Immunoglobulin Production Research Articles

Transcriptomic Analysis of Metastatic Colorectal Tumor with Low Mutational Burden

Objective: To identify potential drug targets for metastasis colorectal cancer (CRC) patients with low mutational burden by examining differences in immune-related gene expression. Methods: For this study, 623 samples were collected from The Cancer Genome Atlas (TCGA) database, comprising tumor mutational burden (TMB), RNA sequencing (RNA-Seq), and clinical data. Differential gene expression analysis, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of the identified genes were conducted using the R package. Additionally, a comparative analysis of immune infiltrating cell composition in metastatic and non-metastatic groups was performed. Hub genes, exhibiting high levels of interaction, were selected using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. The Drug Gene Interaction Database (DGIdb) was then utilized to estimate drugs targeting the identified hub genes. Results: The transcriptome data of 326 colorectal cancer patients with low TMB were analyzed, comprising 58 patients with metastasis and 268 patients without metastasis. Among the differential expression in 1,111 genes for patients with metastasis compared to those without metastasis, 733 genes were upregulated, and 378 genes were downregulated. KEGG and GO enrichment analysis indicated significant differences in gene expression in CRC metastatic patients with low TMB compared to non-metastasis patients with low TMB. Enriched pathways included humoral immuneresponse, immunoglobulin production, and regulation of AMPA receptor activity. Two genes related to interleukin-12 were identified through secondary enrichment for immune-related genes. Analysis of tumor-infiltrating immune cell data revealed significant differences in memory-activated T cell CD4 and T cell CD8. Conclusions: This analysis of RNA sequencing data and immune-filtrating cell data revealed significant differences between metastatic colorectal cancer patients with low TMB and their non-metastatic counterparts. These distinctions suggest the possibility of identifying more effective drugs or therapies for metastatic colorectal cancer patients with low TMB.

A preliminary study of the immunogenic response of plant-derived multi-epitopic peptide vaccine candidate of Mycoplasma gallisepticum in chickens.

Mycoplasma gallisepticum (MG) is responsible for chronic respiratory disease in avian species, characterized by symptoms like respiratory rales and coughing. Existing vaccines for MG have limited efficacy and require multiple doses. Certain MG cytoadherence proteins (GapA, CrmA, PlpA, and Hlp3) play a crucial role in the pathogen's respiratory tract colonization and infection. Plant-based proteins and therapeutics have gained attention due to their safety and efficiency. In this study, we designed a 21.4-kDa multi-epitope peptide vaccine (MEPV) using immunogenic segments from cytoadherence proteins. The MEPV's effectiveness was verified through computational simulations. We then cloned the MEPV, introduced it into the plant expression vector pSiM24-eGFP, and expressed it in Nicotiana benthamiana leaves. The plant-produced MEPV proved to be immunogenic when administered intramuscularly to chickens. It significantly boosted the production of immunoglobulin Y (IgY)-neutralizing antibodies against cytoadherence protein epitopes in immunized chickens compared to that in the control group. This preliminary investigation demonstrates that the plant-derived MEPV is effective in triggering an immune response in chickens. To establish an efficient poultry health management system and ensure the sustainability of the poultry industry, further research is needed to develop avian vaccines using plant biotechnology.

Viral Hepatitis

Background: The primary goals of conducting surveillance for viral hepatitis are to direct prevention and control activities for these diseases and to evaluate the impact of these activities. Any person with a hepatitis virus infection is a potential source of infection to others. Surveillance would help accomplish the goals by providing information on:
 
 Creating a network of laboratories for diagnosis of viral hepatitis. 2. Monitor trends in incidence of and risk factors for disease.
 Assess burden of disease 4. Identify infected persons requiring counseling and /or post exposure prophylaxis. 5. Identify and control outbreaks.
 
