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J Clin Immunol. 2024 Apr 8;44(4):96. doi: 10.1007/s10875-024-01688-8.

ABSTRACT

PURPOSE: The interleukin-7 receptor (IL-7R) is primarily expressed on lymphoid cells and plays a crucial role in the development, proliferation, and survival of T cells. Autosomal recessive mutations that disrupt IL-7Rα chain expression give rise to a severe combined immunodeficiency (SCID), which is characterized by lymphopenia and a T^–B⁺NK⁺ phenotype. The objective here was to diagnose two siblings displaying the T^–B⁺NK⁺ SCID phenotype as initial clinical genetic testing did not detect any variants in known SCID genes.

METHODS: Whole genome sequencing (WGS) was utilized to identify potential variants causing the SCID phenotype. Splicing prediction tools were employed to assess the deleterious impact of the mutation. Polymerase Chain Reaction (PCR), Sanger sequencing, flow cytometry, and ELISA were then used to validate the pathogenicity of the detected mutation.

RESULTS: We discovered a novel homozygous synonymous mutation in the IL7R gene. Our functional studies indicate that this variant is pathogenic, causing exon 6, which encodes the transmembrane domain, to be preferentially spliced out.

CONCLUSION: In this study, we identified a novel rare synonymous mutation causing a loss of IL-7Rα expression at the cellular membrane. This case demonstrates the value of reanalyzing genetic data based on the clinical phenotype and highlights the significance of functional studies in determining the pathogenicity of genetic variants.

PMID:38587703 | DOI:10.1007/s10875-024-01688-8

Pediatr Nephrol. 2024 Apr 8. doi: 10.1007/s00467-024-06334-4. Online ahead of print.

ABSTRACT

Nuclear factor kappa B (NF-κB) family plays a central role in the human immune system. Heterozygous variants in NFKB2 typically cause immunodeficiency with various degrees of central adrenal insufficiency, autoimmunity, and ectodermal dysplasia. No reported case has presented kidney failure as an initial symptom. Moreover, documentation of kidney involvement of this disease is limited. CASE DIAGNOSIS: A 2-year-old female who presented with dyspnea and hypertensive emergency in the setting of new-onset nephrotic syndrome with acute-on chronic kidney injury with resultant chronic kidney disease (CKD) was found to have a novel heterozygous N-terminal variant in NFKB2 (c.880del: p. Tyr294Ilefs*4) with mild hypogammaglobulinemia, but no adrenal insufficiency or ectodermal dysplasia. She became dialysis-dependent during her initial hospitalization and developed CKD stage 5D, requiring continued peritoneal dialysis. She is currently awaiting kidney transplantation. CONCLUSIONS: Whether nephrotic syndrome or kidney injury or failure is the primary symptom of this variant or secondary to some event remains unknown. Further case accumulation is warranted.

PMID:38587560 | DOI:10.1007/s00467-024-06334-4

J Allergy Clin Immunol Glob. 2024 Mar 7;3(2):100241. doi: 10.1016/j.jacig.2024.100241. eCollection 2024 May.

ABSTRACT

BACKGROUND: Reported outcomes in patients with primary immunodeficiency (PID) infected by coronavirus disease 2019 (COVID-19) have been variable owing to a combination of viral strain heterogeneity, differences in patient populations and health systems, and local availability of vaccination and specific COVID-19 therapies. There are few reports on the experience of Australian patients with PID during the pandemic.

OBJECTIVES: In this retrospective study, we describe the baseline characteristics and short-term outcomes of patients with PID who were infected by COVID-19 and known to the Royal Melbourne Hospital, a major tertiary center in Victoria, Australia.

METHODS: Between April 2021 and April 2022, a total of 31 of 138 patients with PID were affected by COVID-19. More than half of them had 3 vaccine doses at the time of infection (which at the time was considered being fully vaccinated) and received COVID-19-targeted treatment.

RESULTS: All of the infected patients had ambulatory disease, with no cases of morbidity or mortality. In line with the current literature, the PID subtypes described did not appear to independently predict worse outcomes.

