Publications by authors named "Julie Niemela"

Purpose: In this study, we retrospectively reviewed the use of flow cytometry (FCM) in the diagnosis of inborn errors of immunity (IEIs) at a single center in Algeria. Sharing insights into our practical experience, we present FCM based diagnostic approaches adapted to different clinical scenarios.

Methods: Between May 2017 and February 2024, pediatric and adult patients presenting with clinical features suggestive of immunodeficiency were subjected to FCM evaluation, including lymphocyte subset analysis, detection of specific surface or intracellular proteins, and functional analysis of immune cells.

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  • The linear ubiquitin assembly complex (LUBAC), made up of HOIP, HOIL-1, and SHARPIN, is crucial for immune responses, with deficiencies leading to severe issues like immunodeficiency and autoinflammation.
  • Two individuals with SHARPIN deficiency exhibited autoinflammatory symptoms but did not have the expected skin problems seen in other cases, and their cells showed reduced immune responses.
  • Treatment with anti-TNF therapies successfully resolved the autoinflammatory symptoms in one case, highlighting LUBAC's important role in managing immune cell death and maintaining immune balance in humans.
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IKAROS, encoded by IKZF1, is a tumor suppressor and a key hematopoietic transcription factor responsible for lymphoid and myeloid differentiation. IKZF1 mutations result in inborn errors of immunity presenting with increased susceptibility to infections, immune dysregulation, and malignancies. In particular, patients carrying IKZF1 gain-of-function (GOF) mutations mostly exhibit symptoms of immune dysregulation and polyclonal plasma cell proliferation.

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Introduction: Mulibrey nanism (MUL) is a rare disorder caused by gene variants characterized by growth failure, dysmorphic features, congestive heart failure (CHF), and an increased risk of Wilms' tumor. Although immune system impairment has been documented in MUL, the underlying mechanisms remain poorly understood.

Methods: We present a case of MUL with progressive lymphopenia and review similar cases from the literature.

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  • * 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.
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  • Deleterious RUNX1 variants cause familial platelet disorder with myeloid malignancy (FPDMM), leading to symptoms like low platelet counts, dysfunctional platelets, and increased risk of blood cancers.
  • A study enrolled 214 participants from 2019 to 2021, revealing that many patients experienced thrombocytopenia and other blood abnormalities; some also had blood malignancies like leukemia.
  • Findings emphasize the need for a multidisciplinary approach to detect and manage these inherited disorders, aiming to improve understanding of FPDMM and guide future treatments.
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  • Mutations in genes related to proteasome function cause a chronic inflammatory condition known as CANDLE or PRAAS, characterized by elevated temperatures and immune system issues.
  • Five unrelated patients were studied, revealing novel genetic variants that contribute to the disease, with four carrying mutations in well-known CANDLE/PRAAS genes and one having mutations in less recognized genes.
  • The findings enhance understanding of genetic factors behind PRAAS and aid in better diagnosis and genetic counseling for affected individuals.
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  • 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
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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.
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Background: TCF3 is a transcription factor contributing to early lymphocyte differentiation. Germline monoallelic dominant negative and biallelic loss-of-function (LOF) null TCF3 mutations cause a fully penetrant severe immunodeficiency. We identified 8 individuals from 7 unrelated families with monoallelic LOF TCF3 variants presenting with immunodeficiency with incomplete clinical penetrance.

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  • 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.
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  • - 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.
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  • 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
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  • This study focused on a holistic genetic evaluation of patients with immune-related issues, recognizing that multiple genetic factors might contribute to their health conditions rather than just a single gene explanation.
  • Researchers analyzed genetic data from 1505 individuals, uncovering 361 molecular diagnoses linked to various immune presentations, with significant updates obtained through reanalysis and new gene discoveries.
  • The findings indicate that the majority of molecular diagnoses could inform treatment options, highlighting the potential for whole exome analysis to enhance our understanding of genetic contributions to health on a large scale.
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Germline gain-of-function (GOF) mutation of the signal transducer and activator of transcription 3 (STAT3) gene causes a disease clinically characterized by a significant lymphoproliferation, including lymphadenopathy and/or hepatosplenomegaly, as well as childhood onset autoimmunity. Here we present an adult patient who, during his early years of life, presented recurrent infections, autoimmune hemolytic anemia and benign lymphoproliferative disease, characterized by hepatosplenomegaly and lymphadenopathy, being diagnosed with common variable immunodeficiency (CVID) at 13 years of age. He was diagnosed with lymphocytic interstitial pneumonia at the age of 20.

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Background: CARD9 deficiency is an autosomal recessive primary immunodeficiency underlying increased susceptibility to fungal infection primarily presenting as invasive CNS Candida and/or cutaneous/invasive dermatophyte infections. More recently, a rare heterozygous dominant negative CARD9 variant c.1434 + 1G > C was reported to be protective from inflammatory bowel disease.

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  • * 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.
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  • 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.
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Mutations in recombinase activating genes 1 and 2 (RAG1/2) result in human severe combined immunodeficiency (SCID). The products of these genes are essential for V(D)J rearrangement of the antigen receptors during lymphocyte development. Mutations resulting in null-recombination activity in RAG1 or RAG2 are associated with the most severe clinical and immunological phenotypes, whereas patients with hypomorphic mutations may develop leaky SCID, including Omenn syndrome (OS).

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  • 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.
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