Publications by authors named "Julie E NiemeLa"
Background: Heterozygous immunoproteasome subunit beta-type 10 (PSMB10) mutations can cause severe combined immunodeficiency (SCID) and Omenn syndrome (OS). Hematopoietic stem cell transplantation in these patients is associated with severe complications and poor immune reconstitution, often resulting in death.
Objective: To perform immunological and molecular characterization of an infant with a PSMB10 heterozygous variant.
Article Synopsis
- * In a study of 9 individuals from 3 families, two variants of AIOLOS (Q402* and E82K) were found to cause haploinsufficiency through different mechanisms, affecting the protein’s DNA binding and stability.
- * Patients with AIOLOS haploinsufficiency experienced symptoms like reduced immune response, recurrent infections, and autoimmunity, highlighting the broader implications of AIOLOS mutations on health.
Article Synopsis
- Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare type of skin cancer linked to certain immune cell abnormalities, particularly involving CD8 T cells, and its genetic causes are not fully understood.* -
- The article discusses two cases of patients with B cell Expansion with NF-κB and T cell Anergy (BENTA) disease who presented novel forms of SPTCL, showcasing distinct symptoms and genetic mutations related to their conditions.* -
- Patient 1 had recurrent infections linked to a mutation and developed SPTCL and kidney issues early in life, while Patient 2 exhibited splenomegaly and underwent a bone marrow transplant, leading to remission of SPTCL despite ongoing B
Infections are among the most serious complications in patients with systemic lupus erythematosus (SLE), with bacterial and viral infections being the most common. Non-tuberculous mycobacterial (NTM) infections are quite rare and are typically seen in older patients with SLE with longstanding disease duration treated with corticosteroids. Here, we describe a 39-year-old woman with SLE and an unusual pattern of recurrent NTM disseminated infections.
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- The article discusses the discovery of germline biallelic null mutations in the ARPC5 gene, affecting the Arp2/3 actin nucleator complex, in two patients with severe recurrent infections, early-onset autoimmunity, and other health issues.
- The mutations lead to compromised functions across multiple cell types, but restoring protein expression in vitro can rescue the complex's conformation and functions.
- The study reveals that IL-6 signaling is uniquely affected, with important distinctions between classical and trans-signaling pathways, suggesting potential therapeutic targets for treatment.
Article Synopsis
- STAT6 is a key transcription factor involved in allergic inflammation, and researchers identified 16 patients from 10 families across three continents with severe allergic conditions related to its dysfunction.
- These patients exhibited various symptoms like early-onset immune issues, treatment-resistant skin conditions, asthma, and food allergies, all linked to rare mutations in the STAT6 gene that lead to a gain-of-function phenotype.
- The study suggests that these mutations cause a novel autosomal dominant allergic disorder and highlights the successful use of the anti-IL-4Rα antibody, dupilumab, as a precision treatment for managing symptoms and improving immune responses.
A multimorphic mutation in IRF4 causes human autosomal dominant combined immunodeficiency.
Sci Immunol
January 2023
Article Synopsis
- - Researchers discovered a recurrent mutation in the IRF4 gene, identified as p.T95R, linked to an autosomal dominant combined immunodeficiency (CID) in seven patients from six different families, leading to severe vulnerability to opportunistic infections and low antibody levels.
- - The mutation caused significant defects in the maturation of B cells and alterations in T cell populations, resulting in impaired immune responses, as demonstrated in both human patients and a knock-in mouse model with similar symptoms.
- - The altered IRF4 protein exhibited unusual behaviors, including stronger DNA binding but reduced activity on typical target genes, while also activating noncanonical genes, showcasing a complex interaction that disrupts normal immune function and leads to disease.
Article Synopsis
- Disseminated coccidioidomycosis (DCM) is a serious illness caused by Coccidioides fungi, primarily affecting individuals in the southwestern U.S. and Mexico, with only 30% of infected individuals showing symptoms and less than 1% developing DCM.
- Through whole-exome sequencing of 67 DCM patients, researchers identified genetic mutations, including haploinsufficient STAT3 and defects in β-glucan sensing and response, in a significant number of cases, influencing disease dissemination.
- A validation study with an additional 111 patients confirmed specific variants in genes like CLEC7A and PLCG2 that linked to weakened immune responses, indicating that impaired recognition of the fungi and lowered cytok
Article Synopsis
- * Patients with the AIOLOS p.N160S mutation showed issues with immune responses, including abnormal B cell development and impaired T cell differentiation, leading to increased susceptibility to infections and potential cancer.
- * Research indicated that the mutant AIOLOS protein impaired DNA binding and disrupted normal cellular functions, confirming its critical role in T and B cell development and the link between this mutation and immunological disorders.
Cushing syndrome and glucocorticoids: T-cell lymphopenia, apoptosis, and rescue by IL-21.
J Allergy Clin Immunol
January 2022
Article Synopsis
- Pediatric endogenous Cushing syndrome (eCs) is caused by pituitary tumors that produce corticotropin, leading to symptoms similar to long-term glucocorticoid therapy, which allows researchers to study its effects on immunity.
- The study involved immunologic analyses of healthy pediatric eCs patients before and after tumor removal, using various advanced techniques to investigate T-cell function and responses.
