Blog

Related Articles

The negative charge of the 343 site is essential for maintaining physiological functions of CXCR4.

BMC Mol Cell Biol. 2021 Jan 23;22(1):8

Authors: Wang L, Xiong Q, Li P, Chen G, Tariq N, Wu C

Abstract
BACKGROUND: Warts, hypogammaglobulinemia, recurrent bacterial infections and myelokathexis (WHIM) syndrome is a primary immunodeficiency disease (PID) usually caused by autosomal dominant mutations in the chemokine receptor CXCR4 gene. To date, a total of nine different mutations including eight truncation mutations and one missense mutation (E343K, CXCR4E343K) distributed in the C-terminus of CXCR4 have been identified in humans. Studies have clarified that the loss of phosphorylation sites in the C-terminus of truncated CXCR4 impairs the desensitization process, enhances the activation of G-protein, prolongs downstream signaling pathways and introduces over immune responses, thereby causing WHIM syndrome. So far, there is only one reported case of WHIM syndrome with a missense mutation, CXCR4E343K, which has a full length of C-terminus with entire phosphorylation sites, no change in all potential phosphorylation sites. The mechanism of the missense mutation (CXCR4E343K) causing WHIM syndrome is unknown. This study aimed to characterize the effect of mutation at the 343 site of CXCR4 causing the replacement of arginine/E with glutamic acid/K on the receptor signal transduction, and elucidate the mechanism underling CXCR4E343K causing WHIM in the reported family.
RESULTS: We completed a series of mutagenesis to generate different mutations at the 343 site of CXCR4 tail, and established a series of HeLa cell lines stably expressing CXCR4WT or CXCR4E343D (glutamic acid/E replaced with aspartic acid/D) or CXCR4E343K (glutamic acid/E replaced with lysine/K) or CXCR4E343R (glutamic acid/E replaced with arginine/R) or CXCR4E343A (glutamic acid/E replaced with alanine/A) and then systematically analyzed functions of the CXCR4 mutants above. Results showed that the cells overexpressing of CXCR4E343D had no functional changes with comparison that of wild type CXCR4. However, the cells overexpressing of CXCR4E343K or CXCR4E343R or CXCR4E343A had enhanced cell migration, prolonged the phosphorylation of ERK1/2, p38, JNK1/2/3, aggravated activation of PI3K/AKT/NF-κB signal pathway, introduced higher expression of TNFa and IL6, suggesting over immune response occurred in CXCR4 mutants with charge change at the 343 site of receptor tail, as a result, causing WHIM syndrome. Biochemical analysis of those mutations at the 343 site of CXCR4 above shows that CXCR4 mutants with no matter positive or neutral charge have aberrant signal pathways downstream of activated mutated CXCR4, only CXVR4 with negative charge residues at the site shows normal signal pathway post activation with stromal-derived factor (SDF1, also known as CXCL12).
CONCLUSION: Taken together, our results demonstrated that the negative charge at the 343 site of CXCR4 plays an essential role in regulating the down-stream signal transduction of CXCR4 for physiological events, and residue charge changes, no matter positive or neutral introduce aberrant activities and functions of CXCR4, thus consequently lead to WHIM syndrome.

PMID: 33485325 [PubMed – in process]

Powered by WPeMatico

Related Articles

Novel genetic variants of inborn errors of immunity.

