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1.
Article in English | MEDLINE | ID: mdl-38710235

ABSTRACT

BACKGROUND: LCP1 encodes L-plastin, an actin-bundling protein primarily expressed in hematopoietic cells. In mouse and fish models, LCP1 deficiency has been shown to result in hematologic and immune defects. OBJECTIVE: This study aimed to determine the nature of a human inborn error of immunity resulting from a novel genetic variant of LCP1. METHODS: We performed genetic, protein, and cellular analysis of PBMCs from a kindred with apparent autosomal dominant immune deficiency. We identified a candidate causal mutation in LCP1, which we evaluated by engineering the orthologous mutation in mice and Jurkat cells. RESULTS: A splice-site variant in LCP1 segregated with lymphopenia, neutropenia, and thrombocytopenia. The splicing defect resulted in at least 2 aberrant transcripts, producing an in-frame deletion of 24 nucleotides, and a frameshift deletion of exon 8. Cellular analysis of the kindred revealed a proportionate reduction of T and B cells and a mild expansion of transitional B cells. Similarly, mice carrying the orthologous genetic variant exhibited the same in-frame aberrant transcript, reduced expression Lcp1 and gene dose-dependent leukopenia, mild thrombocytopenia, and lymphopenia, with a significant reduction of T-cell populations. Functional analysis revealed that LCP1c740-1G>A confers a defect in platelet development and function with aberrant spreading on collagen. Immunologic analysis revealed defective actin organization in T cells, reduced migration of PBMCs from patients, splenocytes from mutant mice, and a mutant Jurkat cell line in response to CXCL12; impaired germinal center B-cell expansion after immunization; and reduced cytokinesis during T cell proliferation. CONCLUSIONS: We describe a unique human hematopoietic defect affecting neutrophils, lymphocytes, and platelets arising from partial LCP1 deficiency.

2.
Nat Commun ; 15(1): 2345, 2024 Mar 25.
Article in English | MEDLINE | ID: mdl-38528069

ABSTRACT

Loss-of-function mutations have provided crucial insights into the immunoregulatory actions of Foxp3+ regulatory T cells (Tregs). By contrast, we know very little about the consequences of defects that amplify aspects of Treg function or differentiation. Here we show that mice heterozygous for an Ikbkb gain-of-function mutation develop psoriasis. Doubling the gene dose (IkbkbGoF/GoF) results in dactylitis, spondylitis, and characteristic nail changes, which are features of psoriatic arthritis. IkbkbGoF mice exhibit a selective expansion of Foxp3 + CD25+ Tregs of which a subset express IL-17. These modified Tregs are enriched in both inflamed tissues, blood and spleen, and their transfer is sufficient to induce disease without conventional T cells. Single-cell transcriptional and phenotyping analyses of isolated Tregs reveal expansion of non-lymphoid tissue (tissue-resident) Tregs expressing Th17-related genes, Helios, tissue-resident markers including CD103 and CD69, and a prominent NF-κB transcriptome. Thus, IKK2 regulates tissue-resident Treg differentiation, and overactivity drives dose-dependent skin and systemic inflammation.


Subject(s)
Gain of Function Mutation , I-kappa B Kinase , T-Lymphocytes, Regulatory , Animals , Mice , Forkhead Transcription Factors/genetics , I-kappa B Kinase/genetics , Inflammation/genetics
3.
Sci Immunol ; 9(93): eadj4748, 2024 Mar 29.
Article in English | MEDLINE | ID: mdl-38330097

ABSTRACT

CD11c+ atypical B cells (ABCs) are an alternative memory B cell lineage associated with immunization, infection, and autoimmunity. However, the factors that drive the transcriptional program of ABCs have not been identified, and the function of this population remains incompletely understood. Here, we identified candidate transcription factors associated with the ABC population based on a human tonsillar B cell single-cell dataset. We identified CD11c+ B cells in mice with a similar transcriptomic signature to human ABCs, and using an optimized CRISPR-Cas9 knockdown screen, we observed that loss of zinc finger E-box binding homeobox 2 (Zeb2) impaired ABC formation. Furthermore, ZEB2 haplo-insufficient Mowat-Wilson syndrome (MWS) patients have decreased circulating ABCs in the blood. In Cd23Cre/+Zeb2fl/fl mice with impaired ABC formation, ABCs were dispensable for efficient humoral responses after Plasmodium sporozoite immunization but were required to control recrudescent blood-stage malaria. Immune phenotyping revealed that ABCs drive optimal T follicular helper (TFH) cell formation and germinal center (GC) responses and they reside at the red/white pulp border, likely permitting better access to pathogen antigens for presentation. Collectively, our study shows that ABC formation is dependent on Zeb2, and these cells can limit recrudescent infection by sustaining GC reactions.


