Do ribosomopathies explain some cases of common variable immunodeficiency?

Abstract

SummaryThe considerable clinical heterogeneity of patients with common variable immunodeficiency disorders (CVID) shares some similarity with bonemarrow failure disorders such as Diamond-Blackfan anaemia (DBA) and Shwachman-Diamond syndrome (SDS), now recognized as defects in ribosome biogenesis or ribosomopathies. The recognition of a patient with DBA who subsequently developed CVID lends support to our previous finding of a heterozygous mutation in the SBDS gene of SBDS in another CVID patient, suggesting that ribosome biogenesis defects are responsible for a subset of CVID. Genetic defects in the ribosomal translational machinery responsible for various bone marrow failure syndromes are recognized readily when they manifest in children, but diagnosing these in adults presenting with complex phenotypes and hypogammaglobulinaemia can be a challenge. In this perspective paper, we discuss our clinical experience in CVID patients with ribosomopathies, and review the immunological abnormalities in other conditions associated with ribosomal dysfunction. With genetic testing available for various bone marrow failure syndromes, our hypothesis that ribosomal abnormalities may be present in patients with CVID could be proved in future studies by testing for mutations in specific ribosomal genes. New knowledge might then be translated into novel therapeutic strategies for patients in this group of immunodeficiency disorders.

Immune status of patients with inherited bone marrow failure syndromes

“…It is also possible that we lacked samples on severely affected patients due to non-enrolment of many such patients (needing active treatment) on our study. This may explain some of the inconsistencies between our results and published reports, particularly in patients with DBA or SDS 3,5,24 .…”

“…They also have increased risks of myelodysplastic syndrome (MDS), acute leukemia, and specific solid tumors 1 . Subtle immunologic abnormalities have been reported in each of these syndromes, without correlation with disease status 2–5 .…”

“…Patients with the Hoyeraal-Hreidarsson (HH) variant of DC may present with immunodeficiency, in addition to cerebellar hypoplasia, microcephaly, intrauterine growth retardation, and early onset aplastic anemia, as well as extremely short telomeres 22,23 . Studies of immune function in DBA and SDS are limited to small numbers of patients and suggest hypogammaglobulinemia, lymphopenia and decreases in specific lymphocyte subsets in nearly half of the patients tested 3,5,24 .…”

Clinical features, mutations and treatment of 104 patients of Diamond-Blackfan anemia in China: a single-center retrospective study

“…Immunodeficiency had been reported in some DBA patients [31,32]. In our clinical observation, infection was the most common reason for a poor response to the treatment and a decrease in the Hb or even a relapse.…”

Eri1 regulates microRNA homeostasis and mouse lymphocyte development and antiviral function

“…52 Lymphocyte deficiency is a common feature of many ribosomopathies including DBA, Shwachman-Diamond syndrome, and dyskeratosis congenita. 53 Of note, we were unable to detect NK-cell homeostasis defects in Rps19 mutant mice (Dsk3) or Rps20 mutants (Dsk4; data not shown). 54 Studies are currently under way to determine whether NK-cell deficiency occurs in other mouse strains with mutations in ribosome-associated proteins.…”