We have proposed that significant subsets of individuals with IgA deficiency (IgA-D) and common variable immunodeficiency (CVID) may represent polar ends of a clinical spectrum reflecting a single underlying genetic defect. This proposal was supported by our finding that individuals with these immunodeficiencies have in common a high incidence of C4A gene deletions and C2 rare gene alleles. Here we present our analysis of the MHC haplotypes of 12 IgA-D and 19 CVID individuals from 21 families and of 79 of their immediate relatives. MHC haplotypes were defined by analyzing polymorphic markers for 11 genes or their products between the HLA-DQB1 and the HLA-A genes. Five of the families investigated contained more than one immunodeficient individual and all of these included both IgA-D and CVID members. Analysis of the data indicated that a small number of MHC haplotypes were shared by the majority of immunodeficient individuals. At least one of two of these haplotypes was present in 24 ofthe 31 (77%) immunodeficient individuals. No differences in the distribution of these haplotypes were observed between IgA-D and CVID individuals. Detailed analysis of these haplotypes suggests that a susceptibility gene or genes for both immunodeficiencies are located within the class III region of the MHC, possibly between the C4B and C2 genes. (J. Clin. Invest. 1992.89:1914-1922
IgA deficiency and common variable immunodeficiency are heritable disorders that can occur within the same family. Both immunodeficiencies are characterized by arrests in B-cell differentiation that vary in the extent of the immunoglobulin isotypes involved. A high frequency of major histocompatibility complex supratypes associated with a null allele of the gene encoding the C4A isotype of complement component C4 has been observed in IgA-deficient individuals. In search of a genetic linkage between the two immunodeficiencies, we examined the major histocompatibility complex (MHC) class HI genes encoding complement components C2, C4A, and C4B and steroid 21-hydroxylase in addition to the HLA serotypes in individuals with either common variable immunodeficiency or IgA deficiency. Twelve of 19 patients with common variable immunodeficiency (63%, P < 0.001) and 9 of 16 patients with IgA deficiency (56%, P < 0.01) had rare C2 alleles and/or C4A and 21-hydroxylase A deletions, whereas these gene features were seen in only 5 of 34 healthy individuals (15%) in the control group. Nine of 11 patients with C4A deletion had an HLA haplotype consistent with the MHC
A family with 13 members included 2 subjects with selective IgA deficiency (IgA-D) and 3 subjects with common-variable immune deficiency (CVID), diseases which usually occur sporadically. Reciprocal combinations of B and T cells in vitro between one normal and two immune-deficient family members and normal subjects revealed that defective Ig synthesis was determined by the B cells, while the patient T cells functioned normally. Normal T helper and suppressor function was demonstrated even in one patient with CVID who developed a T-cell lymphoproliferative disorder associated with elevated IgM; this patient's B cells made only IgM in vitro. Immune deficiencies were inherited in this family in a pattern consistent with an autosomal dominant trait with incomplete penetrance. All the immune-deficient patients in this family possessed at least one copy of an MHC haplotype previously shown to be abnormally frequent in IgA-D and CVID: HLA-DQB1*0201, HLA-DR3, C4B-Sf, C4A-deleted, G11-15, Bf-0.4, C2-a, HSP70-7.5, TNF alpha-5, HLA-B8, and HLA-A1. The patient who developed the lymphoproliferative disorder was homozygous for this haplotype. Four immunologically normal members, one of whom was 80 years old, also possessed this MHC haplotype, indicating that its presence is not sufficient for disease expression. A small segment of another MHC haplotype associated with Ig deficiency in the population also occurred in this family, but it was not associated with immune deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)
The pathogenetic mechanism of many hearing disorders have not been fully defined. Studies of certain hearing disorders in man have suggested a role for the major histocompatibility complex (MHC)-encoded genes in disease pathogenesis. In a cohort of unrelated patients with Meniere's Disease, otosclerosis and strial presbycusis as well as other types of sensorineural hearing losses, we have identified an extended MHC haplotype common to the majority of these patients, supporting a hypothesis that a gene(s) within the MHC domain may confer susceptibility to these hearing ailments. In addition, a preliminary study of 27 individuals with various hearing maladies, a striking finding is that 44% of the patients express the following extended MHC haplotype in contrast to only 7% of the general population: DQw2-DR3-C4BSf-C4A0-G11:15-Bf:0.4-C2a-HSP70:7.5-TNF a5-B8-Cw7-A1. The expression of this haplotype by subsets of patients with hearing loss is significant in comparison to regional and international controls.
Background Self-administered allergen immunotherapy is considered controversial. We believe the implementation of a self-administration protocol characterized by patient preselection and a slow buildup phase is safe. Methods We analyzed 23,614 patient records and associated immunotherapy injections for systemic reactions (SR) during a 1-year period (2011 to 2012). SRs were graded in accordance with the World Allergy Organization (WAO) criteria. Results Thirty-seven SRs were reported for 23,614 patients who self-administered 2,021,600 injections yielding an annual SR rate of 0.16% (per patient) or 0.002% (per injection). Only 9 of 4643 pediatric (0.19%) and 28 of 18,971 adult patients (0.15%) experienced 1 or more SRs. No deaths (grade V SR) occurred. From 2009 through early 2014, over 90,000 patients received more than 10 million injections in accordance with the United Allergy Services (UAS) protocol without fatalities. Conclusion We believe this safety profile is due to a preselection of patients to exclude those with a high risk for adverse reactions and a slow immunotherapy buildup phase. In contrast, previous studies documented office-based SRs ranging from approximately 3% to greater than 14%. Thus, the UAS home-immunotherapy SR rate is significantly lower than office-based immunotherapy SR rates (p < 0.0001). The enhanced safety of this protocol results in a decreased frequency and severity of SRs. This safety report, derived from analyses of one of the largest patient cohorts studied, corroborates and expands the observations of previous studies of self-administered subcutaneous immunotherapy in a low-risk patient population by assessing self-administered allergen immunotherapy during the buildup and maintenance phases.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.