Analysis of LRBA pathogenic variants and the association with functional protein domains and clinical presentation.

LRBA is a cytoplasmic protein that is ubiquitously distributed. Almost all LRBA domains have a scaffolding function. In 2012, it was reported that homozygous variants in LRBA are associated with early-onset hypogammaglobulinemia. Since its discovery, more than 100 pathogenic variants have been reported. This review focuses on the variants reported in LRBA and their possible associations with clinical phenotypes. In this work LRBA deficiency cases reported more than 11 years ago have been revised. A database was constructed to analyze the type of variants, age at onset, clinical diagnosis, infections, autoimmune diseases, and cellular and immunoglobulin levels. The review of cases from 2012 to 2023 showed that LRBA deficiency was commonly diagnosed in patients with a clinical diagnosis of Common Variable Immunodeficiency, followed by enteropathy, neonatal diabetes mellitus, ALPS, and X-linked-like syndrome. Most cases show early onset of presentation at <6 years of age. Most cases lack protein expression, whereas hypogammaglobulinemia is observed in half of the cases, and IgG and IgA levels are isotypes reported at low levels. Patients with elevated IgG levels exhibited more than one autoimmune manifestation. Patients carrying pathogenic variants leading to a premature stop codon show a severe phenotype as they have an earlier onset of disease presentation, severe autoimmune manifestations, premature death, and low B cells and regulatory T cell levels. Missense variants were more common in patients with low IgG levels and cytopenia. This work lead to the conclusion that the type of variant in LRBA has association with disease severity, which leads to a premature stop codon being the ones that correlates with severe disease.

Efficacy of the Bm86 antigen against immature instars and adults of the dog tick Rhipicephalus sanguineus (Latreille, 1806) (Acari: Ixodidae).

The Bm86 antigen has been used to control ticks of the Boophilus genera in integrated programs that also include the use of acaricides. Because of recent phylogenetic studies have lead to the inclusion of all Boophilus species within the Rhipicephalus genera, we aimed to investigate the efficacy of the Bm86 antigen on the biotic potential of Rhipicephalus sanguineus. Domestic dogs were vaccinated with Bm86 and challenged with the three instars of R. sanguineus. Male and female mongrel dogs were divided into two groups of four animals each, comprising non-vaccinated and vaccinated animals. Immunized dogs were given two doses of an experimental formulation containing 50mug of recombinant Bm86, at 21 days interval while the other group was given placebo, consisting of the same preparation without Bm86. Each dog was challenged 21 days after the last dose with 250 larvae, 100 nymphs and 55 adults (25 females and 30 males) released inside feeding chambers (one per instar) glued to their shaved flank. The effect of the vaccination was evaluated by determining biological parameters of ticks including the yield rates of larvae, nymphs and adult females. Adult females engorged weight, egg mass weight, efficiency rate of conversion to eggs (ERCE) and hatchability. In addition, sera were collected from dogs at 0, 21, 36, 45 and 75 days after the vaccination and used for the detection of specific antibodies by ELISA. Collection rates of larvae, nymphs and adult females fed on vaccinated dogs were significantly (p<0.05) reduced by 38%, 29% and 31%, respectively, as compared with non-vaccinated controls. Significant reductions were also observed in weight of engorged females and egg mass, in ERCE, but not in the hatch rate of ticks fed on immunized dogs. ELISA data revealed a marked and significant increase in optical densities of sera from vaccinated animals after the second dose of Bm86. We concluded that the Bm86 antigen used as a vaccine for dogs reduced the viability and biotic potential of the R. sanguineus.