Clinical and Immunologic Characteristics of Non-Hematologic Cancers in Patients with Inborn Errors of Immunity.

Inborn errors of immunity (IEI) are a heterogeneous group of inherited disorders, and almost 500 genes associated with these disorders have been identified. Defects in IEI genes lead to diverse clinical manifestations including increased susceptibility to recurrent or prolonged infections, immune dysregulation phenotypes (such as severe atopy, allergy, autoimmunity, and uncontrolled inflammation, lymphoproliferation), as well as predisposition to malignancies. Although the majority of IEI patients present hematologic cancers, the characteristics of other types of cancers are not well described in these groups of patients. By investigating 5384 IEI patients registered in the Iranian national registry the clinical and immunologic phenotypes of patients with non-hematologic cancers were compared with other malignant and non-malignant patients. Solid tumors were reported <20% of malignant IEI patients (n = 27/144 patients) and appeared to be very heterogeneous by type and localization as well as molecular defects (mainly due to DNA repair defect resulted from ATM deficiency). The correlation between the type of malignancy and survival status was remarkable as patients with non-hematologic cancers survive higher than IEI patients with hematologic cancers. Our findings showed that different types of malignancy could be associated with specific entities of IEI. Therefore, the education of physicians about the risk of malignancies in IEI is required for personalized treatment and appropriate management of patients.

Diversity of malignancies in patients with different types of inborn errors of immunity.

Genetic defects in the development, maturation, and/or function of the immune cells can lead to Inborn errors of immunity (IEI) which may predispose patients to malignancies. The overall risk for cancer in children with IEI ranges from 4 to 25% and the type of malignancy is highly dependent on the specific mutant gene underlying IEI. We investigated 3056 IEI patients registered in the Iranian national registry between the years 1999 and 2020 in this retrospective cohort study. The frequency of malignancy and its association with the type of IEI in these patients were evaluated. A total of 82 IEI patients with malignancy were enrolled in this study. Among them, predominantly lymphoma was the most common type of malignancy (67.1%), followed by leukemia (11%), and cancers of the head and neck (7.3%). Among identified lymphoma cancers, non-Hodgkin's lymphomas were the most frequent type (43.9%) followed by different subtypes of Hodgkin's lymphoma (23.2%). Solid tumors (18.3%) appeared to be very heterogeneous by type and localization. The correlation between the type of malignancy and survival status and the association between the type of malignancy and IEI entities were unremarkable. The awareness of the association between the presence of IEI and cancer highlights the importance of a synergistic effort by oncologists and immunologists in the early diagnosis of malignancy and personalized therapeutic strategies in IEI patients.

Autoimmunity in monogenic combined immune deficiencies with associated or syndromic features.

Background: Combined immune deficiencies (CIDs) with associated or syndromic features are a highly heterogeneous subgroup of inherited immune disorders. These patients represent specific clinical complications with an increased risk of autoimmune conditions. Methods: We analyzed data of monogenic patients with syndromic CIDs adopted from the Iranian inborn errors of immunity registry up to January 2022. A comprehensive comparison in terms of demographic, clinical, and immunological features was performed between patients with and without autoimmunity and also among four mutation groups with the most registered cases including ATM, STAT3 (AD-LOF), DNMT3B/ZBTB24, and WAS mutations. Results: A total of 137 patients with monogenic syndromic CIDs were included. Most commonly mutated genes were the ATM [80 (58.4%)] and STAT3 (AD-LOF) [19 (13.9%)], followed by DNMT3B [11 (8%)], and WAS [11 (8%)]. More than 18% of all patients with syndromic CIDs, including most DNMT3B/ZBTB24 mutations patients, were clinically diagnosed with antibody deficiencies before genetic evaluation. Patients with ATM and WAS mutations had the latest age of onset and the lowest age of diagnosis, respectively. Autoimmune disorders were diagnosed in 24 patients at a median age of 3.5 (2.6-6.0) years, 70.6% of which were diagnosed prior to the diagnosis of immunodeficiency. Lymphoproliferation, particularly hepatosplenomegaly, was significantly higher in patients with autoimmunity (p=0.004). Syndromic CID patients with autoimmunity had significantly lower IgG levels. Hematologic autoimmunity mainly immune thrombocytopenic purpura was the most frequent autoimmunity among major groups of ATM, STAT3 (AD-LOF), DNMT3B/ZBTB24, and WAS mutations, however ATM-mutated patients present more diversified involved organs including rheumatologic, gastrointestinal and dermatologic autoimmunity. Conclusion: About 18% of patients with monogenic syndromic CIDs developed autoimmunity, mainly in the form of hematological immune diseases. Autoimmunity could be an early-onset involvement with a potential diagnostic impact on suspicious cases of syndromic CIDs.

miR-146b-5p and miR-520h Expressions Are Upregulated in Serum of Women with Recurrent Spontaneous Abortion.

