiency patients had significantly lower B cells and increased percentage of memory T cells. CTLA4 levels were lower in LRBA-deficient T regulatory cells in comparison to healthy donors at resting conditions and significantly increased upon stimulation of T cells. We identified 11 novel mutations in LRBA gene ranging from large deletions to point mutations. Finally, we were able to differentiate LRBA-deficient patients from healthy control and common variable immunodeficiency patients using a simple flow cytometry test performed on whole blood and without need to prior stimulation. LRBA deficiency has heterogeneous phenotypes with poor phenotype-genotype correlation since the same mutation may manifest differently even within the same family. Low LRBA expression, low numbers of B cells, increased numbers of memory T cells, and defective CTLA4 expression (which increase to normal level upon T cell stimulation) are useful laboratory tests to establish the diagnosis of LRBA deficiency. Screening of the siblings of affected patients is very important as patients may be asymptomatic at the beginning of the disease course. 10.1007/s10875-020-00799-2
    Phenotypic and Genotypic Characterisation of Inflammatory Bowel Disease Presenting Before the Age of 2 years. Kammermeier Jochen,Dziubak Robert,Pescarin Matilde,Drury Suzanne,Godwin Heather,Reeve Kate,Chadokufa Sibongile,Huggett Bonita,Sider Sara,James Chela,Acton Nikki,Cernat Elena,Gasparetto Marco,Noble-Jamieson Gabi,Kiparissi Fevronia,Elawad Mamoun,Beales Phil L,Sebire Neil J,Gilmour Kimberly,Uhlig Holm H,Bacchelli Chiara,Shah Neil Journal of Crohn's & colitis OBJECTIVES:Inflammatory bowel disease [IBD] presenting in early childhood is extremely rare. More recently, progress has been made to identify children with monogenic forms of IBD predominantly presenting very early in life. In this study, we describe the heterogeneous phenotypes and genotypes of patients with IBD presenting before the age of 2 years and establish phenotypic features associated with underlying monogenicity. METHODS:Phenotype data of 62 children with disease onset before the age of 2 years presenting over the past 20 years were reviewed. Children without previously established genetic diagnosis were prospectively recruited for next-generation sequencing. RESULTS:In all, 62 patients [55% male] were identified. The median disease onset was 3 months of age (interquartile range [IQR]: 1 to 11). Conventional IBD classification only applied to 15 patients with Crohn's disease [CD]-like [24%] and three with ulcerative colitis [UC]-like [5%] phenotype; 44 patients [71%] were diagnosed with otherwise unclassifiable IBD. Patients frequently required parenteral nutrition [40%], extensive immunosuppression [31%], haematopoietic stem-cell transplantation [29%], and abdominal surgery [19%]. In 31% of patients, underlying monogenic diseases were established [EPCAM, IL10, IL10RA, IL10RB, FOXP3, LRBA, SKIV2L, TTC37, TTC7A]. Phenotypic features significantly more prevalent in monogenic IBD were: consanguinity, disease onset before the 6th month of life, stunting, extensive intestinal disease and histological evidence of epithelial abnormalities. CONCLUSIONS:IBD in children with disease onset before the age of 2 years is frequently unclassifiable into Crohn's disease and ulcerative colitis, particularly treatment resistant, and can be indistinguishable from monogenic diseases with IBD-like phenotype. 10.1093/ecco-jcc/jjw118
    Pediatric Evans syndrome is associated with a high frequency of potentially damaging variants in immune genes. Hadjadj Jérôme,Aladjidi Nathalie,Fernandes Helder,Leverger Guy,Magérus-Chatinet Aude,Mazerolles Fabienne,Stolzenberg Marie-Claude,Jacques Sidonie,Picard Capucine,Rosain Jérémie,Fourrage Cécile,Hanein Sylvain,Zarhrate Mohammed,Pasquet Marlène,Abou Chahla Wadih,Barlogis Vincent,Bertrand Yves,Pellier Isabelle,Colomb Bottollier Elodie,Fouyssac Fanny,Blouin Pascale,Thomas Caroline,Cheikh Nathalie,Dore Eric,Pondarre Corinne,Plantaz Dominique,Jeziorski Eric,Millot Frédéric,Garcelon Nicolas,Ducassou Stéphane,Perel