Publications by authors named "Hassan Abolhassani"

182 Publications

Genetic Risk Variants for Class Switching Recombination Defects in Ataxia-Telangiectasia Patients.

J Clin Immunol 2021 Oct 10. Epub 2021 Oct 10.

Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran, Iran.

Background: Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder caused by mutations in the ataxia telangiectasia mutated (ATM) gene. A-T patients manifest considerable variability in clinical and immunological features, suggesting the presence of genetic modifying factors. A striking heterogeneity has been observed in class switching recombination (CSR) in A-T patients which cannot be explained by the severity of ATM mutations.

Methods: To investigate the cause of variable CSR in A-T patients, we applied whole-exome sequencing (WES) in 20 A-T patients consisting of 10 cases with CSR defect (CSR-D) and 10 controls with normal CSR (CSR-N). Comparative analyses on modifier variants found in the exomes of these two groups of patients were performed.

Results: For the first time, we identified some variants in the exomes of the CSR-D group that were significantly associated with antigen processing and presentation pathway. Moreover, in this group of patients, the variants in four genes involved in DNA double-strand breaks (DSB) repair signaling, in particular, XRCC3 were observed, suggesting an association with CSR defect.

Conclusion: Additional impact of certain variants, along with ATM mutations, may explain the heterogeneity in CSR defect phenotype among A-T patients. It can be concluded that genetic modulators play an important role in the course of A-T disease and its clinical severity.
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http://dx.doi.org/10.1007/s10875-021-01147-8DOI Listing
October 2021

Hallmarks of Cancers: Primary Antibody Deficiency Other Inborn Errors of Immunity.

Front Immunol 2021 17;12:720025. Epub 2021 Aug 17.

Division of Clinical Immunology, Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.

Inborn Errors of Immunity (IEI) comprise more than 450 inherited diseases, from which selected patients manifest a frequent and early incidence of malignancies, mainly lymphoma and leukemia. Primary antibody deficiency (PAD) is the most common form of IEI with the highest proportion of malignant cases. In this review, we aimed to compare the oncologic hallmarks and the molecular defects underlying PAD with other IEI entities to dissect the impact of avoiding immune destruction, genome instability, and mutation, enabling replicative immortality, tumor-promoting inflammation, resisting cell death, sustaining proliferative signaling, evading growth suppressors, deregulating cellular energetics, inducing angiogenesis, and activating invasion and metastasis in these groups of patients. Moreover, some of the most promising approaches that could be clinically tested in both PAD and IEI patients were discussed.
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http://dx.doi.org/10.3389/fimmu.2021.720025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416062PMC
August 2021

Adverse reactions in a large cohort of patients with inborn errors of immunity receiving intravenous immunoglobulin.

Clin Immunol 2021 09 19;230:108826. Epub 2021 Aug 19.

Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran.

Background: Intravenous immunoglobulins (IVIg) are the major treatment in inborn errors of immunity (IEI) disorders; However, IVIg infusions show some adverse effects. We aimed to assess the adverse reactions of IVIg infusions.

Methods: Data of IVIg infusions in IEI patients were collected from 2011 to 2021. Totally, 363 IEI patients received IVIg regularly in Iran entered the study. The adverse reactions are classified regarding their severity and chronicity.

Results: 22,667 IVIg infusions were performed in the study. 157 patients (43.2%) and 1349 (5.9%) infusions were associated with at least one type of adverse reaction. The highest rates of adverse reactions were seen in severe combined immunodeficiency. Myalgia, chills, headache, fever, and hypotension were the most frequent adverse effects of IVIg.

Conclusion: The reactions affect almost half of the patients mainly in the first infusions which necessitate the close observation of IEI patients receiving IVIg.
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http://dx.doi.org/10.1016/j.clim.2021.108826DOI Listing
September 2021

X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19.

Sci Immunol 2021 08;6(62)

Specialized Immunology Laboratory of Dr. Shahrooei, Sina Medical Complex, Ahvaz, Iran.

Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked variants in 16 unrelated male individuals aged 7 to 71 years (mean: 36.7 years) from a cohort of 1,202 male patients aged 0.5 to 99 years (mean: 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean: 38.7 years) tested carry such variants ( = 3.5 × 10). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (=2, 5 and 38 years), or moderate (=1, 5 years), severe (=1, 27 years), or critical (=1, 29 years) pneumonia. Two boys (aged 7 and 12 years) from a cohort of 262 male patients with severe COVID-19 pneumonia (mean: 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious variants in the male general population is < 6.5x10 We also show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type The patients' blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract.
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http://dx.doi.org/10.1126/sciimmunol.abl4348DOI Listing
August 2021

Impaired respiratory burst contributes to infections in PKCδ-deficient patients.

J Exp Med 2021 Sep 15;218(9). Epub 2021 Jul 15.

Department of Pediatrics, Division of Allergy and Clinical Immunology, Tehran University of Medical Sciences, Tehran, Iran.

Patients with autosomal recessive protein kinase C δ (PKCδ) deficiency suffer from childhood-onset autoimmunity, including systemic lupus erythematosus. They also suffer from recurrent infections that overlap with those seen in patients with chronic granulomatous disease (CGD), a disease caused by defects of the phagocyte NADPH oxidase and a lack of reactive oxygen species (ROS) production. We studied an international cohort of 17 PKCδ-deficient patients and found that their EBV-B cells and monocyte-derived phagocytes produced only small amounts of ROS and did not phosphorylate p40phox normally after PMA or opsonized Staphylococcus aureus stimulation. Moreover, the patients' circulating phagocytes displayed abnormally low levels of ROS production and markedly reduced neutrophil extracellular trap formation, altogether suggesting a role for PKCδ in activation of the NADPH oxidase complex. Our findings thus show that patients with PKCδ deficiency have impaired NADPH oxidase activity in various myeloid subsets, which may contribute to their CGD-like infectious phenotype.
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http://dx.doi.org/10.1084/jem.20210501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288504PMC
September 2021

Lymphocytes subsets in correlation with clinical profile in CVID patients without monogenic defects.

