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Front Immunol. 2023 Oct 5;14:1279652. doi: 10.3389/fimmu.2023.1279652. eCollection 2023.

ABSTRACT

INTRODUCTION: The diagnosis and treatment of inborn errors of immunity (IEI) is a major challenge as the individual conditions are rare and often characterized by a variety of symptoms, which are often non disease-specific. Ideally, patients are treated in dedicated centers by physicians who specialize in the management of primary immune disorders. In this study, we used the example of Activated PI3Kδ syndrome (APDS), a rare IEI with an estimated prevalence of 1:1,000,000. We conducted surveys by questionnaire and interviewed physicians at different IEI centers in Germany.

METHODS: We queried structural aspects of IEI care in Germany, diagnostic procedures in IEI care (including molecular diagnostics), distribution of APDS patients, APDS symptoms and severity, treatment algorithms in APDS, the role of stem cell transplantation and targeted therapies in IEI with focus on APDS. We were especially interested in how genetic diagnostics may influence treatment decisions, e.g. with regard to targeted therapies.

RESULTS/DISCUSSION: Most centers care for both pediatric and adult patients. A total of 28 APDS patients are currently being treated at the centers we surveyed. Patient journeys vary considerably, as does severity of disease. Genetic diagnosis continues to gain importance – whole genome sequencing is likely to become routine in IEI in the next few years. According to the experts interviewed, stem cell transplantation and – with new molecules being approved – targeted therapies, will gain in importance for the treatment of APDS and IEI in general.

PMID:37868971 | PMC:PMC10588788 | DOI:10.3389/fimmu.2023.1279652

Am J Transl Res. 2023 Sep 15;15(9):5574-5593. eCollection 2023.

ABSTRACT

BACKGROUND: Kidney renal clear cell carcinoma (KIRC) is the most prevalent type of renal cell carcinoma (RCC), with a high incidence and mortality rate. There is a lack of sensitive biomarkers. Therefore, the discovery of accurate biomarkers for KIRC patients is critical to improve prognosis.

METHODS: We determined hub genes and their associated pathways involved in the pathogenesis of KIRC from the GSE66272 dataset consisting of KIRC (n = 26) and corresponding control (n = 26) samples and later validated the expression and methylation level of the identified hub genes on The Cancer Genomic Atlas (TCGA) datasets and Human RCC 786-O and normal HK-2 cell lines through RNA sequencing (RNA-seq), Reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and targeted bisulfite sequencing (bisulfite-seq) analyses.

RESULTS: The identified up-regulated four hub genes include TYROBP (Transmembrane Immune Signaling Adaptor TYROBP), PTPRC (Protein tyrosine phosphatase, receptor type, C), LCP2 (Lymphocyte cytosolic protein 2), and ITGB2 (Integrin Subunit Beta 2). Moreover, the higher expression of TYROBP, PTPRC, LCP2, and ITGB2 in KIRC patients insignificantly correlates with a poor prognosis in KIRC patients. In addition, hub genes were involved in the “Fc epsilon RI signaling pathway, asthma, natural cell killer mediated cytotoxicity, T cell receptor signaling pathway, primary immunodeficiency, Fc gamma R-mediated phagocytosis, malaria, leukocyte transendothelial migration, and legionellosis” pathways and associated with the infiltration level of CD8+ T, CD4+ T, and macrophage cells.

CONCLUSION: Our integrated in silico and in vitro analysis identified important hub genes (TYROBP, PTPRC, LCP2, and ITGB2) involved in the pathogenesis of KIRC as possible diagnostic biomarkers.

PMID:37854221 | PMC:PMC10579006

Am J Hematol. 2023 Oct 19. doi: 10.1002/ajh.27137. Online ahead of print.

ABSTRACT

ZAP70 has a prognostic value in chronic lymphocytic leukemia (CLL), through altered B-cell receptor signaling, which is important in CLL pathogenesis. A good correlation between ZAP70 expression in CLL cells and the occurrence of autoimmune phenomena has been reported. Yet, the great majority of CLL-associated autoimmune cytopenia is due to polyclonal immunoglobulin (Ig) G synthesized by nonmalignant B cells, and this phenomenon is poorly understood. Here, we show, using flow cytometry, that a substantial percentage of CD5- nonmalignant B cells from CLL patients expresses ZAP70 compared with CD5- B cells from healthy subjects. This ZAP70 expression in normal B cells from CLL patients was also evidenced by the detection of ZAP70 mRNA at single-cell level with polyclonal Ig heavy- and light-chain gene transcripts. ZAP70+ normal B cells belong to various B-cell subsets and their presence in the naïve B-cell subset suggests that ZAP70 expression may occur during early B-cell development in CLL patients and potentially before malignant transformation. The presence of ZAP70+ normal B cells is associated with autoimmune cytopenia in CLL patients in our cohort of patients, and recombinant antibodies produced from these ZAP70+ nonmalignant B cells were frequently autoreactive including anti-platelet reactivity. These results provide a better understanding of the implication of ZAP70 in CLL leukemogenesis and the mechanisms of autoimmune complications of CLL.

