Autoimmune and autoinflammatory manifestations in inborn errors of immunity

Abstract

Purpose of reviewAutoimmune and inflammatory complications have been shown to arise in all age groups and across the spectrum of inborn errors of immunity (IEI). This review aims to highlight recent ground-breaking research and its impact on our understanding of IEI.Recent findingsThree registry-based studies of unprecedented size revealed the high prevalence of autoimmune, inflammatory and malignant complications in IEI. Two novel IEI were discovered: an autoinflammatory relopathy, cleavage-resistant RIPK1-induced autoinflammatory syndrome, as well as an inheritable phenocopy of PD-1 blockade-associated complication (as seen in cancer therapy) manifesting with multiorgan autoimmunity and Mycobacterium tuberculosis infection. A study examining patients with partial RAG deficiency pinpointed the specific defects leading to the failure of central and peripheral tolerance resulting in wide-ranging autoimmunity. A novel variant of Immunodeficiency Polyendocrinopathy Enteropathy X-linked syndrome was described, associated with preferential expression of a FOXP3 isoform lacking exon 2, linking exon-specific functions and the phenotypes corresponding to their absence. Lastly, we touch on recent findings pertaining actinopathies, the prototypical IEI with autoimmune, inflammatory and atopic complications.SummaryDysregulated immunity has been associated with IEI since their discovery. Recently, large concerted efforts have shown how common these complications actually are while providing insight into normal and dysregulated molecular mechanisms, as well as describing novel diseases.

B cell abnormalities and autoantibody production in patients with partial RAG deficiency

“…Moreover, CD11c hi CXCR5 lo B cell population, which is part of the CD21 low CD19 high cells and resembles murine age-associated B cells (ABCs) ( 77 ), was present at a higher frequency at several B cell developmental stages in these patients ( 38 ). Consistently, the expression of T-bet, a transcription factor found in ABCs and in B cells of patients with immune dysregulation ( 77 – 79 ), was increased in the CD21 low CD11c high compartment ( 38 ). In addition, such CD21 low or CD11c high B cells were found to be expanded in CVID and IEI caused by loss-of-function mutations in CTLA4 , LRBA , AICDA , ADA2 , NFKB1 or gain-of-function mutations in PIK3CD , STAT1 , STAT3 and TLR7 ( 80 – 83 ).…”

The Scope and Impact of Viral Infections in Common Variable Immunodeficiency (CVID) and CVID-like Disorders: A Literature Review

“…Over half of CVID patients—the so-called ‘CVID+’ cohort—suffer from inflammatory and/or autoimmune complications, with autoimmunity alone reported in around one quarter of individuals [ 43 , 44 , 45 ]. Regarding autoimmune complications, the role of regulatory immune cells, including CD4 regulatory T cells (CD4 Tregs) and the more newly described CD8 regulatory T cells (CD8 Tregs) and B regulatory cells (Bregs) and T follicular helper regulatory T cells (T FR ), have become targets for investigation [ 43 , 44 , 46 ]. There is a known association between CD4 Tregs, peripheral tolerance and autoimmune disease, so it stands to reason that dysfunction of regulatory processes in CVID might be driving its autoimmune phenomena.…”

Editorial: Immune dysregulation in inborn errors of immunity

“…The number of inborn errors of immunity (IEI) is growing rapidly ( 1 ). They can be challenging to diagnose given the expanding and variable clinical phenotypes ( 2 , 3 ). Specifically, there is an increasing recognition that immune dysregulation can be an initial or predominant manifestation of a substantive portion of IEIs ( 4 , 5 ).…”