- Findings revealed that eCs patients had decreased thymic output and T-cell levels, alongside increased apoptosis, but these issues normalized post-surgery; additionally, the introduction of IL-21 showed potential in mitigating the adverse effects of glucocorticoids on T-cells.
Article Synopsis
- The SASH3 protein is an adaptor involved in orchestrating signaling in lymphocytes, and its gene is located on the X-chromosome.
- Researchers found 3 harmful mutations in the SASH3 gene in 4 unrelated male patients who displayed symptoms of combined immunodeficiency and immune dysregulation, leading to infections and autoimmune issues.
- The study reveals that SASH3 is crucial for proper lymphocyte function and survival, suggesting a new form of X-linked combined immunodeficiency in humans similar to defects seen in mouse models.
Article Synopsis
- IKZF1 mutations, which affect the Ikaros transcription factor, are linked to various serious health issues including recurrent infections and autoimmune diseases.
- The study investigated a specific IKZF1 variant found in a 3-month-old patient with multiple complications and revealed that this variant affects the protein's ability to bind DNA and localize properly within cells.
- The findings suggest that clinicians should consider IKZF1 mutations when diagnosing conditions like autoimmune hemolytic anemia and immunodeficiency in newborns.
Due to typesetting mistake, the caption of Figure 2 was mistakenly replaced with the caption of Figure 3.
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- IKAROS is a transcription factor essential for lymphocyte development, and mutations in its DNA binding domain can lead to immunodeficiency.
- The study presents four families with germline heterozygous variants in the IKAROS C-terminal dimerization domain, leading to blood disorders and malignancies, though the wild-type allele function remains intact.
- These dimerization mutations disrupt key regulatory mechanisms of the IKAROS gene, demonstrate haploinsufficiency and incomplete clinical penetrance, and expand the understanding of IKAROS-associated diseases with specific genotype-phenotype links.
Article Synopsis
- * A family is reported with a heterozygous mutation in NFKB2 that results in no protein expression and reduced mRNA, leading to decreased NFKB2 activity (haploinsufficiency) and associated clinical immunodeficiency.
- * Key immunological features include abnormal B cell development, low antibody levels, and specific signaling issues, which further clarify the genetics behind NFKB2-related immunodeficiency disorders.
Article Synopsis
- Chronic active Epstein-Barr virus (CAEBV) is characterized by high levels of EBV in the blood, particularly in natural killer (NK) cells, and the presence of immature NK cells, but its underlying causes are not well understood.* -
- A study of two patients with NK cell CAEBV revealed increased phosphorylation of signaling proteins (Akt, S6, STAT1) in their NK cells, indicating abnormal signaling pathways typically associated with the disease.* -
- The use of JAK inhibitors in the lab was effective in normalizing STAT1 phosphorylation in the patients' NK cells, suggesting a potential new treatment strategy for CAEBV.*
Article Synopsis
- Interleukin-2-inducible T cell kinase (ITK) is essential for T cell signaling, especially in controlling Epstein-Barr virus (EBV), and a patient with a specific mutation in ITK developed EBV-positive granulomatosis.
- The mutation (D540N) affects ITK's functionality, leading to low levels of critical immune cells, and persistent high EBV DNA even after treatment was administered.
- Notably, adding magnesium to the patient's CD8 T cells improved their ability to kill infected cells, suggesting that magnesium supplements could potentially help patients with ITK deficiencies.
Article Synopsis
- APECED is a genetic disorder linked to autoimmune diseases, with over 40% of affected individuals experiencing pneumonitis, often misdiagnosed despite clear respiratory symptoms.
- The study highlighted specific autoantibodies and a genetic mutation related to the development of pneumonitis, revealing distinct immune responses in the lungs of these patients.
- Immunomodulation targeting T and B lymphocytes proved effective in managing symptoms and improving lung function in patients with APECED pneumonitis, demonstrating the significance of understanding lung autoimmunity in this condition.
Article Synopsis
- Phosphoinositide 3-kinase (PI3K) is crucial for lymphocyte function, and mutations in its p110δ and p85α subunits lead to heightened activity and immune issues.
- The text discusses unique cases of a mother and child both suffering from severe toxoplasmosis due to a shared mutation affecting PI3K.
- It examines how this mutation and similar ones contribute to an increased risk of severe infections in activated PI3Kδ syndrome (APDS) and other primary immunodeficiencies.
Article Synopsis
- Severe Combined Immunodeficiency (SCID) is a critical primary immunodeficiency disorder marked by weak immune response, with a study of 57 Indian patients revealing symptoms like recurrent pneumonia and failure to thrive predominantly appearing in infants under 6 months.
- Hematopoietic Stem Cell Transplantation (HSCT) is the only effective treatment, though only four patients in the study received it, resulting in poor survival rates, and a significant 63% of patients exhibited lymphopenia.
- Genetic analysis revealed a diverse array of mutations contributing to SCID, with 32 novel variants identified, while 14% of cases remained uncharacterized despite advanced sequencing techniques; most cases involved T
Article Synopsis
- * Researchers identified seven patients with a new type of early-onset combined immunodeficiency related to new mutations in the IKZF1 gene, affecting its ability to bind DNA.
- * The immunodeficiency was marked by various immune system defects, including low counts of certain blood cells and T cell dysfunction, demonstrating that the mutations have a dominant negative effect, broadening the understanding of IKZF1-related diseases.