Immune cytopenias as a continuum in inborn errors of immunity: An in‐depth clinical and immunological exploration

Abstract

Background Immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and autoimmune neutropenia (AIN) are disorders characterized by immune‐mediated destruction of hematopoietic cell lineages. A link between pediatric immune cytopenias and inborn errors of immunity (IEI) was established in particular in the combined and chronic forms. Objective Aim of this study is to provide clinical‐immunological parameters to hematologists useful for a prompt identification of children with immune cytopenias deserving a deeper immunological and genetic evaluation. Methods We retrospectively collected 47 pediatric patients with at least one hematological disorder among which persistent/chronic ITP, AIHA, and AIN, aged 0–18 years at onset of immune cytopenias and/or immune‐dysregulation. The cohort was divided into two groups (IEI+ and IEI−), based on the presence/absence of underlying IEI diagnosis. IEI+ group, formed by 19/47 individuals, included: common variable immune deficiency (CVID; 9/19), autoimmune lymphoproliferative syndrome (ALPS; 4/19), DiGeorge syndrome (1/19), and unclassified IEI (5/19). Results IEI prevalence among patients with ITP, AIHA, AIN, and Evans Syndrome was respectively of 42%, 64%, 36%, and 62%. In IEI+ group the extended immunophenotyping identified the presence of statistically significant (p < .05) specific characteristics, namely T/B lymphopenia, decrease in naїve T‐cells%, switched memory B‐cells%, plasmablasts%, and/or immunoglobulins, increase in effector/central memory T‐cells% and CD21low B‐cells%. Except for DiGeorge and three ALPS patients, only 2/9 CVID patients had a molecular diagnosis for IEI: one carrying the pathogenic variant CR2:c.826delT, the likely pathogenic variant PRF1:c.272C> and the compound heterozygous TNFRSF13B variants p.Ser144Ter (pathogenic) and p.Cys193Arg (variant of uncertain significance), the other one carrying the likely pathogenic monoallelic variant TNFRSF13B:p.Ile87Asn. Conclusion The synergy between hematologists and immunologists can improve and fasten diagnosis and management of patients with immune cytopenias through a wide focused clinical/immunophenotypical characterization, which identifies children worthy of IEI‐related molecular analysis, favouring a genetic IEI diagnosis and potentially unveiling new targeted‐gene variants responsible for IEI phenotype.

Autoimmune Cytopenias and Dysregulated Immunophenotype Act as Warning Signs of Inborn Errors of Immunity: Results From a Prospective Study

“…Importantly, genetic analysis showed that IEI-causing mutations were detected in patients displaying suggestive clinical features or a positive family history (AIC-sIEI group, Table 1 ). This finding confirms previous results of a recent retrospective study ( 13 ), highlighting that associated clinical signs together with extended immunophenotyping ( 16 ) should guide physicians in the decision of performing genetic testing. Notably, 12/21 AIC-sIEI subjects had an inconclusive genetic analysis and are undergoing additional investigations, as well as P11 ( AIRE ), P16 ( CARD11 ) and P22 ( UNC13D ) whose WES is currently being processed to rule out whether other mutations may cause the clinical phenotype.…”

“…This study confirms the strong relationship between AICs and IEI ( 13 , 16 ), focusing on the potential role of extensive multiparametric flow cytometry and PCA as screening tools for an underlying genetic disorder. T cell phenotypes analyzed before 2 nd - or 3 rd -line treatment revealed an imbalanced T CD4+ and CD8+ profile in patients with AIC-sIEI.…”

“…Interestingly, we observed a lower frequency of AIC-alone patients in our cohort compared to recently published studies ( 13 , 16 ), which could be ascribable to the different inclusion criteria and to the prospective nature of our work. Moreover, two AIC-sIEI patients presenting with multi-lineage cytopenia (P27 and P28) also displayed autoimmune hepatitis (AIH), which it is known to be associated with severe aplastic anemia (SAA).…”

“…Moreover, immunophenotyping was mainly performed during acute clinical presentation, therefore we cannot exclude that these abnormalities are due to the concomitant inflammatory status, rather than the underlying immune dysregulation. However, a recent retrospective study pointed out similar immunologic alterations in patients affected by AICs with a known genetic etiology ( 16 ). Coherent findings in two differently designed studies potentially confirm that the immunologic imbalance detected in our AIC-sIEI population should not be ascribable to the concurrent inflammatory background.…”

“…Indeed, some specific immunological alterations, if accompanied with AIHA, ITP, autoimmune neutropenia (AIN), or their combinations (Evans syndrome, ES) could be significant red flags for an associated IEI ( 13 ). These include both humoral and cell-mediated immune defects, like reduced serum immunoglobulin levels and low T cell counts ( 3 , 12 , 14 , 15 ), while only scant evidence regarding deeper immunological studies in AICs is available ( 16 ).…”