Unexplained recurrent spontaneous abortion (URSA) is characterized by two or more consecutive pregnancy losses before the 20th week of gestation with unknown etiology. Dysregulation of microRNAs (miRNAs) expression has been reported in reproductive diseases. This study aimed to compare differentially expressed miRNAs in the serum samples between URSA patients and healthy individuals. URSA cases were confirmed by a gynecologist. Peripheral blood sample was gathered from 9 URSA patients, 15 normal pregnant, and 10 non-pregnant women without abortion history. After separating serum, the expression levels of the miR-101-3p, miR-517c-3p, miR-146b-5p, miR-221-3p, and miR-520 h were measured by qRT-PCR assay. The circulating level of miR-520 h in URSA patients was significantly up-regulated compared with healthy pregnant (P < 0.01) and healthy non-pregnant (P = 0.002) women. Furthermore, miR-520 h expression was significantly different between healthy non-pregnant and pregnant women (P = 0.002). Statistical analysis indicated miR-146b-5p expression was significantly up-regulated in URSA patients compared to normal pregnant women (P = 0.018). However, the transcription level of miR-146b-5p was insignificantly different between normal non-pregnant women and the other two groups. Also, circulating levels of miR-101-3p, miR-221-3p, and miR-517c-3p were not significantly different in the studied groups. Statistical analysis showed significant correlations between both miR-221-3p and miR-517c-3p and other miRNAs (P < 0.05). The circulating levels of miR-520 h and miR-146b-5p could be considered biomarkers for URSA diagnosis. Also, miR-517c-3p and miR-221-3p might play a regulatory role in other miRNAs expressions during pregnancy. Previous work, in contrary to our findings, claims that the expression levels of miR-221-3p, miR-101-3p, and miR-517c-3p increased in plasma and tissue samples of patients with URSA. However, our research for the first time indicates that the expression level of miR-520 h and miR-146b-5p in the serum of these patients has increased. Future investigations are necessary to confirm these findings.

Transient increased immunoglobulin levels in a hyper-IgM syndrome patient with COVID-19 infection.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has affected millions of people around the world. This zoonotic-enveloped virus is primarily transmitted through inhalation. Infected people are commonly asymptomatic or manifest mild symptoms, including fever, cough, diarrhea, and fatigue. However, it may lead to severe patterns associated with multiple organ failure in individuals with an impaired immune system. OBJECTIVE: Here we report a 7-year-old girl with hyper-immunoglobulin M (IgM) (HIgM) phenotype, admitted to the hospital emergency department with fever, cough, and pneumonia symptoms because of the COVID-19 infection. Coronavirus infection was confirmed by a positive real-time polymerase chain reaction test. Surprisingly, serum levels of both IgG and IgA of the patient were transiently normalized during the COVID-19 infection when tested prior to the monthly injection of intravenous immunoglobulin. After she recovered from the COVID infection, her immunoglobulin levels returned to the primary stage and she demonstrated HIgM phenotype. CONCLUSION: Since this transient increase in the levels of immunoglobulins was solely observed during the COVID-19 infection, and no other infectious episodes were diagnosed in the patient, clarifying the exact cause would help to understand in a better manner the implications and specification of humoral immunity in patients with primary antibody deficiencies.

Transient increased immunoglobulin levels in a hyper-IgM syndrome patient with COVID-19 infection

Background The coronavirus disease 2019 (COVID-19) pandemic has affected millions of people around the world. This zoonotic-enveloped virus is primarily transmitted through inhalation. Infected people are commonly asymptomatic or manifest mild symptoms, including fever, cough, diarrhea, and fatigue. However, it may lead to severe patterns associated with multiple organ failure in individuals with an impaired immune system. Objective Here we report a 7-year-old girl with hyper-immunoglobulin M (IgM) (HIgM) phenotype, admitted to the hospital emergency department with fever, cough, and pneumonia symptoms because of the COVID-19 infection. Coronavirus infection was confirmed by a positive real-time polymerase chain reaction test. Surprisingly, serum levels of both IgG and IgA of the patient were transiently normalized during the COVID-19 infection when tested prior to the monthly injection of intravenous immunoglobulin. After she recovered from the COVID infection, her immunoglobulin levels returned to the primary stage and she demonstrated HIgM phenotype. Conclusion Since this transient increase in the levels of immunoglobulins was solely observed during the COVID-19 infection, and no other infectious episodes were diagnosed in the patient, clarifying the exact cause would help to understand in a better manner the implications and specification of humoral immunity in patients with primary antibody deficiencies (AU)

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

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.

