Autoimmunity/inflammation in a monogenic primary immunodeficiency cohort

Abstract

Primary immunodeficiencies (PIDs) are rare inborn errors of immunity that have a heterogeneous phenotype that can include severe susceptibility to life-threatening infections from multiple pathogens, unique sensitivity to a single pathogen, autoimmune/inflammatory (AI/I) disease, allergies and/or malignancy. We present a diverse cohort of monogenic PID patients with and without AI/I diseases who underwent clinical, genetic and immunological phenotyping. Novel pathogenic variants were identified in IKBKG, CTLA4, NFKB1, GATA2, CD40LG and TAZ as well as previously reported pathogenic variants in STAT3, PIK3CD, STAT1, NFKB2 and STXBP2. AI/I manifestations were frequently encountered in PIDs, including at presentation. Autoimmunity/inflammation was multisystem in those effected, and regulatory T cell (Treg) percentages were significantly decreased compared with those without AI/I manifestations. Prednisolone was used as the first-line immunosuppressive agent in all cases, however steroid monotherapy failed long-term control of autoimmunity/inflammation in the majority of cases and additional immunosuppression was required. Patients with multisystem autoimmunity/inflammation should be investigated for an underlying PID, and in those with PID early assessment of Tregs may help to assess the risk of autoimmunity/inflammation.

Figure 1

T-cell subgroups compared between the groups, PID without AI/I (PID −AI/I) and PID with AI/I (PID +AI/I) (median and interquartile range). Tregs were significantly reduced in PID +AI/I compared with PID −AI/I (P=0.0079). n=2. *P<0.01.

Figure 2

Diagram illustrating the treatments for AI/I manifestations within the cohort. Participants had multisystem AI/I and often treatments were only efficacious for a single AI/I manifestation in individuals. Prednisolone monotherapy appeared ineffective for the majority of AI/I conditions encountered in PID. Remission, complete normalisation of laboratory parameters and/or clinical symptoms; partial response, improvement to near normal and stabilisation in laboratory parameters and/or clinical symptoms; relapse, no improvement/continue deterioration in laboratory parameters and/or clinical symptoms.