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.
Background The clinical and immunologic features of CD27 deficiency remain obscure because only a few patients have been identified to date. Objective We sought to identify novel mutations in TNFRSF7 .../ CD27 and to provide an overview of clinical, immunologic, and laboratory phenotypes in patients with CD27 deficiency. Methods Review of the medical records and molecular, genetic, and flow cytometric analyses of the patients and family members were performed. Treatment outcomes of previously described patients were followed up. Results In addition to the previously reported homozygous mutations c.G24A/p.W8X (n = 2) and c.G158A/p.C53Y (n = 8), 4 novel mutations were identified: homozygous missense c.G287A/p.C96Y (n = 4), homozygous missense c.C232T/p.R78W (n = 1), heterozygous nonsense c.C30A/p.C10X (n = 1), and compound heterozygous c.C319T/p.R107C-c.G24A/p.W8X (n = 1). EBV-associated lymphoproliferative disease/hemophagocytic lymphohistiocytosis, Hodgkin lymphoma, uveitis, and recurrent infections were the predominant clinical features. Expression of cell-surface and soluble CD27 was significantly reduced in patients and heterozygous family members. Immunoglobulin substitution therapy was administered in 5 of the newly diagnosed cases. Conclusion CD27 deficiency is potentially fatal and should be excluded in all cases of severe EBV infections to minimize diagnostic delay. Flow cytometric immunophenotyping offers a reliable initial test for CD27 deficiency. Determining the precise role of CD27 in immunity against EBV might provide a framework for new therapeutic concepts.
Recent findings strongly support hematopoietic stem cell transplantation (HSCT) in patients with severe presentation of LPS-responsive beige-like anchor protein (LRBA) deficiency, but long-term ...follow-up and survival data beyond previous patient reports or meta-reviews are scarce for those patients who do not receive a transplant.
This international retrospective study was conducted to elucidate the longitudinal clinical course of patients with LRBA deficiency who do and do not receive a transplant.
We assessed disease burden and treatment responses with a specially developed immune deficiency and dysregulation activity score, reflecting the sum and severity of organ involvement and infections, days of hospitalization, supportive care requirements, and performance indices.
Of 76 patients with LRBA deficiency from 29 centers (median follow-up, 10 years; range, 1-52), 24 underwent HSCT from 2005 to 2019. The overall survival rate after HSCT (median follow-up, 20 months) was 70.8% (17 of 24 patients); all deaths were due to nonspecific, early, transplant-related mortality. Currently, 82.7% of patients who did not receive a transplant (43 of 52; age range, 3-69 years) are alive. Of 17 HSCT survivors, 7 are in complete remission and 5 are in good partial remission without treatment (together, 12 of 17 70.6%). In contrast, only 5 of 43 patients who did not receive a transplant (11.6%) are without immunosuppression. Immune deficiency and dysregulation activity scores were significantly lower in patients who survived HSCT than in those receiving conventional treatment (P = .005) or in patients who received abatacept or sirolimus as compared with other therapies, and in patients with residual LRBA expression. Higher disease burden, longer duration before HSCT, and lung involvement were associated with poor outcome.
The lifelong disease activity, implying a need for immunosuppression and risk of malignancy, must be weighed against the risks of HSCT.
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Abstract Selective IgA deficiency in early life is quite common in Caucasian populations, but it is unclear whether it increases the risk of infections and allergic diseases during childhood. Serum ...IgA levels were measured in 2423 children at 4 years of age in a Swedish population based birth cohort (BAMSE). Parental questionnaires were repeatedly sent out during the child's first 8 years of life, collecting information about infections and allergic diseases. 14 children (1:173) were found to be IgA deficient at 4 years of age. These children had an increased risk of pseudocroup at year 1 ( p < 0.01) and food hypersensitivity at year 4 ( p < 0.05) as compared to IgA sufficient children. No increased risk was observed in the partial IgA deficiency group. The findings suggest that selective IgA deficiency may increase the risk of parentally reported pseudocroup and food hypersensitivity during early childhood.
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.