Expert Rev Clin Immunol 2021 Sep 27;17(9):1041-1051. Epub 2021 Jul 27.

Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.

Common variable immunodeficiency (CVID) patients experience clinical manifestations rather than recurrent respiratory infections including autoimmunity, enteropathy, and lymphoproliferation. We evaluated the correlation of lymphocyte subpopulations with such manifestations. Twenty-six genetically unsolved CVID patients were subdivided into four phenotypes: infection only (IO), autoimmunity (AI), chronic enteropathy (CE), and lymphoproliferative disorders (LP) and examined for lymphocyte subsets by flow cytometry and TCD4 proliferation by Carboxyfluorescein succinimidyl ester (CFSE) test. We detected reduced memory B and increased total, effector memory (EM), cytotoxic, and activated TCD8 in IO, AI and CE, decreased plasmablasts, total and naive TCD4, Regulatory TCD4 (Treg) and naive TCD8 in IO and CE, elevated CD21 B and terminally differentiated effector memory (T) TCD8 in IO and AI, increased helper T (Th2) and Th17 in IO, decreased Th1 in AI and defective total and naive B and central memory (CM) TCD4 in CE. IO showed reduced TCD4 proliferation response. In genetically unsolved CVID patients, increased Th2 and Th17 and reduced Treg is associated with IO, increased CD21 B and T TCD8 and reduced Th1 is contributed to AI and reduced total and naive B, CM TCD4 and naive TCD8 and expanded total TCD8 is correlated with CE.
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http://dx.doi.org/10.1080/1744666X.2021.1954908DOI Listing
September 2021

Approach to genetic diagnosis of inborn errors of immunity through next-generation sequencing.

Mol Immunol 2021 09 30;137:57-66. Epub 2021 Jun 30.

Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran, Iran; Division of Clinical Immunology, Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden; Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden. Electronic address:

Patients with inborn errors of immunity (IEI) present with a heterogeneous clinical and immunological phenotype, therefore a correct molecular diagnosis is crucial for the classification and subsequent therapeutic management. On the other hand, IEI are a group of rare congenital diseases with highly diverse features and, in most cases, an as yet unknown genetic etiology. Next generation sequencing has facilitated genetic examinations of rare inherited disorders during the recent years, thus allowing a suitable molecular diagnosis in the IEI patients. This review aimed to investigate the current findings about these techniques in the field of IEI, suggesting an efficient stepwise approach to molecular diagnosis of inborn errors of immunity.
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http://dx.doi.org/10.1016/j.molimm.2021.06.018DOI Listing
September 2021

Known and potential molecules associated with altered B cell development leading to predominantly antibody deficiencies.

Pediatr Allergy Immunol 2021 Jun 28. Epub 2021 Jun 28.

Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.

Predominantly antibody deficiencies (PADs) encompass a heterogeneous group of disorders characterized by low immunoglobulin serum levels in the presence or absence of peripheral B cells. Clinical presentation of affected patients may include recurrent respiratory and gastrointestinal infections, invasive infections, autoimmune manifestations, allergic reactions, lymphoproliferation, and increased susceptibility to malignant transformation. In the last decades, several genetic alterations affecting B-cell development/maturation have been identified as causative of several forms of PADs, adding important information on the genetic background of PADs, which in turn should lead to a better understanding of these disorders and precise clinical management of affected patients. This review aimed to present a comprehensive overview of the known and potentially involved molecules in the etiology of PADs to elucidate the pathogenesis of these disorders and eventually offer a better prognosis for affected patients.
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http://dx.doi.org/10.1111/pai.13589DOI Listing
June 2021

Consensus Middle East and North Africa Registry on Inborn Errors of Immunity.

J Clin Immunol 2021 Aug 29;41(6):1339-1351. Epub 2021 May 29.

Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.

Background: Inborn errors of immunity (IEIs) are a heterogeneous group of genetic defects of immunity, which cause high rates of morbidity and mortality mainly among children due to infectious and non-infectious complications. The IEI burden has been critically underestimated in countries from middle- and low-income regions and the majority of patients with IEI in these regions lack a molecular diagnosis.

Methods: We analyzed the clinical, immunologic, and genetic data of IEI patients from 22 countries in the Middle East and North Africa (MENA) region. The data was collected from national registries and diverse databases such as the Asian Pacific Society for Immunodeficiencies (APSID) registry, African Society for Immunodeficiencies (ASID) registry, Jeffrey Modell Foundation (JMF) registry, J Project centers, and International Consortium on Immune Deficiency (ICID) centers.

Results: We identified 17,120 patients with IEI, among which females represented 39.4%. Parental consanguinity was present in 60.5% of cases and 27.3% of the patients were from families with a confirmed previous family history of IEI. The median age of patients at the onset of disease was 36 months and the median delay in diagnosis was 41 months. The rate of registered IEI patients ranges between 0.02 and 7.58 per 100,000 population, and the lowest rates were in countries with the highest rates of disability-adjusted life years (DALY) and death rates for children. Predominantly antibody deficiencies were the most frequent IEI entities diagnosed in 41.2% of the cohort. Among 5871 patients genetically evaluated, the diagnostic yield was 83% with the majority (65.2%) having autosomal recessive defects. The mortality rate was the highest in patients with non-syndromic combined immunodeficiency (51.7%, median age: 3.5 years) and particularly in patients with mutations in specific genes associated with this phenotype (RFXANK, RAG1, and IL2RG).

