Medina-Acosta, E. | bioRxiv Science

bioRxiv2019

An Exclusively Skewed Distribution of Pediatric Immune Reconstitution Inflammatory Syndrome Towards the Female Sex is Associated with Advanced Acquired Immune Deficiency Syndrome

In human immunodeficiency virus and acquired immune deficiency syndrome (HIV/AIDS) patients with very low CD4 cell counts, there is a temporal relationship between administration of antiretroviral therapy (ART) and an increased inflammatory response state known as the immune reconstitution inflammatory syndrome (IRIS). The predominant clinical presentation of IRIS is an infectious disease that can be life-threatening. IRIS-related infectious events are distributed similarly between adult males and females, albeit a few studies have shown a skewing towards the male sex in pediatric IRIS. Here, we assessed sex-specific differences in the causes and extent of IRIS infectious events in HIV-infected pediatric patients on ART. We carried out a prospective clinical analysis (from 2000 to 2018) of IRIS-related infectious events after ART in a cohort of 82 Brazilian children and adolescents infected with HIV-1 through mother-to-child transmission as well as a comprehensive cross-referencing with public records on IRIS-related infectious causes in pediatric HIV/AIDS. Twelve events fulfilling the criteria of IRIS occurred exclusively in eleven females in our cohort. The median age at IRIS events was 3.6 years. The infectious causes included Mycobacterium bovis, varicella-zoster virus, molluscum contagiosum virus, human papillomavirus, cytomegalovirus, and Mycobacterium tuberculosis. In one female, there was regional bacillus Calmette-Guerin dissemination and cytomegalovirus esophagitis. There was complete health recovery after ten IRIS events without the use of corticosteroids or ART interruption. One case of IRIS-associated miliary tuberculosis was fatal. The biological female sex was a significant risk factor for IRIS events (odds ratio: 23.67; 95% confidence interval 95%: 1.341 - 417.7; P = 0.0016). We observed an effect of the advanced HIV/AIDS variable in IRIS females as compared with non-IRIS females (mean CD4+ T cell percentage 13.36% versus 18.63%; P = 0.0489), underpinning the exclusively skewed distribution towards the female sex of this cohort. Moreover, the IRIS females in our cohort had higher mean CD4+ T cell percentages before (13.36%) and after IRIS (26.56%) than those of the IRIS females (before IRIS, 4.978%; after IRIS, 13.81%) in previous studies conducted worldwide. We concluded that the exclusively skewed distribution of pediatric IRIS towards females is associated with more advanced AIDS.

epidemiology↗

bioRxiv2019

A Differentially Methylated CpG Site in the IL4 Gene Associated with Anti-FVIII Inhibitor Antibody Development in Hemophilia A

Hemophilia A is the most common clotting disorder in humans. It affects one in five thousand live-born children. Mutations in the X-chromosome linked F8 gene lead to the deficiency of circulating factor VIII (FVIII). The defect is characterized by severe bleeding. The standard therapy is to replace the deficient factor intravenously. The main adverse event of the therapy is the development of anti-FVIII inhibitor antibodies that impair coagulation and result in increased complications and risk of death. Several risk factors have been described for the development of inhibitor antibodies, among them age, type of FVIII administered, ethnicity, and variant alleles in immune response genes. Epigenetic risks factors have not yet been explored. This work aimed to evaluate the methylation statuses at thirteen CpG sites (5meCpG) in regulatory regions of the IL1B, IL2, IL4, IL6, IL10, TNF, IFNG, CTLA4, CD28, and CST7 immune regulation genes in hemophilia A affected males on replacement therapy who develop or do not develop inhibitor antibodies. At each of the thirteen specific CpG sites, we observed one of three possible statuses: hypermethylated, hypomethylated or intermediate methylated. We found a statistically significant (p = 0.04) decrease in the methylation level at one CpG site in the IL4 intron 1 (CpG-3) in the affected group of patients presenting with anti-FVIII inhibitors as compared with the group of patients without inhibitors. The differential 5meCpG-3 maps within a predicted enhancer region in IL4 intron 1 that overlaps DNase I hypersensitive chromatin region of the Th2 IL5, IL13, and IL4 cytokine gene cluster and, therefore, permissive for gene expression. Six-bp upstream of the differentially 5meCpG-3 is the rs2227282 cis expression quantitative trait locus that influences the transcript levels of the PDLIM4, SLC22A4, SLC22A5, RAD50, IL4, KIF3A, SEPT8 genes. We consider the IL4 (CpG-3) site a promising lead epigenetic mark, the potential value of which must be appraised in a larger group of patients. The methodology employed also allowed to evaluate the distribution of the IL6 rs35081782 insertion/deletion variant, associated with white blood cell count traits in genome-wide association studies, and which showed no difference in distribution between the groups of patients.

genetics↗