Yves,Leblanc Thierry,Neven Bénédicte,Fischer Alain,Rieux-Laucat Frédéric, Blood Evans syndrome (ES) is a rare severe autoimmune disorder characterized by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. In most cases, the underlying cause is unknown. We sought to identify genetic defects in pediatric ES (pES), based on a hypothesis of strong genetic determinism. In a national, prospective cohort of 203 patients with early-onset ES (median [range] age at last follow-up: 16.3 years ([1.2-41.0 years]) initiated in 2004, 80 nonselected consecutive individuals underwent genetic testing. The clinical data were analyzed as a function of the genetic findings. Fifty-two patients (65%) received a genetic diagnosis (the M+ group): 49 carried germline mutations and 3 carried somatic variants. Thirty-two (40%) had pathogenic mutations in 1 of 9 genes known to be involved in primary immunodeficiencies (, , , , , , , , and ), whereas 20 patients (25%) carried probable pathogenic variants in 16 genes that had not previously been reported in the context of autoimmune disease. Lastly, no genetic abnormalities were found in the remaining 28 patients (35%, the M- group). The M+ group displayed more severe disease than the M- group, with a greater frequency of additional immunopathologic manifestations and a greater median number of lines of treatment. Six patients (all from the M+ group) died during the study. In conclusion, pES was potentially genetically determined in at least 65% of cases. Systematic, wide-ranging genetic screening should be offered in pES; the genetic findings have prognostic significance and may guide the choice of a targeted treatment. 10.1182/blood-2018-11-887141
    Prevalence and Clinical Features of Inflammatory Bowel Diseases Associated With Monogenic Variants, Identified by Whole-Exome Sequencing in 1000 Children at a Single Center. Crowley Eileen,Warner Neil,Pan Jie,Khalouei Sam,Elkadri Abdul,Fiedler Karoline,Foong Justin,Turinsky Andrei L,Bronte-Tinkew Dana,Zhang Shiqi,Hu Jamie,Tian David,Li Dalin,Horowitz Julie,Siddiqui Iram,Upton Julia,Roifman Chaim M,Church Peter C,Wall Donna A,Ramani Arun K,Kotlarz Daniel,Klein Christoph,Uhlig Holm,Snapper Scott B,Gonzaga-Jauregui Claudia,Paterson Andrew D,McGovern Dermot P B,Brudno Michael,Walters Thomas D,Griffiths Anne M,Muise Aleixo M Gastroenterology BACKGROUND & AIMS:A proportion of infants and young children with inflammatory bowel diseases (IBDs) have subtypes associated with a single gene variant (monogenic IBD). We aimed to determine the prevalence of monogenic disease in a cohort of pediatric patients with IBD. METHODS:We performed whole-exome sequencing analyses of blood samples from an unselected cohort of 1005 children with IBD, aged 0-18 years (median age at diagnosis, 11.96 years) at a single center in Canada and their family members (2305 samples total). Variants believed to cause IBD were validated using Sanger sequencing. Biopsies from patients were analyzed by immunofluorescence and histochemical analyses. RESULTS:We identified 40 rare variants associated with 21 monogenic genes among 31 of the 1005 children with IBD (including 5 variants in XIAP, 3 in DOCK8, and 2 each in FOXP3, GUCY2C, and LRBA). These variants occurred in 7.8% of children younger than 6 years and 2.3% of children aged 6-18 years. Of the 17 patients with monogenic Crohn's disease, 35% had abdominal pain, 24% had nonbloody loose stool, 18% had vomiting, 18% had weight loss, and 5% had intermittent bloody loose stool. The 14 patients with monogenic ulcerative colitis or IBD-unclassified received their diagnosis at a younger age, and their most predominant feature was bloody loose stool (78%). Features associated with monogenic IBD, compared to cases of IBD not associated with a single variant, were age of onset younger than 2 years (odds ratio [OR], 6.30; P = .020), family history of autoimmune disease (OR, 5.12; P = .002), extra-intestinal manifestations (OR, 15.36; P < .0001), and surgery (OR, 3.42; P = .042). Seventeen patients had variants in genes that could be corrected with allogeneic hematopoietic stem cell transplantation. CONCLUSIONS:In whole-exome sequencing analyses of more than 1000 children with IBD at a single center, we found that 3% had rare variants in genes previously associated with pediatric IBD. These were associated with different IBD phenotypes, and 1% of the patients had variants that could be potentially corrected with allogeneic hematopoietic stem cell transplantation. Monogenic IBD is rare, but should be considered in analysis of all patients with pediatric onset of IBD. 10.1053/j.gastro.2020.02.023
    Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases. de Jesus Adriana A,Hou Yangfeng,Brooks Stephen,Malle Louise,Biancotto Angelique,Huang Yan,Calvo Katherine R,Marrero Bernadette,Moir Susan,Oler Andrew J,Deng Zuoming,Montealegre Sanchez Gina A,Ahmed Amina,Allenspach Eric,Arabshahi Bita,Behrens Edward,Benseler Susanne,Bezrodnik Liliana,Bout-Tabaku Sharon,Brescia AnneMarie C,Brown Diane,Burnham Jon M,Caldirola Maria Soledad,Carrasco Ruy,Chan Alice Y,Cimaz Rolando,Dancey Paul,Dare Jason,DeGuzman Marietta,Dimitriades Victoria,Ferguson Ian,Ferguson Polly,Finn Laura,Gattorno Marco,Grom Alexei A,Hanson Eric P,Hashkes Philip J,Hedrich Christian M,Herzog Ronit,Horneff Gerd,Jerath Rita,Kessler Elizabeth,Kim Hanna,Kingsbury Daniel J,Laxer Ronald M,Lee Pui Y,Lee-Kirsch Min Ae,Lewandowski Laura,Li Suzanne,Lilleby Vibke,Mammadova Vafa,Moorthy Lakshmi N,Nasrullayeva Gulnara,O'Neil Kathleen M,Onel Karen,Ozen Seza,Pan Nancy,Pillet Pascal,Piotto Daniela Gp,Punaro Marilynn G,Reiff Andreas,Reinhardt Adam,Rider Lisa G,Rivas-Chacon Rafael,Ronis Tova,Rösen-Wolff Angela,Roth Johannes,Ruth Natasha Mckerran,Rygg Marite,Schmeling Heinrike,Schulert Grant,Scott Christiaan,Seminario Gisella,Shulman Andrew,Sivaraman Vidya,Son Mary Beth,Stepanovskiy Yuriy,Stringer Elizabeth,Taber Sara,Terreri Maria Teresa,Tifft Cynthia,Torgerson Troy,Tosi Laura,Van Royen-Kerkhof Annet,Wampler Muskardin Theresa,Canna Scott W,Goldbach-Mansky Raphaela The Journal of clinical investigation BACKGROUNDUndifferentiated systemic autoinflammatory diseases (USAIDs) present diagnostic and therapeutic challenges. Chronic interferon (IFN) signaling and cytokine dysregulation may identify diseases with available targeted treatments.METHODSSixty-six consecutively referred USAID patients underwent underwent screening for the presence of an interferon signature using a standardized type-I IFN-response-gene score (IRG-S), cytokine profiling, and genetic evaluation by next-generation sequencing.RESULTSThirty-six USAID patients (55%) had elevated IRG-S. Neutrophilic panniculitis (40% vs. 0%), basal ganglia calcifications (46% vs. 0%), interstitial lung disease (47% vs. 5%), and myositis (60% vs. 10%) were more prevalent in patients with elevated IRG-S. Moderate IRG-S elevation and highly elevated serum IL-18 distinguished 8 patients with pulmonary alveolar proteinosis (PAP) and recurrent macrophage activation syndrome (MAS). Among patients with panniculitis and progressive cytopenias, 2 patients were compound heterozygous for potentially novel LRBA mutations, 4 patients harbored potentially novel splice variants in IKBKG (which encodes NF-κB essential modulator [NEMO]), and 6 patients had de novo frameshift mutations in SAMD9L. Of additional 12 patients with elevated IRG-S and CANDLE-, SAVI- or Aicardi-Goutières syndrome-like (AGS-like) phenotypes, 5 patients carried mutations in either SAMHD1, TREX1, PSMB8, or PSMG2. Two patients had anti-MDA5 autoantibody-positive juvenile dermatomyositis, and 7 could not be classified. Patients with LRBA, IKBKG, and SAMD9L mutations showed a pattern of IRG elevation that suggests prominent NF-κB activation different from the canonical interferonopathies CANDLE, SAVI, and AGS.CONCLUSIONSIn patients with elevated IRG-S, we identified characteristic clinical features and 3 additional autoinflammatory diseases: IL-18-mediated PAP and recurrent MAS (IL-18PAP-MAS), NEMO deleted exon 5-autoinflammatory syndrome (NEMO-NDAS), and SAMD9L-associated autoinflammatory disease (SAMD9L-SAAD). The IRG-S expands the diagnostic armamentarium in evaluating USAIDs and points to different pathways regulating IRG expression.TRIAL REGISTRATIONClinicalTrials.gov NCT02974595.FUNDINGThe Intramural Research Program of the NIH, NIAID, NIAMS, and the Clinical Center. 10.1172/JCI129301
