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Clinical Applications of Gene Therapy for Immuno-Deficiencies
Published in Yashwant Pathak, Gene Delivery, 2022
Khushboo Faldu, Sakshi Gurbani, Jigna Shah
Primary immunodeficiencies (PIDS) are the inherited birth defects of the immune system (innate or adaptive) that affects 1:10,000 born individuals [1, 2]. There exists >400 PIDS and have been categorized as immune regulatory disorders, combined immunodeficiencies, defects in natural immunity, lack of antibodies, deficiency of the complement system, defective phagocytosis, and autoinflammatory diseases [3]. The immune system deficiencies are mostly diagnosed in juvenile and adolescent patients, but the mild phenotype of PID may not present itself until adulthood. Thus, increased numbers of individuals are being diagnosed in adulthood [4].
Mucosal manifestations of immunodeficiencies
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Scott Snapper, Jodie Ouahed, Luigi D. Notarangelo
Combined immunodeficiencies are those disorders that are genetically determined and lead to loss of both B- and T-cell function. As such, afflicted individuals exhibit a much more profound immune defect along their mucosal surfaces and are thus susceptible to a much broader combination of pathogens and associated clinical problems.
Wiskott–Aldrich Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Differential diagnoses for WAS include idiopathic thrombocytopenic purpura (ITP; males presenting early in life with transient and self-limited thrombocytopenia; increased platelet size, and increased reticulated platelet count), Wiskott−Aldrich syndrome 2 (WAS2; recurrent infections, eczema, and thrombocytopenia; show low numbers of B and T cells, defective T cell proliferation and chemotaxis, low NK cell function, and abnormal WASP; normal platelet volumes; rare autosomal recessive immunodeficiency due to biallelic pathogenic variants in WIPF1 on chromosome 2q31.1), X-linked severe combined immunodeficiency (X-SCID, persistent infections, lymphocytopenia, growth failure, and thymic hypoplasia; near-complete absence of T and natural killer lymphocytes; nonfunctional B lymphocytes; due to hemizygous pathogenic variant in the common gamma chain gene IL2RG), X-linked hyper IgM syndrome (recurrent otitis media, sinusitis, pneumonias; autoimmune hematologic disorders such as neutropenia, thrombocytopenia, and hemolytic anemia; lymphomas and other malignancies; serious gastrointestinal complications, and neurologic deterioration; elevated IgM in the absence of other immunoglobulins; due to pathogenic variants in CD40LG), autosomal recessive severe combined immunodeficiencies (T- and B-cell dysfunction, recurrent infections, but rarely persistent thrombocytopenia), GATA1-related X-linked cytopenia (thrombocytopenia [easy bruising and mucosal bleeding, such as epistaxis], anemia [mild dyserythropoiesis, hydrops fetalis requiring in utero transfusion]; platelet dysfunction, mild β-thalassemia, neutropenia, and congenital erythropoietic porphyria [CEP] in males), and human immunodeficiency virus (HIV; gradual destruction of the immune system; risk for opportunistic infections and neoplasms) [1,15].
The role of TNF-α and anti-TNF-α agents in the immunopathogenesis and management of immune dysregulation in primary immunodeficiency diseases
Published in Immunopharmacology and Immunotoxicology, 2022
Sharafudeen Dahiru Abubakar, Stella Amarachi Ihim, Amir Farshchi, Shayan Maleknia, Hamisu Abdullahi, Takanori Sasaki, Gholamreza Azizi
Primary immunodeficiency diseases (PIDs) consist of a heterogeneous group of genetically disorders that affect distinct components of the immune system. They manifest as increased severe susceptibility to life-threatening infections from multiple pathogens, as well as autoimmunity and inflammatory diseases, allergies and/or malignancy. They now comprise more than 400 entities listed in the report by 2019 International Union of Immunological Societies (IUIS) Expert Committee which are divided into 10 tables [10]. The principal groups include immunodeficiencies affecting cellular and humoral immunity combined immunodeficiencies (CIDs), combined immunodeficiencies with associated or syndromic features, predominantly antibody deficiencies (PADs), diseases of immune dysregulation, congenital defects of phagocytosis number or function, defects in intrinsic and innate immunity, autoinflammatory disorders, complement deficiencies bone marrow failure and phenocopies of PID [10]. Among them patients with PADs, diseases of immune dysregulation and autoinflammatory disorders are more complicated with autoimmunity [5,11].
Appropriate lung management in patients with primary antibody deficiencies
Published in Expert Review of Respiratory Medicine, 2019
Francesco Cinetto, Riccardo Scarpa, Federica Pulvirenti, Isabella Quinti, Carlo Agostini, Cinzia Milito
Compared to cellular or combined immunodeficiencies, defects of the humoral immune response tend to have a better long-term prognosis and are often diagnosed in the adulthood, with a peak around the third decade of life [9]. A recent paper based on ESID registry reported a median age at diagnosis of 31 and a mean of 31.4 years for CVID [10]. Respiratory disease is a relevant cause of morbidity and mortality in PAD patients [11]. Pulmonary complications may be classified as infection-related (acute and chronic), immune-mediated and neoplastic [12]. Respiratory tract infections (RTI) need an immediate and appropriate diagnostic approach. Due to recurrence, underlying immune defects, diagnostic delay, and not always appropriate management, infections may lead to long-term consequences on airways architecture and function, inducing bronchiectasis, COPD and poor asthma control. Immune-mediated complications encompass a range of interstitial lung diseases (ILDs), that might all be part of a specific entity called GLILD (Granulomatous-Lymphocytic Interstitial Lung Disease). Finally, malignancies are a major cause of morbidity and mortality in PAD and may involve the respiratory tract [5,6,11,13].
CD40 ligand deficiency: treatment strategies and novel therapeutic perspectives
Published in Expert Review of Clinical Immunology, 2019
Tabata T. França, Lucila A. Barreiros, Basel K. al-Ramadi, Hans D. Ochs, Otavio Cabral-Marques, Antonio Condino-Neto
The overall less favorable outcome of HSCT for CD40L deficiency may be a direct result of infection reactivation, organ damage, comorbidities at the time of the procedure or the lack of a matched donor [60,62,64]. The timing of the transplant was shown to be the major challenge, as seen in other combined immunodeficiencies, such as Wiskott-Aldrich (WAS) and Severe Combined Immunodeficiency (SCID) [81,82]. Older CD40L-deficient patients have generally more severe pre-transplant infections and may have developed serious liver and/or lung damage frequently associated with Cryptosporidium sp. and Pneumocystis sp [50,62]. HSCT performed in patients 5 years or younger at the time of transplantation was associated with improved survival [60,62]. Importantly, the risk of unsuccessful HSCT has decreased in the past two decades and patients treated with HSCT expressed a better quality of life [60]. Due to recent advances in awareness of PIDs and improved technologies that result in the diagnosis of CD40L deficiency early in life [83,84], the incidence of clinical factors associated with poor HSCT outcomes such as chronic liver and pulmonary diseases have been reduced.