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Inherited Defects in Immune Defenses Leading to Pulmonary Disease
Published in Stephen D. Litwin, Genetic Determinants of Pulmonary Disease, 2020
Selective immunodeficiency may involve the IgG subclasses [90], IgA (see below), IgM [91], kappa or lambda chains [92-94], and allotypes of human Ig [87,89,95]. In general, the symptoms are less severe than when a panhypogammaglobulinemia is encountered. The genetic control of most of the above rare disorders is unclear. "Dysgammaglobulinemia" describes a disorder in which IgM is increased and other Igs decreased; several families with dysgammaglobulinemia show an X-linked mode of inheritance [96].
LPD Associated with Epstein–Barr Virus Infection
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Clinical presentations: (i) fatal or near-fatal EBV infection/severe fulminant infectious mononucleosis; (ii) HLH resulting from EBV or other viral illness, especially in childhood or adolescence, or HLH without an identifiable trigger, (iii) dysgammaglobulinemia, (iv) malignant lymphoma (XLP1), (v) inflammatory bowel disease (XLP2), (vi) family history of one or more maternally related males with an XLP phenotype [14].
Primary Immunodeficiencies
Published in Gérard Chaouat, The Immunology of the Fetus, 2020
Alain Fischer, Durandy Anne, Claude Griscelli
This syndrome, also called Type I dysgammaglobulinemia, can be inherited as an X-linked disease or according to an autosomal recessive inheritance. It is also described as an acquired syndrome, for instance following rubella fetopathy. The physiopathology of this B-cell ID is unknown. There is an apparent IgM switch defect, since patients’ B-lymphocytes do not produce other immunoglobulin isotypes than IgM. The question remains as to whether the disease is a primary B-cell defect or abnormal B-cell function secondary to a cell defect. Recently, Mayer et al. have shown that products from a T-cell line can induce patients’ B-cells to produce IgG and IgA, suggesting a primary T-cell defect.15 If confirmed, these data are of major importance, since they will definitively prove that the switch of IgM to other isotypes is T-cell dependent.
Very-Early Onset Chronic Active Colitis with Heterozygous Variants in LRBA1 and CARD11, a Case of “Immune TOR-Opathies”
Published in Fetal and Pediatric Pathology, 2023
Mai He, Amanda Wong, Kimberly Sutton, Mercia Jeanne Bezerra Gondim, Charles Samson
Decreased CTLA4 protein levels were observed within regulatory and conventional T cells isolated from LRBA-deficient patients compared those seen in analogous T cells from healthy controls. In the same study, abatacept, a CTLA-4-immunoglobulin fusion protein that mimics the biologic function of CTLA-4, ameliorated symptoms in a cohort of nine patients with novel biallelic loss-of-function mutations in LRBA [10]. A wide spectrum of clinical phenotypes has been reported for patients with homozygous or compound heterozygous mutations in LRBA. In a cohort of 22 patients with biallelic mutations in LRBA, a wide range of clinical manifestations was seen: immune dysregulation (seen in 95% of patients), organomegaly (86%), recurrent infections (71%), enteropathy (62%), and hypo/dysgammaglobulinemia (71) [14]. The vast majority of patients showed a reduction in regulatory T cells and multiple B-cell subsets (non-switched memory B cells, switched memory B cells, and plasmablasts). LRBA deficiency is associated with impaired mTOR/S6K Signaling in T Cells [6]. Targeted therapy for LRBA deficiency includes CTLA-Fc fusion protein (abatacept) and hydroxychloquine [15]. It was not surprising that a mTOR inhibitor (sirolimus) was a targeted therapy for LRBA deficiency [15],