Blog

J Clin Immunol. 2022 Dec 1. doi: 10.1007/s10875-022-01415-1. Online ahead of print.

ABSTRACT

PURPOSE: Only some allergists/immunologists provide care throughout the lifespan despite their training. Although transition of care (TOC) guidelines exist, research on provider perspectives on TOC for pediatric primary immunodeficiency (PID) patients is lacking. We aimed to characterize knowledge, attitudes, and practices and establish clinician needs using a needs assessment survey.

METHODS: The 15-min online survey was adapted from an existing rheumatology TOC survey and was emailed to the American Academy of Allergy Asthma and Immunology (AAAAI) and Clinical Immunology Society (CIS) members. Our primary hypothesis was that both AAAAI and CIS providers report being underprepared for TOC and would express interest in TOC resources and consensus.

RESULTS: Forty-nine of 1250 eligible AAAAI and 67 of 698 eligible CIS participants completed the survey (4.8% vs 11.3% participation rate). Many (53.1% vs 59.7%) respondents transition their own patients but also retain adult patients (59.2% vs 52.2%). Many accepted transition patients (85.7% vs 92.5%). In total, 24.1% of respondents did not have a TOC policy while 18.9% have an informal policy. Only 25.0% were satisfied with their current practices while 43.9% agreed that a consensus statement would be useful.

CONCLUSION: Despite a small sample size and high rate of unanswered questions, our findings show that TOC remains overlooked in our specialty and that providers want and need additional training and resources. There is a clear need to develop and evaluate the effectiveness of evidence-based TOC guidelines, resources, and best practices for PID patients.

PMID:36454452 | DOI:10.1007/s10875-022-01415-1

Case Rep Urol. 2022 Nov 21;2022:3817554. doi: 10.1155/2022/3817554. eCollection 2022.

ABSTRACT

Chylous ascites is an uncommon complication after surgery that can result in malnutrition and immunodeficiency. Therefore, surgical interventions are reserved for refractory patients, and the primary success factor for these interventions is locating the point of leakage, which is often tricky. We describe a case of a 56-year-old male with chylous ascites after laparoscopic radical nephrectomy and lumbo-aortic lymphadenectomy for kidney cancer. The patient was initially managed with dietary modifications and drainage placement. Afterward, lymphography with Lipiodol, percutaneous embolization of the leakage point, and total parenteral nutrition were established. Finally, the patient underwent laparoscopic repair after identifying the leakage point by injecting methylene blue through an inguinal node. Complete resolution was achieved, and no complications related to the procedure were recorded. Intranodal methylene blue injection can be an invaluable tool to identify the point of leakage in selected patients to improve the outcomes of surgical repair of refractory chylous ascites.

PMID:36452185 | PMC:PMC9705082 | DOI:10.1155/2022/3817554

Gastric Cancer. 2022 Nov 30. doi: 10.1007/s10120-022-01353-2. Online ahead of print.

ABSTRACT

BACKGROUND: Primary gastric linitis plastica (GLP) is a distinct phenotype of gastric cancer with poor survival. Comprehensive molecular profiles and putative therapeutic targets of GLP remain undetermined.

METHODS: We subjected 10 tumor-normal tissue pairs to whole exome sequencing (WES) and whole transcriptome sequencing (WTS). 10 tumor samples were all GLP which involves 100% of the gastric wall macroscopically. TCGA data were compared to generate the top mutated genes and the overexpressed genes in GLP.

RESULTS: Our results reveal that GLP has distinctive genomic and transcriptomic features, dysfunction in the Hippo pathway is likely to be a key step during GLP development. 6 genes were identified as significantly highly mutated genes in GLP, including AOX1, ANKRD36C, CPXM1, PTPN14, RPAP1, and DCDC1). MUC6, as a previously identified gastric cancer driver gene, has a high mutation rate (20%) in GLP. 20% of patients in our GLP cohort had CDH1 mutations, while none had RHOA mutations. GLP exhibits high immunodeficiency and low AMPK pathway activity. Our WTS results showed that 3 PI3K-AKT pathway-related genes (PIK3R2, AKT3, and IGF1) were significantly up-regulated in GLP. Two genes were identified using immunohistochemistry (IHC), IGF2BP3 and MUC16, which specifically expressed in diffuse-type-related gastric cancer cell lines, and its knockdown inhibits PI3K-AKT pathway activity.