Conclusions: This comprehensive registry highlights the importance of a detailed investigation of IEI patients in the MENA region. The high yield of genetic diagnosis of IEI in this region has important implications for prevention, prognosis, treatment, and resource allocation.
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http://dx.doi.org/10.1007/s10875-021-01053-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310844PMC
August 2021

International retrospective study of allogeneic hematopoietic cell transplantation for activated PI3K-delta syndrome.

J Allergy Clin Immunol 2021 May 24. Epub 2021 May 24.

Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.

Background: Activated phosphoinositide 3-kinase delta syndrome (APDS) is a combined immunodeficiency with a heterogeneous phenotype considered reversible by allogeneic hematopoietic cell transplantation (HCT).

Objectives: This study sought to characterize HCT outcomes in APDS.

Methods: Retrospective data were collected on 57 patients with APDS1/2 (median age, 13 years; range, 2-66 years) who underwent HCT.

Results: Pre-HCT comorbidities such as lung, gastrointestinal, and liver pathology were common, with hematologic malignancy in 26%. With median follow-up of 2.3 years, 2-year overall and graft failure-free survival probabilities were 86% and 68%, respectively, and did not differ significantly by APDS1 versus APDS2, donor type, or conditioning intensity. The 2-year cumulative incidence of graft failure following first HCT was 17% overall but 42% if mammalian target of rapamycin inhibitor(s) (mTORi) were used in the first year post-HCT, compared with 9% without mTORi. Similarly, 2-year cumulative incidence of unplanned donor cell infusion was overall 28%, but 65% in the context of mTORi receipt and 23% without. Phenotype reversal occurred in 96% of evaluable patients, of whom 17% had mixed chimerism. Vulnerability to renal complications continued post-HCT, adding new insights into potential nonimmunologic roles of phosphoinositide 3-kinase not correctable through HCT.

Conclusions: Graft failure, graft instability, and poor graft function requiring unplanned donor cell infusion were major barriers to successful HCT. Post-HCT mTORi use may confer an advantage to residual host cells, promoting graft instability. Longer-term post-HCT follow-up of more patients is needed to elucidate the kinetics of immune reconstitution and donor chimerism, establish approaches that reduce graft instability, and assess the completeness of phenotype reversal over time.
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http://dx.doi.org/10.1016/j.jaci.2021.04.036DOI Listing
May 2021

Specific Immune Response and Cytokine Production in CD70 Deficiency.

Front Pediatr 2021 30;9:615724. Epub 2021 Apr 30.

Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.

Collective clinical and immunologic findings of defects in the CD27-CD70 axis indicate a primary immunodeficiency associated with terminal B-cell development defect and immune dysregulation leading to autoimmunity, uncontrolled viral infection, and lymphoma. Since the molecular mechanism underlying this entity of primary immunodeficiency has been recently described, more insight regarding the function and profile of immunity is required. Therefore, this study aimed to investigate stimulated antibody production, polyclonal vs. virus-specific T-cell response, and cytokine production of a CD70-deficient patient reported previously with early-onset antibody deficiency suffering from chronic viral infections and B-cell lymphoma. The patient and her family members were subjected to clinical evaluation, immunological assays, and functional analyses. The findings of this study indicate an impaired ability of B cells to produce immunoglobulins, and a poor effector function of T cells was also associated with the severity of clinical phenotype. Reduced proportions of cells expressing the memory marker CD45RO, as well as T-bet and Eomes, were observed in CD70-deficient T cells. The proportion of 2B4 and PD-1 virus-specific CD8 T cells was also reduced in the patient. Although the -mutated individuals presented with early-onset clinical manifestations that were well-controlled by using conventional immunological and anticancer chemotherapies, with better prognosis as compared with CD27-deficient patients, targeted treatment toward specific disturbed immune profile may improve the management and even prevent secondary complications.
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http://dx.doi.org/10.3389/fped.2021.615724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120026PMC
April 2021

Coronavirus: Pure Infectious Disease or Genetic Predisposition.

Adv Exp Med Biol 2021 ;1318:91-107

Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes novel coronavirus disease (COVID-19), is the seventh pathogenic coronavirus recently discovered in December 2019 in Wuhan, China. To date, our knowledge about its effect on the human host remains limited. It is well known that host genetic factors account for the individual differences in the susceptibility to infectious diseases. The genetic susceptibility factors to COVID-19 and its severity are associated with several unanswered questions. However, the experience gained from an earlier strain of coronavirus, SARS-CoV-1, which shows 78% genetic similarity to SARS-CoV-2 and uses the same receptor to bind to host cells, could provide some clues. It, therefore, seems possible to assemble new evidence in order to solve a potential genetic predisposition puzzle for COVID-19. In this chapter, the puzzle pieces, including virus entry receptors, immune response, and inflammation-related genes, as well as the probable genetic predisposition models to COVID-19, are discussed.
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http://dx.doi.org/10.1007/978-3-030-63761-3_6DOI Listing
May 2021

Clinical, immunological, and genetic features in 780 patients with autoimmune lymphoproliferative syndrome (ALPS) and ALPS-like diseases: A systematic review.

Pediatr Allergy Immunol 2021 Oct 27;32(7):1519-1532. Epub 2021 May 27.

Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran.