CONCLUSIONS: Some protective factors include this cohort’s relatively younger average age and its high uptake of vaccination and COVID-19 therapies.

PMID:38585448 | PMC:PMC10997894 | DOI:10.1016/j.jacig.2024.100241

J Allergy Clin Immunol. 2024 Apr 3:S0091-6749(24)00330-0. doi: 10.1016/j.jaci.2024.03.018. Online ahead of print.

ABSTRACT

BACKGROUND: Monoallelic loss-of-function IKZF1 (IKAROS) variants cause B-cell deficiency or combined immunodeficiency, whereas monoallelic gain-of-function IKZF1 variants have recently been reported to cause hypergammaglobulinemia, abnormal plasma cell differentiation, autoimmune and allergic manifestations, and infections.

METHODS: We studied seven relatives with autoimmune/inflammatory diseases and lymphoproliferative diseases. We analysed biopsy results and performed whole-exome sequencing and immunological studies.

RESULTS: Disease onset occurred at a mean age of 25.2 years (range: 10-64, years). Six patients suffered from autoimmune/inflammatory diseases, four had confirmed immunoglobulin G4-related disease (IgG4-RD), and five developed B-cell malignancies: lymphoma in four and multiple myeloma in the remaining patient. Patients without immunosuppression were not particularly prone to infectious diseases. Three patients suffered from life-threatening COVID-19 pneumonia, one of whom had autoantibodies neutralizing interferon (IFN)-α. The recently described IKZF1 gain-of-function p.R183H variant was found in the five affected relatives tested and in a six-year-old asymptomatic girl. Immunological analysis revealed hypergammaglobulinemia and high frequencies of certain lymphocyte subsets (exhausted B cells, effector memory CD4 T cells, T_EMRA and CD28^–CD57⁺ CD4+ and CD8+ T cells, Th2 and Tfh2 cells) attesting to immune dysregulation. Partial clinical responses to rituximab and corticosteroids were observed, and treatment with lenalidomide, which promotes IKAROS degradation, was initiated in three patients.

CONCLUSION: Heterozygosity for gain-of-function IKZF1 variants underlies autoimmunity/inflammatory diseases, IgG4-RD and B-cell malignancies, the onset of which may occur in adulthood. Clinical and immunological data are similar to those for patients with unexplained IgG4-RD. Patients may therefore benefit from treatments inhibiting pathways displaying IKAROS-mediated overactivity.

PMID:38579942 | DOI:10.1016/j.jaci.2024.03.018

J Clin Immunol. 2024 Apr 5;44(4):94. doi: 10.1007/s10875-024-01682-0.

ABSTRACT

PURPOSE: Deficiency of stromal interaction molecule 1 (STIM1) results in combined immunodeficiency accompanied by extra-immunological findings like enamel defects and myopathy. We here studied a patient with a STIM1 loss-of-function mutation who presented with severe lymphoproliferation. We sought to explore the efficacy of the mTOR inhibitor rapamycin in controlling disease manifestations and reversing aberrant T-cell subsets and functions, which has never been used previously in this disorder.

METHODS: Clinical findings of the patient were collected over time. We performed immunological evaluations before and after initiation of rapamycin treatment, including detailed lymphocyte subset analyses, alterations in frequencies of circulating T follicular helper (cT_FH) and regulatory T (Treg) cells and their subtypes as well as T cell activation and proliferation capacities.

RESULTS: A novel homozygous exon 2 deletion in STIM1 was detected in a 3-year-old girl with severe lymphoproliferation, recurrent infections, myopathy, iris hypoplasia, and enamel hypoplasia. Lymphoproliferation was associated with severe T-cell infiltrates. The deletion resulted in a complete loss of protein expression, associated with a lack of store-operated calcium entry response, defective T-cell activation, proliferation, and cytokine production. Interestingly, patient blood contained fewer cT_FH and increased circulating follicular regulatory (cT_FR) cells. Abnormal skewing towards T_H2-like responses in certain T-cell subpopulations like cT_FH, non-cT_FH memory T-helper, and Treg cells was associated with increased eosinophil numbers and serum IgE levels. Treatment with rapamycin controlled lymphoproliferation, improved T-cell activation and proliferation capacities, reversed T-cell responses, and repressed high IgE levels and eosinophilia.

