Manish Butte

J Clin Immunol. 2022 Nov 3. doi: 10.1007/s10875-022-01394-3. Online ahead of print.

ABSTRACT

PURPOSE: Early identification of inborn errors of immunity (IEIs) is crucial due to the significant risk of morbidity and mortality. This study aimed to describe the genetic causes, clinical features, and survival rate of IEIs in Omani patients.

METHODS: A prospective study of all Omani patients evaluated for immunodeficiency was conducted over a 17-year period. Clinical features and diagnostic immunological findings were recorded. Targeted gene testing was performed in cases of obvious immunodeficiency. For cases with less conclusive phenotypes, a gene panel was performed, followed by whole-exome sequencing if necessary.

RESULTS: A total of 185 patients were diagnosed with IEIs during the study period; of these, 60.5% were male. Mean ages at symptom onset and diagnosis were 30.0 and 50.5 months, respectively. Consanguinity and a family history of IEIs were present in 86.9% and 50.8%, respectively. Most patients presented with lower respiratory infections (65.9%), followed by growth and development manifestations (43.2%). Phagocytic defects were the most common cause of IEIs (31.9%), followed by combined immunodeficiency (21.1%). Overall, 109 of 132 patients (82.6%) who underwent genetic testing received a genetic diagnosis, while testing was inconclusive for the remaining 23 patients (17.4%). Among patients with established diagnoses, 37 genes and 44 variants were identified. Autosomal recessive inheritance was present in 81.7% of patients with gene defects. Several variants were novel. Intravenous immunoglobulin therapy was administered to 39.4% of patients and 21.6% received hematopoietic stem cell transplantation. The overall survival rate was 75.1%.

CONCLUSION: This study highlights the genetic causes of IEIs in Omani patients. This information may help in the early identification and management of the disease, thereby improving survival and quality of life.

PMID:36324046 | DOI:10.1007/s10875-022-01394-3

Br J Haematol. 2022 Nov 2. doi: 10.1111/bjh.18532. Online ahead of print.

ABSTRACT

Management of acquired immunodeficiency syndrome (AIDS)-related diffuse large B-cell (DLBCL) and plasmablastic lymphomas (PBL) poses significant challenges. The evidence supports use of dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin) with or without rituximab as first-line therapy. The need for central venous access, growth factors and significant toxicities limits its use in resource-constrained settings. To address these challenges, we have developed a novel regimen, CVEP (cyclophosphamide, vinblastine, etoposide, and prednisolone) based on the pharmacodynamic principles of dose-adjusted EPOCH. This single-centre phase II study evaluated the efficacy and safety of CVEP regimen in patients with de novo systemic AIDS-related DLBCL and PBL. The primary objective was complete response (CR) rates as assessed by positron emission tomography-computed tomography. The secondary objectives were incidence of Grade 3/4 toxicities, toxicities requiring hospitalisation, and disease-free survival. From May 2011 to February 2017, 42 patients were enrolled. At the end of therapy the CR rates were 69% (29/42) in the intention-to-treat population and 80.5% (29/36) in evaluable patients. At a median follow-up of 69 months, the 5-year disease-free survival was 65.3%. Out of 217 cycles administered, febrile neutropenia occurred in 19.3% and hospitalisation was required in 18.3% of cycles. There were two treatment-related deaths. The CVEP regimen is an active and safe regimen for AIDS-related DLBCL and PBL.

PMID:36323643 | DOI:10.1111/bjh.18532

Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2022 Nov 10;39(11):1257-1261. doi: 10.3760/cma.j.cn511374-20211113-00904.

ABSTRACT

OBJECTIVE: To explore the genetic basis for a child featuring Chediak-Higashi syndrome (CHS).

METHODS: Clinical manifestations and results of auxiliary examination of the proband were analyzed. The proband was subjected to whole exome sequencing, and the results were verified by Sanger sequencing. Correlation between the genotype and clinical phenotype was analyzed.

RESULTS: The proband showed partial skin albinism, recurrent respiratory infection and other immune deficiencies. Genetic testing showed that he has harbored c.2437C>T (p.Arg813*) and c.6077dupA (p.Tyr2026fs) (NM_000081) compound heterozygous variants of the LYST gene, for which his parents were both carriers. Neither variant was reported previously. HEAT repeats domain was frequently associated with more severe phenotype of CHS (81.6%), whilst no variant has been found in the PH_BEACH domain.