Exploring genetic variations in threatened medicinal orchids using start codon targeted (SCoT) polymorphism and marker-association with seed morphometric traits.

We aimed to study the genetic diversity and population structure of eight Iranian terrestrial orchid species, including Anacamptis coriophora (L.) R. M. Bateman, Pridgeon and M. W. Chase, Dactylorhiza umbrosa (Kar. & Kir.) Nevski, Himantoglossum affine (Boiss.) Schltr., Orchis collina Banks and Solander, Orchis mascula (L.) L., Orchis simia Lam., Ophrys schulzei Bornm. and Fleischm., and Ophrys straussii H. Fleischm. and Bornm. using start target codon markers (SCoT) and finding markers associated with seed morphometric traits. A total of 254 reproducible SCoT fragments were generated, of which 248 fragments were polymorphic (average polymorphism of 96.18%). The SCoT markers showed a narrow range of polymorphism information content (PIC) varied from 0.397 for S9 primer to 0.499 for S11 and S20 primers. Based on the population analysis results, the Orchis simia accessions collected from Paveh region (Os.P) represented the lowest observed number of alleles (Na) (1.13) and effective number of alleles (Ne) (1.09). At the same time, the highest Na (1.29) and Ne (1.18) values were obtained in O. schulzei collected from Javanrood (Oyst.JA). Shannon's information index (I) was ranged from 0.03 for D. umbrosa accessions collected from Marivan (Du.M population) to 0.263 for Ha.Ja population (H. affine accessions collected from Javanrood). The UPGMA dendrogram obtained with the Jaccard similarity coefficient (r = 0.97295) divided 97 studied terrestrial orchid accessions into eight groups mainly based on species type and geographical origin. Based on the Bayesian statistical index, the highest probability of the data was achieved when accessions were divided into eight groups (K = 8). Multiple association analysis (MRA) revealed significant associations between some of SCoT bands with seed morphometric traits. Our findings can be useful for germplasm characterization, conservation, and improvement of Iranian terrestrial orchid species. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12298-021-00978-4.

Molecular characterization of endangered Iranian terrestrial orchids using ISSR markers and association with floral and tuber-related phenotypic traits.

We aimed to study the genetic diversity, population structure, and phylogeny of Iranian orchids using inter-simple sequence repeat (ISSR) markers to find markers associated with phenotypic traits. Based on the phenotypic analysis, the inflorescence length and the flower number of studied accessions ranged from 3.92 to 27.13 cm and 5 to 50, respectively. On the other hand, the tuber length ranged from 1.80 to 9.35 cm. A total of 310 reproducible ISSR fragments with a size range of 150 to 3000 bp were amplified. ISSR primers provided an average polymorphism information content of 0.391, varied from 0.488 for UBC-876 to 0.351 for UBC-842. Os.J population showed the lowest genetic diversity (H = 0.057 and I = 0.075), while Oyst.JA population showed the highest genetic diversity (H = 0.114 and I = 0.158). At species level, the average coefficient of genetic differentiation (G ST) ranged from 0.265 for Orchis simia to 0.587 for Himantoglossum affine. Gene flow (Nm) varied from 1.38 (O. simia) to 0.756 (Anacamptis collina). The UPGMA genetic similarity dendrogram using Jaccard coefficients (r = 0.973) revealed six main clusters. Based on the Bayesian clustering method, the highest probability of the data was achieved when accessions were divided into eight groups. Floral and tuber-related phenotypic traits represented high correlations together, and they were associated with some ISSR bands based on the multiple association analysis. Altogether, ISSR markers proved to be useful for discrimination and clarification of the relationships among species and populations collected from geographically different locations. Furthermore, it could identify the polymorphism among accessions within each population and species. SUPPLEMENTARY INFORMATION: The online version of this article (10.1007/s12298-020-00920-0) contains supplementary material, which is available to authorized users.

Potassium-enriched clinoptilolite zeolite mitigates the adverse impacts of salinity stress in perennial ryegrass (Lolium perenne L.) by increasing silicon absorption and improving the K/Na ratio.