CONCLUSIONS: This study enhances our understanding of STIM1 deficiency by uncovering additional abnormal T-cell responses, and reveals for the first time the potential therapeutic utility of rapamycin for this disorder.

PMID:38578569 | DOI:10.1007/s10875-024-01682-0

Eur Ann Allergy Clin Immunol. 2024 Apr 5. doi: 10.23822/EurAnnACI.1764-1489.340. Online ahead of print.

NO ABSTRACT

PMID:38578199 | DOI:10.23822/EurAnnACI.1764-1489.340

J Investig Med High Impact Case Rep. 2024 Jan-Dec;12:23247096241239544. doi: 10.1177/23247096241239544.

ABSTRACT

Citrobacter koseri (formerly classified as Citrobacter diversus) is a gram-negative bacillus (GNB) that occurs as an opportunistic pathogen in neonates and immunocompromised patients. Citrobacter species have been implicated in nosocomial settings leading to infections involving the urinary tract, respiratory tract, liver, biliary tract, meninges, and even in rarer conditions-blood stream infection and infective endocarditis (IE). Gram-negative bacilli are responsible for 3% to 4% of all IE cases and have been traditionally associated with intravenous drug users. Patients with non-HACEK (species other than Haemophilus species, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, or Kinglella species) GNB IE have poor clinical outcomes with higher rates of in-hospital mortality and complications. The American Heart Association (AHA) and Infectious Diseases Society of America (IDSA) both recommend the use of combination antibiotic therapy with a beta-lactam (penicillins, cephalosporins, or carbapenems) and either an aminoglycoside or fluoroquinolones for 6 weeks (about 1 and a half months) to treat IE due to non-HACEK GNB. Citrobacter koseri is becoming more recognized due to its inherent resistance to ampicillin and emerging drug resistance to beta lactams and aminoglycosides requiring carbapenem therapy. Our case is of a 75-year-old male with no previously reported history of primary or secondary immunodeficiency disorders who developed C koseri blood stream infection. His infectious work-up revealed mitral valve IE and septic cerebral emboli resulting in ischemic infarcts. This case illustrates the importance of recognizing GNB organisms as rising human pathogens in IE cases even without active injection drug use or nosocomial exposure.

PMID:38577758 | DOI:10.1177/23247096241239544

J Med Access. 2024 Mar 28;8:27550834241236596. doi: 10.1177/27550834241236596. eCollection 2024 Jan-Dec.

ABSTRACT

BACKGROUND: Secondary immunodeficiency (SID) disorders are known to occur in patients with haematological malignancies (HM) due to immunosuppressive treatments. Recurring infections causing subsequent morbidity and mortality commonly occur in this patient cohort. Immunoglobulin replacement therapy (IgRT) benefits patients with primary antibody deficiencies. However, evidence supporting their therapeutic role is not as explicit in SID-associated antibody deficiencies, which raises the questions regarding its use in SID and the knock-on effects of this use on its access and availability more generally.

OBJECTIVES: This study aimed to learn about the use of immunoglobulins in SID, identify themes concerning its use and access and suggest methods for improving access.

DESIGN: This study included a thematic analysis of a published data set of 43 articles concerning immunoglobulin use and access in SID.

DATA SOURCES AND METHODS: The data set used to perform the thematic analysis is based on research articles identified from Excerpta Medica Database (EMBASE) and PubMed databases, published as part of a systematic review and part 1 of this two-part publication series.

