Manish Butte

Coordinated regulation of scaffold opening and enzymatic activity during CARD11 signaling.

J Biol Chem. 2019 Aug 07;:

Authors: Wang Z, Hutcherson SM, Yang C, Jattani RP, Tritapoe JM, Yang YK, Pomerantz JL

Abstract
The activation of key signaling pathways downstream of antigen receptor engagement is critically required for normal lymphocyte activation during the adaptive immune response.  CARD11 is a multidomain signaling scaffold protein required for antigen receptor signaling to NF-κB, c-Jun N-terminal Kinase (JNK), and mTOR. Germline mutations in the CARD11 gene result in at least four types of primary immunodeficiency, and somatic CARD11 gain-of-function mutations drive constitutive NF-κB activity in Diffuse Large B Cell Lymphoma and other lymphoid cancers.  In response to antigen receptor triggering, CARD11 transitions from a closed, inactive state to an open, active scaffold that recruits multiple signaling partners into a complex to relay downstream signaling. However, how this signal-induced CARD11 conversion occurs remains poorly understood.  Here we investigate the role of IE1, a short regulatory element in the CARD11 Inhibitory Domain, in the CARD11 signaling cycle.  We find that IE1 controls the signal-dependent Opening Step that makes CARD11 accessible to the binding of cofactors, including Bcl10, MALT1, and the HOIP catalytic subunit of the Linear Ubiquitin Chain Assembly Complex.  Surprisingly, we find that IE1 is also required at an independent step for the maximal activation of HOIP and MALT1 enzymatic activity after cofactor recruitment to CARD11.  This role of IE1 reveals that there is an Enzymatic Activation Step in the CARD11 signaling cycle that is distinct from the Cofactor Association Step.  Our results indicate that CARD11 has evolved to actively coordinate scaffold opening and the induction of enzymatic activity among recruited cofactors during antigen receptor signaling.

PMID: 31391255 [PubMed – as supplied by publisher]

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Immunoglobulin A and microbiota in primary immunodeficiency diseases.

Curr Opin Allergy Clin Immunol. 2019 Aug 05;:

Authors: Berbers RM, Franken IA, Leavis HL

Abstract
PURPOSE OF REVIEW: With the emergence of the microbiota as a potential driver of host inflammation, the role of iIgA is becoming increasingly important. This review discusses the current evidence regarding the effects of clinical IgA deficiency on the microbiota, and the possible role of microbial dysbiosis in driving inflammation in PID patients.
RECENT FINDINGS: The gut microbiota has been investigated in selective IgA deficiency and common variable immunodeficiency, revealing an important role for IgA in maintaining gut microbiota homeostasis, with disparate effects of IgA on symbionts and pathobionts. Although IgA deficiency is associated with microbial translocation and systemic inflammation, this may be partially compensated by adequate IgG and IgM induction in IgA deficiency but not in common variable immunodeficiency. Therapeutic strategies aimed at correction of the microbiota mostly focus on fecal microbiota transplantation. Whether this may reduce systemic inflammation in PID is currently unknown.
SUMMARY: Clinical IgA deficiency is associated with microbial dysbiosis and systemic inflammation. The evidence for microbiota-targeted therapies in PID is scarce, but indicates that IgA-based therapies may be beneficial, and that fecal microbiota transplantation is well tolerated in patients with antibody deficiency.

PMID: 31389816 [PubMed – as supplied by publisher]

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Leishmaniasis and autoimmunity in patient with LPS-responsive beige-like anchor protein (LRBA) deficiency.

Endocr Metab Immune Disord Drug Targets. 2019 Aug 07;:

Authors: Salami F, Shirkani A, Shahrooei M, Azizi G, Yazdani R, Abolhassani H, Aghamohammadi A

Abstract
BACKGROUND/OBJECTIVE: LPS-responsive beige-like anchor protein (LRBA) deficiency is a combined immunodeficiency and immune dysregulation. The authors present a case report of LPS-responsive beige-like anchor protein (LRBA) deficiency with the history of autoimmunity, enteropathy and visceral leishmaniasis. Sirolimus therapy was started for autoimmunity and enteropathy but was discontinued due to recurrent leishmaniasis. Therefore, a common side-effect of many immunosuppressive drugs in patients with LRBA deficiency is increased susceptibility to infections.
METHODS: Whole exome sequencing was performed to detect the underlying genetic mutation and Leishmania DNA was detected by the PCR technique in this patient.
RESULTS: Whole exome sequencing of the patient reported a homozygous frameshift deletion mutation in the LRBA gene (NM_006726: exon29: c.4638delC, p. S1546fs). Leishmania DNA PCR was positive in this case.
CONCLUSION: Parasite infections manifestations report in LRBA deficiency. Leishmania infections in patients with chronic diarrhea and autoimmunity should be considered for immunodeficiency.