 Methodology: Laboratory based targeted sousveillance in sentinel geographical regions/population. Clinical Case Definition: An acute illness with discrete onset of symptoms (e.g., fatigue, abdominal pain, loss of appetite, intermittent nausea, vomiting), and jaundice. (sourcewww.cdc.gov.in) NCDC will be the nodal agency for implementation of the project.
 Results: HBV, HCV and HDV are transmitted through contaminated blood or blood components or through the use of contaminated needles and syringes. In several populations, a common route of transmission of HBV infection is from infected pregnant women to their infants around the time of delivery. In many people with HBV or HCV infection, no route of transmission can be identified. In addition, specific vaccines and/or passive immune prophylaxis (use of specific immunoglobulin products) are also useful in preventing transmission of some infections. and also HAV vaccine is the most effective method for specific pre-exposure prophylaxis. and two different vaccines based on inactivated cell culture are available. Both vaccines are highly antigenic, especially in adults, and induce protective antibody levels in more than 95% of recipients after the first dose of vaccine. Individuals at high risk of repeated exposure to HBV, such as personnel Health Care Anti-HBs titer should be evaluated one month after the third dose. An Anti-HBs titer of 10 IU/L (or 10 mIU/mL) is protective. After reaching this titer, there is no need for further booster doses.
 Conclusion: Viral hepatitis is a systemic infection affecting predominantly the liver and causing its inflammation. It may be acute (recent infection, relatively rapid onset) or chronic. Viral hepatitis is caused by infection with one of the five known hepatotropic viruses, which are named as hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), and hepatitis E virus (HEV), respectively. These viruses are quite divergent in their structure, epidemiology, routes of transmission, incubation period, clinical presentations, natural history, diagnosis, and preventive and treatment options.

Dendrobium officinale leaf polysaccharide has a dual effect of alleviating the syndromes of immunosuppressed mice and modulating immune system of normal mice

This study aimed to explore the immunomodulatory activity of Dendrobium officinale leaf polysaccharide (DOLP) in both immunosuppressed and normal mice. The data showed that DOLP significantly reversed thymic and splenic damage in immunosuppressed mice, regulated their peripheral blood cells (PLT, etc.), immune-related cytokines (TNF-α, INF-γ and IL-6) and immunoglobulins (IgA, IgG and IgM) production, and increased the relative abundance of beneficial bacteria (Lactobacillus and Bifidobacterium, etc.) while decreased that of pathogenic bacteria (Desulfovibrio, etc.). In normal mice, DOLP significantly increased immune-related cytokines (TNF-α, INF-γ, and IL-6), gut microbiota diversity, and the relative abundance of beneficial bacteria (unclassified_f_Lachnospiraceae_NK4A136_group, etc.). The results indicated that DOLP could exert immune modulating effects both on immunosuppressed mice and normal mice by modulating immune parameters and gut microbiota. These findings provide new insights into the immune-modulating effects of DOLP and a solid basis for the thorough utilization of DOLP.

Mesenchymal Stem Cell-derived Exosome; An Interesting Nanocarrier to Improve Allergen-specific Intranasal Immunotherapy.

Increasing the efficacy of allergen-specific intranasal immunotherapy (INIT) has recently been the main goal of several studies to establish this route as a safe delivery method through mucosal pathways. In this case, the present study evaluated the potential of INIT using ovalbumin (OVA)-loaded mesenchymal stromal/stem cell (MSC)-derived exosomes (Exo-OVA) in an allergic asthma mouse model. Together with control groups, sensitized Balb/c mice underwent intranasal immunotherapy with Exo-OVA (10 μg OVA per dose) for three consecutive weeks. Serum-specific immunoglobulin E (IgE) levels, transforming growth factor-beta (TGF-β), interleukin (IL)-4, and interferon-gamma (IFN-γ) production by cultured spleen cells, lung histopathologic analysis, and nasopharyngeal lavage fluid cellular examinations were then conducted. The results showed that INIT using Exo-OVA significantly increased IFN-γ and TGF-β secretion, while allergen-specific IgE and IL-4 production were dramatically decreased compared to the control group receiving phosphate-buffered saline. In addition, the eosinophil and total cell counts in the nasopharyngeal lavage fluid were reduced, and inflammatory conditions and cell accumulation in lung tissue were ameliorated. In conclusion, the Exo-OVA improved the INIT efficacy compared to free OVA. Therefore, this formulation could be introduced as an effective approach for immunomodulatory purposes with a shorter treatment duration and reduced side effects.