Subject(s)
Germinal Center , Persistent Infection , Animals , Humans , Mice , Immunization , Vaccination , Zinc Finger E-box Binding Homeobox 2/genetics
4.
J Exp Med ; 221(4)2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38417019

ABSTRACT

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a clear genetic component. While most SLE patients carry rare gene variants in lupus risk genes, little is known about their contribution to disease pathogenesis. Amongst them, SH2B3-a negative regulator of cytokine and growth factor receptor signaling-harbors rare coding variants in over 5% of SLE patients. Here, we show that unlike the variant found exclusively in healthy controls, SH2B3 rare variants found in lupus patients are predominantly hypomorphic alleles, failing to suppress IFNGR signaling via JAK2-STAT1. The generation of two mouse lines carrying patients' variants revealed that SH2B3 is important in limiting the number of immature and transitional B cells. Furthermore, hypomorphic SH2B3 was shown to impair the negative selection of immature/transitional self-reactive B cells and accelerate autoimmunity in sensitized mice, at least in part due to increased IL-4R signaling and BAFF-R expression. This work identifies a previously unappreciated role for SH2B3 in human B cell tolerance and lupus risk.


Subject(s)
Autoimmunity , Lupus Erythematosus, Systemic , Animals , Humans , Mice , Autoimmunity/genetics , B-Cell Activating Factor/metabolism , B-Lymphocytes , Lupus Erythematosus, Systemic/genetics , Precursor Cells, B-Lymphoid
5.
Case Rep Oncol ; 17(1): 329-336, 2024.
Article in English | MEDLINE | ID: mdl-38404406

ABSTRACT

Introduction: Acquired angioedema due to C1 esterase inhibitor deficiency (C1INH-AAE) is most associated with lymphoproliferative disorders (LPDs), particularly low-grade B-cell subtypes. The condition remains under-recognized with long diagnostic delays due to various challenges including a lack of awareness of the condition. Case Presentation: We discuss 4 cases of C1INH-AAE associated with low-grade B-cell LPDs, including various diagnostic and management challenges. As our cases illustrate, constitutional symptoms or overt manifestations of LPD at diagnosis are often absent. Hence, a comprehensive multimodal approach to screening for an underlying B-LPD is important when a diagnosis of acquired angioedema is made. Levels of complement C4, C1q, and C1INH are useful for diagnosing C1INH-AAE and for monitoring disease activity. Changes in these parameters may also indicate relapse of the underlying hematological malignancy. Treating the underlying disorder is important as this commonly leads to clinical improvement with decreased episodes of angioedema and normalization of complement studies. Conclusion: Awareness of C1INH-AAE can lead to an early diagnosis of hematological malignancies. The absence of constitutional symptoms emphasizes the need for a comprehensive multimodal approach to screening for LPD in C1INH-AAE. C4, C1INH level, and function are useful for monitoring disease activity.

6.
J Allergy Clin Immunol ; 153(4): 1125-1139, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38072195

ABSTRACT

BACKGROUND: Inborn errors of immunity (IEI) often lack specific disease models and personalized management. Signal transducer and activator of transcription (STAT)-1 gain of function (GoF) is such example of an IEI with diverse clinical phenotype with unclear pathomechanisms and unpredictable response to therapy. Limitations in obtaining fresh samples for functional testing and research further highlights the need for patient-specific ex vivo platforms. OBJECTIVE: Using STAT1-GoF as an example IEI, we investigated the potential of patient-derived expanded potential stem cells (EPSC) as an ex vivo platform for disease modeling and personalized treatment. METHODS: We generated EPSC derived from individual STAT1-GoF patients. STAT1 mutations were confirmed with Sanger sequencing. Functional testing including STAT1 phosphorylation/dephosphorylation and gene expression with or without Janus activating kinase inhibitors were performed. Functional tests were repeated on EPSC lines with GoF mutations repaired by CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) editing. RESULTS: EPSC were successfully reprogrammed from STAT1-GoF patients and expressed the same pluripotent makers as controls, with distinct morphologic differences. Patient-derived EPSC recapitulated the functional abnormalities of index STAT1-GoF patients with STAT1 hyperphosphorylation and increased expression of STAT1 and its downstream genes (IRF1, APOL6, and OAS1) after IFN-γ stimulation. Addition of ruxolitinib and baricitinib inhibited STAT1 hyperactivation in STAT1-GoF EPSC in a dose-dependent manner, which was not observed with tofacitinib. Corrected STAT1 phosphorylation and downstream gene expression were observed among repaired STAT1-GoF EPSC cell lines. CONCLUSION: This proof-of-concept study demonstrates the potential of our patient-derived EPSC platform to model STAT1-GoF. We propose this platform when researching, recapitulating, and repairing other IEI in the future.