PMID: 31389321 [PubMed – as supplied by publisher]

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Predicting the Occurrence of Variants in RAG1 and RAG2.

J Clin Immunol. 2019 Aug 06;:

Authors: Lawless D, Lango Allen H, Thaventhiran J, NIHR BioResource–Rare Diseases Consortium, Hodel F, Anwar R, Fellay J, Walter JE, Savic S

Abstract
While widespread genome sequencing ushers in a new era of preventive medicine, the tools for predictive genomics are still lacking. Time and resource limitations mean that human diseases remain uncharacterized because of an inability to predict clinically relevant genetic variants. A strategy of targeting highly conserved protein regions is used commonly in functional studies. However, this benefit is lost for rare diseases where the attributable genes are mostly conserved. An immunological disorder exemplifying this challenge occurs through damaging mutations in RAG1 and RAG2 which presents at an early age with a distinct phenotype of life-threatening immunodeficiency or autoimmunity. Many tools exist for variant pathogenicity prediction, but these cannot account for the probability of variant occurrence. Here, we present a method that predicts the likelihood of mutation for every amino acid residue in the RAG1 and RAG2 proteins. Population genetics data from approximately 146,000 individuals was used for rare variant analysis. Forty-four known pathogenic variants reported in patients and recombination activity measurements from 110 RAG1/2 mutants were used to validate calculated scores. Probabilities were compared with 98 currently known human cases of disease. A genome sequence dataset of 558 patients who have primary immunodeficiency but that are negative for RAG deficiency were also used as validation controls. We compared the difference between mutation likelihood and pathogenicity prediction. Our method builds a map of most probable mutations allowing pre-emptive functional analysis. This method may be applied to other diseases with hopes of improving preparedness for clinical diagnosis.

PMID: 31388879 [PubMed – as supplied by publisher]

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BAFF/APRIL System Is Functional in B-Cell Acute Lymphoblastic Leukemia in a Disease Subtype Manner.

Front Oncol. 2019;9:594

Authors: Sevdali E, Katsantoni E, Smulski CR, Moschovi M, Palassopoulou M, Kolokotsa EN, Argentou N, Giannakoulas N, Adamaki M, Vassilopoulos G, Polychronopoulou S, Germenis AE, Eibel H, Speletas M

Abstract
BAFF, APRIL and their receptors regulate the survival, maturation and homeostasis of mature B-cells. Despite the lack of a functional role of BAFF/APRIL system during normal early B-cell development, previous studies indicated a contribution of these molecules in the pathogenesis of B-lineage acute lymphoblastic leukemia (B-ALL). Here, we evaluated the expression of this system in B-ALL and its involvement in spontaneous and drug-induced apoptosis of B-lymphoblasts, taking into consideration the distinct disease subtypes. We found that BAFFR is the most predominant aberrantly expressed receptor in B-ALL and that its expression, along with BCMA and APRIL, positively correlates with the maturation stage of B-lymphoblasts. Moreover, the binding of the E2A-PBX1 chimeric protein to the BAFFR promoter suggests that the transcriptional activator promotes the increase in BAFFR expression observed in about 50% of pre-B-ALL patients carrying the t (1, 19) translocation. BAFF binding to BAFFR led to the processing of NF-κB2 p100 in pre-B ALL cells suggesting that BAFFR can activate the NF-κB2 pathway in pre-B ALL cells. Surprisingly, we found that BAFF treatment promotes the cell death of primary BCR-ABL+ BAFFR+ pre-B-lymphoblasts in adult B-ALL. It also enhances glucocorticoid-induced apoptosis in the E2A-PBX1+ pre-B-ALL cell line 697. These data suggest that BAFF/BAFFR signaling in B-ALL cells differs from normal B cells and that it may affect the pathogenesis of the disease.

PMID: 31380267 [PubMed]

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Whole Exome Sequencing of an X-linked Thrombocytopenia Patient with Normal Sized Platelets.