Immunoglobulin replacement products protect against SARS-CoV-2 infection in vivo despite poor neutralizing activity.

Immunoglobulin (IG) replacement products are used routinely in patients with immune deficiency and other immune dysregulation disorders who have poor responses to vaccination and require passive immunity conferred by commercial antibody products. The binding, neutralizing, and protective activity of intravenously administered IG against SARS-CoV-2 emerging variants remains unknown. Here, we tested 198 different IG products manufactured from December 2019 to August 2022. We show that prepandemic IG had no appreciable cross-reactivity or neutralizing activity against SARS-CoV-2. Anti-spike antibody titers and neutralizing activity against SARS-CoV-2 WA1/2020 D614G increased gradually after the pandemic started and reached levels comparable to vaccinated healthy donors 18 months after the diagnosis of the first COVID-19 case in the United States in January 2020. The average time between production to infusion of IG products was 8 months, which resulted in poor neutralization of the variant strain circulating at the time of infusion. Despite limited neutralizing activity, IG prophylaxis with clinically relevant dosing protected susceptible K18-hACE2-transgenic mice against clinical disease, lung infection, and lung inflammation caused by the XBB.1.5 Omicron variant. Moreover, following IG prophylaxis, levels of XBB.1.5 infection in the lung were higher in FcγR-KO mice than in WT mice. Thus, IG replacement products with poor neutralizing activity against evolving SARS-CoV-2 variants likely confer protection to patients with immune deficiency disorders through Fc effector function mechanisms.

Aspergillus fumigatus-Derived Extracellular Vesicles Mitigate Fungal Keratitis by Modulating the Immune Cell Function.

Fungal keratitis (FK) is a refractory global disease characterized by a high incidence of blindness and a lack of effective therapeutic options, and Aspergillus fumigatus (A. fumigatus, AF) is one of the most common causative fungi. This study aimed to investigate the role of extracellular vesicles (EVs) from A. fumigatus in the immune cell function and their protective role in A. fumigatus keratitis in order to explore their therapeutic potential. First, we isolated and characterized the EVs (AF-derived EVs). In vitro, we stimulated RAW264.7 cells and polymorphonuclear cells with AF-derived EVs. The expression levels of inflammatory factors increased in both immune cells along with an M1 polarization variation of RAW264.7 cells. After being incubated with AF-derived EVs, both immune cells exhibited an increased conidia-phagocytic index and a decreased conidia survival rate. In vivo, we injected EVs subconjunctivally on mice resulting in a heightened production of secretory immunoglobulin A (sIgA) in tear fluid. By the injection of EVs on mice in advance, a significant reduction in severity of A. fumigatus FK was witnessed by lower clinical scores, inflammatory appearances, and mitigated fungal load. Collectively, these results positioned AF-derived EVs as a promising and innovative immune therapy for combating FK, while also providing a platform for further investigation into developing an optimal formulation for modulating inflammation in the context of FK.

Long-term Survival in a Patient With Transformation of Waldenström's Macroglobulinemia into DLBCL.

