CD40LG duplication-associated autoimmune disease is silenced by nonrandom X-chromosome inactivation

• Published in: Journal of allergy and clinical immunology Vol. 141; no. 6; pp. 2308 - 2311.e7
• Main Authors: Le Coz, Carole, Trofa, Melissa, Syrett, Camille M., Martin, Anna, Jyonouchi, Harumi, Jyonouchi, Soma, Anguera, Montserrat C., Romberg, Neil
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2018; Elsevier Limited
• Subjects: Adult; Apoptosis; Autoimmune diseases; Autoimmune Diseases - genetics; CD40 Ligand - genetics; Chromosome Duplication - genetics; Chromosomes; Deoxyribonucleic acid; Disease; DNA; DNA methylation; Epigenetics; Female; Females; Genes; Genomics; Humans; Immunoglobulins; Infant; Laboratories; Lymphocytes; Male; Mutation; Pedigree; X Chromosome Inactivation - genetics
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2018.02.010

Furthermore, in heterologous cocultures, anti-CD3/anti-CD28–stimulated III.1's CD4+ T cells compelled control naive B cells to express more activation-induced cytidine deaminase transcripts (Fig 1, E) and undergo more class-switching than when cocultured with stimulated heterologous control CD4+ T cells (Fig 1, F). Because other immunomodulatory treatments were ineffective, we sought to control III.1's CD40L expression by blocking nuclear factor of activated T cells nuclear translocation with cyclosporine A7 and found low concentrations (50-100 ng/mL) of normalized CD40L expression in vitro (see Fig E2 in this article's Online Repository at www.jacionline.org) and ex vivo (Fig 1, D). [...]CD40-mediated apoptosis preferentially affects CD40L-overexpressing cells, which, in a female, produces nonrandom XCI. On this basis, we speculate that the temporary reactivation of the CD40LG-duplicated X-chromosome, with resultant functional trisomy, may have contributed to the development of subject II.2's historical autoimmune disorders and the resumption of epigenetic control, to resolution of her disease. Because XCI is unavailable to males, subject III.1 has been continuously susceptible to the deleterious effects of his CD40LG duplication until his CD40L expression was normalized through pharmacological intervention.