    Hijacking antibody-induced CTLA-4 lysosomal degradation for safer and more effective cancer immunotherapy. Zhang Yan,Du Xuexiang,Liu Mingyue,Tang Fei,Zhang Peng,Ai Chunxia,Fields James K,Sundberg Eric J,Latinovic Olga S,Devenport Martin,Zheng Pan,Liu Yang Cell research It remains unclear why the clinically used anti-CTLA-4 antibodies, popularly called checkpoint inhibitors, have severe immunotherapy-related adverse effects (irAEs) and yet suboptimal cancer immunotherapeutic effects (CITE). Here we report that while irAE-prone Ipilimumab and TremeIgG1 rapidly direct cell surface CTLA-4 for lysosomal degradation, the non-irAE-prone antibodies we generated, HL12 or HL32, dissociate from CTLA-4 after endocytosis and allow CTLA-4 recycling to cell surface by the LRBA-dependent mechanism. Disrupting CTLA-4 recycling results in robust CTLA-4 downregulation by all anti-CTLA-4 antibodies and confers toxicity to a non-irAE-prone anti-CTLA-4 mAb. Conversely, increasing the pH sensitivity of TremeIgG1 by introducing designed tyrosine-to-histidine mutations prevents antibody-triggered lysosomal CTLA-4 downregulation and dramatically attenuates irAE. Surprisingly, by avoiding CTLA-4 downregulation and due to their increased bioavailability, pH-sensitive anti-CTLA-4 antibodies are more effective in intratumor regulatory T-cell depletion and rejection of large established tumors. Our data establish a new paradigm for cancer research that allows for abrogating irAE while increasing CITE of anti-CTLA-4 antibodies. 10.1038/s41422-019-0184-1
    LRBA deficiency: a new genetic cause of monogenic lupus. Liphaus Bernadete L,Caramalho Iris,Rangel-Santos Andreia,Silva Clóvis A,Demengeot Jocelyne,Carneiro-Sampaio Magda Maria Salles Annals of the rheumatic diseases 10.1136/annrheumdis-2019-216410
    Long-term outcome of LRBA deficiency in 76 patients after various treatment modalities as evaluated by the immune deficiency and dysregulation activity (IDDA) score. Tesch Victoria Katharina,Abolhassani Hassan,Shadur Bella,Zobel Joachim,Mareika Yuliya,Sharapova Svetlana,Karakoc-Aydiner Elif,Rivière Jacques G,Garcia-Prat Marina,Moes Nicolette,Haerynck Filomeen,Gonzales-Granado Luis I,Santos Pérez Juan Luis,Mukhina Anna,Shcherbina Anna,Aghamohammadi Asghar,Hammarström Lennart,Dogu Figen,Haskologlu Sule,İkincioğulları Aydan I,Köstel Bal Sevgi,Baris Safa,Kilic Sara Sebnem,Karaca Neslihan Edeer,Kutukculer Necil,Girschick Hermann,Kolios Antonios,Keles Sevgi,Uygun Vedat,Stepensky Polina,Worth Austen,van Montfrans Joris M,Peters Anke M J,Meyts Isabelle,Adeli Mehdi,Marzollo Antonio,Padem Nurcicek,Khojah Amer M,Chavoshzadeh Zahra,Avbelj Stefanija Magdalena,Bakhtiar Shahrzad,Florkin Benoit,Meeths Marie,Gamez Laura,Grimbacher Bodo,Seppänen Mikko R J,Lankester Arjan,Gennery Andrew R,Seidel Markus G, The Journal of allergy and clinical immunology BACKGROUND:Recent findings strongly support hematopoietic stem cell transplantation (HSCT) in patients with severe presentation of LPS-responsive beige-like anchor protein (LRBA) deficiency, but long-term follow-up and survival data beyond previous patient reports or meta-reviews are scarce for those patients who do not receive a transplant. OBJECTIVE:This international retrospective study was conducted to elucidate the longitudinal clinical course of patients with LRBA deficiency who do and do not receive a transplant. METHOD:We assessed disease burden and treatment responses with a specially developed immune deficiency and dysregulation activity score, reflecting the sum and severity of organ involvement and infections, days of hospitalization, supportive care requirements, and performance indices. RESULTS:Of 76 patients with LRBA deficiency from 29 centers (median follow-up, 10 years; range, 1-52), 24 underwent HSCT from 2005 to 2019. The overall survival rate after HSCT (median follow-up, 20 months) was 