Background: Autoimmune lymphoproliferative syndrome (ALPS) is a group of genetic disorders characterized by early-onset lymphoproliferation, autoimmune cytopenias, and susceptibility to lymphoma. The majority of ALPS patients carry heterozygous germline mutations in the TNFRSF6 gene. In this study, we conducted a systematic review of patients with ALPS and ALPS-like syndrome.

Methods: The literature search was performed in Web of Science, Scopus, and PubMed databases to find eligible studies. Additionally, the reference list of all included papers was hand-searched for additional studies. Demographic, clinical, immunological, and molecular data were extracted and compared between the ALPS and ALPS-like syndrome.

Results: Totally, 720 patients with ALPS (532 genetically determined and 189 genetically undetermined ALPS) and 59 cases with ALPS-like phenotype due to mutations in genes other than ALPS genes were assessed. In both ALPS and ALPS-like patients, splenomegaly was the most common clinical presentation followed by autoimmune cytopenias and lymphadenopathy. Among other clinical manifestations, respiratory tract infections were significantly higher in ALPS-like patients than ALPS. The immunological analysis showed a lower serum level of IgA, IgG, and lymphocyte count in ALPS-like patients compared to ALPS. Most (85%) of the ALPS and ALPS-like cases with determined genetic defects carry mutations in the FAS gene. About one-third of patients received immunosuppressive therapy with conventional or targeted immunotherapy agents. A small fraction of patients (3.3%) received hematopoietic stem cell transplantation with successful engraftment, and all except two patients survived after transplantation.

Conclusion: Our results showed that the FAS gene with 85% frequency is the main etiological cause of genetically diagnosed patients with ALPS phenotype; therefore, the genetic defect of the majority of suspected ALPS patients could be confirmed by mutation analysis of FAS gene.
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http://dx.doi.org/10.1111/pai.13535DOI Listing
October 2021

Clinical, immunological, and genetic features in 938 patients with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED): a systematic review.

Expert Rev Clin Immunol 2021 Aug 3;17(8):807-817. Epub 2021 Jun 3.

Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.

: Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a rare inborn immune error characterized by a triad of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism (HP), and adrenal insufficiency (ADI).: Literature search was conducted in PubMed, Web of Science, and Scopus databases using related keywords, and included studies were systematically evaluated.: We reviewed 938 APECED patients and the classic triad of APECED was detected in 57.3% (460 of 803) of patients. CMC (82.5%) was reported as the earliest, HP (84.2%) as the most prevalent, and ADI (72.2%) as the latest presentation within the classic triad. A broad spectrum of non-triad involvements has also been reported; mainly included ectodermal dystrophy (64.5%), infections (58.7%), gastrointestinal disorders (52.0%), gonadal failure (42.0%), neurologic involvements (36.4%), and ocular manifestations (34.3%). A significant positive correlation was detected between certain tissue-specific autoantibodies and particular manifestations including ADI and HP. Neutralizing autoantibodies were detected in at least 60.0% of patients. Nonsense and/or frameshift insertion-deletion mutations were detected in 73.8% of patients with CMC, 70.9% of patients with HP, and 74.6% of patients with primary ADI.: Besides penetrance diversity, our review revealed a diverse affected ethnicity (mainly from Italy followed by Finland and Ireland). APECED can initially present in adolescence as 5.2% of the patients were older than 18 years at the disease onset. According to the variety of clinical conditions, which in the majority of patients appear gradually over time, clinical management deserves a separate analysis.
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http://dx.doi.org/10.1080/1744666X.2021.1925543DOI Listing
August 2021

Activation-induced deaminase is critical for the establishment of DNA methylation patterns prior to the germinal center reaction.

Nucleic Acids Res 2021 05;49(9):5057-5073

Epigenetics and Immune Disease Group, Josep Carreras Research Institute (IJC), 08916 Badalona, Barcelona, Spain.

Activation-induced deaminase (AID) initiates antibody diversification in germinal center B cells by deaminating cytosines, leading to somatic hypermutation and class-switch recombination. Loss-of-function mutations in AID lead to hyper-IgM syndrome type 2 (HIGM2), a rare human primary antibody deficiency. AID-mediated deamination has been proposed as leading to active demethylation of 5-methycytosines in the DNA, although evidence both supports and casts doubt on such a role. In this study, using whole-genome bisulfite sequencing of HIGM2 B cells, we investigated direct AID involvement in active DNA demethylation. HIGM2 naïve and memory B cells both display widespread DNA methylation alterations, of which ∼25% are attributable to active DNA demethylation. For genes that undergo active demethylation that is impaired in HIGM2 individuals, our analysis indicates that AID is not directly involved. We demonstrate that the widespread alterations in the DNA methylation and expression profiles of HIGM2 naïve B cells result from premature overstimulation of the B-cell receptor prior to the germinal center reaction. Our data support a role for AID in B cell central tolerance in preventing the expansion of autoreactive cell clones, affecting the correct establishment of DNA methylation patterns.
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http://dx.doi.org/10.1093/nar/gkab322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136777PMC
May 2021

Autoimmune manifestations among 461 patients with monogenic inborn errors of immunity.

Pediatr Allergy Immunol 2021 08 13;32(6):1335-1348. Epub 2021 May 13.

Department of Pediatrics, Hamedan University of Medical Sciences, Hamedan, Iran.

Background: The inborn errors of immunity (IEIs) are a group of heterogeneous disorders mainly characterized by severe and recurrent infections besides other complications including autoimmune and inflammatory diseases. In this study, we aim to evaluate clinical, immunologic, and molecular data of monogenic IEI patients with and without autoimmune manifestations.

