Research

Front Immunol. 2021 Dec 13;12:803459. doi: 10.3389/fimmu.2021.803459. eCollection 2021.

ABSTRACT

Primary immunodeficiency (PID) is primarily characterized by susceptibility to infectious diseases. In addition, patients with some type of PID are prone to develop autoimmune, autoinflammatory, or malignant diseases. Therefore, the term, inborn errors of immunity (IEI), has been more used rather than PID. In recent years, the number of diseases which belong to PID has been increasing. There were approximately 110 diseases in the report of International Union of Immunological Societies in 1999. Since then, the number increased to 430 diseases in the latest IUIS report in 2019. We conducted PID nationwide survey in Japan for 3 times in the last 15 years. These studies were focused on incidence and complications of PID, the clinical course of viral infection, and methods to prevent infectious diseases in PID patients. For the awareness of PID, it is essential to know the general and fundamental information of PID patients. Needless to say, we need it to offer appropriate medical services for PID patients. Moreover, chances to provide answers to the questionnaires and seeing the results of the analysis should contribute to the awareness of PID among doctors. In this review, I am going to summarize the results of 3 nationwide survey in Japan, and pick up interleukin-1 receptor-associated kinase 4 (IRAK4) deficiency as an example for creating awareness for its appropriate management.

PMID:34966393 | PMC:PMC8710485 | DOI:10.3389/fimmu.2021.803459

J Allergy Clin Immunol. 2021 Dec 24:S0091-6749(21)02686-5. doi: 10.1016/j.jaci.2021.12.775. Online ahead of print.

ABSTRACT

Our understanding of risk factors and interventions influencing outcomes from COVID-19 has continued to evolve, revealing advances emerging from hypotheses formed at the start of the pandemic. Epidemiologic studies have shown that asthma control, rather than a diagnosis of asthma, is a determinant of COVID-19 severity. Clinical outcomes in patients with primary immunodeficiencies, even in those with impaired cellular immunity, are variable. IL-6 has emerged as a reliable biomarker of COVID-19 severity and large clinical trials have shown the potential for improving outcomes through inhibition of IL-6 signaling in some patients. Studies of genetic risk factors for severe COVID-19 have also revealed the importance of IFN homeostasis in the defense against SARS-CoV-2. As COVID-19 vaccines constitute the primary tool for ending this pandemic, strategies have been developed to address potential allergic and immune-mediated reactions. Here, we discuss advances in our understanding of COVID-19 risk factors and outcomes within the context of allergic and immunologic mechanisms.

PMID:34958811 | DOI:10.1016/j.jaci.2021.12.775

Aging (Albany NY). 2021 Dec 26;13(undefined). doi: 10.18632/aging.203798. Online ahead of print.

ABSTRACT

OBJECTIVE: Tertiary lymphoid structure (TLS), also known as ectopic lymphoid organs, are found in cancer, chronic inflammation, and autoimmune diseases. However, the heterogeneity of TLS in gliomas is unclear. Therefore, it is necessary to identify TLS differences and define TLS subtypes.

METHODS: The TLS gene profile of 697 gliomas from The Cancer Genome Atlas (TCGA) was used for consensus clustering to identify robust clusters, and the reproducibility of the stratification method was assessed in Chinese Glioma Genome Atlas (CGGA) cohort1, CGGA_cohort2, and GSE16011. Analyses of clinical characteristics, immune infiltration, and potential biological functions were performed for each subtype.

RESULTS: Three resulting clusters (A, B, and C) were identified based on consensus clustering on the gene expression profile of TLS genes. There was a significant prognostic difference among the clusters, with a shorter survival for C than B and A. In comparison with the A and B subtypes, the C subtype was significantly enriched in primary immunodeficiency, intestinal immune network for lgG production, antigen processing and presentation, natural killer cell-mediated cytotoxicity, complement and coagulation cascades, cytokine-cytokine receptor interaction, leukocyte transendothelial migration, and some immune-related diseases. The levels of 23 immune cell types were higher in the C subtype than in the A and B subtypes. Finally, we developed and validated a riskscore based on TLS subtypes with better performance of prognosis prediction.

CONCLUSIONS: This study presents a new stratification method according to the TLS gene profile and highlights TLS heterogeneity in gliomas.

PMID:34954691 | DOI:10.18632/aging.203798

J Allergy Clin Immunol. 2021 Dec 21:S0091-6749(21)02667-1. doi: 10.1016/j.jaci.2021.11.022. Online ahead of print.

ABSTRACT

BACKGROUND: Data on the safety and efficacy of COVID-19 vaccination in people with a range of primary immune deficiencies are lacking since these patients were excluded from COVID-19 vaccine trials. This information may help in clinical management of this vulnerable patient group.