Waldenström's macroglobulinemia (WM) is a rare slow-growing B-cell lymphoma that is characterized by lymphoplasmacytic bone marrow infiltration and the production of monoclonal immunoglobulin M (IgM) paraprotein. In 5-10% of patients, WM undergoes transformation into diffuse large B-cell lymphoma (DLBCL), which is more aggressive, with poor prognosis and a low survival rate. Α 69-year-old woman was diagnosed with WM in 2009. She received six cycles of chemoimmunotherapy and a remarkable remission was achieved. However, in 2013 the disease transformed into DLBCL. The patient received chemotherapy and after the completion of the first cycle of therapy, the disease was significantly minimized. At the end of the therapy, there was no evidence of disease, and the patient remains disease-free. The cytogenetic profile of the patient did not reveal expression of BCL2 apoptosis regulator, BCL6 transcription repressor, Epstein-Barr virus small RNA, syndecan 1 nor cyclin D1. According to a staging system based on the platelet count, lactate dehydrogenase and previous treatment for WM, the described patient was classified as being at intermediate risk with an expected 2-year survival probability of 47% after WM transformation into DLBCL. However, the patient unexpectedly exceeded these prognostic indications. The findings for this patient are of great interest compared with the existing literature which suggests that the survival and prognosis for patients with transformed DLBCL are not favorable.

Efficacy and Safety of Probiotics for Dental Caries in Preschool Children: A Systematic Review and Meta-analysis.

Early childhood caries is one of the most serious and high-priced oral health conditions among young children. With advancing dental sciences, the focus of dental caries treatment is shifted from restorative procedures to preventive measures, and a modality grabbing attention is probiotics. Probiotics exert their effects in many ways as chemical inhibition of pathogenic bacteria and stimulation of the immune response through the production of immunoglobulin A and many more. This systematic review aims to explore the efficacy and safety of probiotics in dental caries in preschool children. The study was registered in the PROSPERO International Prospective Register of Systematic Reviews (registration number: CRD42020159058). The search was done for randomized control trials in electronic databases such as Cochrane, PubMed, ClinicalTrials.gov, Medline, and Embase. It has further included manual searches of journals, conference abstracts, and books. Three reviewers done the selection of the study as per the criteria and also did the risk of bias assessment independently and wherever required, a fourth reviewer resolved the discrepancy in case of disagreement. The nine randomized control trials were included in the study, and the pooled analysis revealed probiotics as an effective intervention in preschool children with dental caries. The results about the efficacy of probiotics in the prevention of dental caries are very encouraging, though the level of evidence is still inadequate.

Urban living can rescue Darwin's finches from the lethal effects of invasive vampire flies.

Human activity changes multiple factors in the environment, which can have positive or negative synergistic effects on organisms. However, few studies have explored the causal effects of multiple anthropogenic factors, such as urbanization and invasive species, on animals and the mechanisms that mediate these interactions. This study examines the influence of urbanization on the detrimental effect of invasive avian vampire flies (Philornis downsi) on endemic Darwin's finches in the Galápagos Islands. We experimentally manipulated nest fly abundance in urban and non-urban locations and then characterized nestling health, fledging success, diet, and gene expression patterns related to host defense. Fledging success of non-parasitized nestlings from urban (79%) and non-urban (75%) nests did not differ significantly. However, parasitized, non-urban nestlings lost more blood, and fewer nestlings survived (8%) compared to urban nestlings (50%). Stable isotopic values (δ15 N) from urban nestling feces were higher than those from non-urban nestlings, suggesting that urban nestlings are consuming more protein. δ15 N values correlated negatively with parasite abundance, which suggests that diet might influence host defenses (e.g., tolerance and resistance). Parasitized,urban nestlings differentially expressed genes within pathways associated with red blood cell production (tolerance) and pro-inflammatory response (innate immunological resistance), compared to parasitized,non-urban nestlings. In contrast, parasitized non-urban nestlings differentially expressed genes within pathways associated with immunoglobulin production (adaptive immunological resistance). Our results suggest that urban nestlings are investing more in pro-inflammatory responses to resist parasites but also recovering more blood cells to tolerate blood loss. Although non-urban nestlings are mounting an adaptive immune response, it is likely a last effort by the immune system rather than an effective defense against avian vampire flies since few nestlings survived.