Methods: We have retrospectively screened cases of monogenic IEI in the Iranian PID registry for the occurrence of autoimmunity and immune dysregulation. A questionnaire was filled for all qualified patients with monogenic defects to evaluate demographic, laboratory, clinical, and molecular data.

Results: A total of 461 monogenic IEI patients (290 male and 171 female) with a median (IQR) age of 11.0 (6.0-20.0) years were enrolled in this study. Overall, 331 patients (72.1%) were born to consanguineous parents. At the time of the study, 330 individuals (75.7%) were alive and 106 (24.3%) were deceased. Autoimmunity was reported in 92 (20.0%) patients with a median (IQR) age at autoimmune diagnosis of 4.0 (2.0-7.0) years. Sixteen patients (3.5%) showed autoimmune complications (mostly autoimmune cytopenia) as the first presentation of the disease. Most of the patients with autoimmunity were diagnosed clinically with common variable immunodeficiency (42.4%). The frequency of sinusitis and splenomegaly was significantly higher in patients with autoimmunity than patients without autoimmunity. In patients with autoimmunity, the most common pathogenic variants were identified in LRBA (in 21 patients, 23.0%), ATM (in 13 patients, 14.0%), and BTK (in 9 patients, 10.0%) genes. In the evaluation of autoimmunity by different genes, 4 of 4 IL10RB (100%), 3 of 3 AIRE (100%), and 21 of 30 LRBA (70.0%) mutated genes had the highest prevalence of autoimmunity.

Conclusions: Autoimmune phenomena are common features among patients with monogenic IEI and are associated with a more complicated course of the disease. Therefore, when encountering autoimmune disorders, especially in the setting of dysgammaglobulinemia, it would be appropriate to conduct next-generation sequencing to discover responsible genes for the immune dysregulation at an early stage of the disease.
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http://dx.doi.org/10.1111/pai.13510DOI Listing
August 2021

Evidence-Based Immunotherapeutic Effects of Herbal Compounds on Humoral Immunity: Ancient and New Approaches.

Chin J Integr Med 2021 Apr 24;27(4):313-320. Epub 2021 Mar 24.

Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, 14194, Iran.

The human immune system represents a dynamic multiscale system with high complexity in biology. Humoral immunity, as the main branch of adaptive immunity, is characterized by differentiated stages of the B lymphocytes, producing the final product of antibodies that has a diversity of the tuning mechanisms within genetic and epigenetic levels in confrontation with environmental exposures. Disorders because of disturbed humoral immunity are linked with dysregulation of feedback-regulated signaling and the dynamic of immune components that determine the overall response. Food products, mainly herbal components have a significant role in tailoring the immune system micro-ecosystem which can diversify the adaptive nature of humoral immunity. Herein, we review the current evidence-based approaches for the impact of medicinal herbs on humoral immunity signaling and antibody production with a focus on immunotherapeutic applications.
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http://dx.doi.org/10.1007/s11655-021-3332-7DOI Listing
April 2021

Primary Immunodeficiency Diseases in Iran: Past, Present and Future.

Arch Iran Med 2021 02 1;24(2):118-124. Epub 2021 Feb 1.

Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.

Clinical immunology and its subset topics are rather newly emerging medical fields in Iran as well as other developing countries. Primary immunodeficiency diagnosis and treatment were revolutionized in the late 1970s; a period of time that coincided with the establishment of the Division of Clinical Immunology and Allergy at the Children's Medical Center, Tehran. Subsequently, the launch of fellowship training programs (in 1988), the development of a national Iranian Primary Immunodeficiency Diseases Registry (in 1999), the inauguration of Research Center for Immunodeficiencies (in 2009), and recently, the national primary immunodeficiency network (in 2016) significantly changed the picture of disease management during the last 40 years. In this review, we seek to elucidate the most important past events, current challenges and future directions regarding the field of primary immunodeficiency.
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http://dx.doi.org/10.34172/aim.2021.18DOI Listing
February 2021

Persistence of SARS-CoV-2-specific B and T cell responses in convalescent COVID-19 patients 6-8 months after the infection.

Med (N Y) 2021 Mar 10;2(3):281-295.e4. Epub 2021 Feb 10.

Division of Clinical Immunology and Transfusion Medicine, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden.

Background: Monitoring the adaptive immune responses during the natural course of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection provides useful information for the development of vaccination strategies against this virus and its emerging variants. We thus profiled the serum anti-SARS-CoV-2 antibody (Ab) levels and specific memory B and T cell responses in convalescent coronavirus disease 2019 (COVID-19) patients.

Methods: A total of 119 samples from 88 convalescent donors who experienced mild to critical disease were tested for the presence of elevated anti-spike and anti-receptor binding domain Ab levels over a period of 8 months. In addition, the levels of SARS-CoV-2 neutralizing Abs and specific memory B and T cell responses were tested in a subset of samples.

Findings: Anti-SARS-CoV-2 Abs were present in 85% of the samples collected within 4 weeks after the onset of symptoms in COVID-19 patients. Levels of specific immunoglobulin M (IgM)/IgA Abs declined after 1 month, while levels of specific IgG Abs and plasma neutralizing activities remained relatively stable up to 6 months after diagnosis. Anti-SARS-CoV-2 IgG Abs were still present, although at a significantly lower level, in 80% of the samples collected at 6-8 months after symptom onset. SARS-CoV-2-specific memory B and T cell responses developed with time and were persistent in all of the patients followed up for 6-8 months.

Conclusions: Our data suggest that protective adaptive immunity following natural infection of SARS-CoV-2 may persist for at least 6-8 months, regardless of disease severity. Development of medium- or long-term protective immunity through vaccination may thus be possible.