Subject(s)
Gain of Function Mutation , STAT1 Transcription Factor , Stem Cells , Humans , Mutation , Phosphorylation , STAT1 Transcription Factor/genetics , STAT1 Transcription Factor/metabolism , Stem Cells/immunology , Stem Cells/metabolism
7.
Sci Adv ; 9(49): eadi9566, 2023 12 08.
Article in English | MEDLINE | ID: mdl-38055819

ABSTRACT

Autosomal dominant loss-of-function (LoF) variants in cytotoxic T-lymphocyte associated protein 4 (CTLA4) cause immune dysregulation with autoimmunity, immunodeficiency and lymphoproliferation (IDAIL). Incomplete penetrance and variable expressivity are characteristic of IDAIL caused by CTLA-4 haploinsufficiency (CTLA-4h), pointing to a role for genetic modifiers. Here, we describe an IDAIL proband carrying a maternally inherited pathogenic CTLA4 variant and a paternally inherited rare LoF missense variant in CLEC7A, which encodes for the ß-glucan pattern recognition receptor DECTIN-1. The CLEC7A variant led to a loss of DECTIN-1 dimerization and surface expression. Notably, DECTIN-1 stimulation promoted human and mouse regulatory T cell (Treg) differentiation from naïve αß and γδ T cells, even in the absence of transforming growth factor-ß. Consistent with DECTIN-1's Treg-boosting ability, partial DECTIN-1 deficiency exacerbated the Treg defect conferred by CTL4-4h. DECTIN-1/CLEC7A emerges as a modifier gene in CTLA-4h, increasing expressivity of CTLA4 variants and acting in functional epistasis with CTLA-4 to maintain immune homeostasis and tolerance.


Subject(s)
Haploinsufficiency , Lectins, C-Type , Animals , Humans , Mice , Autoimmunity , CTLA-4 Antigen/genetics , Lectins, C-Type/genetics
9.
Clin Immunol ; 252: 109646, 2023 07.
Article in English | MEDLINE | ID: mdl-37209807

ABSTRACT

BACKGROUND: Kikuchi-Fujimoto disease (KFD) is a self-limited inflammatory disease of unknown pathogenesis. Familial cases have been described and defects in classical complement components C1q and C4 have been identified in some patients. MATERIAL AND METHODS: We describe genetic and immune investigations of a 16 years old Omani male, a product of consanguineous marriage, who presented with typical clinical and histological features of KFD. RESULTS: We identified a novel homozygous single base deletion in C1S (c.330del; p. Phe110LeufsTer23) resulting in a defect in the classical complement pathway. The patient was negative for all serological markers of SLE. In contrast, two female siblings (also homozygous for the C1S mutation), one has autoimmune thyroid disease (Hashimoto thyroiditis) and a positive ANA and the other sibling has serology consistent with SLE. CONCLUSION: We report the first association between C1s deficiency and KFD.


Subject(s)
Histiocytic Necrotizing Lymphadenitis , Adolescent , Humans , Male , Complement C1s/genetics , Histiocytic Necrotizing Lymphadenitis/genetics , Histiocytic Necrotizing Lymphadenitis/complications , Histiocytic Necrotizing Lymphadenitis/pathology , Loss of Function Mutation
10.
Cell Mol Immunol ; 20(7): 777-793, 2023 07.
Article in English | MEDLINE | ID: mdl-37161048

