Manish Butte

A Tale of Two Immunodeficiencies: A Case of Multiple Myeloma Associated with Profound Immune Defect Mimicking Common Variable Immunodeficiency Syndrome.

Perm J. 2019;24:

Authors: Yavorkovsky LL, Hope A

Abstract
INTRODUCTION: Multiple myeloma (MM) is a clonal plasma cell disorder commonly associated with secondary immune deficiency. By contrast, common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by low serum levels of immunoglobulins (IgG, IgA, and/or IgM) and inability to produce specific protective antibodies in response to infections and immunizations. Besides a defective immune system and susceptibility to infections, CVID is associated with autoimmune disorders, gastrointestinal tract inflammation, granulomatous disease, and malignancies. Although MM and CVID both manifest an abnormal immune system homeostasis, the pathogenesis of the immune defect is distinctly different: Quantitative deficiency of the normal plasma cells in the former and qualitative defect in plasma cell maturation in the latter.
CASE PRESENTATION: An unusual case of MM associated with profound immunodeficiency mimicking CVID occurred in a 51-year-old man with a history of numerous bacterial infections and low γ-globulin levels.
DISCUSSION: A hypothetical connection between MM and CVID is discussed. Patients with MM who have an unusually high burden of infections and profound immune deficit persisting even after successful myeloma therapy merit recognition as a distinct cohort that warrants heightened attention from clinicians and scientists.

PMID: 31852056 [PubMed – in process]

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EBV-directed viral-specific T-lymphocyte therapy for the treatment of EBV-driven lymphoma in two patients with primary immunodeficiency and DNA repair defects.

Pediatr Blood Cancer. 2019 Dec 18;:e28126

Authors: Rubinstein JD, Burns K, Absalon M, Lutzko C, Leemhuis T, Chandra S, Hanley PJ, Keller MD, Davies SM, Nelson A, Grimley M

Abstract
Children with ataxia telangiectasia (AT), a primary immunodeficiency caused by mutations in ATM, which is critical for repairing DNA defects, are at risk for the development of hematologic malignancy, frequently driven by infection with Epstein-Barr virus (EBV). Conventional chemotherapy is poorly tolerated by patients with AT, with excessive toxicity even when doses are reduced. Here, we report on two patients with AT and EBV-positive neoplasms who were treated with EBV-targeted viral-specific T cells (VST). One patient had a prolonged complete response to VSTs while the other had a partial response. Therapy was well tolerated without infusion toxicity or graft-versus-host disease.

PMID: 31850668 [PubMed – as supplied by publisher]

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Flow Cytometry Contributions for the Diagnosis and Immunopathological Characterization of Primary Immunodeficiency Diseases With Immune Dysregulation.

Front Immunol. 2019;10:2742

Authors: Cabral-Marques O, Schimke LF, de Oliveira EB, El Khawanky N, Ramos RN, Al-Ramadi BK, Segundo GRS, Ochs HD, Condino-Neto A

Abstract
Almost 70 years after establishing the concept of primary immunodeficiency disorders (PIDs), more than 320 monogenic inborn errors of immunity have been identified thanks to the remarkable contribution of high-throughput genetic screening in the last decade. Approximately 40 of these PIDs present with autoimmune or auto-inflammatory symptoms as the primary clinical manifestation instead of infections. These PIDs are now recognized as diseases of immune dysregulation. Loss-of function mutations in genes such as FOXP3, CD25, LRBA, IL-10, IL10RA, and IL10RB, as well as heterozygous gain-of-function mutations in JAK1 and STAT3 have been reported as causative of these disorders. Identifying these syndromes has considerably contributed to expanding our knowledge on the mechanisms of immune regulation and tolerance. Although whole exome and whole genome sequencing have been extremely useful in identifying novel causative genes underlying new phenotypes, these approaches are time-consuming and expensive. Patients with monogenic syndromes associated with autoimmunity require faster diagnostic tools to delineate therapeutic strategies and avoid organ damage. Since these PIDs present with severe life-threatening phenotypes, the need for a precise diagnosis in order to initiate appropriate patient management is necessary. More traditional approaches such as flow cytometry are therefore a valid option. Here, we review the application of flow cytometry and discuss the relevance of this powerful technique in diagnosing patients with PIDs presenting with immune dysregulation. In addition, flow cytometry represents a fast, robust, and sensitive approach that efficiently uncovers new immunopathological mechanisms underlying monogenic PIDs.

PMID: 31849949 [PubMed – in process]

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Phenotypical T Cell Differentiation Analysis: A Diagnostic and Predictive Tool in the Study of Primary Immunodeficiencies.