Funding: This project was supported by the European Union's Horizon 2020 research and innovation programme (ATAC, no. 101003650), the Italian Ministry of Health (Ricerca Finalizzata grant no. GR-2013-02358399), the Center for Innovative Medicine, and the Swedish Research Council. J.A. was supported by the SciLifeLab/KAW national COVID-19 research program project grant 2020.
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http://dx.doi.org/10.1016/j.medj.2021.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874960PMC
March 2021

The spectrum of ATM gene mutations in Iranian patients with ataxia-telangiectasia.

Pediatr Allergy Immunol 2021 08 2;32(6):1316-1326. Epub 2021 Mar 2.

Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran, Iran.

Background: Ataxia-telangiectasia (A-T) is a rare genetic disorder characterized by a distinct range of clinical manifestations, including progressive ataxia, immunodeficiency, and radiosensitivity.

Methods: Clinical data, laboratory results, and genetic data were collected from forty-three A-T patients. Whole-exome sequencing and Sanger sequencing were done for the patients clinically diagnosed as suffering from A-T. Based on the phenotype severity of the disease, patients were divided into severe and mild subgroups.

Results: The median (IQR) age of diagnosis in this cohort was 5 (3-7) years, and various types of clinical manifestations, including fever (P =.005), lower respiratory tract infection (P = .033), diarrhea (P = .014), and hepatosplenomegaly (P = .032), were significantly higher among patients diagnosed with the severe phenotype. Our results showed a correlation between phenotype severity and mutation type. The chance of having severe phenotype in patients who have severe mutations, including frameshift and nonsense, was 7.3 times higher than in patients who were categorized in the mild genotype group (odds ratio = 7.3, P = .006). Thirty-four types of mutations including 9 novel mutations were observed in our study.

Conclusion: Molecular analysis provides the opportunity for accurate diagnosis and timely management in A-T patients with chronic progressive disease, especially infections and the risk of malignancies. This study characterizes for the first time the broad spectrum of mutations and phenotypes in Iranian A-T patients, which is required for carrier detection and reducing the burden of disease in the future using the patients' families and for the public healthcare system.
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http://dx.doi.org/10.1111/pai.13461DOI Listing
August 2021

Primary Immunodeficiency and Thrombocytopenia.

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

Research Center for Immunodeficiencies, Tehran University of Medical Sciences, Tehran, Iran.

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.
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http://dx.doi.org/10.1080/08830185.2020.1868454DOI Listing
January 2021

The First Case Report of Kabuki Syndrome from the National Iranian Registry of Primary Immunodeficiencies.

Endocr Metab Immune Disord Drug Targets 2021 Jan 14. Epub 2021 Jan 14.

Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran. Iran.

Kabuki syndrome is a rare congenital anomaly/mental retardation syndrome characterized by intellectual disability, developmental delay, short stature, facial dysmorphic features including ectropion of the lateral third of the lower eyelids and long palpebral fissures, and prominent finger pads. Pathogenic variants of KMT2D (MLL2) and KDM6A are found to be the major causes of Kabuki syndrome. Here, we report the first Iranian case with Kabuki syndrome with an IQ of 79, two episodes of viral pneumonia and distinctive facial features, prominent ears and persistent fetal fingertip pads. These characteristics raised our suspicion for performing whole-exome sequencing (WES), which revealed 2 heterozygous pathogenic missense variants in the KMT2D gene: c.C10024T in exon 34 leading to p.R3342C and c.G15005A in exon 48 leading to p.R5002Q. Hence, the definitive diagnosis of Kabuki syndrome was made based on molecular findings along with the intellectual disability and characteristic facial features.
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http://dx.doi.org/10.2174/1871530321666210114153920DOI Listing
January 2021

The First Iranian Cohort of Pediatric Patients with Activated Phosphoinositide 3-Kinase-δ (PI3Kδ) Syndrome (APDS).

Immunol Invest 2021 Jan 6:1-16. Epub 2021 Jan 6.

Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran, Iran.

: Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently defined combined primary immunodeficiency disease (PID) characterized by recurrent respiratory tract infections, lymphoproliferation, autoimmunity and lymphoma. Gain-of-function mutations in and loss-of-function of genes lead to APDS1 and APDS2, respectively.: Demographic, clinical, immunological and genetic data were collected from medical records of 15 pediatric patients, who were genetically identified using the whole-exome sequencing method.: Fifteen patients (6 APDS1 and 9 APDS2) were enrolled in this study. Recurrent respiratory tract infections followed by lymphoproliferation and autoimmunity were the most common manifestations (86.7%, 53.3% and 26.7%, respectively). Five patients (33.3%) had a Hyper-IgM-syndrome-like immunoglobulin profile. In the APDS1 group, splice site and missense mutations were found in half of the patients and the C-lobe domain of was the most affected region (50%). In the APDS2 group, splice site mutation was the most frequent mutation (77.8%) and the inter-SH2 domain was the most affected region of (66.7%). Mortality rate was significantly higher in APDS2 group ( = .02) mainly due to chronic lung infections.: Respiratory tract infections and humoral immunodeficiency are commonly the most important complication in pediatric APDS patients, and they can be fatal by ultimately causing catastrophic damage to the structure of lungs. Hence, physicians should be aware of its significance and further work-up of patients with recurrent respiratory tract infections especially in patients with lymphoproliferation. Moreover, delineation of genotype-phenotype associations with disease severity could be helpful in the timely application of appropriate management and patients' survival.
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http://dx.doi.org/10.1080/08820139.2020.1863982DOI Listing
January 2021

Somatic reversion of pathogenic DOCK8 variants alters lymphocyte differentiation and function to effectively cure DOCK8 deficiency.