Pediococcus pentosaceus KF159 alleviates house dust mite-induced atopic dermatitis by promoting IL10 production and regulatory T cell induction.

Atopic dermatitis (AD) is a chronic immune disease that requires long-term management owing to its relative ease of recurrence. However, steroid treatment is limited owing to the side effects. Therefore, research on therapeutics with proven safety is required. Here, we evaluated the anti-allergic activity of the probiotic strain Pediococcus pentosaceus KF159 (PPKF159) with an ex vivo mouse model sensitized with ovalbumin (OVA) and a mouse model of AD induced by house dust mites. Changes in pathological symptoms were confirmed based on the clinical status of the AD-induced lesion site and the levels of T helper type 2 (Th2)-derived cytokines and immunoglobulin E (IgE). In addition, cell-mediated responses and related mechanisms were elucidated using various kinds of primary cells including splenocytes, mesenteric lymph nodes, Peyer's patch, and bone marrow-derived dendritic cells (BMDCs) in vitro and ex vivo. Oral administration of PPKF159 alleviated AD-like clinical symptoms such as erythema, edema, hemorrhage, and increased tissue thickness, and suppressed the production of Th2-associated cytokines and serum IgE while increasing T helper type 1 (Th1)-mediated cytokine production. PPKF159 induced tolerogenic dendritic cells (tol-DCs) by increasing the expression of ICOS-L, PD-L1, and IDO which were closely related to Treg induction in PPKF159-treated BMDCs. In addition, BMDCs and naive T cells co-cultured in the presence of PPKF159 had elevated IL10 production and increased proportions of CD4+CD25+Foxp3+ Tregs compared to the absence of PPKF159. This study showed that PPKF159 relieved AD-like clinical symptoms, modulated the Th1/Th2 immune balance, and inhibited IgE production in a mouse AD model. PPKF159 induced the transformation of dendritic cells into tolerogenic versions. These induced tol-DCs directly enhanced the production of IL10 or improved the secretion of IL10 through the induction of CD4+CD25+Foxp3+ Treg cells, thereby improving AD. These results suggest that PPKF159 can be applied as a functional food material for the treatment and prevention of AD.

Anti-allergic effect of Cyclopia (honeybush) extracts via anti-degranulation activity in a murine allergy model for inhaled antigen.

The anti-allergic effects of extracts prepared from two species of honeybush, Cyclopia genistoides and Cyclopia subternata, were demonstrated in vivo in a murine allergy model for inhaled antigen induced with ovalbumin (OVA) inhalation to mimic pollen allergy. Intake of the extracts increased the production of OVA-specific immunoglobulin (Ig) E (IgE), IgG1, and IgG2a antibodies in serum and significantly suppressed anaphylactic reaction-induced body temperature decline. Moreover, the extracts significantly inhibited antigen-antibody-induced degranulation in RBL-2H3 cells. They also inhibited body temperature decline when the allergic mice were given them after antigen sensitization, indicating that anti-degranulation activity is the major mechanism underlying the anti-allergic effect of Cyclopia extracts. Despite their qualitative and quantitative differences in phenolic composition, the two extracts exhibited similar effects, suggesting that several active compounds might be involved in the activity. Therefore, oral administration of either Cyclopia extract potentially exerts a systemic anti-allergic effect, supporting the increased consumption of honeybush tea for general wellness and improved quality of life.

Intradermal Immunization with Formaldehyde Inactivated Pseudomonas Aeruginosa Leading to the Production of Protective Immunoglobulin G against Protein of Specific Molecular Weight in Swiss Albino Mice

Intradermal Immunization with Formaldehyde Inactivated Pseudomonas Aeruginosa Leading to the Production of Protective Immunoglobulin G against Protein of Specific Molecular Weight in Swiss Albino Mice

The Expression of Non B Cell-Derived Immunoglobulins.