CONCLUSIONS: We provide the first integrative genomic and transcriptomic profiles of GLP, which may facilitate its diagnosis, prognosis, and treatment.

PMID:36450891 | DOI:10.1007/s10120-022-01353-2

Hum Genet. 2022 Nov 29. doi: 10.1007/s00439-022-02506-0. Online ahead of print.

ABSTRACT

Loss-of-function variants in AP3D1 have been linked to Hermansky-Pudlak syndrome (HPS) 10, a severe multisystem disorder characterized by oculocutaneous albinism, immunodeficiency, neurodevelopmental delay, hearing loss (HL), and neurological abnormalities, fatal in early childhood. Here, we report a consanguineous family who presented with presumably isolated autosomal recessive (AR) HL. Whole-exome sequencing was performed on all core family members, and selected patients were screened using array-based copy-number analysis and karyotyping. Candidate variants were validated by Sanger sequencing and assessed in silico. A homozygous, likely pathogenic p.V711I missense variant in AP3D1 segregated with the HL. The family was characterized by thorough medical and laboratory examination. The HL was consistent across patients and accompanied by neurological manifestations in two brothers. The sole female patient was diagnosed with premature ovarian failure. Further findings, including mild neutropenia and reduced NK-cell cytotoxicity in some as well as brain alterations in all homozygous patients, were reminiscent of HPS10, though milder and lacking the characteristic albinism. Previously unrecognized, milder, isolated HL was identified in all heterozygous carriers. A protein model indicates that the variant interferes with protein-protein interactions. These results suggest that a missense variant alters inner-ear-specific functions leading to HL with mild HPS10-like symptoms of variable penetrance. Milder HL in heterozygous carriers may point towards semi-dominant inheritance of this trait. Since all previously reported HPS10 cases were pediatric, it is unknown whether the observed primary ovarian insufficiency recapitulates the subfertility in Ap3d1-deficient mice.

PMID:36445457 | DOI:10.1007/s00439-022-02506-0

Ann Allergy Asthma Immunol. 2022 Oct 29:S1081-1206(22)01898-1. doi: 10.1016/j.anai.2022.10.019. Online ahead of print.

NO ABSTRACT

PMID:36441081 | DOI:10.1016/j.anai.2022.10.019

Front Pharmacol. 2022 Nov 9;13:1023522. doi: 10.3389/fphar.2022.1023522. eCollection 2022.

ABSTRACT

Hemophagocytic disorders are severe and life-threatening conditions that can be genetic in origin [i.e., primary hemophagocytic lymphohistiocytosis (HLH)] or result from infections (i.e., secondary hemophagocytic lymphohistiocytosis), rheumatologic disease [i.e., macrophage activation syndrome (MAS)], and less frequently immunodeficiency or metabolic disease. Although rare, drug-induced hemophagocytosis needs to be considered in the work-up as it requires specific management strategies. Most drug-induced hemophagocytic disorders are related to Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). We present the case of a 7-year-old girl who initially presented with fever, maculopapular rash, and unilateral lymphadenopathy, who went on to develop hemophagocytosis secondary to DRESS caused by prolonged combination treatment with amoxicillin/clavulanic acid and trimethoprim/sulfamethoxazole. This case illustrates the importance of considering adverse drug reactions in the evaluations of patients with a hemophagocytic process.

PMID:36438790 | PMC:PMC9681788 | DOI:10.3389/fphar.2022.1023522

Clin Exp Immunol. 2022 Nov 26:uxac109. doi: 10.1093/cei/uxac109. Online ahead of print.

ABSTRACT

IKAROS/IKZF1 plays a pivotal role in lymphocyte differentiation and development. Germline mutations in IKZF1, which have been shown to associated with primary immunodeficiency, can be classified through four different mechanisms of action depending on the protein expression and its functional defects: haploinsufficiency, dimerization defective, dominant negative, and gain-of-function. These different mechanisms are associated with variable degrees of susceptibility to infectious diseases, autoimmune disorders, allergic diseases, and malignancies. To date, more than 30 heterozygous IKZF1 germline variants have been reported in patients with primary immunodeficiency. Here we review recent discoveries and clinical/immunological characterization of IKAROS-associated disorders that are linked to different mechanisms of action in IKAROS function.

PMID:36433803 | DOI:10.1093/cei/uxac109

J Clin Med. 2022 Nov 17;11(22):6795. doi: 10.3390/jcm11226795.