PLoS One. 2021;16(1):e0245888

Authors: Almarzooqi F, Souid AK, Vijayan R, Al-Hammadi S

Abstract
OBJECTIVES: Inborn errors of immunity (IEI) are prevalent in tribal cultures due to frequent consanguineous marriages. Many of these disorders are autosomal recessive, resulting from founder mutations; hence they are amenable to prevention. The primary objective of this study was to evaluate the pathogenicity of novel variants of IEI found among Emiratis.
METHODS: This retrospective data collection study reports novel variants of IEI detected by diagnostic exome sequencing. Pathogenicity prediction was based on scoring tools, amino acid alignment, and Jensen-Shannon divergence values.
RESULTS: Twenty-one novel variants were identified; nine were frameshift, three nonsense, four intronic (one pathogenic), and five missense (two pathogenic). Fifteen variants were likely pathogenic, of which 13 were autosomal recessive and two uncertain inheritance. Their clinical spectra included combined immunodeficiency, antibody deficiency, immune dysregulation, defects in intrinsic/innate immunity, and bone marrow failure.
CONCLUSION: The described novel pathogenic variants are core to a planned national screening program that aims toward IEI prevention. Future studies, however, are needed to confirm their natural history in individual patients and estimate their prevalence in the community.

PMID: 33481921 [PubMed – as supplied by publisher]

Powered by WPeMatico

Related Articles

Stepwise Reversal of Immune Dysregulation Due to STAT1 Gain-of-Function Mutation Following Ruxolitinib Bridge Therapy and Transplantation.

J Clin Immunol. 2021 Jan 21;:

Authors: Kayaoglu B, Kasap N, Yilmaz NS, Charbonnier LM, Geckin B, Akcay A, Eltan SB, Ozturk G, Ozen A, Karakoc-Aydiner E, Chatila TA, Gursel M, Baris S

Abstract
PURPOSE: Patients with heterozygous gain-of-function (GOF) mutations in STAT1 frequently exhibit chronic mucocutaneous candidiasis (CMC), immunodeficiency and autoimmune manifestations. Several treatment options including targeted therapies and hematopoietic stem cell transplantation (HSCT) are available for STAT1 GOF patients but modalities and outcomes are not well established. Herein, we aimed to unravel the effect of ruxolitinib as a bridge therapy in a patient with sporadic STAT1 T385M mutation to manage infections and other disease manifestations.
METHODS: Peripheral blood mononuclear cells were isolated from the patient prior to, during ruxolitinib treatment and 6 months after HSCT. IFN-β-induced STAT1 phosphorylation/dephosphorylation levels and PMA/ionomycin-stimulated intracellular IL-17A/IFN-γ production in CD4+ T cells were evaluated. Differentially expressed genes between healthy controls and the patient prior to, during ruxolitinib treatment and post-transplantation were investigated using Nanostring nCounter Profiling Panel.
RESULTS: Ruxolitinib provided favorable responses by controlling candidiasis and autoimmune hemolytic anemia in the patient. Dysregulation in STAT1 phosphorylation kinetics improved with ruxolitinib treatment and was completely normalized after transplantation. TH17 deficiency persisted after ruxolitinib treatment, but normalized following HSCT. Consistent with the impairment in JAK/STAT signaling, multiple immune related pathways were found to be dysregulated in the patient. At baseline, genes related to type I IFN-related pathways, antigen processing, T-cell and B-cell functions were upregulated, while NK-cell function and cytotoxicity related genes were downregulated. Dysregulated gene expression was partially improved with ruxolitinib treatment and normalized after transplantation.
CONCLUSION: Our findings suggest that improved disease management and immune dysregulatory profile can be achieved with ruxolitinib treatment before transplantation and this would be beneficial to reduce the risk of adverse outcome of HSCT.

PMID: 33475942 [PubMed – as supplied by publisher]

Powered by WPeMatico

Related Articles

Clinical and Laboratory Characteristics of Primary Immunodeficiency Patients from a Tertiary Care Center in Pakistan.