Although V(D)J recombination and immunoglobulin (Ig) production are traditionally recognised to occur only in B lymphocytes and plasma cells, the expression of Igs in non-lymphoid cells, which we call nonB cell-derived Igs (nonB Igs), has been documented by growing studies. It has been demonstrated that nonB-Igs can be widely expressed in most cell types, including, but not limited to, epithelial cells, cardiomyocytes, hematopoietic stem/progenitor cells, myeloid cells, and cells from immune-privileged sites, such as neurons and spermatogenic cells. In particular, malignant tumour cells express high level of IgG. Moreover, different from B-Igs that mainly localised on the B cell membrane and in the serum and perform immune defence function mainly, nonB-Igs have been found to distribute more widely and play critical roles in immune defence, maintaining cell proliferation and survival, and promoting progression. The findings of nonB-Igs may provide a wealthier breakthrough point for more therapeutic strategies for a wide range of immune-related diseases.

Inhibition of Myeloma Cell Function by Cannabinoid-Enriched Product Associated With Regulation of Telomere and TP53.

Multiple myeloma is a hematological cancer caused by the uncontrolled proliferation of abnormal plasma cells in the bone marrow, leading to excessive immunoglobulin production. Our study aimed to examine the anticancer properties of BRF1A, a cannabinoid (CBD)-enriched product, on 2 myeloma cell lines: U266 and ARH-7. We treated U266 and ARH-77 myeloma cells with varying doses of BRF1A and measured the production of IgE and IgG antibodies using ELISA. Cell viability was assessed using trypan blue and CCK-8 assays. We measured the expression of genes related to the production of IgE and IgG antibodies, IgEH, and IgGH. We determined its effect on the expression of telomerase and its phosphorylated form as an indicator of telomere stabilization. Furthermore, we determined its effect on other cancer-related targets such as NF-ĸB, c-Myc, and TP53 in U266 cells using reverse transcription polymerase chain reaction (RT-PCR) and western blotting. BRF1A reduced myeloma cell IgE and IgG production in a time and dose-dependent manner. It also suppressed the expression of p-IκBα, p-NFκB (p65), and total NFκB protein, as well as XBP1u and XBP1s. It increased the gene and protein expression of telomere and hTERT and significantly increased cancer suppressor TP53 gene and p53 protein expression. Additionally, BRF1A decreased the c-Myc gene and protein expression. Our study has shown that a CBD-enriched product can reduce the growth of myeloma cells by suppressing the critical functions of IgE- and IgG-producing cells. This study could help bridge the gap in understanding how cannabinoid-containing products affect cancer, aging, telomere, and cancer-suppressor gene activity.

Immune interactions and regulation with CD39+ extracellular vesicles from platelet concentrates.

CD39 plays an important role in the immunoregulation and inhibition of effector cells. It is expressed on immune cells, including Tregs, and on extracellular vesicles (EVs) budding from the plasma membrane. Platelet transfusion may induce alloimmunization against HLA-I antigens, leading to refractoriness to platelet transfusion with severe consequences for patients. Tregs may play a key role in determining whether alloimmunization occurs in patients with hematologic disorders. We hypothesized that CD39+ EVs might play an immunoregulatory role, particularly in the context of platelet transfusions in patients with hematologic disorders. Such alloimmunization leads to the production of alloantibodies and is sensitive to the regulatory action of CD39. We characterized CD39+ EVs in platelet concentrates by flow cytometry. The absolute numbers and cellular origins of CD39+ EVs were evaluated. We also performed functional tests to evaluate interactions with immune cells and their functions. We found that CD39+ EVs from platelet concentrates had an inhibitory phenotype that could be transferred to the immune cells with which they interacted: CD4+ and CD8+ T lymphocytes (TLs), dendritic cells, monocytes, and B lymphocytes (BLs). Moreover, the concentration of CD39+ EVs in platelet concentrates varied and was very high in 10% of concentrates. The number of these EVs present was determinant for EV-cell interactions. Finally, functional interactions were observed with BLs, CD4+ TLs and CD39+ EVs for immunoglobulin production and lymphoproliferation, with potential implications for the immunological management of patients.