J Clin Invest 2021 02;131(3)

Garvan Institute of Medical Research, Sydney, New South Wales, Australia.

Inborn errors of immunity cause monogenic immune dysregulatory conditions such as severe and recurrent pathogen infection, inflammation, allergy, and malignancy. Somatic reversion refers to the spontaneous repair of a pathogenic germline genetic variant and has been reported to occur in a number of inborn errors of immunity, with a range of impacts on clinical outcomes of these conditions. DOCK8 deficiency due to biallelic inactivating mutations in DOCK8 causes a combined immunodeficiency characterized by severe bacterial, viral, and fungal infections, as well as allergic disease and some cancers. Here, we describe the clinical, genetic, and cellular features of 3 patients with biallelic DOCK8 variants who, following somatic reversion in multiple lymphocyte subsets, exhibited improved clinical features, including complete resolution of infection and allergic disease, and cure over time. Acquisition of DOCK8 expression restored defective lymphocyte signalling, survival and proliferation, as well as CD8+ T cell cytotoxicity, CD4+ T cell cytokine production, and memory B cell generation compared with typical DOCK8-deficient patients. Our temporal analysis of DOCK8-revertant and DOCK8-deficient cells within the same individual established mechanisms of clinical improvement in these patients following somatic reversion and revealed further nonredundant functions of DOCK8 in human lymphocyte biology. Last, our findings have significant implications for future therapeutic options for the treatment of DOCK8 deficiency.
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http://dx.doi.org/10.1172/JCI142434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843233PMC
February 2021

Impact of SARS-CoV-2 Pandemic on Patients with Primary Immunodeficiency.

J Clin Immunol 2021 02 1;41(2):345-355. Epub 2020 Dec 1.

Research Center for Primary Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.

Although it is estimated that COVID-19 life-threatening conditions may be diagnosed in less than 1:1000 infected individuals below the age of 50, but the real impact of this pandemic on pediatric patients with different types of primary immunodeficiency (PID) is not elucidated. The current prospective study on a national registry of PID patients showed that with only 1.23 folds higher incidence of infections, these patients present a 10-folds higher mortality rate compared to population mainly in patients with combined immunodeficiency and immune dysregulation. Therefore, further management modalities against COVID-19 should be considered to improve the survival rate in these two PID entities using hematopoietic stem cell transplantation and immunomodulatory agents.
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http://dx.doi.org/10.1007/s10875-020-00928-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707812PMC
February 2021

Autoimmunity in common variable immunodeficiency: a systematic review and meta-analysis.

Expert Rev Clin Immunol 2020 12 7;16(12):1227-1235. Epub 2020 Dec 7.

Non-communicable Diseases Research Center, Alborz University of Medical Sciences , Karaj, Iran.

: Common variable immunodeficiency (CVID) is the most common symptomatic inborn error of immunity characterized by variable clinical manifestations. : Web of Science, Scopus, and PubMed databases were searched systemically to find eligible studies from the earliest available date to February 2020 with standard keywords. Pooled estimates of the autoimmunity prevalence and the corresponding 95% confidence intervals (CI) were calculated using random-effects models. : The overall prevalence of autoimmunity was 29.8% (95% CI: 26.4-33.3; I2 = 82.8%). The prevalences of hematologic autoimmune diseases, autoimmune gastrointestinal disorders, autoimmune rheumatologic disorders, autoimmune skin disorders, and autoimmune endocrinopathy in CVID patients were 18.9%, 11.5%, 6.4%, 5.9%), and 2.5%, respectively. There were significantly higher lymphocyte, CD3 + T cell, and CD4 + T cell count among CVID patients without autoimmunity (< 0.05). Furthermore, failure to thrive, organomegaly, enteropathy, and meningitis was significantly higher in CVID patients with autoimmunity(< 0.05). : Many CVID patients could present with autoimmunity as part of the disease or even as the first or only clinical manifestation of the disease. Care providers may need to pay particular attention to the possible association of these two disorders since the co-occurrence of CVID and autoimmunity could be a misleading clue.
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http://dx.doi.org/10.1080/1744666X.2021.1850272DOI Listing
December 2020

Evaluation of Expression of LRBA and CTLA-4 Proteins in Common Variable Immunodeficiency Patients.

Immunol Invest 2020 Nov 15:1-14. Epub 2020 Nov 15.

Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.

Common variable immunodeficiency (CVID) is a primary immunodeficiency disease with a heterogeneous genetic background. Lipopolysaccharide-responsive beige-like anchor (LRBA), as well as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have important regulatory roles in the immune responses. Here, we have investigated the expression of LRBA and CTLA-4 proteins in CVID patients with at least one presentation of early-onset occurrence, autoimmunity, or enteropathy. In this study, 20 newly diagnosed CVID patients without infection only phenotype, and ten healthy individuals were enrolled. The expressions of LRBA and CTLA-4 proteins were assessed by western blotting and flow cytometry, respectively. The patients were divided into two groups of autoimmunity-positive (11 cases) and autoimmunity-negative (9 patients). LRBA and CTLA-4 expressions were significantly lower in autoimmune-positive patients than in healthy individuals ( = .03 and = .03, respectively). Autoimmune-negative patients had lower expression of LRBA and CTLA-4 than the control group, although it was not significant. There was a positive correlation between the expressions of LRBA and CTLA-4 in both groups of patients ( < .05). Furthermore, the highest frequency of LRBA (85.7%) and CTLA-4 (71.4%) defects was detected in those with concomitant presence of autoimmunity, enteropathy, and early-onset occurrence. Concurrent presence of autoimmunity, enteropathy, and early-onset occurrence in CVID patients could be indicative of a lack of expression in LRBA and CTLA-4 proteins. This could be helpful in early diagnosis and initiation of appropriate treatment in these patients prior to genetic confirmation.
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http://dx.doi.org/10.1080/08820139.2020.1833029DOI Listing
November 2020

Variable Abnormalities in T and B Cell Subsets in Ataxia Telangiectasia.