CONCLUSION: This study has enriched the spectrum of LYST gene variants associated with CHS and enabled clinical diagnosis, prenatal diagnosis and prognostic evaluation for the child.

PMID:36317214 | DOI:10.3760/cma.j.cn511374-20211113-00904

Cureus. 2022 Sep 28;14(9):e29703. doi: 10.7759/cureus.29703. eCollection 2022 Sep.

ABSTRACT

Common variable immune deficiency (CVID) is the most common of all primary immunodeficiency rare diseases characterized by hypogammaglobulinemia. This is caused by the defective functioning of B-cells and T-cells, resulting in recurrent infections. Its etiology is unknown but most commonly initiated due to epigenetic factors and epistatic interactions. Moreover, it has a bimodal age distribution and can be more evident from infancy to after 4th decade of life. Herein, a seven-year-old female, the first product of consanguineous marriage with no family history of immunodeficiency disorders, presented predominantly with sinopulmonary involvement. It manifested as severe pulmonary pneumonia, atelectasis, patchy alveolar infiltrates, and lung nodules. She also had a history of diarrhea and otitis media. Despite having a history of recurrent infections since three years of age, she was diagnosed late due to a lack of awareness and knowledge about the presentation of CVID and its different manifestations among the medical community in Pakistan. The diagnosis of CVID is based on the clinical and immunological manifestation of the patient with respect to the European Society of Immune Deficiencies (ESID) diagnostic criteria. Therefore, genetics help detect mutations leading to CVID and establish a genetic diagnosis for CVID-like disorders. However, genetic panel testing is not used as a diagnostic tool in Pakistan due to the unavailability of resources. Instead, the clinical presentation, abnormal lymphocytic counts, and immunoglobulin levels may help diagnose CVID. Early diagnosis will help in the timely utilization of the most effective treatment and management options available. These include intravenous immunoglobulin (IVIG) and hematopoietic stem cell therapy. Ig replacement therapy has shown a beneficial role in halting the cycle of recurrent infections and improving the prognosis of CVID. However, it’s a bit expensive therapy. Moreover, the role of hematopoietic stem cell therapy in treating CVID has been documented, but it’s not so common and practical.

PMID:36321039 | PMC:PMC9616553 | DOI:10.7759/cureus.29703

Cureus. 2022 Sep 27;14(9):e29642. doi: 10.7759/cureus.29642. eCollection 2022 Sep.

ABSTRACT

The lungs, kidneys, liver, and pancreas are just some of the organs that can be affected by tuberculosis. Tuberculosis is a disease that can affect many organs of the human body. Rarely can tuberculosis (TB) manifest itself in the digestive tract; in fact, the gastrointestinal tract ranks as the sixth most common site of extrapulmonary TB. However, involvement of the esophagus by tuberculosis is extremely uncommon. We present a case of esophageal tuberculosis in a 27-year-old man with epigastric pain and weight loss as his only symptoms. There were no complaints of odynophagia or dysphagia, nor was there any evidence of immunodeficiency. Upper gastrointestinal endoscopy found an ulcer 26 centimeters from the incisor. Histopathology and a biopsy confirmed the diagnosis of primary esophageal tuberculosis. Six months after beginning anti-TB therapy, he was confirmed to be free of tuberculosis.

PMID:36320941 | PMC:PMC9608034 | DOI:10.7759/cureus.29642

iScience. 2022 Oct 28:105455. doi: 10.1016/j.isci.2022.105455. Online ahead of print.