Expression of IL-17RA in Innate Cells of Patients with Common Variable Immunodeficiency (CVID) and its Clinical Implications.

Background. Common Variable Immunodeficiency (CVID) is a primary immunodeficiency disorder characterized by B-cell dysfunction and immunoglobulin production deficiency. Dysregulation of interleukin-17 (IL-17) and its receptor IL-17RA have been reported in various immune disorders. This study aimed to investigate the expression of IL-17RA in innate immune cells of CVID patients and its correlation with clinical manifestations. Methods. A cross-sectional study included 22 CVID patients and 14 age- and sex-matched healthy controls. IL-17RA expression was assessed in various immune cell subsets using flow cytometry. Demographic and clinical data were collected, and statistical analysis was performed. Results. CVID patients had elevated IL-17RA expression in neutrophils, non-classical monocytes, and dendritic cells compared to healthy controls. Patients with a history of intestinal microbial colonization, particularly with Campylobacter jejuni and Giardia intestinalis, showed significantly higher IL-17RA expression in innate cells. Elevated IL-17RA expression in monocytes and dendritic cells also correlated with higher fecal calprotectin levels in CVID patients, regardless of microbial colonization. Conclusions. The study suggests that despite previous reports of reduced circulating Th17 cells and IL-17 levels in CVID patients, IL-17RA expression in innate cells may be elevated, potentially indicating altered IL-17 signaling. This heightened IL-17RA expression could contribute to a persistent pro-inflammatory state, possibly due to microbial translocation or other inflammatory factors. The association of IL-17RA expression with gastrointestinal microbial colonization and its correlation with fecal calprotectin underscores the complexity of IL-17RA's role in CVID pathophysiology. Further research in larger cohorts could elucidate the implications of IL-17RA expression in both infectious and non-infectious inflammatory aspects of CVID.

Omega-5-gliadin-specific immunoglobulin E-positive, but wheat-specific immunoglobulin E-negative wheat allergy dependent on augmentation factors—a frequent presentation

Aim: Most patients with wheat allergy dependent on augmentation factors (WALDA) show specific immunoglobulin E (sIgE) to ω5-gliadin. However, some WALDA patients may show negative results when testing for sIgE to total wheat extract. This is the first study to investigate potential clinical and serological differences in patients with ω5-gliadin-positive, challenge-confirmed WALDA dependent on their sensitization to total wheat extract. Methods: Clinical and serological characteristics of patients with challenge-confirmed, ω5-gliadin-positive WALDA were analyzed based on the absence or presence of sIgE to wheat (cut-off 0.35 kUA/L). Results: Thirty-six patients with challenge-confirmed WALDA were included (19 female; median age 50.5 years; median sIgE to ω5-gliadin 6.5 kUA/L). SIgE levels to grass pollen were related to the presence of any atopic comorbidity (P < 0.001) and showed a correlation with sIgE to wheat (P = 0.003), but not to the gluten-related allergens [all not significant (ns)]. Thirty-nine percent of patients (n = 14) showed sIgE levels to wheat lower than 0.35 kUA/L; in 19.4% (n = 7) levels were even below the detection limit of 0.01 kUA/L. WALDA patients without sIgE to wheat showed lower levels of total immunoglobulin E (IgE) and sIgE to wheat gluten, gliadins, and ω5-gliadin (all P < 0.001) as well as to grass pollen (P = 0.03). No significant differences in clinical characteristics like delay until diagnosis, the presence of an atopic condition, reaction severity, or threshold in the oral challenge test were observed. Conclusions: SIgE to wheat extract was associated not only with sensitization against gluten allergens but also reflected total IgE production and concomitant grass pollen allergy, making it an insensitive and unspecific biomarker for WALDA. There were no clinical divergences between WALDA patients without or with sIgE to wheat. SIgE to total wheat extract does not appear to be clinically relevant and remains negative in a significant proportion of WALDA patients.