70.8% (17 of 24 patients); all deaths were due to nonspecific, early, transplant-related mortality. Currently, 82.7% of patients who did not receive a transplant (43 of 52; age range, 3-69 years) are alive. Of 17 HSCT survivors, 7 are in complete remission and 5 are in good partial remission without treatment (together, 12 of 17 [70.6%]). In contrast, only 5 of 43 patients who did not receive a transplant (11.6%) are without immunosuppression. Immune deficiency and dysregulation activity scores were significantly lower in patients who survived HSCT than in those receiving conventional treatment (P = .005) or in patients who received abatacept or sirolimus as compared with other therapies, and in patients with residual LRBA expression. Higher disease burden, longer duration before HSCT, and lung involvement were associated with poor outcome. CONCLUSION:The lifelong disease activity, implying a need for immunosuppression and risk of malignancy, must be weighed against the risks of HSCT. 10.1016/j.jaci.2019.12.896
    Enhanced susceptibility to chemically induced colitis caused by excessive endosomal TLR signaling in LRBA-deficient mice. Wang Kuan-Wen,Zhan Xiaoming,McAlpine William,Zhang Zhao,Choi Jin Huk,Shi Hexin,Misawa Takuma,Yue Tao,Zhang Duanwu,Wang Ying,Ludwig Sara,Russell Jamie,Tang Miao,Li Xiaohong,Murray Anne R,Moresco Eva Marie Y,Turer Emre E,Beutler Bruce Proceedings of the National Academy of Sciences of the United States of America LPS-responsive beige-like anchor (LRBA) protein deficiency in humans causes immune dysregulation resulting in autoimmunity, inflammatory bowel disease (IBD), hypogammaglobulinemia, regulatory T (T) cell defects, and B cell functional defects, but the cellular and molecular mechanisms responsible are incompletely understood. In an ongoing forward genetic screen for -ethyl--nitrosourea (ENU)-induced mutations that increase susceptibility to dextran sodium sulfate (DSS)-induced colitis in mice, we identified two nonsense mutations in Although T cells have been a main focus in LRBA research to date, we found that dendritic cells (DCs) contribute significantly to DSS-induced intestinal inflammation in LRBA-deficient mice. DCs exhibited excessive IRF3/7- and PI3K/mTORC1-dependent signaling and type I IFN production in response to the stimulation of the Toll-like receptors (TLRs) 3, TLR7, and TLR9. Substantial reductions in cytokine expression and sensitivity to DSS in LRBA-deficient mice were caused by knockout of , a chaperone necessary for trafficking of TLR3, TLR7, and TLR9 to endosomes. Our data support a function for LRBA in limiting endosomal TLR signaling and consequent intestinal inflammation. 10.1073/pnas.1901407116
    Deficiency of base excision repair enzyme NEIL3 drives increased predisposition to autoimmunity. Massaad Michel J,Zhou Jia,Tsuchimoto Daisuke,Chou Janet,Jabara Haifa,Janssen Erin,Glauzy Salomé,Olson Brennan G,Morbach Henner,Ohsumi Toshiro K,Schmitz Klaus,Kyriacos Markianos,Kane Jennifer,Torisu Kumiko,Nakabeppu Yusaku,Notarangelo Luigi D,Chouery Eliane,Megarbane Andre,Kang Peter B,Al-Idrissi Eman,Aldhekri Hasan,Meffre Eric,Mizui Masayuki,Tsokos George C,Manis John P,Al-Herz Waleed,Wallace Susan S,Geha Raif S The Journal of clinical investigation Alterations in the apoptosis of immune cells have been associated with autoimmunity. Here, we have identified a homozygous missense mutation in the gene encoding the base excision repair enzyme Nei endonuclease VIII-like 3 (NEIL3) that abolished enzymatic activity in 3 siblings from a consanguineous family. The NEIL3 mutation was associated with fatal recurrent infections, severe autoimmunity, hypogammaglobulinemia, and impaired B cell function in these individuals. The same homozygous NEIL3 mutation was also identified in an asymptomatic individual who exhibited elevated levels of serum autoantibodies and defective peripheral B cell tolerance, but normal B cell function. Further analysis of the patients revealed an absence of LPS-responsive beige-like anchor (LRBA) protein expression, a known cause of immunodeficiency. We next examined