ABSTRACT

As chronic antigenic stimulation from infection and autoimmunity is a feature of primary antibody deficiency (PAD), analysis of affected patients could yield insights into T-cell differentiation and explain how environmental exposures modify clinical phenotypes conferred by single-gene defects. CD57 marks dysfunctional T cells that have differentiated after antigenic stimulation. Indeed, while circulating CD57+ CD4+ T cells are normally rare, we found that they are increased in patients with PAD and markedly increased with CTLA4 haploinsufficiency or blockade. We performed single-cell RNA-seq analysis of matched CD57+ CD4+ T cells from blood and tonsil samples. Circulating CD57+ CD4+ T cells (CD4cyt) exhibited a cytotoxic transcriptome similar to that of CD8+ effector cells, could kill B cells, and inhibited B-cell responses. CTLA4 restrained the formation of CD4cyt. While CD57 also marked an abundant subset of follicular helper T cells, which is consistent with their antigen-driven differentiation, this subset had a pre-exhaustion transcriptomic signature marked by TCF7, TOX, and ID3 expression and constitutive expression of CTLA4 and did not become cytotoxic even after CTLA4 inhibition. Thus, CD57+ CD4+ T-cell cytotoxicity and exhaustion phenotypes are compartmentalised between blood and germinal centers. CTLA4 is a key modifier of CD4+ T-cell cytotoxicity, and the pathological CD4cyt phenotype is accentuated by infection.


Subject(s)
B-Lymphocytes , CD4-Positive T-Lymphocytes , B-Lymphocytes/metabolism , CD57 Antigens/metabolism , Cell Differentiation , CTLA-4 Antigen , Humans
11.
Nature ; 605(7909): 349-356, 2022 05.
Article in English | MEDLINE | ID: mdl-35477763

ABSTRACT

Although circumstantial evidence supports enhanced Toll-like receptor 7 (TLR7) signalling as a mechanism of human systemic autoimmune disease1-7, evidence of lupus-causing TLR7 gene variants is lacking. Here we describe human systemic lupus erythematosus caused by a TLR7 gain-of-function variant. TLR7 is a sensor of viral RNA8,9 and binds to guanosine10-12. We identified a de novo, previously undescribed missense TLR7Y264H variant in a child with severe lupus and additional variants in other patients with lupus. The TLR7Y264H variant selectively increased sensing of guanosine and 2',3'-cGMP10-12, and was sufficient to cause lupus when introduced into mice. We show that enhanced TLR7 signalling drives aberrant survival of B cell receptor (BCR)-activated B cells, and in a cell-intrinsic manner, accumulation of CD11c+ age-associated B cells and germinal centre B cells. Follicular and extrafollicular helper T cells were also increased but these phenotypes were cell-extrinsic. Deficiency of MyD88 (an adaptor protein downstream of TLR7) rescued autoimmunity, aberrant B cell survival, and all cellular and serological phenotypes. Despite prominent spontaneous germinal-centre formation in Tlr7Y264H mice, autoimmunity was not ameliorated by germinal-centre deficiency, suggesting an extrafollicular origin of pathogenic B cells. We establish the importance of TLR7 and guanosine-containing self-ligands for human lupus pathogenesis, which paves the way for therapeutic TLR7 or MyD88 inhibition.


Subject(s)
Gain of Function Mutation , Lupus Erythematosus, Systemic , Toll-Like Receptor 7 , Animals , Autoimmunity/genetics , B-Lymphocytes , Cyclic GMP/analogs & derivatives , Guanosine , Humans , Lupus Erythematosus, Systemic/genetics , Mice , Myeloid Differentiation Factor 88/genetics , Myeloid Differentiation Factor 88/metabolism , Toll-Like Receptor 7/genetics , Toll-Like Receptor 7/metabolism
12.
Clin Immunol ; 236: 108938, 2022 03.
Article in English | MEDLINE | ID: mdl-35121105

ABSTRACT

Many patients with immunodeficiencies require lifelong immunoglobulin replacement therapy (IgRT). In a multicenter, randomized, open-label, crossover, non-inferiority 3-month-trial, we compared the impact of the subcutaneous immunoglobulin Gammanorm® administered via pump or syringe (rapid push). Primary endpoint was the life quality index (LQI), secondary endpoints were QoL (SF36v2), satisfaction (TSQM-11), disease and treatment burden (PRISM), incidence of infections and adverse events (AE), treatment costs, and IgG levels. 28/30 patients completed the study. Most of the endpoints were comparable. Drug administrations with rapid push were more frequent, but reduced total time expenditure and some costs. Of the TSQM-11/LQI/SF36 components only "treatment interference with daily activities" was superior with pump and two QoL domains with rapid push. Both delivery devices showed favorable safety. Rapid push was preferred by 34.5% of patients. It proved to be an efficacious and cost-effective alternative to pumps adding to patient choice and increasing flexibility during long-term IgRT.