J Pak Med Assoc. 2020 Dec;70(12(B)):2403-2407

Authors: Tipu HN, Ahmed D

Abstract
OBJECTIVE: The aim of this study was to describe and identify clinical presentation of primary immunodeficiency disorders (PIDs). Characteristic quantitative and qualitative immunological abnormalities have been described which help in establishing a definitive PID diagnosis.
METHODS: This was a cross sectional study conducted in the Immunology department of the Armed Forces Institute of Pathology, Rawalpindi, Pakistan, from Jan 2016 to Dec 2018. Sixty patients of different PIDs including humoral defects, combined immunodeficiency, phagocytic defects and other miscellaneous disorders, were diagnosed over a period of 3 years in our institute. Their clinical presentation and laboratory data are presented in this study.
RESULTS: In 3 years, 40 (66%) males and 20 (33%) females were diagnosed, with 13 (21.6%) patients of humoral deficiency, 22 (36.6%) of severe combined immunodeficiency, 18 (30%) of phagocytic defects and 7 (11.6%) of other miscellaneous disorders. Maximum patients belonged to Punjab province, i.e., 23 (38.3%). Their mean age for initiation of symptoms was 7±12.6 months, while diagnosis was made at mean age of 26±39.28 months, in all groups combined. Respiratory infections were commonest presentation, in 46 (76.6%) patients. Also 46 (76.6%) patients had consanguineous parents. Presence of family history of PID in 27 (45%) patients was not associated with an earlier diagnosis (p 0.955). Each group of patients carried characteristic laboratory findings.
CONCLUSIONS: PIDs should be suspected in offsprings with warning signs coming from consanguineous parents. There is a need to introduce genetic diagnosis of PIDs in order to timely diagnose less characteristic PID presentations.

PMID: 33475552 [PubMed – as supplied by publisher]

Powered by WPeMatico

Related Articles

Primary Immunodeficiency and Thrombocytopenia.

Int Rev Immunol. 2021 Jan 19;:1-43

Authors: Mohtashami M, Razavi A, Abolhassani H, Aghamohammadi A, Yazdani R

Abstract
Primary immunodeficiency (PID) or Inborn errors of immunity (IEI) refers to a heterogeneous group of disorders characterized by immune system impairment. Although patients with IEI manifest highly variable symptoms, the most common clinical manifestations are recurrent infections, autoimmunity and malignancies. Some patients present hematological abnormality including thrombocytopenia due to different pathogenic mechanisms. This review focuses on primary and secondary thrombocytopenia as a complication, which can occur in IEI. Based on the International Union of Immunological Societies phenotypic classification for IEI, the several innate and adaptive immunodeficiency disorders can lead to thrombocytopenia. This review, for the first time, describes manifestation, mechanism and therapeutic modalities for thrombocytopenia in different classes of IEI.

PMID: 33464134 [PubMed – as supplied by publisher]

Powered by WPeMatico

Related Articles

An Unexpected Infection in Loss-of-Function Mutations in STAT3: Malignant Alveolar Echinococcosis in Liver.

Iran J Allergy Asthma Immunol. 2020 Dec 19;19(6):667-675

Authors: Haskologlu S, Dogu F, Gollu Bahadır G, Akyuzluer S, Ciftci E, Altun D, Keles S, Kologlu M, Ikinciogullari A

Abstract
Loss-of-function (LOF) mutations in signal transducer and activator of transcription 3 (STAT3) gene causes autosomal dominant hyper immunoglobulin E syndrome (AD-HIES or Job’s Syndrome), a rare and complex primary immunodeficiency (PID) syndrome characterized by increased levels of IgE (>2000 IU/mL), eosinophilia, recurrent staphylococcal skin abscesses, eczema, recurrent pneumonia, skeletal and connective tissue abnormalities. Although bacterial and fungal infections are common in AD-HIES, susceptibility to parasitic infections has not been reported. Alveolar echinococcosis (AE), a zoonosis caused by the growth of the Echinococcus multilocularis (EM) metacestode, mimics slow-growing liver cancer. The mortality rate of AE is very high when it is diagnosed late or under-treated. Here, we report a 14-year-old boy with AE infections of the liver and the lung resulting in liver failure and diagnosed as STAT3-LOF. To our knowledge, the association between these two conditions has not been reported in the literature before.

PMID: 33463136 [PubMed – in process]

Powered by WPeMatico

Related Articles

The Critical Role of Prenatal Genetic Study in Prevention of Primary Immunodeficiency in High-risk Families: The Largest Report of 107 Cases.

