Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency

Abstract

Biallelic inactivating mutations in IL21R causes a combined immunodeficiency that is often complicated by cryptosporidium infections. While eight IL-21R-deficient patients have been reported previously, the natural course, immune characteristics of disease, and response to hematopoietic stem cell transplantation (HSCT) remain to be comprehensively examined. In our study, we have collected clinical histories of 13 patients with IL-21R deficiency from eight families across seven centers worldwide, including five novel patients identified by exome or NGS panel sequencing. Eight unique mutations in IL21R were identified in these patients, including two novel mutations. Median age at disease onset was 2.5 years (0.5-7 years). The main clinical manifestations were recurrent bacterial (84.6%), fungal (46.2%), and viral (38.5%) infections; cryptosporidiosis-associated cholangitis (46.2%); and asthma (23.1%). Inflammatory skin diseases (15.3%) and recurrent anaphylaxis (7.9%) constitute novel phenotypes of this combined immunodeficiency. Most patients exhibited hypogammaglobulinemia and reduced proportions of memory B cells, circulating T follicular helper cells, MAIT cells and terminally differentiated NK cells. However, IgE levels were elevated in 50% of IL-21R-deficient patients. Overall survival following HSCT (6 patients, mean follow-up 1.8 year) was 33.3%, with pre-existing organ damage constituting a negative prognostic factor. Mortality of non-transplanted patients (n = 7) was 57.1%. Our detailed analysis of the largest cohort of IL-21R-deficient patients to date provides in-depth clinical, immunological and immunophenotypic features of these patients, thereby establishing critical non-redundant functions of IL-21/IL-21R signaling in lymphocyte differentiation, humoral immunity and host defense against infection, and mechanisms of disease pathogenesis due to IL-21R deficiency. Outcome following HSCT depends on prior chronic infections and organ damage, which should thus be considered as early as possible following molecular diagnosis.

Genetic variation in genes of inborn errors of immunity in children with unexplained encephalitis

“…and a VUS variant. Biallelic IL21R mutations cause immunodeficiency affecting both T and B cell compartments, with impaired immunoglobulin synthesis, T and NK cell dysfunction, and recurrent viral infections [ 24 , 25 ].…”

GVHD, IBD, and primary immunodeficiencies: The gut as a target of immunopathology resulting from impaired immunity

“…The pathogenesis in this disease is complex including not only the genetic background, but also absent IgA regulating the nature and invasiveness of the microbiome, reduced regulatory T cells, altered local cytokine production with a strong shift toward an Th1 environment, and microbiome enriched for proinflammatory pathobionts and chronic viral infection especially by Norovirus [130,131]. The complexity of the protection of the gastrointestinal border is shown also by the enteropathy in most patients with IL21R/Il21 deficiency [132]. While IL-21 is known to be important in the pathology of celiac disease [133], the deficiency of this signal is associated with a lack of local IgA production, dysbiosis, and disturbed local immune homeostasis [134].…”

Tip of the iceberg: A comprehensive review of liver disease in Inborn errors of immunity

“…[58] IL-21 receptor deficiency is an autosomal recessive combined immunodeficiency characterized by hypogammaglobulinemia and recurrent bacterial, viral, and fungal infections, resulting in primarily, respiratory, and gastrointestinal illnesses. [58] Liver. With a total of 13 patients reported all over the world, 6 are reported to have Cryptosporidium-related chronic cholangitis.…”

“…[ 58 ] IL‐21 receptor deficiency is an autosomal recessive combined immunodeficiency characterized by hypogammaglobulinemia and recurrent bacterial, viral, and fungal infections, resulting in primarily, respiratory, and gastrointestinal illnesses. [ 58 ]…”