PMID:37853951 | DOI:10.1002/ajh.27137

Front Pediatr. 2023 Oct 2;11:1260296. doi: 10.3389/fped.2023.1260296. eCollection 2023.

ABSTRACT

INTRODUCTION: This study presents the results of a real-life, multicenter, prospective, post-approval safety evaluation of Clairyg® 50 mg/mL, a 5% intravenous immunoglobulin (IVIg) liquid, in 59 children (aged < 12 years) with primary immunodeficiency diseases (PID) (n = 32) or immune thrombocytopenia (ITP) (n = 27) in France.

METHODS: The primary objective of the study was to assess the safety and tolerability of Clairyg®, recording all serious and non-serious adverse events (AEs), whether related (rAEs) or not related to the product. Secondary objectives aimed at evaluating the administration of Clairyg® under routine conditions and the available efficacy data to better document the benefit/risk ratio in this pediatric population. An exploratory objective was added to evaluate the potential factors associated with the occurrence of rAEs. Patients received Clairyg® according to the approved dosage under normal conditions of prescriptions over a median follow-up period of 11.8 months.

RESULTS: A total of 549 infusions (PID: n = 464 and ITP: n = 85), were administered, of which 58.8% were preceded by premedication. The most frequent rAEs were headache, vomiting, and pyrexia in both indications. Most of them were considered non-serious and mild or moderate in intensity. A severe single rAE was observed (aseptic meningitis) in a 4-year-old girl presenting with chronic ITP. The exploratory multivariate analysis of potential co-factors showed that the occurrence of rAEs is significantly linked to high IVIg doses and possibly to female gender. The annualized rate of serious bacterial infections was 0.11 for patients with PID. For patients with ITP, 74.1% experienced at least one bleeding episode during the follow-up, mostly a cutaneous one, and none had gastrointestinal, genitourinary, or central nervous system bleeding.

CONCLUSION: Clairyg® was well tolerated and allowed for control of serious bacterial infection in PID and serious bleeding in ITP, which are the main complications in these respective pediatric disorders. No new safety signal was detected in children less than 12 years-old in real-life conditions of use.

PMID:37849499 | PMC:PMC10577179 | DOI:10.3389/fped.2023.1260296

Exp Dermatol. 2023 Oct 17. doi: 10.1111/exd.14954. Online ahead of print.

ABSTRACT

Pyoderma gangrenosum (PG) is a rare ulcerative neutrophilic dermatosis that is occasionally associated with primary immunodeficiency. Though contributions from dysregulation of the innate immune system, neutrophil dysfunction and genetic predisposition have been postulated, the precise pathogenesis of PG has not yet been elucidated. This article reviews reported cases of coexisting PG and primary immunodeficiency in order to gain insight into the complex pathophysiology of PG. Our findings suggest that variations in genes such as RAG1, ITGB2, IRF2BP2 and NFκB1 might play a role in genetically predisposing patients to develop PG. These studies support the feasibility of the role of somatic gene variation in the pathogenesis of PG which warrants further exploration to guide targeted therapeutics.

PMID:37846943 | DOI:10.1111/exd.14954

Cureus. 2023 Sep 13;15(9):e45159. doi: 10.7759/cureus.45159. eCollection 2023 Sep.

ABSTRACT

Severe combined immunodeficiency (SCID) is an inborn error of immunity invariably resulting in mortality in infancy until managed by hematopoietic stem cell transplant (HSCT). We present an unusual case of SCID with a rare mutation involving the non-homologous end-joining 1 (NHEJ1) gene, where a haploidentical HSCT was carried out with modified conditioning and graft versus host prophylaxis regimen using proteasome inhibitor bortezomib with a successful outcome.

PMID:37842439 | PMC:PMC10572685 | DOI:10.7759/cureus.45159

Front Pediatr. 2023 Sep 29;11:1269396. doi: 10.3389/fped.2023.1269396. eCollection 2023.

ABSTRACT

BACKGROUND: Bare lymphocyte syndrome type II (BLS II) is a rare form of severe combined immunodeficiency caused by mutations in the CIITA gene, which regulates major histocompatibility complex class II (MHC II) expression.

OBJECTIVE: We report the case of a Saudi boy with a novel mutation in the CIITA gene who presented with acute and late meningoencephalomyelitis, resulting in severe neurodevelopmental regression.

METHODS: We reviewed the patient’s clinical and laboratory data obtained from medical records and performed a literature search on BLS II.

RESULTS: The patient presented with acute meningoencephalomyelitis confirmed by MRI findings and was later found to carry a homozygous pathogenic variant in the CIITA gene p.(Leu473Hisfs*15). The patient had no MCH II expression, confirming the genetic diagnosis of autosomal recessive BLS II. Surprisingly, the patient’s prior clinical history was unremarkable for significant infections or autoimmunity.

CONCLUSIONS: We report a case with a novel CIITA gene mutation presenting atypically with a late and isolated severe infection. Isolated severe meningoencephalomyelitis may be a manifestation of primary immunodeficiency.