Front Immunol. 2019;10:2735

Authors: Attardi E, Di Cesare S, Amodio D, Giancotta C, Cotugno N, Cifaldi C, Chiriaco M, Palma P, Finocchi A, Di Matteo G, Rossi P, Cancrini C

Abstract
Multiparametric flow cytometry (MFC) represents a rapid, highly reproducible, and sensitive diagnostic technology for primary immunodeficiencies (PIDs), which are characterized by a wide range of T cell perturbations and a broad clinical and genetic heterogeneity. MFC data from CD4+ and CD8+ T cell subsets were examined in 100 patients referred for Primary Immunodeficiencies to our center. Naïve, central memory, effector memory, and terminal effector memory cell differentiation stages were defined by the combined expression CD45RA/CD27 for CD4 and CD45RA/CCR7 for CD8. Principal component analysis (PCA), a non-hypothesis driven statistical analysis, was applied to analyze MFC data in order to distinguish the diverse PIDs. Among severe lymphopenic patients, those affected by severe combined and combined immunodeficiency (SCID and CID) segregated in a specific area, reflecting a homogenous, and a more severe T cell impairment, compared to other lymphopenic PID, such as thymectomized and partial DiGeorge syndrome patients. PID patients with predominantly antibody defects were distributed in a heterogeneous pattern, but unexpectedly PCA was able to cluster some patients’ resembling CID, hence warning for additional and more extensive diagnostic tests and a diverse clinical management. In conclusion, PCA applied to T cell MFC data might help the physician to estimate the severity of specific PID and to diversify the clinical and diagnostic approach of the patients.

PMID: 31849946 [PubMed – in process]

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Pharmacokinetic properties of Privigen® in Japanese patients with primary immunodeficiency.

Immunol Med. 2019 Dec 17;:1-7

Authors: Morio T, Baheti G, Tortorici MA, Hofmann J, Rojavin MA

Abstract
This prospective, Phase 3, open-label, study (EudraCT: 2016-001631-12) evaluated pharmacokinetic (PK) characteristics of 3-/4-weekly Privigen® (IgPro10, CSL Behring, King of Prussia, PA, USA) in Japanese patients with PID. PK parameters including serum trough immunoglobulin (IgG) level before next infusion during the wash-in/wash-out phase (Ctrough), area under the concentration-time curve from time point zero to the last time point with quantifiable concentration (AUC0-last), dose-adjusted AUC0-last (dAUC), lowest and highest observed IgG levels (Cmin, Cmax), time to reach Cmax (Tmax), and total clearance (CL) were analyzed for both regimens of Privigen® (dose: 138-554 mg/kg body weight). Ten patients were included in this analysis (3-/4-weekly: n = 2/n = 8). Ctrough levels achieved ranged 7.96-10.05 g/L. Cmax was observed approximately 1 h after the start of the infusion in both regimens. Mean (SD [not applicable for 3-weekly data]) PK parameters: Cmax, 16.60 and 14.20 (5.53) g/L; Cmin, 10.60 and 8.53 (3.89) g/L; AUC0-last, 5971 and 6591 (2633) g*h/L; dAUC, 0.41 and 0.46 (0.19) g*h/L/mg; CL, 2.53 and 2.53 (1.00) mL/h and median Tmax was 1.19 and 1.14 h, for 3-/4-weekly dosing regimens, respectively. Privigen® PK characteristics in Japanese patients were similar between dosing regimens and to previously-reported results in non-Japanese patients with PID.

PMID: 31847720 [PubMed – as supplied by publisher]

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Dysregulation of Cell Death in Human Chronic Inflammation.

Cold Spring Harb Perspect Biol. 2019 Dec 16;:

Authors: Li Y, Klein C, Kotlarz D

Abstract
Inflammation is a fundamental biological process mediating host defense and wound healing during infections and tissue injury. Perpetuated and excessive inflammation may cause autoinflammation, autoimmunity, degenerative disorders, allergies, and malignancies. Multimodal signaling by tumor necrosis factor receptor 1 (TNFR1) plays a crucial role in determining the transition between inflammation, cell survival, and programmed cell death. Targeting TNF signaling has been proven as an effective therapeutic in several immune-related disorders. Mouse studies have provided critical mechanistic insights into TNFR1 signaling and its potential role in a broad spectrum of diseases. The characterization of patients with monogenic primary immunodeficiencies (PIDs) has highlighted the importance of TNFR1 signaling in human disease. In particular, patients with PIDs have revealed paradoxical connections between immunodeficiency, chronic inflammation, and dysregulated cell death. Importantly, studies on PIDs may help to predict beneficial effects and side-effects of therapeutic targeting of TNFR1 signaling.

PMID: 31843991 [PubMed – as supplied by publisher]

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