Primary immune regulatory disorders: Undiagnosed needles in the haystack?

Abstract

Primary Immune Regulatory Disorders (PIRD) describe a group of conditions characterized by loss of normal inflammatory control and immune tolerance mechanisms, with autoimmunity as a predominant clinical feature. PIRD can arise due to defects in the number or function of regulatory T-lymphocytes, defects in the immune mechanisms required to ‘turn off’ inflammation such as in perforin-dependent cytotoxicity or alterations in cytokine signalling pathways. Diagnosis of PIRD is a significant challenge to physicians due to their rarity, complexity, and diversity in clinical manifestations. Many of these individual conditions lack a genotype–phenotype correlation and display incomplete penetrance. However, establishing a diagnosis is integral in optimizing patient management, including the use of individualized treatment approaches. Increasing awareness among physicians is necessary as patients are likely to present to different subspecialties. Due to the rarity of these conditions, worldwide collaboration and data-sharing is essential to improve our knowledge of the clinical spectrum and disease course in PIRD, and to optimize therapeutic strategies including identification of which patients can benefit from hematopoietic stem cell transplant.

Targeted RNAseq Improves Clinical Diagnosis of Very Early-Onset Pediatric Immune Dysregulation

“…The patient was started on Abatacept [ 66 ], a CTLA-4 fusion protein that binds to CD80/CD86 and inhibits T-cell activation, as well as the immunosuppressant sirolimus (rapamycin) [ 67 , 68 ], and subsequently underwent bone marrow transplantation. Two other family members were found to harbor the same variant with only mild symptoms, a common finding among families with CTLA4 LOF variants that suggests other factors may be involved in disease severity [ 23 ]. One explanation is compensation by the wild-type allele, which could potentially be observed by targeted RNAseq of relatives in addition to the proband.…”

“…PIDs have historically been branded as monogenic disorders with traditional Mendelian inheritance [ 21 ], but as more PIDs have been identified and we have gained better understanding of immune function and clinical pathogenesis, it has been recognized that these disorders often display variable penetrance and severity [ 22 ]. The term complex immune dysregulation syndrome captures the idea that many cases of aberrant immune activity that share similar presentation nevertheless may have heterogeneous, and sometimes oligogenic, causes [ 23 ].…”

“…These are termed very early-onset IBD (VEOIBD) and are generally thought to have a simpler genetic basis [ 27 , 28 , 29 ]. VEOIBD has also been associated with PIDs, both through symptoms as well as gene involvement [ 23 , 28 , 30 , 31 , 32 ]. Previous exome studies of patients with VEOIBD have identified monogenic causes for a small percentage, but most cases remain without a genetic diagnosis.…”

“…For both PIDs and VEOIBD, identifying the specific underlying genomic cause is important for treatment [ 21 , 23 , 30 , 33 ]. Gene-specific targeted therapies enable improved patient management and have been successfully used for several immune conditions [ 1 , 18 , 34 ].…”

“…This group of highly heterogenous disorders often exhibit cascading effects where multiple genes or pathways are pathogenically altered. In some cases, targeting an affected but not causal gene results in worse patient outcomes [ 23 ]. Since diagnostic yield from exome sequencing remains well under 50%, the accessibility of immune cells for genomic profiling of peripheral blood samples obtained by standard phlebotomy raises prospects of RNA-based analyses, specifically RNAseq, that might identify aberrant molecular events such as altered splicing or gene expression [ 5 , 35 , 36 , 37 , 38 , 39 ].…”