Avicenna J Med Biotechnol. 2019 Jul-Sep;11(3):253-258

Authors: Fathi M, Shahraki H, Sharif Rahmani E, Rahimi H, Omidi P, Darvishi S, Abazari MF, Hosseini A

Abstract
Wiskott-Aldrich Syndrome (WAS) is a rare X-linked recessive Primary Immunodeficiency (PID) caused by mutations in WAS gene which encodes a protein known as WASp. WASp plays important roles in cytoskeletal functions that compromise multiple aspects of normal cellular activity including proliferation, phagocytosis, immune synapse formation, adhesion and directed migration. WASp defect particularly causes platelets abnormality which is presented in forms of decrease of Mean Platelet Volume (MPV) and thrombocytopenia in most WAS conditions; nevertheless, some studies reported WAS patients with a normal or large size of platelets in recent years. This phenomenon is unique and the exact mechanism of thrombocytopenia with a normal or large size of platelets is still unknown. In this study, Next Generation Sequencing (NGS) was utilized to discover the causing mutation in WAS gene; furthermore, an attempt was made to evaluate the possibility of other mutations or genes especially WASp interacting proteins and inherited platelet disorder genes in patient clinical symptoms for the purpose of understanding the origin of such unique symptom and to perform further analysis if it is required. Therefore, clinical manifestations and immunologic functions of the patient were checked and Whole Exome Sequencing (WES) was performed to analyze all exonic variations which can be associated with patient phenotypes. Finally, a novel de novo mutation in WAS gene which truncates WASp to half of its normal size was determined as the only cause of clinical manifestation.

PMID: 31379999 [PubMed]

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Does Natural Killer Cell Deficiency (NKD) Increase the Risk of Cancer? NKD May Increase the Risk of Some Virus Induced Cancer.

Front Immunol. 2019;10:1703

Authors: Moon WY, Powis SJ

Abstract
Natural killer cell deficiency (NKD) is a primary immunodeficiency where the main defect lies in CD56+CD3- natural killer (NK) cells which mediate cytotoxicity against tumors. Most cases are observed in children and adolescents with recurrent viral infections and cancer. GATA2 and MCM4 mutations are found in NKD patients with cancer. However, the question remains unclear whether NKD increases the risk of cancer. Mutations in the second zinc finger of GATA2 cause both NKD and haematopoietic malignancies. MCM4 splice site mutations are found in NKD patients and they increase susceptibility to DNA instability during replication. IRF8, RTEL1, and FCGR3A mutations are associated with NKD but their associations with cancer are unknown. Based on the studies, it is hypothesized that genetic mutations alone are sufficient to cause cancer. However, a number of NKD patients developed oncogenic viral infections which progressed into cancer. Here, we review the evidence of genetic mutations responsible for both NKD and cancer to identify whether NKD contributes to development of cancer. The findings provide insights into the role of NK cells in the prevention of cancer and the significance of assessing NK cell functions in susceptible individuals.

PMID: 31379882 [PubMed – in process]

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Refractory Chronic Spontaneous Urticaria Treated With Omalizumab in an Adolescent With Common Variable Immunodeficiency.

Front Immunol. 2019;10:1700

Authors: Comberiati P, Costagliola G, Carli N, Legitimo A, D’Elios S, Consolini R, Peroni DG

Abstract
Chronic spontaneous urtcaria (CSU) can represent the leading sign of a wide spectrum of systemic diseases, including primary immunodeficiencies. We describe the case of a young adult female with coexisting CSU and common variable immunodeficiency (CVID) successfully treated with omalizumab. The patient, with a history of recurrent respiratory infections during childhood, was referred to clinical attention due to the development of refractory CSU. During the diagnostic workup for the research of secondary causes of urticaria, an immunological assessment was performed, showing markedly reduced levels of IgG and IgM, poor antibody response against vaccinating antigens in absence of a T cellular deficiency. Therefore, the diagnosis of CVID was posed. Despite the immunoglobulin replacement and a trial with intravenous immunoglobulin at immunomodulatory dosage, the patient continued to experience severe urticaria, with significant impairment in the quality of life. After 2 years from the diagnosis of CVID, a treatment with omalizumab was started, showing complete remission of cutaneous symptoms after the first injection. The drug was well-tolerated, and the patient did not experience adverse effects during a 12-months follow-up.

PMID: 31379880 [PubMed – in process]

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A 30-Year Prospective Follow-Up Study Reveals Risk Factors for Early Death in Cartilage-Hair Hypoplasia.