ABSTRACT

Mass vaccination campaigns reduced COVID-19 incidence and severity. Here, we evaluated the immune responses developed in SARS-CoV-2-uninfected patients with predominantly antibody-deficiencies (PAD) after three mRNA-1273 vaccine doses. PAD patients were classified based on their immunodeficiency: unclassified primary antibody-deficiency (unPAD, n=9), common variable immunodeficiency (CVID, n=12), combined immunodeficiency (CID, n=1), and thymoma with immunodeficiency (TID, n=1). unPAD patients and healthy controls (HCs, n=10) developed similar vaccine-induced humoral responses after two doses. However, CVID patients showed reduced binding and neutralizing titers compared to HCs. Interestingly, these PAD groups showed lower levels of Spike-specific IFN-γ-producing cells. CVID individuals also presented diminished CD8+ T cells. CID and TID patients developed cellular but not humoral responses. While the third vaccine dose boosted humoral responses in most PAD patients, it had limited effect on expanding cellular immunity. Vaccine-induced immune responses in PAD individuals are heterogeneous, and should be immunomonitored to define a personalized therapeutic strategies.

PMID:36320330 | PMC:PMC9613776 | DOI:10.1016/j.isci.2022.105455

World J Clin Cases. 2022 Oct 16;10(29):10735-10741. doi: 10.12998/wjcc.v10.i29.10735.

ABSTRACT

BACKGROUND: Dedicator of cytokinesis 8 (DOCK 8) deficiency, also known as autosomal recessive hyper immunoglobulin E (IgE) syndrome, is a combined immunodeficiency disease that was first recognized in 2009. It is caused by genetic alterations (mutations or deletions) in the DOCK 8 gene and is characterized by multiple allergies, elevated IgE levels, and susceptibility to viral and bacterial infections. Early diagnosis is critical to optimize the success of stem cell transplantation.

CASE SUMMARY: This study reports the case of a pediatric patient with DOCK 8 deficiency who had negative genetic testing using multiplex primary immunodeficiency (PID) panel and whole-exome sequencing (WES) with a next-generation sequencing method. He presented with chronic diarrhea and was managed as celiac disease based on previous negative workup for immunodeficiency and duodenal biopsy. He developed a generalized vesicular rash which was thought to be dermatitis herpetiformis associated with celiac disease. However, it turned out to be Eczema herpeticum based on positive herpes simplex virus from blood and lesions. The diagnosis was re-evaluated after the child was found to have multiple viral, bacterial, and parasitic co-infections (herpes simplex virus, cytomegalovirus, Epstein-Barr virus, Salmonella, and cryptosporidiosis). Re-evaluation with target gene testing with copy number variation (CNV) analysis and Multiplex Ligation Probe Amplification (MLPA) showed a large homozygous deletion in the DOCK 8 gene, confirming the diagnosis of DOCK 8 deficiency.

CONCLUSION: Targeted gene testing with CNV analysis might detect deletions that can be missed by WES for diagnosing patients with PID.

PMID:36312485 | PMC:PMC9602220 | DOI:10.12998/wjcc.v10.i29.10735

J Clin Immunol. 2022 Oct 29. doi: 10.1007/s10875-022-01378-3. Online ahead of print.

ABSTRACT

PURPOSE: Binding of the B cell activating factor (BAFF) to its receptor (BAFFR) activates in mature B cells many essential pro-survival functions. Null mutations in the BAFFR gene result in complete BAFFR deficiency and cause a block in B cell development at the transition from immature to mature B cells leading therefore to B lymphopenia and hypogammaglobulinemia. In addition to complete BAFFR deficiency, single nucleotide variants encoding BAFFR missense mutations were found in patients suffering from common variable immunodeficiency (CVID), autoimmunity, or B cell lymphomas. As it remained unclear to which extent such variants disturb the activity of BAFFR, we performed genetic association studies and developed a cellular system that allows the unbiased analysis of BAFFR variants regarding oligomerization, signaling, and ectodomain shedding.

METHODS: In addition to genetic association studies, the BAFFR variants P21R, A52T, G64V, DUP92-95, P146S, and H159Y were expressed by lentiviral gene transfer in DG-75 Burkitt’s lymphoma cells and analyzed for their impacts on BAFFR function.

RESULTS: Binding of BAFF to BAFFR was affected by P21R and A52T. Spontaneous oligomerization of BAFFR was disturbed by P21R, A52T, G64V, and P146S. BAFF-dependent activation of NF-κB2 was reduced by P21R and P146S, while interactions between BAFFR and the B cell antigen receptor component CD79B and AKT phosphorylation were impaired by P21R, A52T, G64V, and DUP92-95. P21R, G64V, and DUP92-95 interfered with phosphorylation of ERK1/2, while BAFF-induced shedding of the BAFFR ectodomain was only impaired by P21R.

