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Immunodeficiency Diseases
Published in Pudupakkam K Vedanthan, Harold S Nelson, Shripad N Agashe, PA Mahesh, Rohit Katial, Textbook of Allergy for the Clinician, 2021
Monogenic diseases affecting T regulatory cell biology, the role of T cell associated molecules and regulation of peripheral T cell tolerance are called Tregopathies (Cepka et al. 2018). They manifest with recurrent infections, autoimmunity and malignancy. In 2017 the International Union of Immunological Societies (IUIS) classified them as inborn errors of immunity. Each of these genes encode proteins that uniquely contribute to the function of thymus-derived forkhead box P3 (FOXP3) regulatory T cells or Tregs. They are caused by Loss-Of-Function (LOF) mutations in FOXP3, cytotoxic T lymphocyte-associated antigen 4 (CTLA4), LPS- Responsive and Beige-like Anchor protein (LRBA), CD25, BTB domain and CNC homolog 2 (BACH2) and Gain Of Function (GOF) mutation in Signal Transducer and activator of Transcription 3 (STAT3). A description of the specific entity, the molecular defect and clinical phenotype/lab findings are depicted below in Table 29.14.
Targeted next-generation sequencing revealed a novel homozygous mutation in the LRBA gene causes severe haemolysis associated with Inborn Errors of Immunity in an Indian family.
Published in Hematology, 2022
Prabhakar Kedar, Rashmi Dongerdiye, Shanmukhaiah Chandrakala, Umair Ahmed Bargir, Manisha Madkaikar
Lymphocyte subset analysis showed marginally elevated absolute lymphocyte count with elevated number of B cells 1787 cells/cmm (390-1400), T cells 4403 cells/cmm (1400-3700), Th cells 2935 cells/cmm (700-2200), normal Tc cells 1276 cells/cmm (490-1300), and borderline low NK cells 64 cells/cmm (130-720). She had normal double-negative T cells at 1.3% (CD4-CD8-TCR αβ). Her memory B cells (CD19 + CD27+) and class-switched memory B cells (CD19 + CD27 + IgD-IgM-) were normal. Her CD21 low B cells were 3.2%. Her Serum Immunoglobulin levels were normal (Table 2). The patients’ Coombs test (DAT) was strongly positive. Considering underlying autoimmune hemolysis, she was prescribed a low dose of oral steroids, and the least incompatible packed cell unit was transfused under constant medical supervision in view of positive DAT. The immunological analysis for affected individuals with an inborn error of immunity and severe transfusion history are shown in Table 2. Also, with suspicion of underlying inborn errors of immunity, a screening work-up was done that included LSSA, Immunoglobulin levels, and NBT. All reports were within normal limits except borderline IgG (4.3 g /dl) was detected. Her PNH work-up was carried on FLAER, and it was normal. Her autoimmune work-up showed the presence of anti-ANA antibodies (weak +). All her laboratory investigations are shown in Table 2.
Immune dysfunction in inborn errors of immunity causing malignancies
Published in Expert Review of Clinical Immunology, 2021
In recent years, numerous new genetic reasons for human inborn errors of immunity (IEI) have been identified [1,2]. Knowing the monogenic causes helps us predict future encountering illness, especially malignancies that determine prognosis. Regarding immune defense during diseases, the model of surveillance was first used by Burnet in 1963 [3], later extended by immunoediting encompassing immunosurveillance that describes the active role of the immune system in maintaining self-protection by destroying invaders and pre-malignant cells [4,5]. Defective immunosurveillance poses individuals to increased risk of malignancy. Following infections, malignancy is the second leading cause of death among immunodeficient patients [4,6]. The type of malignancy and the mechanisms underlying this predisposition is varied among different categories of IEI [7]. The combination of diagnostic delay/challenge, increased comorbidity, infections and toxicity usually results in a poorer outcome and survival compared to immunocompetent patients [8–10]. Herein, we discuss the concept of malignancy in IEI by dissecting the diseases based on their molecular defects.
Gene therapy for primary immunodeficiencies: up-to-date
Published in Expert Opinion on Biological Therapy, 2021
Primary immunodeficiencies (PIDs) are monogenic-inherited disorders of the immune system characterized by increased susceptibility to infection and an increased risk of autoimmunity, inflammation, and malignancy. Often presenting in childhood, they encompass abnormalities in the innate and adaptive immune system. The innate immune system is a nonspecific, immediate first line of defense against pathogens, while adaptive immunity utilizes T and B cells to mount a fine-tuned and highly specific response. The evolution of sophisticated genome sequencing techniques, including next-generation sequencing, has rapidly increased the number of disorders recognized, with over 400 gene defects now identified [1]. Individually, the prevalence of inborn errors of immunity is rare, however collectively they have an overall prevalence of approximately 1:10 000 live births, with greater rates in populations with high rates of consanguinity or populations that are genetically isolated [2,3].