J Clin Immunol 2021 01 14;41(1):76-88. Epub 2020 Oct 14.

Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.

Background: Ataxia-telangiectasia (AT) is a rare genetic condition, caused by biallelic deleterious variants in the ATM gene, and has variable immunological abnormalities. This study aimed to examine immunologic parameters reflecting cell development, activation, proliferation, and class switch recombination (CSR) and determine their relationship to the clinical phenotype in AT patients.

Methods: In this study, 40 patients with a confirmed diagnosis of AT from the Iranian immunodeficiency registry center and 28 age-sex matched healthy controls were enrolled. We compared peripheral B and T cell subsets and T cell proliferation response to CD3/CD28 stimulation in AT patients with and without CSR defects using flow cytometry.

Results: A significant decrease in naïve, transitional, switched memory, and IgM only memory B cells, along with a sharp increase in the marginal zone-like and CD21 B cells was observed in the patients. We also found CD4 and CD8 naïve, central memory, and terminally differentiated effector memory CD4 (T) T cells were decreased. CD4 and CD8 effector memory, CD8 T, and CD4 regulatory T cells were significantly elevated in our patients. CD4 T cell proliferation was markedly impaired compared to the healthy controls. Moreover, immunological investigations of 15 AT patients with CSR defect revealed a significant reduction in the marginal zone, switched memory, and more intense defects in IgM only memory B cells, CD4 naïve and central memory T cells.

Conclusion: The present study revealed that patients with AT have a broad spectrum of cellular and humoral deficiencies. Therefore, a detailed evaluation of T and B cell subsets increases understanding of the disease in patients and the risk of infection.
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http://dx.doi.org/10.1007/s10875-020-00881-9DOI Listing
January 2021

Protein Kinase C-Delta Defect in Autoimmune Lymphoproliferative Syndrome-Like Disease: First Case from the National Iranian Registry and Review of the Literature.

Immunol Invest 2020 Oct 13:1-12. Epub 2020 Oct 13.

Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.

Background: Protein kinase C is a family of serine/threonine kinases that play a key role in the adaptive immune cell signaling, as well as regulation of growth, apoptosis, and differentiation of a variety of cell types. Patients homozygous for a null mutation of the Protein Kinase C Delta gene, present clinical feature of immune dysregulation with susceptibility to Epstein-Barr virus infection. However, a minority of patients present the autoimmune lymphoproliferative syndrome (ALPS).

Methods: The data were collected by direct interview and examining the patient's clinical record. Whole-exome sequencing was performed to detect the underlying genetic mutation in the patient. We also conducted electronic searches for ALPS-like reported patients in PubMed, Web of Science, and Scopus databases.

Results: In this study, we reported a 13-year-old boy who presented with autoimmunity, lymphoproliferation, recurrent pneumonia, cardiomyopathy, and dermatological manifestations. An elevation of double-negative T cells, CD8 T cells, serum IgG level, as well as a reduction in NK cells, was observed in the patient. A homozygous frameshift mutation (c.1293_1294insA) in exon 13 of the PRKCD gene was confirmed. The literature search showed 39 ALPS-like patients with monogenic defects which only six (15.3%) of them were due to PRKCD genes.

Conclusion: PRKCD should be considered in the context of ALPS clinical manifestations with prominent dermatological involvements.
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http://dx.doi.org/10.1080/08820139.2020.1829638DOI Listing
October 2020

Infectious Complications Reporting in Common Variable Immunodeficiency: A Systematic Review and Meta-analysis.

Oman Med J 2020 Jul 30;35(4):e157. Epub 2020 Jul 30.

Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran.

Objectives: Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by hypogammaglobulinemia and increased susceptibility to recurrent infections.

Methods: We searched PubMed, Web of Science, and Scopus databases to find eligible studies from the earliest available date to January 2018 with standard keywords. Pooled estimates of the infection prevalence and the corresponding 95% confidence intervals were calculated using random-effects models.

Results: We found that pneumonia (67.7%) was the most prevalent infection followed by upper respiratory tract (59.0%) and gastrointestinal infections (36.3%). Furthermore, bacterial complications (41.7%) were higher in CVID patients compared to viral (25.4%), parasitic (18.8%), or fungal (3.4%) infections. Patients with longer age at diagnosis presented with fewer disease comorbidities. There was an inverse correlation between T lymphocyte count and viral infections. Moreover, we found that immunoglobulin M (IgM) serum level was inversely correlated with hepatitis C and gastrointestinal infections, and IgG serum level was inversely correlated with infectious arthritis. Higher numbers of CD4 and CD8 T cells were associated with the lower frequencies of otitis media. CVID patients with infections had significantly lower percentages of CD3 T cells. In contrast, higher percentages of CD19 lymphocytes were found in CVID patients who had a history of infections.

Conclusions: Our findings demonstrated that in addition to hypogammaglobulinemia, patients with CVID have an imbalance in the frequency of T lymphocytes, which is in parallel with the higher frequency of infectious complications.
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http://dx.doi.org/10.5001/omj.2020.64DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417520PMC
July 2020
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