CONCLUSION: Although all variants change BAFFR function and have the potential to contribute as modifiers to the development of primary antibody deficiencies, autoimmunity, and lymphoma, P21R is the only variant that was found to correlate positively with CVID.

PMID:36308663 | DOI:10.1007/s10875-022-01378-3

Cell Mol Immunol. 2022 Oct 27. doi: 10.1038/s41423-022-00928-4. Online ahead of print.

ABSTRACT

Calcium signaling is essential for lymphocyte activation, with genetic disruptions of store-operated calcium (Ca²⁺) entry resulting in severe immunodeficiency. The inositol 1,4,5-trisphosphate receptor (IP₃R), a homo- or heterotetramer of the IP₃R1-3 isoforms, amplifies lymphocyte signaling by releasing Ca²⁺ from endoplasmic reticulum stores following antigen stimulation. Although knockout of all IP₃R isoforms in mice causes immunodeficiency, the seeming redundancy of the isoforms is thought to explain the absence of variants in human immunodeficiency. In this study, we identified compound heterozygous variants of ITPR3 (a gene encoding IP₃R subtype 3) in two unrelated Caucasian patients presenting with immunodeficiency. To determine whether ITPR3 variants act in a nonredundant manner and disrupt human immune responses, we characterized the Ca²⁺ signaling capacity, the lymphocyte response, and the clinical phenotype of these patients. We observed disrupted Ca²⁺ signaling in patient-derived fibroblasts and immune cells, with abnormal proliferation and activation responses following T-cell receptor stimulation. Reconstitution of IP₃R3 in IP₃R knockout cell lines led to the identification of variants as functional hypomorphs that showed reduced ability to discriminate between homeostatic and induced states, validating a genotype-phenotype link. These results demonstrate a functional link between defective endoplasmic reticulum Ca²⁺ channels and immunodeficiency and identify IP₃Rs as diagnostic targets for patients with specific inborn errors of immunity. These results also extend the known cause of Ca²⁺-associated immunodeficiency from store-operated entry to impaired Ca²⁺ mobilization from the endoplasmic reticulum, revealing a broad sensitivity of lymphocytes to genetic defects in Ca²⁺ signaling.

PMID:36302985 | DOI:10.1038/s41423-022-00928-4

Melanoma Res. 2022 Oct 28:CMR.0000000000000860. doi: 10.1097/CMR.0000000000000860. Online ahead of print.

ABSTRACT

Uveal melanoma is the most common intraocular malignancy in adults. Despite the effective primary treatment, up to 50% of patients with uveal melanoma will develop metastatic lesions mainly in the liver, which are resistant to conventional chemotherapy and lead to patient’s death. To date, no orthotopic murine models of uveal melanoma which can develop spontaneous metastasis are available for preclinical studies. Here, we describe a spontaneous metastatic model of uveal melanoma based on the orthotopic injection of human uveal melanoma cells into the suprachoroidal space of immunodeficient NSG mice. All mice injected with bioluminescent OMM2.5 (n = 23) or MP41 (n = 19) cells developed a primary tumor. After eye enucleation, additional bioluminescence signals were detected in the lungs and in the liver. At necropsy, histopathological studies confirmed the presence of lung metastases in 100% of the mice. Liver metastases were assessed in 87 and in 100% of the mice that received OMM2.5 or MP41 cells, respectively. All tumors and metastatic lesions expressed melanoma markers and the signaling molecules insulin-like growth factor type I receptor and myristoylated alanine-rich C-kinase substrate, commonly activated in uveal melanoma. The novelty of this orthotopic mouse xenograft model is the development of spontaneous metastases in the liver from the primary site, reproducing the organoespecificity of metastasis observed in uveal melanoma patients. The faster growth and the high metastatic incidence may be attributed at least in part, to the severe immunodeficiency of NSG mice. This model may be useful for preclinical testing of targeted therapies with potential uveal melanoma antimetastatic activity and to study the mechanisms involved in liver metastasis.

PMID:36302215 | DOI:10.1097/CMR.0000000000000860