the contribution of NEIL3 to the maintenance of self-tolerance in Neil3-/- mice. Although Neil3-/- mice displayed normal B cell function, they exhibited elevated serum levels of autoantibodies and developed nephritis following treatment with poly(I:C) to mimic microbial stimulation. In Neil3-/- mice, splenic T and B cells as well as germinal center B cells from Peyer's patches showed marked increases in apoptosis and cell death, indicating the potential release of self-antigens that favor autoimmunity. These findings demonstrate that deficiency in NEIL3 is associated with increased lymphocyte apoptosis, autoantibodies, and predisposition to autoimmunity. 10.1172/JCI85647
    LRBA gene deletion in a patient presenting with autoimmunity without hypogammaglobulinemia. Burns Siobhan O,Zenner Helen L,Plagnol Vincent,Curtis James,Mok Kin,Eisenhut Michael,Kumararatne Dinakantha,Doffinger Rainer,Thrasher Adrian J,Nejentsev Sergey The Journal of allergy and clinical immunology 10.1016/j.jaci.2012.07.035
    A Successful HSCT in a Girl with Novel LRBA Mutation with Refractory Celiac Disease. Sari Sinan,Dogu Figen,Hwa Vivian,Haskologlu Sule,Dauber Andrew,Rosenfeld Ron,Polat Meltem,Kuloglu Zarife,Kansu Aydan,Dalgic Buket,Ikinciogullari Aydan Journal of clinical immunology 10.1007/s10875-015-0220-y
    Loss of B Cells in Patients with Heterozygous Mutations in IKAROS. Kuehn H S,Boisson B,Cunningham-Rundles C,Reichenbach J,Stray-Pedersen A,Gelfand E W,Maffucci P,Pierce K R,Abbott J K,Voelkerding K V,South S T,Augustine N H,Bush J S,Dolen W K,Wray B B,Itan Y,Cobat A,Sorte H S,Ganesan S,Prader S,Martins T B,Lawrence M G,Orange J S,Calvo K R,Niemela J E,Casanova J-L,Fleisher T A,Hill H R,Kumánovics A,Conley M E,Rosenzweig S D The New England journal of medicine BACKGROUND:Common variable immunodeficiency (CVID) is characterized by late-onset hypogammaglobulinemia in the absence of predisposing factors. The genetic cause is unknown in the majority of cases, and less than 10% of patients have a family history of the disease. Most patients have normal numbers of B cells but lack plasma cells. METHODS:We used whole-exome sequencing and array-based comparative genomic hybridization to evaluate a subset of patients with CVID and low B-cell numbers. Mutant proteins were analyzed for DNA binding with the use of an electrophoretic mobility-shift assay (EMSA) and confocal microscopy. Flow cytometry was used to analyze peripheral-blood lymphocytes and bone marrow aspirates. RESULTS:Six different heterozygous mutations in IKZF1, the gene encoding the transcription factor IKAROS, were identified in 29 persons from six families. In two families, the mutation was a de novo event in the proband. All the mutations, four amino acid substitutions, an intragenic deletion, and a 4.7-Mb multigene deletion involved the DNA-binding domain of IKAROS. The proteins bearing missense mutations failed to bind target DNA sequences on EMSA and confocal microscopy; however, they did not inhibit the binding of wild-type IKAROS. Studies in family members showed progressive loss of B cells and serum immunoglobulins. Bone marrow aspirates in two patients had markedly decreased early B-cell precursors, but plasma cells were present. Acute lymphoblastic leukemia developed in 2 of the 29 patients. CONCLUSIONS:Heterozygous mutations in the transcription factor IKAROS caused an autosomal dominant form of CVID that is associated with a striking decrease in B-cell numbers. (Funded by the National Institutes of Health and others.). 10.1056/NEJMoa1512234