An Update on the Genetics of IgA Nephropathy.

Immunoglobulin A (IgA) nephropathy (IgAN), the most common form of glomerulonephritis, is one of the leading causes of end-stage kidney disease (ESKD). It is widely believed that genetic factors play a significant role in the development of IgAN. Previous studies of IgAN have provided important insights to unravel the genetic architecture of IgAN and its potential pathogenic mechanisms. The genome-wide association studies (GWASs) together have identified over 30 risk loci for IgAN, which emphasizes the importance of IgA production and regulation in the pathogenesis of IgAN. Follow-up fine-mapping studies help to elucidate the candidate causal variant and the potential pathogenic molecular pathway and provide new potential therapeutic targets. With the rapid development of next-generation sequencing technologies, linkage studies based on whole-genome sequencing (WGS)/whole-exome sequencing (WES) also identify rare variants associated with IgAN, accounting for some of the missing heritability. The complexity of pathogenesis and phenotypic variability may be better understood by integrating genetics, epigenetics, and environment. We have compiled a review summarizing the latest advancements in genetic studies on IgAN. We similarly summarized relevant studies examining the involvement of epigenetics in the pathogenesis of IgAN. Future directions and challenges in this field are also proposed.

Genetic profile of adaptive immune traits and relationships with parasite resistance and productivity in Scottish Blackface sheep

Gastrointestinal (GI) parasites cause significant production losses in grazing ruminants which can be mitigated by breeding animals resistant to disease. Lymphocyte cytokine production and parasite-specific Immunoglobulin A (IgA) are adaptive immune traits associated with immunity to GI parasites. To explore the utility of these traits for selective breeding purposes, this study estimated the genetic parameters of the immune traits in sheep and assessed their relationship with disease and productivity traits. Whole blood stimulation assays were performed on 1 040 Scottish Blackface lambs at two months of age in 2016–2017. Blood was stimulated with either pokeweed mitogen (PWM), a non-specific activator of lymphocytes, and Teladorsagia circumcincta (T-ci) larval antigen to activate parasite-specific T lymphocytes. The type of adaptive immune response was determined by quantifying production of cytokines interferon-gamma (IFN-γ), interleukin (IL)-4, and IL-10, which relate to T-helper type (Th) 1, Th2 and regulatory T cell responses, respectively. Serum T-ci specific IgA was also quantified. Heritabilities were estimated for each immune trait by univariate analyses. Genetic and phenotypic correlations were estimated between different immune traits, and between immune traits vs. disease and productivity traits that were recorded at three months of age. Disease phenotypes were expressed as faecal egg counts (FEC) of nematode parasites (Strongyles and Nematodirus), faecal oocyst counts (FOC) of coccidian parasites, and faecal soiling score; production was measured as lamb live weight. Significant genetic variation was observed in all immune response traits. Heritabilities of cytokine production varied from low (0.14 ± 0.06) to very high (0.77 ± 0.09) and were always significantly greater than zero (P < 0.05). IgA heritability was found to be moderate (0.41 ± 0.09). Negative associations previously identified between IFN-γ production and FOC, and IL-4 production and strongyle FEC, were not evident in this study, potentially due to the time-lag between immune and parasitology measures. Instead, a positive genetic correlation was found between FOC and PWM-induced IFN-γ production, while a negative genetic correlation was found between FOC and T-ci induced IL-10. Live weight was negatively genetically correlated with IFN-γ responses. Overall, IFN-γ and IL-4 responses were positively correlated, providing little evidence of cross-regulation of Th1 and Th2 immunity within individual sheep. Furthermore, T-ci specific IgA was highly positively correlated with PWM-induced IL-10, indicating a possible role for this cytokine in IgA production. Our results suggest that while genetic selection for adaptive immune response traits is possible and may be beneficial for parasite control, selection of high IFN-γ responsiveness may negatively affect productivity.