RESULTS: A thematic synthesis was conducted to identify recurrent themes. The three primary themes included (1) the context for IgRT prescription, which included patient characteristics and cost burden of IgRT administration, and its use in different countries; (2) factors contributing to inappropriate IgRT use, including health care professionals’ awareness of IgRT, disparity between guidelines and actual clinical practice, and the effect of shortages on prescription and chemotherapy-induced hypogammaglobulinemia (HGG); and (3) measures identified to improve IgRT use and access, which included multidisciplinary involvement, improved diagnostic tools and safer withdrawal and stewardship protocols.

CONCLUSIONS: IgRT use is increasing in HM as a supportive therapy but without comprehensive clinical guidelines and appropriate prescribing recommendations, medication wastage may occur with consequences for immunoglobulin access.

PMID:38559466 | PMC:PMC10981255 | DOI:10.1177/27550834241236596

Cent Eur J Immunol. 2023;48(4):350-357. doi: 10.5114/ceji.2023.133949. Epub 2023 Dec 21.

ABSTRACT

Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described disease characterized by recurrent infections, lymphoproliferation with a high risk of malignancy, early-onset cytopenia, and a propensity for autoimmune diseases. Hematopoietic stem cell transplantation (HSCT) has proven to be an effective treatment method; however, the recovery process after HSCT is prolonged and accompanied by complications. In this study, we present the case of a patient with APDS type 1. Despite showing signs of immunodeficiency at the age of 6 months, it took almost 6 years to reach a definitive diagnosis. The patient experienced recurrent infections, often accompanied by anemia requiring transfusions, and multifocal nonmalignant lymphoproliferation. Only after receiving the appropriate diagnosis was it possible to implement proper and accurate treatment. HSCT was performed when the patient was 6 years old, leading to significant improvement in his condition. At the 17-month post-HSCT follow-up, the boy is asymptomatic and in good general health, although close monitoring continues due to mixed chimerism and delayed humoral immune recovery. Applying HSCT before the patient develops malignancy contributes to expanding the use of HSCT as a treatment option for APDS type 1.

PMID:38558560 | PMC:PMC10976654 | DOI:10.5114/ceji.2023.133949

J Allergy Clin Immunol. 2024 Mar 29:S0091-6749(24)00326-9. doi: 10.1016/j.jaci.2024.03.014. Online ahead of print.

ABSTRACT

BACKGROUND: Prior studies have reported that renal insufficiency occurs in a small percentage of patients with predominantly antibody deficiency (PAD) and in about 2% of patients with common variable immunodeficiency (CVID).

OBJECTIVE: The goal of our study was to understand and evaluate the prevalence and type of renal complications in PAD patients in the United States Immunodeficiency Network (USIDNET) cohort. We hypothesized there is an association between certain renal complications and severity of immunophenotype in patients with PAD.

METHODS: We performed a query of patients with PAD from the USIDNET cohort with renal complications. Patients with documented renal disease such as chronic kidney disease (CKD), nephrolithiasis, nephritis, and renal failure syndrome were included. We compared immunophenotype, flow cytometry and immunoglobulin (Ig) levels of PAD patients with renal complications to the total PAD USIDNET cohort.

RESULTS: We identified that 140/2071 (6.8%) of PAD patients had renal complications. Of these 50 (35.7%) had CKD, 46 (32.9%) had nephrolithiasis, 18 (12.9 %) had nephritis, and 50 (35.7%) had other renal complications. Compared to the total USIDNET cohort of patients with PAD, patients with CKD had lower ALCs, CD3+ T-cells, CD4+ T-cells, CD19+ B-cells, CD20+ B-cells and CD27+IgD- B-cells (p<0.05 for all). Patients with nephritis had lower ALCs, CD19+ B-cells, CD27+ B-cells and IgE levels (p<0.05 for all) compared to PAD patients without renal disease.

CONCLUSIONS: We identified that 6.8% of PAD patients in the USIDNET cohort had a documented renal complication. The patients with nephritis and CKD had a more severe immunophenotype compared to the overall PAD cohort.

PMID:38555979 | DOI:10.1016/j.jaci.2024.03.014