    Atypical manifestation of LRBA deficiency with predominant IBD-like phenotype. Serwas Nina Kathrin,Kansu Aydan,Santos-Valente Elisangela,Kuloğlu Zarife,Demir Arzu,Yaman Aytaç,Gamez Diaz Laura Yaneth,Artan Reha,Sayar Ersin,Ensari Arzu,Grimbacher Bodo,Boztug Kaan Inflammatory bowel diseases BACKGROUND:Inflammatory bowel diseases (IBDs) denote a heterogeneous group of disorders associated with an imbalance of gut microbiome and the immune system. Importance of the immune system in the gut is endorsed by the presence of IBD-like symptoms in several primary immunodeficiencies. A fraction of early-onset IBDs presenting with more severe disease course and incomplete response to conventional treatment is assumed to be inherited in a Mendelian fashion, as exemplified by the recent discovery of interleukin (IL)-10 (receptor) deficiency. METHODS:We analyzed a patient born to consanguineous parents suffering from severe intestinal manifestations since 6 months of age and later diagnosed as IBD. Eventually, she developed autoimmune manifestations including thyroiditis and type I diabetes at the age of 6 and 9 years, respectively. Combined single-nucleotide polymorphism array-based homozygosity mapping and exome sequencing was performed to identify the underlying genetic defect. Protein structural predictions were calculated using I-TASSER. Immunoblot was performed to assess protein expression. Flow cytometric analysis was applied to investigate B-cell subpopulations. RESULTS:We identified a homozygous missense mutation (p.Ile2824Pro) in lipopolysaccharide-responsive and beige-like anchor (LRBA) affecting the C-terminal WD40 domain of the protein. In contrast to previously published LRBA-deficient patients, the mutant protein was expressed at similar levels to healthy controls. Immunophenotyping of the index patient revealed normal B-cell subpopulations except increased CD21 B cells. CONCLUSIONS:We describe a patient with a novel missense mutation in LRBA who presented with IBD-like symptoms at early age, illustrating that LRBA deficiency should be considered in the differential diagnosis for IBD(-like) disease even in the absence of overt immunodeficiency. 10.1097/MIB.0000000000000266
    Autoimmune lymphoproliferative syndrome-like disease in patients with LRBA mutation. Revel-Vilk Shoshana,Fischer Ute,Keller Bärbel,Nabhani Schafiq,Gámez-Díaz Laura,Rensing-Ehl Anne,Gombert Michael,Hönscheid Andrea,Saleh Hani,Shaag Avraham,Borkhardt Arndt,Grimbacher Bodo,Warnatz Klaus,Elpeleg Orly,Stepensky Polina Clinical immunology (Orlando, Fla.) Mutations in LPS-responsive and beige-like anchor (LRBA) gene were recently described in patients with combined immunodeficiency, enteropathy and autoimmune cytopenia. Here, we extend the clinical and immunological phenotypic spectrum of LRBA associated disorders by reporting on three patients from two unrelated families who presented with splenomegaly and lymphadenopathy, cytopenia, elevated double negative T cells and raised serum Fas ligand levels resembling autoimmune lymphoproliferative syndrome (ALPS) and one asymptomatic patient. Homozygous loss of function mutations in LRBA were identified by whole exome analysis. Similar to ALPS patients, Fas mediated apoptosis was impaired in LRBA deficient patients, while apoptosis in response to stimuli of the intrinsic mitochondria mediated apoptotic pathway was even enhanced. This manuscript illustrates the phenotypic overlap of other primary immunodeficiencies with ALPS-like disorders and strongly underlines the necessity of genetic diagnosis in order to provide early correct diagnosis and subsequent care. 10.1016/j.clim.2015.04.007
    Abatacept alleviates severe autoimmune symptoms in a patient carrying a de novo variant in CTLA-4. Lee Sangmoon,Moon Jin Soo,Lee Cho-Rong,Kim Hye-Eun,Baek Sun-Mi,Hwang Solha,Kang Gyeong Hoon,Seo Jeong Kee,Shin Choong Ho,Kang Hyoung Jin,Ko Jae Sung,Park Sung Gyoo,Choi Murim The Journal of allergy and clinical immunology 10.1016/j.jaci.2015.08.036
    Successful Hematopoietic Stem Cell Transplantation in a Patient with LPS-Responsive Beige-Like Anchor (LRBA) Gene Mutation. Tesi Bianca,Priftakis Peter,Lindgren Fredrik,Chiang Samuel C C,Kartalis Nikolaos,Löfstedt Alexandra,Lörinc Esther,Henter Jan-Inge,Winiarski Jacek,Bryceson Yenan T,Meeths Marie Journal of clinical immunology PURPOSE:Autosomal recessive mutations in LRBA, encoding for LPS-responsive beige-like anchor protein, were described in patients with a common variable immunodeficiency (CVID)-like disease characterized by hypogammaglobulinemia, autoimmune cytopenias, and enteropathy. Here, we detail the clinical, immunological, and