Subject(s)
Immunologic Deficiency Syndromes , Quality of Life , Adult , Humans , Immunization, Passive , Immunoglobulin G , Immunologic Deficiency Syndromes/therapy , Infusions, Subcutaneous
13.
J Exp Med ; 219(1)2022 01 03.
Article in English | MEDLINE | ID: mdl-34889940

ABSTRACT

B cell self-tolerance is maintained through multiple checkpoints, including restraints on intracellular signaling and cell trafficking. P2RY8 is a receptor with established roles in germinal center (GC) B cell migration inhibition and growth regulation. Somatic P2RY8 variants are common in GC-derived B cell lymphomas. Here, we identify germline novel or rare P2RY8 missense variants in lupus kindreds or the related antiphospholipid syndrome, including a "de novo" variant in a child with severe nephritis. All variants decreased protein expression, F-actin abundance, and GPCR-RhoA signaling, and those with stronger effects increased AKT and ERK activity and cell migration. Remarkably, P2RY8 was reduced in B cell subsets from some SLE patients lacking P2RY8 gene variants. Low P2RY8 correlated with lupus nephritis and increased age-associated B cells and plasma cells. By contrast, P2RY8 overexpression in cells and mice restrained plasma cell development and reinforced negative selection of DNA-reactive developing B cells. These findings uncover a role of P2RY8 in immunological tolerance and lupus pathogenesis.


Subject(s)
Antiphospholipid Syndrome/immunology , Immune Tolerance/immunology , Lupus Erythematosus, Systemic/immunology , Mutation, Missense/immunology , Receptors, Purinergic P2Y/immunology , Animals , Antiphospholipid Syndrome/genetics , Antiphospholipid Syndrome/metabolism , B-Lymphocyte Subsets/immunology , B-Lymphocyte Subsets/metabolism , Cell Line, Tumor , Female , HEK293 Cells , Humans , Immune Tolerance/genetics , Lupus Erythematosus, Systemic/genetics , Lupus Erythematosus, Systemic/metabolism , Lupus Nephritis/genetics , Lupus Nephritis/immunology , Lupus Nephritis/metabolism , Male , Mice, Inbred C57BL , Mutation, Missense/genetics , Pedigree , Plasma Cells/immunology , Plasma Cells/metabolism , Receptors, Purinergic P2Y/genetics , Receptors, Purinergic P2Y/metabolism , Signal Transduction/genetics , Signal Transduction/immunology
14.
Front Pediatr ; 10: 1098426, 2022.
Article in English | MEDLINE | ID: mdl-36733767

ABSTRACT

More than 400 single gene defects have been identified as inborn errors of immunity, including many arising from genes encoding proteins that affect NF-κB activity. We summarise the skin phenotypes in this subset of disorders and provide an overview of pathogenic mechanisms. NF-κB acts cell-intrinsically in basal epithelial cells during differentiation of skin appendages, influences keratinocyte proliferation and survival, and both responses to and amplification of inflammation, particularly TNF. Skin phenotypes include ectodermal dysplasia, reduction and hyperproliferation of keratinocytes, and aberrant recruitment of inflammatory cells, which often occur in combination. Phenotypes conferred by these rare monogenic syndromes often resemble those observed with more common defects. This includes oral and perineal ulceration and pustular skin disease as occurs with Behcet's disease, hyperkeratosis with microabscess formation similar to psoriasis, and atopic dermatitis. Thus, these genotype-phenotype relations provide diagnostic clues for this subset of IEIs, and also provide insights into mechanisms of more common forms of skin disease.

15.
Eur J Med Genet ; 64(12): 104347, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34619368

ABSTRACT

We present a case with congenital syndromic asplenia associated with immune deficiency, glandular hypospadias and cryptorchidism. Genetic analysis identified a likely pathogenic de novo variant in NR2F2. Pathogenic NR2F2 variants have been associated with other congenital anomalies affecting the central axis, such as congenital heart disease and diaphragmatic hernia, which were not part of our patient's clinical features. The association between NR2F2 and asplenia (including glandular hypospadias and cryptorchidism) has been described in animal models and our report is the first expanding the NR2F2 clinical spectrum in humans to include asplenia.