Nonhomologous end-joining (NHEJ) is one of the major DNA double-strand break repair pathways in mammalian cells and is required for both V(D)J recombination and class switch recombination (CSR), two ...Ig gene-diversification processes occurring during B cell development. DNA-dependent protein kinase, catalytic subunit (DNA-PKcs) is a component of the classical NHEJ machinery and has a critical function during V(D)J recombination. However, its role in CSR has been controversial. In this study, we examined the pattern of recombination junctions from in vivo-switched B cells from two DNA-PKcs-deficient patients. One of them harbored mutations that did not affect DNA-PKcs kinase activity but caused impaired Artemis activation; the second patient had mutations resulting in diminished DNA-PKcs protein expression and kinase activity. These results were compared with those from DNA-PKcs-deficient mouse B cells. A shift toward the microhomology-based alternative end-joining at the recombination junctions was observed in both human and mouse B cells, suggesting that the classical NHEJ pathway is impaired during CSR when DNA-PKcs is defective. Furthermore, cells from the second patient showed additional or more severe alterations in CSR and/or NHEJ, which may suggest that DNA-PKcs and/or its kinase activity have additional, Artemis-independent functions during these processes.
A series of expression cassettes which mediate secretion or surface display of antibody fragments was stably integrated in the chromosome of Lactobacillus paracasei. L. paracasei producing ...surface-anchored variable domain of llama heavy chain (VHH) (ARP1) directed against rotavirus showed efficient binding to rotavirus and protection in the mouse model of rotavirus infection.
Information concerning the longevity of immunity to SARS-CoV-2 following natural infection may have considerable implications for durability of immunity induced by vaccines. Here, we monitored the ...SARS-CoV-2 specific immune response in COVID-19 patients followed up to 15 months after symptoms onset. Following a peak at day 15–28 postinfection, the IgG antibody response and plasma neutralizing titers gradually decreased over time but stabilized after 6 months. Compared to G614, plasma neutralizing titers were more than 8-fold lower against variants Beta, Gamma, and Delta. SARS-CoV-2-specific memory B and T cells persisted in the majority of patients up to 15 months although a significant decrease in specific T cells, but not B cells, was observed between 6 and 15 months. Antiviral specific immunity, especially memory B cells in COVID-19 convalescent patients, is long-lasting, but some variants of concern may at least partially escape the neutralizing activity of plasma antibodies.
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•Plasma neutralizing antibodies persist in the majority of patients up to 15 months•Neutralizing activity is lower against variants of concern Delta, Beta, and Gamma•Specific memory B and T cells were present in 95% of patients up to 15 months•Specific T cells, but not B cells, were decreased between 6 and 15 months
Immunology; Immune response; Virology
Purpose
To investigate the risk of cancer in individuals with IgA deficiency compared with the general population.
Methods
Prospective nationwide population-based cohort study. We identified 2320 ...individuals with IgA deficiency (IgA levels < 0.07 g/L) diagnosed between 1980 and 2010 in six Swedish university hospitals. Individuals with IgA deficiency were then matched on age, sex, place of residence, and year of diagnosis with up to 10 general population controls (
n
= 23,130). Through linkage with the Swedish Cancer Register we calculated conditional hazard ratios (HRs) for cancer diagnosed after IgA deficiency diagnosis in patients without a previous cancer diagnosis.
Results
During follow-up, 125 individuals with IgA deficiency (61/10,000 person-years) and 984 controls (47/10,000 person-years) developed cancer (HR 1.31; 95%CI = 1.09–1.58). In cause-specific analyses, we found an increased risk of any gastrointestinal cancer (HR = 1.64; 95%CI = 1.07–2.50), but not for lymphoproliferative malignancy (HR 1.68; 95%CI = 0.89–3.19). Relative risk estimates for overall cancer were very high in the first year of follow-up (overall: HR = 2.80; 95%CI = 1.74–4.49), but failed to reach statistical significance thereafter. IgA deficiency diagnosed in childhood (
n
= 487) was not associated with overall cancer (HR = 3.26; 0.88–12.03).
Conclusions
Individuals with IgA deficiency are at a moderately increased risk of cancer, with excess risks of gastrointestinal cancer. This excess risk is highest just after diagnosis suggesting a degree of surveillance bias. Children with IgA deficiency were at no increased risk of cancer but the statistical power was limited in subanalyses.
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