genetic features of a patient with severe autoimmune manifestations. METHODS:Whole exome sequencing was performed to establish a molecular diagnosis. Evaluation of lymphocyte subsets was performed for immunological characterization. Medical files were reviewed to collect clinical and immunological data. RESULTS:A 7-year-old boy, born to consanguineous parents, presented with autoimmune hemolytic anemia, hepatosplenomegaly, autoimmune thyroiditis, and severe autoimmune gastrointestinal manifestations. Immunological investigations revealed low immunoglobulin levels and low numbers of B and NK cells. Treatment included immunoglobulin replacement and immunosuppressive therapy. Seven years after disease onset, the patient developed severe neurological symptoms resembling acute disseminated encephalomyelitis, prompting allogeneic hematopoietic stem cell transplantation (HSCT) with the HLA-identical mother as donor. Whole exome sequencing of the patient uncovered a homozygous 1 bp deletion in LRBA (c.7162delA:p.T2388Pfs*7). Importantly, during 2 years of follow-up post-HSCT, marked clinical improvement and recovery of immune function was observed. CONCLUSIONS:Our data suggest a beneficial effect of HSCT in patients with LRBA deficiency. 10.1007/s10875-016-0289-y
    CHAI and LATAIE: new genetic diseases of CTLA-4 checkpoint insufficiency. Lo Bernice,Fritz Jill M,Su Helen C,Uzel Gulbu,Jordan Michael B,Lenardo Michael J Blood CTLA-4 is a critical inhibitory "checkpoint" molecule of immune activation. Several recent reports have described patients with immune dysregulation and lymphoproliferative disease resulting from 2 different genetic diseases that directly or indirectly cause CTLA-4 deficiency. Numerous articles have also been published describing CTLA-4 blockade in cancer immunotherapy and its side effects, which are ultimately the consequence of treatment-induced CTLA-4 deficiency. Here, we review these 2 diseases and CTLA-4 blockade therapy, emphasizing the crucial role of CTLA-4 in immune checkpoint regulation. 10.1182/blood-2016-04-712612
    Respiratory manifestations in LPS-responsive beige-like anchor (LRBA) protein-deficient patients. Shamriz Oded,Shadur Bella,NaserEddin Adeeb,Zaidman Irina,Simanovsky Natalia,Elpeleg Orly,Kerem Eitan,Reiter Joel,Stepensky Polina European journal of pediatrics 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. 10.1007/s00431-018-3171-5
    The BEACH protein LRBA is required for hair bundle maintenance in cochlear hair cells and for hearing. Vogl Christian,Butola Tanvi,Haag Natja,Hausrat Torben J,Leitner Michael G,Moutschen Michel,Lefèbvre Philippe P,Speckmann Carsten,Garrett Lillian,Becker Lore,Fuchs Helmut,Hrabe de Angelis Martin,Nietzsche Sandor,Kessels Michael M,Oliver Dominik,Kneussel Matthias,Kilimann Manfred W,Strenzke Nicola EMBO reports Lipopolysaccharide-responsive beige-like anchor protein (LRBA) belongs to the enigmatic class of BEACH domain-containing proteins, which have been attributed various cellular functions, typically involving intracellular protein and membrane transport processes. Here, we show that LRBA deficiency in mice leads to progressive sensorineural hearing loss. In LRBA knockout mice, inner and outer hair cell stereociliary bundles initially develop normally, but then partially degenerate during the second postnatal week. LRBA deficiency is associated with a reduced abundance of radixin and Nherf2, two adaptor proteins, which are important for the mechanical stability of the basal taper region of stereocilia. Our data suggest that due to the loss of structural integrity of the central parts of the hair bundle, the hair cell receptor potential is reduced, resulting in a loss of cochlear sensitivity and functional loss of the fraction of spiral ganglion neurons with low spontaneous firing rates. Clinical data obtained from two human patients with protein-truncating nonsense or frameshift mutations suggest that LRBA deficiency may likewise cause syndromic sensorineural hearing impairment in humans, albeit less severe than in our mouse model. 10.15252/embr.201643689