Subject(s)
COUP Transcription Factor II/genetics , Genetic Variation/genetics , Heterotaxy Syndrome/genetics , Child , Humans , Male , Phenotype
16.
Lupus ; 30(11): 1756-1763, 2021 Oct.
Article in English | MEDLINE | ID: mdl-34266320

ABSTRACT

OBJECTIVE: To compare the frequency of rare variants in genes of the pathophysiologically relevant endosomal Toll-like receptor (eTLR) pathway and any quantifiable differences in variant rarity, predicted deleteriousness, or molecular proximity in patients with systemic lupus erythematosus (SLE) and healthy controls. PATIENTS AND METHODS: 65 genes associated with the eTLR pathway were identified by literature search and pathway analysis. Using next generation sequencing techniques, these were compared in two randomised cohorts of patients with SLE (n = 114 and n = 113) with 197 healthy controls. Genetically determined ethnicity was used to normalise minor allele frequencies (MAF) for the identified genetic variants and these were then compared by their frequency: rare (MAF < 0.005), uncommon (MAF 0.005-0.02), and common (MAF >0.02). This was compared to the results for 65 randomly selected genes. RESULTS: Patients with SLE are more likely to carry a rare nonsynonymous variant affecting proteins within the eTLR pathway than healthy controls. Furthermore, individuals with SLE are more likely to have multiple rare variants in this pathway. There were no differences in rarity, Combined Annotation Dependent Depletion (CADD) score, or molecular proximity for rare eTLR pathway variants. CONCLUSIONS: Rare non-synonymous variants are enriched in patients with SLE in the eTLR pathway. This supports the hypothesis that SLE arises from several rare variants of relatively large effect rather than many common variants of small effect.


Subject(s)
Lupus Erythematosus, Systemic , Toll-Like Receptors , Endosomes/genetics , Gene Frequency , Genetic Predisposition to Disease , Genome-Wide Association Study , High-Throughput Nucleotide Sequencing , Humans , Lupus Erythematosus, Systemic/genetics , Mutation , Toll-Like Receptors/genetics
17.
Europace ; 23(3): 441-450, 2021 03 08.
Article in English | MEDLINE | ID: mdl-33200177

ABSTRACT

AIMS: In 2003, an Australian woman was convicted by a jury of smothering and killing her four children over a 10-year period. Each child died suddenly and unexpectedly during a sleep period, at ages ranging from 19 days to 18 months. In 2019 we were asked to investigate if a genetic cause could explain the children's deaths as part of an inquiry into the mother's convictions. METHODS AND RESULTS: Whole genomes or exomes of the mother and her four children were sequenced. Functional analysis of a novel CALM2 variant was performed by measuring Ca2+-binding affinity, interaction with calcium channels and channel function. We found two children had a novel calmodulin variant (CALM2 G114R) that was inherited maternally. Three genes (CALM1-3) encode identical calmodulin proteins. A variant in the corresponding residue of CALM3 (G114W) was recently reported in a child who died suddenly at age 4 and a sibling who suffered a cardiac arrest at age 5. We show that CALM2 G114R impairs calmodulin's ability to bind calcium and regulate two pivotal calcium channels (CaV1.2 and RyR2) involved in cardiac excitation contraction coupling. The deleterious effects of G114R are similar to those produced by G114W and N98S, which are considered arrhythmogenic and cause sudden cardiac death in children. CONCLUSION: A novel functional calmodulin variant (G114R) predicted to cause idiopathic ventricular fibrillation, catecholaminergic polymorphic ventricular tachycardia, or mild long QT syndrome was present in two children. A fatal arrhythmic event may have been triggered by their intercurrent infections. Thus, calmodulinopathy emerges as a reasonable explanation for a natural cause of their deaths.


Subject(s)
Infanticide , Tachycardia, Ventricular , Arrhythmias, Cardiac , Australia , Child , Child, Preschool , Death, Sudden, Cardiac/etiology , Female , Humans , Infant , Ryanodine Receptor Calcium Release Channel , Tachycardia, Ventricular/diagnosis , Tachycardia, Ventricular/genetics
18.
Intern Med J ; 51(6): 939-947, 2021 06.
Article in English | MEDLINE | ID: mdl-32388900