Front Immunol. 2019;10:1581

Authors: Vakkilainen S, Taskinen M, Klemetti P, Pukkala E, Mäkitie O

Abstract
Cartilage-hair hypoplasia (CHH) is a skeletal dysplasia with combined immunodeficiency, variable clinical course and increased risk of malignancy. Management of CHH is complicated by a paucity of long-term follow-up data, as well as knowledge on prognostic factors. We assessed clinical course and risk factors for mortality in a prospective cohort study of 80 patients with CHH recruited in 1985-1991 and followed up until 2016. For all patients we collected additional health information from health records and from the national Medical Databases and Cause-of-death Registry. The primary outcome was immunodeficiency-related death, including death from infections, lung disease and malignancy. Standardized mortality ratios (SMRs) were calculated using national mortality rates as reference. Half of the patients (57%, n = 46) manifested no symptoms of immunodeficiency during follow-up while 19% (n = 15) and 24% (n = 19) demonstrated symptoms of humoral or combined immunodeficiency, including six cases of adult-onset immunodeficiency. In a significant proportion of patients (17/79, 22%), clinical features of immunodeficiency progressed over time. Of the 15 patients with non-skin cancer, eight had no preceding clinical symptoms of immunodeficiency. Altogether 20 patients had deceased (SMR = 7.0, 95%CI = 4.3-11); most commonly from malignancy (n = 7, SMR = 10, 95%CI = 4.1-21) and lung disease (n = 4, SMR = 46, 95%CI = 9.5-130). Mortality associated with birth length below -4 standard deviation (compared to normal, SMR/SMR ratio = 5.4, 95%CI = 1.5-20), symptoms of combined immunodeficiency (compared to asymptomatic, SMR/SMR ratio = 3.9, 95%CI = 1.3-11), Hirschsprung disease (odds ratio (OR) 7.2, 95%CI = 1.04-55), pneumonia in the first year of life or recurrently in adulthood (OR = 7.6/19, 95%CI = 1.3-43/2.6-140) and autoimmunity in adulthood (OR = 39, 95%CI = 3.5-430). In conclusion, patients with CHH may develop adult-onset immunodeficiency or malignancy without preceding clinical symptoms of immune defect, warranting careful follow-up. Variable disease course and risk factors for mortality should be acknowledged.

PMID: 31379817 [PubMed – in process]

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The Natural History of Untreated Primary Hypogammaglobulinemia in Adults: Implications for the Diagnosis and Treatment of Common Variable Immunodeficiency Disorders (CVID).

Front Immunol. 2019;10:1541

Authors: Ameratunga R, Ahn Y, Steele R, Woon ST

Abstract
Background: Adults with primary hypogammaglobulinemia are frequently encountered by clinicians. Where IgG levels are markedly decreased, most patients are treated with subcutaneous or intravenous immunoglobulin (SCIG/IVIG), because of the presumed risk of severe infections. The natural history of untreated severe asymptomatic hypogammaglobulinemia is thus unknown. Similarly, there are no long-term prospective studies examining the natural history of patients with moderate reductions in IgG. Methods: In 2006, we began a prospective cohort study of patients with symptomatic and asymptomatic reductions in IgG who were not immediately commenced on SCIG/IVIG. Over the course of 12 years, 120 patients were enrolled in the NZ hypogammaglobulinemia study (NZHS) including 59 who were asymptomatic. Results: Five patients with profound primary hypogammaglobulinemia (IgG < 3 g/l), who were not on regular SCIG/IVIG have remained well for a mean duration of 139 months. This study has also shown most asymptomatic patients with moderate hypogammaglobulinemia (IgG 3.0-6.9 g/l) have been in good health for a mean observation period of 96 months. We have only identified one asymptomatic patient with moderate hypogammaglobulinemia who experienced progressive decline in IgG levels to <3 g/l and was accepted for IVIG replacement. Prospective monitoring has shown that none have suffered catastrophic infections or any of the severe autoimmune or inflammatory sequelae associated with Common Variable Immunodeficiency Disorders (CVID). Unexpectedly, 18.1% of asymptomatic and 41.6% of symptomatic hypogammaglobulinemic patients spontaneously increased their IgG into the normal range (≥7.0 g/l) on at least one occasion, which we have termed transient hypogammaglobulinemia of adulthood (THA). In this study, vaccine challenge responses have correlated poorly with symptomatic state and long-term prognosis including subsequent SCIG/IVIG treatment. Conclusions: In spite of our favorable experience, we recommend patients with severe asymptomatic hypogammaglobulinemia are treated with SCIG/IVIG because of the potential risk of severe infections. Patients with moderate asymptomatic hypogammaglobulinemia have a good prognosis. Patients with symptomatic hypogammaglobulinemia are a heterogeneous group where some progress to SCIG/IVIG replacement, while many others spontaneously recover. This study has implications for the diagnosis and treatment of CVID.

PMID: 31379811 [PubMed – in process]

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