PMID:37842025 | PMC:PMC10570541 | DOI:10.3389/fped.2023.1269396

Front Immunol. 2023 Sep 28;14:1257398. doi: 10.3389/fimmu.2023.1257398. eCollection 2023.

ABSTRACT

INTRODUCTION: Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency. CVID is a heterogeneous disorder with a presumed multifactorial etiology. Intravenous or subcutaneous immunoglobulin replacement therapy (IgRT) can prevent severe infections but not underlying immune dysregulation.

METHODS: In this study, we evaluated the serum concentrations of proinflammatory (TNF-α, IL-1β, IL-6) and immunoregulatory cytokines (IL-10), as well as lipopolysaccharide (LPS) and soluble CD14 (sCD14) in CVID individuals with infectious only (INF-CVID), and those with additional systemic autoimmune and inflammatory disorders (NIC-CVID), and healthy donors (HD).

RESULTS: Our results showed increased serum concentrations of TNF-α, IL-1β, IL-6, and IL-10 in both INF-CVID and NIC-CVID subjects compared to HD. However, elevations of TNF-α, IL-1β, IL-6, and IL-10 were significantly more marked in NIC-CVID than INF-CVID. Additionally, LPS concentrations were increased only in NIC-CVID but not in INF-CVID compared to HD. Circulating levels of sCD14 were significantly increased in NIC-CVID compared to both INF-CVID and HD.

DISCUSSION: These findings indicate persistent cytokine dysregulation despite IgRT in individuals with CVID. Moreover, the circulating cytokine profile reveals the heterogeneity of immune dysregulation in different subgroups of CVID subjects.

PMID:37841257 | PMC:PMC10568625 | DOI:10.3389/fimmu.2023.1257398

J Clin Immunol. 2023 Oct 14. doi: 10.1007/s10875-023-01583-8. Online ahead of print.

ABSTRACT

GATA2 deficiency is a rare disorder encompassing a broadly variable phenotype and its clinical picture is continuously evolving. Since it was first described in 2011, up to 500 patients have been reported. Here, we describe a cohort of 31 Italian patients (26 families) with molecular diagnosis of GATA2 deficiency. Patients were recruited contacting all the Italian Association of Pediatric Hematology and Oncology (AIEOP) centers, the Hematology Department in their institution and Italian societies involved in the field of vascular anomalies, otorhinolaryngology, dermatology, infectious and respiratory diseases. Median age at the time of first manifestation, molecular diagnosis and last follow-up visit was 12.5 (age-range, 2-52 years), 18 (age-range, 7-64 years) and 22 years (age-range, 3-64), respectively. Infections (39%), hematological malignancies (23%) and undefined cytopenia (16%) were the most frequent symptoms at the onset of the disease. The majority of patients (55%) underwent hematopoietic stem cell transplantation. During the follow-up rarer manifestations emerged. The clinical penetrance was highly variable, with the coexistence of severely affected pediatric patients and asymptomatic adults in the same pedigree. Two individuals remained asymptomatic at the last follow-up visit. Our study highlights new (pilonidal cyst/sacrococcygeal fistula, cholangiocarcinoma and gastric adenocarcinoma) phenotypes and show that lymphedema may be associated with null/regulatory mutations. Countrywide studies providing long prospective follow-up are essential to unveil the exact burden of rarer manifestations and the natural history in GATA2 deficiency.

PMID:37837580 | DOI:10.1007/s10875-023-01583-8

J Clin Immunol. 2023 Oct 14. doi: 10.1007/s10875-023-01598-1. Online ahead of print.

ABSTRACT

OBJECTIVE: To compare the consumption of antibiotics (AB), systemic steroids, and inhaled bronchodilators/glucocorticoids in the 3 years preceding the diagnosis of common variable immunodeficiency (CVID) among CVID patients and matched controls and to estimate whether the level of consumption was associated with the risk of a subsequent CVID diagnosis.

METHODS: We conducted a nested case-control study, identifying all individuals (n=130 cases) diagnosed with CVID in Denmark (1994-2014) and 45 age- and sex-matched population controls per case (n=5850 controls) from national registers. Drug consumption was estimated as defined daily doses per person-year. We used conditional logistic regression to compute odds ratios and 95% confidence intervals.

RESULTS: In the 3 years preceding a CVID diagnosis, we observed more frequent and higher consumption of all three drug classes. The association between consumption and risk of subsequent CVID diagnosis was statistically significant for all drug classes. The association was stronger with higher consumption and shorter time to CVID diagnosis. The fraction of cases compared to the controls redeeming ≥1 prescription of the included drugs during the study period was higher for AB (97% vs 52%), systemic steroids (35% vs 7.4%), and inhaled bronchodilators/glucocorticoids (46% vs 11.7%) (p<0.001).

CONCLUSION: CVID patients have significantly higher use of AB, systemic steroids, and inhaled bronchodilators/glucocorticoids in the 3 years preceding CVID diagnosis than controls. Prescribing these drugs in primary healthcare could be an opportunity to consider (proactive) screening for CVID. Further studies are needed to identify optimal prescription cutoffs that could endorse its inclusion in public health policies.

PMID:37833619 | DOI:10.1007/s10875-023-01598-1