Salinity is a major abiotic stress that adversely affects turfgrass growth. Clinoptilolite zeolite, a silicon (Si)-rich mineral, may allow these plants to cope with salinity. Therefore, in the present study, the effects of ordinary clinoptilolite zeolite (OZ) and potassium-enriched clinoptilolite zeolite (K-EZ) on the growth of perennial ryegrass (Lolium perenne L.) were assessed under salinity stress. Perennial ryegrass seeds were cultured in soil mixtures amended, or not, with OZ or K-EZ, then exposed to three salinity levels (0, 50 or 100 mM NaCl) for three months. Control plants were grown in the same soil mixture without zeolites, but not exposed to salinity. In salinity, the application of both types of zeolite significantly decreased Na content by 44.36% and 21.31%, but increased K content by 272.34% and 81.59%, as well as the K/Na ratio by 590.47% and 129.43%, in shoots and roots, respectively, compared to the no-zeolite treatment. Similarly, Si content in shoots increased by 28.33%. Amending the soil mixture with zeolite, especially K-EZ, enhanced relative water content, membrane stability index, total chlorophyll content, total soluble proteins, peroxidase and superoxide dismutase activities but reduced the contents of total soluble carbohydrates, hydrogen peroxide, and malondialdehyde in saline conditions. Shoot and root dry weight, root volume and root/shoot ratio also improved. Soil amendment with both forms of zeolite, as a Si-rich mineral, partially offset the negative impacts of salinity on perennial ryegrass, although K-EZ had more noticeable positive and beneficial effects. The amendment of growth media with zeolite may be an effective sustainable management practice for turfgrass used in landscaping and sports fields exposed to saline water.

Evaluation of Radiation Sensitivity in Patients with Hyper IgM Syndrome.

BACKGROUND: HIGM syndrome is a rare form of primary immunodeficiencies characterized by normal/increased amounts of serum IgM and decreased serum levels of other switched immunoglobulin classes. Since the affected patients are continuously infected with various types of pathogens and are susceptible for cancers, diagnostic and therapeutic tests including imaging techniques are recommended for the diagnosis and treatment of these patients, which predispose them to higher accumulated doses of radiation. Given the evidence of class switching recombination machinery defect and its association with an increased rate of DNA repair, we aimed to evaluate radiation sensitivity among a group of patients diagnosed with HIGM syndrome. METHODS: 19 HIGM patients (14 CD40 L and 3 AID deficiencies and 2 unsolved cases without known genetic defects) and 17 control subjects (10 healthy subjects as negative control group, 7 ataxia-telangiectasia patients as positive control group) were enrolled. G2 assay was carried out for the determination of radiosensitivity. RESULTS: Based on radiation-induced chromosomal changes among the studied HIGM patients and their comparison with the controls, almost all (95%) the patients had degrees of radiosensitivity: 6 patients with low to moderate, 1 patient with moderate, 11 patients with severe and 1 patient without radiation sensitivity. CONCLUSION: Today, X-ray radiation plays a very important role in diagnostic and therapeutic procedures; while increased exposure has devastating effects especially in radiosensitive patients. Considering higher sensitivity in HIGM patients, utilizing radiation-free techniques could partly avoid unnecessary and high-level exposure to radiation, thus preventing or reducing its harmful effects on the affected patients.

Agammaglobulinemia: Epidemiology, Pathogenesis, Clinical Phenotype, Diagnosis, Prognosis and Management.

Agammaglobulinemia is a type of primary antibody deficiencies, characterized by severe reduction in serum level of all types of immunoglobulins level and absence of B cells in the peripheral blood. X-linked and various autosomal recessive/dominant mutations have been identified underlying the pathogenesis of this disorder. Affected patients present a broad range of clinical manifestations, including respiratory infections, gastrointestinal complications, Enterovirus infections, autoimmunity, and malignancies. This disease can be controlled by different therapeutic strategies. In this review, we describe different aspects of agammaglobulinemia such as epidemiology, pathogenesis, clinical phenotype, diagnosis, management, and prognosis of congenital agammaglobulinemia.

Current status and biotechnological advances in genetic engineering of ornamental plants.

Cut flower markets are developing in many countries as the international demand for cut flowers is rapidly growing. Developing new varieties with modified characteristics is an important aim in floriculture. Production of transgenic ornamental plants can shorten the time required in the conventional breeding of a cultivar. Biotechnology tools in combination with conventional breeding methods have been used by cut flower breeders to change flower color, plant architecture, post-harvest traits, and disease resistance. In this review, we describe advances in genetic engineering that have led to the development of new cut flower varieties.