ABSTRACT

Selective immunoglobulin E deficiency (SIgED) is still an unrecognised primary immunodeficiency despite several observations supporting its existence. This study aimed to describe the skin manifestations associated with SIgED. We retrospectively assessed medical records of patients with SIgED, the diagnosis being based on serum IgE levels ≤2 Uk/L associated with normal serum levels of immunoglobulins G, M, and A. A total of 25 patients (24 female) with SIgED were included in the study. Eleven patients (44%) presented chronic spontaneous urticaria (CSU), five (20%) angioedema always associated with CSU, five erythema (20%), and six eczema (24%). Other, less frequent manifestations were lichen planus, anaphylactoid purpura, thrombocytopenic purpura, bullous pemphigoid, bullous pyoderma gangrenosum, and atypical skin lymphoproliferative infiltrate associated with reactive lymphadenopathy, chronic cholestasis, arthritis, and fibrosing mediastinitis. Fifteen patients (60%) had different types of associated autoimmune diseases, Hashimoto’s thyroiditis being the most frequent (n = 5, 20%), followed by arthritis (n = 4, 16%), autoimmune hepatitis, neutropenia, vitiligo, and Sjögren’s syndrome (n = 2, 8% each). Five malignancies were diagnosed in four patients (16%). An ultralow IgE serum level may be the only biomarker that reveals the presence of a dysregulated immune system in patients with a broad spectrum of skin manifestations.

PMID:36431272 | DOI:10.3390/jcm11226795

Pathogens. 2022 Nov 16;11(11):1364. doi: 10.3390/pathogens11111364.

ABSTRACT

BACKGROUND: Prophylactic vaccination has proven to be the most effective strategy to fight the COVID-19 pandemic.

METHODS: This was a prospective observational cohort study involving 30 predominantly antibody deficiency disorders (ADD)-afflicted adult patients on immunoglobulin replacement therapy vaccinated with three doses of the mRNA-1273 COVID-19 vaccine, and 10 healthy controls. Anti-RBD IgG antibodies were determined in plasma samples collected just before the first dose of mRNA-based COVID-19 vaccine and on weeks 4, 8, 24, and 28 following the first vaccination. Patients were categorized based on the levels of anti-RBD antibodies determined on w8 as non-, low-, and responders. Chi-square and Kruskal-Wallis tests were used to see if any variables correlated with humoral response levels. Any adverse effects of the mRNA-based vaccine were also noted.

RESULTS: The COVID-19 vaccine was safe and well-tolerated. The humoral response elicited at w8 after vaccination depended on the type of ADD, the type of immunoglobulin deficiency, the presence of granulomatous lymphocytic interstitial lung disease, recent use of immunosuppressive drugs, and the switched memory B cells counts. The third vaccine dose boosted humoral response in previous responders to second dose but seldom in non-responders.

CONCLUSIONS: The humoral response of patients with predominant ADD depends mostly on the type of immunodeficiency and on the frequency of B and T cell populations.

PMID:36422615 | DOI:10.3390/pathogens11111364

Elife. 2022 Nov 24;11:e76387. doi: 10.7554/eLife.76387. Online ahead of print.

ABSTRACT

EROS (Essential for Reactive Oxygen Species) protein is indispensable for expression of gp91phox, the catalytic core of the phagocyte NADPH oxidase. EROS deficiency in humans is a novel cause of the severe immunodeficiency, chronic granulomatous disease (CGD), but its mechanism of action was unknown until now. We elucidate the role of EROS, showing it acts at the earliest stages of gp91phox maturation. It binds the immature 58kDa gp91phox directly, preventing gp91phox degradation and allowing glycosylation via the oligosaccharyltransferase (OST) machinery and the incorporation of the heme prosthetic groups essential for catalysis. EROS also regulates the purine receptors P2X7 and P2X1 through direct interactions and P2X7 is almost absent in EROS deficient mouse and human primary cells. Accordingly, lack of murine EROS results in markedly abnormal P2X7 signalling, inflammasome activation and T cell responses. The loss of both ROS and P2X7 signalling leads to resistance to influenza infection in mice. Our work identifies EROS as a highly selective chaperone for key proteins in innate and adaptive immunity and a rheostat for immunity to infection. It has profound implications for our understanding of immune physiology, ROS dysregulation and possibly gene therapy.

PMID:36421765 | DOI:10.7554/eLife.76387