Iran J Allergy Asthma Immunol. 2020 Oct 18;19(5):478-483

Authors: Modarresi SZ, Sabetkish N, Badalzadeh M, Tajik S, Esmaeili B, Fazlollahi MR, Houshmand M, Gharehdaghi J, Niroomanesh S, Rahimi Sherbaf F, Alizadeh Z, Khodayari Namini N, Maddah M, Pourpak Z, Moin M

Abstract
This study aims to investigate the role of prenatal diagnosis (PND) in Iranian couples with a previous history of primary immunodeficiency disorders (PIDD) in their family. All referred couples with a family history of PIDD and a tendency for PND were included in this project. Based on gestational age, chorionic villus sampling (CVS) was performed to analyze the molecular defect of the fetus according to the previous gene defect of the affected case in the family. Postnatal confirmation was performed by immunological screening tests. In a total of 100 cases, CVS was not evaluated in 19 patients due to unwillingness (n=5), late prenatal referral (n=7), miscarriage before CVS (n=3), and female fetus with x-linked diseases in previous children (n=4). In the remaining 81 patients, heterozygous and homozygous mutations were found in 33 and 23 cases, respectively. The hemizygous mutation was obtained in 6 and no pathogenic mutations were found in 19 individuals. Postnatal evaluations revealed that a total of 65 babies were healthy, 32 fetuses were aborted (3 cases before CVS, 2 spontaneous abortions of a healthy and as affected fetus in the CVS subgroup, and 27 cases were aborted due to therapeutic causes). One fetus from the heterozygous subgroup was spontaneously aborted with severe combined immunodeficiency (SCID) and one fetus from the homozygous subgroup that was supposed to be healthy was affected by the autosomal dominant-chronic granulomatous disease (AR-CGD). The diagnostic error was 1.2%. PND is highly recommended in families with a history of PID in their previous child to prevent an affected baby being born and to reduce the government, family, and personal burden of these diseases.

PMID: 33463115 [PubMed – in process]

Powered by WPeMatico

Related Articles

Increased Expression of B Lymphocyte Induced Maturation Protein 1 (BLIMP1) in Patients with Common Variable Immunodeficiency (CVID).

Iran J Allergy Asthma Immunol. 2020 Aug 25;19(4):437-446

Authors: Farrokhi S, Abbasi-Rad F, Esmaeil N, Sherkat R, Yazdani R, Afshar-Ghasemlou S, Fekrvand S, Ganjalikhani-Hakemi M

Abstract
Common variable immunodeficiency (CVID) is a primary immune deficiency disorder characterized by a failure in B cell differentiation, impaired immunoglobulin production,and defect in response to vaccines. As a result of defective B cell maturation and differentiation in CVID, the affected patients commonly present with reduced numbers of memory B cell and antibody-secreting plasma cells. B-cell lymphoma 6 protein (BCL6) and B lymphocyte induced maturation protein 1 (BLIMP1) molecules are two important transcription factors that have key roles in the maturation of B cells to plasma cells. Hence, in the current survey, we aimed to evaluate the mRNA and protein expression levels of BCL6 and BLIMP1 in B lymphocytes isolated from peripheral blood in CVID patients. We collected blood samples from 12 CVID patients and 12 healthy controls. We isolated peripheral blood mononuclear cells (PBMCs) using Ficoll density gradient separation. Then, CD19+ B cells were purified using MACS. The protein expression and transcriptional level of BCL6 and BLIMP1 were respectively measured using flow cytometry and real-time PCR. Our results showed that the BLIMP1 mRNA expression, as well as BLIMP1 protein expression, were significantly higher in CVID patients compared to control subjects (p=0.009 and p=0.007, respectively). However, we found no significant difference in mRNA and protein expression of BCL6 between patients and healthy controls. According to our findings, increased mRNA and protein expression levels of BLIMP1 could be involved in defective maturation of B cells in patients with CVID and elucidate mechanistic insights into the pathogenesis of this disorder.

PMID: 33463110 [PubMed – in process]

Powered by WPeMatico