OBJECTIVE: To assess humoral and T-cell immune responses after two doses of SARS-CoV-2 mRNA vaccines in patients with PIDs and functional B-cell defects.

METHODS: A double-center retrospective review of patients with PID who completed COVID-19 mRNA vaccination and who had humoral responses assessed through SARS-CoV-2 spike protein receptor binding domain (RBD) IgG antibody levels with reflex assessment of the antibody to block RBD binding to ACE2 (hereafter referred to as ACE2 receptor blocking activity, as a surrogate test for neutralization) and T-cell response evaluated by an interferon-gamma release assay (IGRA). Immunization reactogenicity was also reviewed.

RESULTS: A total of 33 patients with humoral defect were evaluated. 69.6% received BNT162b2 vaccine (Pfizer-BioNTech) and 30.3% received mRNA-1273 (Moderna). The mRNA vaccines were generally well tolerated without severe reactions. The IGRA was positive in 77.4% of our patients (24 of 31). About half of our subjects (16 of 33) had detectable RBD-specific IgG responses but only two of these 16 subjects had an ACE2 receptor blocking activity level of >50%.

CONCLUSION: Vaccination of this cohort of PID patients with COVID-19 mRNA vaccines was safe and cellular immunity was stimulated in a majority. However, antibody responses to the spike protein RBD were less consistent, and, when detected, was not effective at ACE2 blocking.

CLINICAL IMPLICATION: mRNA vaccination may be less effective at preventing acquisition of SARS-CoV-2 in our cohort of PID patients with functional B-cell defects. The Induction of SARS-CoV-2 spike protein-specific T-cell immunity by vaccination might help reduce the severity of disease in these patients.

PMID:34952033 | DOI:10.1016/j.jaci.2021.11.022

Mod Pathol. 2021 Dec 24. doi: 10.1038/s41379-021-01002-6. Online ahead of print.

ABSTRACT

Epstein-Barr virus (EBV)-positive extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT lymphomas) were initially described in solid organ transplant recipients, and, more recently, in other immunodeficiency settings. The overall prevalence of EBV-positive MALT lymphomas has not been established, and little is known with respect to their genomic characteristics. Eight EBV-positive MALT lymphomas were identified, including 1 case found after screening a series of 88 consecutive MALT lymphomas with EBER in situ hybridization (1%). The genomic landscape was assessed in 7 of the 8 cases with a targeted high throughput sequencing panel and array comparative genomic hybridization. Results were compared to published data for MALT lymphomas. Of the 8 cases, 6 occurred post-transplant, 1 in the setting of primary immunodeficiency, and 1 case was age-related. Single pathogenic/likely pathogenic mutations were identified in 4 of 7 cases, including mutations in IRF8, BRAF, TNFAIP3, and SMARCA4. Other than TNFAIP3, these genes are mutated in <3% of EBV-negative MALT lymphomas. Copy number abnormalities were identified in 6 of 7 cases with a median of 6 gains and 2 losses per case, including 4 cases with gains in regions encompassing several IRF family or interacting genes (IRF2BP2, IRF2, and IRF4). There was no evidence of trisomies of chromosomes 3 or 18. In summary, EBV-positive MALT lymphomas are rare and, like other MALT lymphomas, are usually genetically non-complex. Conversely, while EBV-negative MALT lymphomas typically show mutational abnormalities in the NF-κB pathway, other than the 1 TNFAIP3-mutated case, no other NF-κB pathway mutations were identified in the EBV-positive cases. EBV-positive MALT lymphomas often have either mutations or copy number abnormalities in IRF family or interacting genes, suggesting that this pathway may play a role in these lymphomas.

PMID:34952945 | DOI:10.1038/s41379-021-01002-6

Scand J Immunol. 2021 Dec 24:e13130. doi: 10.1111/sji.13130. Online ahead of print.

ABSTRACT

T-cell receptor excision circles (TRECs) and kappa-deleting excision circles (KRECs) are DNA fragments potentially indicative of T- and B-cell development, respectively. Recent thymic emigrants (RTEs) are a subset of peripheral cells that may also represent thymic function. Here, we investigated TREC/KREC copy numbers by quantitative real-time PCR in the peripheral blood of patients with primary immunodeficiencies (PIDs, n=145) and that of healthy controls (HCs, n=86) and assessed the correlation between RTEs and TREC copy numbers. We found that TREC copy numbers were significantly lower in children and adults with PIDs (p<0.0001 and p<0.002, respectively) as compared with their respective age-matched HCs. A moderate correlation was observed between TREC copies and RTE numbers among children with PID (r=0.5114, p<0.01), whereas no significant correlation was detected between RTE values and TREC content in the HCs (r=0.0205, p=0.9208). Additionally, we determined TREC and KREC copy numbers in DNA isolated from the Guthrie cards of 200 newborns and showed that this method is applicable to DNA isolated from both peripheral blood samples and dried blood spots, with the two sample types showing comparable TREC and KREC values. We further showed that RTE values are not always reliable markers of T-cell output. Although additional confirmatory studies with larger cohorts are needed, our results provide thresholds for TREC/KREC copy numbers for different age groups.