ABSTRACT

BACKGROUND: Haemophagocytic lymphohistiocytosis (HLH) is a rare disorder with a poor prognosis characterised by substantial immune activation leading to end-organ failure. In childhood, genetic defects that impair cytotoxic function of natural killer cells and T cells. (HLH) are often identified. In adults, clinical manifestations are similar to those observed in children but the aetiology is often unclear. AIMS: To evaluate whether poor prognosis for adult HLH is in part due to lack of awareness of the disorder, which results in incomplete investigation and failure to implement timely treatment. METHODS: We performed a retrospective case series of adult-onset HLH in a tertiary hospital in Australia. We evaluated clinical characteristics, treatment and outcome, and related these to application of standard diagnostic criteria for HLH. RESULTS: In our centre, incomplete assessment of HLH criteria was common. Serum ferritin was the criterion most commonly assessed. Hyperferritinaemia ≥10 000 µg/L was highly sensitive in detecting patients with adult-onset HLH; however, the majority of patients who had hyperferritinaemia ≥10 000 µg/L did not have adult-onset HLH. CONCLUSION: The present study highlights the importance of comprehensive application of diagnostic criteria to improve accuracy and timelines of the diagnosis of adult onset HLH.


Subject(s)
Lymphohistiocytosis, Hemophagocytic , Adult , Australia , Child , Humans , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/therapy , Retrospective Studies
19.
Front Immunol ; 12: 806043, 2021.
Article in English | MEDLINE | ID: mdl-35154081

ABSTRACT

Elucidating links between genotype and phenotype in patients with rare inborn errors of immunity (IEIs) provides insights into mechanisms of immune regulation. In many autosomal dominant IEIs, however, variation in expressivity and penetrance result in complex genotype-phenotype relations, while some autosomal recessive IEIs are so rare that it is difficult to draw firm conclusions. Phenocopies arise when an environmental or non-genetic factor replicates a phenotype conferred by a specific genotype. Phenocopies can result from therapeutic antibodies or autoantibodies that target a protein to replicate aspects of the phenotype conferred by mutations in the gene encoding the same protein. Here, we consider IEIs arising from rare genetic variants in CTLA4 and PDCD1 and compare clinical and laboratory manifestations arising as drug-induced phenocopies (immune related adverse events, IRAEs) in cancer patients treated with immune checkpoint inhibitors (ICI) and identify outstanding questions regarding mechanism of disease.


Subject(s)
CTLA-4 Antigen/genetics , Genetic Diseases, Inborn/diagnosis , Genetic Diseases, Inborn/genetics , Immune System Diseases/diagnosis , Immune System Diseases/genetics , Phenotype , Programmed Cell Death 1 Receptor/genetics , CTLA-4 Antigen/metabolism , Genetic Association Studies , Genetic Predisposition to Disease , Genetic Variation , Haploinsufficiency , Humans , Immunologic Deficiency Syndromes/diagnosis , Immunologic Deficiency Syndromes/genetics , Loss of Function Mutation , Programmed Cell Death 1 Receptor/metabolism
20.
Cell Rep Med ; 2(12): 100475, 2021 12 21.
Article in English | MEDLINE | ID: mdl-35028616

ABSTRACT

We identify an intronic deletion in VANGL1 that predisposes to renal injury in high risk populations through a kidney-intrinsic process. Half of all SLE patients develop nephritis, yet the predisposing mechanisms to kidney damage remain poorly understood. There is limited evidence of genetic contribution to specific organ involvement in SLE.1,2 We identify a large deletion in intron 7 of Van Gogh Like 1 (VANGL1), which associates with nephritis in SLE patients. The same deletion occurs at increased frequency in an indigenous population (Tiwi Islanders) with 10-fold higher rates of kidney disease compared with non-indigenous populations. Vangl1 hemizygosity in mice results in spontaneous IgA and IgG deposition within the glomerular mesangium in the absence of autoimmune nephritis. Serum transfer into B cell-deficient Vangl1+/- mice results in mesangial IgG deposition indicating that Ig deposits occur in a kidney-intrinsic fashion in the absence of Vangl1. These results suggest that Vangl1 acts in the kidney to prevent Ig deposits and its deficiency may trigger nephritis in individuals with SLE.


Subject(s)
Antibodies/adverse effects , Carrier Proteins/genetics , Gene Deletion , Kidney Diseases/pathology , Membrane Proteins/genetics , Adult , Aged , Animals , Biopsy , Cohort Studies , DNA Copy Number Variations/genetics , Homozygote , Humans , Introns/genetics , Kidney/metabolism , Kidney/pathology , Lupus Nephritis/genetics , Membrane Proteins/deficiency , Membrane Proteins/metabolism , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Risk Factors
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