PMID:34951041 | DOI:10.1111/sji.13130

J Clin Immunol. 2021 Dec 23. doi: 10.1007/s10875-021-01164-7. Online ahead of print.

NO ABSTRACT

PMID:34940925 | DOI:10.1007/s10875-021-01164-7

Pediatr Allergy Immunol. 2021 Dec 22. doi: 10.1111/pai.13725. Online ahead of print.

ABSTRACT

Common variable immunodeficiency disorder (CVID) is a heterogeneous disorder and the most common symptomatic antibody deficiency disease characterized with hypogammaglobulinemia and a broad range of clinical manifestations. Multiple genetic, epigenetic and immunological defects are involved in the pathogenesis of CVID. These immunological defects include abnormalities in the number and/or function of B lymphocytes, T lymphocytes, and other rare immune cells. Although some immune cells have a relatively lower proportion among total immune subsets in the human body, they could have important roles in the pathogenesis of immunological disorders like CVID. To the best of our knowledge, this is the first review that described the role of rare immune cells in the pathogenesis and clinical presentations of CVID.

PMID:34937129 | DOI:10.1111/pai.13725

Nat Immunol. 2021 Dec 22. doi: 10.1038/s41590-021-01093-y. Online ahead of print.

ABSTRACT

We report a pleiotropic disease due to loss-of-function mutations in RHBDF2, the gene encoding iRHOM2, in two kindreds with recurrent infections in different organs. One patient had recurrent pneumonia but no colon involvement, another had recurrent infectious hemorrhagic colitis but no lung involvement and the other two experienced recurrent respiratory infections. Loss of iRHOM2, a rhomboid superfamily member that regulates the ADAM17 metalloproteinase, caused defective ADAM17-dependent cleavage and release of cytokines, including tumor-necrosis factor and amphiregulin. To understand the diverse clinical phenotypes, we challenged Rhbdf2^-/- mice with Pseudomonas aeruginosa by nasal gavage and observed more severe pneumonia, whereas infection with Citrobacter rodentium caused worse inflammatory colitis than in wild-type mice. The fecal microbiota in the colitis patient had characteristic oral species that can predispose to colitis. Thus, a human immunodeficiency arising from iRHOM2 deficiency causes divergent disease phenotypes that can involve the local microbial environment.

PMID:34937930 | DOI:10.1038/s41590-021-01093-y

Biol Reprod. 2021 Dec 22:ioab232. doi: 10.1093/biolre/ioab232. Online ahead of print.

ABSTRACT

During pregnancy, the immune system is modified to allow developmental developmental tolerance of the semi-allogeneic fetus and placenta to term. Pregnant women suffering from stress, anxiety and depression show dysfunctions of their immune system that may be responsible for fetal and/or newborn disorders, provided that provided that placental gene regulation is compromised. The present study explored the effects of maternal chronic self-perceived stress, anxiety and depression during pregnancy on the expression of immune related-genes and pathways in term placenta. Pregnancies were clinically monitored with the Beck’s Anxiety Inventory (BAI) and Edinburgh Postnatal Depression Scale (EPDS). A cutoff threshold for BAI/EPDS of 10 divided patients into two groups: Index group (≥10, n = 11) and a Control group (<10, n = 11), whose placentae were sampled at delivery. The placental samples were subjected to RNA-Sequencing, demonstrating that stress, anxiety and depression during pregnancy induced a major downregulation of placental transcripts related to immune processes such as T-cell regulation, interleukin and cytokine signaling or innate immune responses. Expression differences of main immune related genes such as CD46, CD15, CD8α & β ILR7α and CCR4 among others, were found in the index group (P < 0.05). Moreover, the key immune-like pathway involved in humoral and cellular immunity named “Primary immunodeficiency” was significantly downregulated in the index group compared to controls. Our results show that mechanisms ruling immune system functions are compromised at the maternal-fetal interface following self-perceived depressive symptoms and anxiety during pregnancy. These findings may help unveil mechanisms ruling the impact of maternal psychiatric symptoms and lead to new prevention/intervention strategies in complicated pregnancies.

PMID:34935902 | DOI:10.1093/biolre/ioab232