A Severe Form of Human Combined Immunodeficiency Due to Mutations in DNA Ligase IV

Abstract

DNA ligase IV (LigIV) deficiency was identified as the molecular basis for a severe form of combined immunodeficiency in two microcephalic siblings with cellular radiosensitivity. In one patient the diagnosis was made directly after birth, allowing analysis of the role of LigIV in the development of specific immune cells. Absolute numbers of B cells were reduced 100-fold and αβ T cells 10-fold, whereas γδ T cells were normal. Spectratyping of all three cell populations showed a diverse repertoire, but sequencing of IgH V(D)J junctions revealed shorter CDR3 regions due to more extensive nucleotide deletions among D and J elements and fewer N nucleotide insertions. Clonal restriction of IgG-expressing, but not IgM-expressing, B cells and the lack of primary and secondary lymph node follicles indicated impaired class switch recombination. Observations in the older sibling showed that this rudimentary immune system was able to mount specific responses to infection. However, partial Ab responses and extensive amplification of γδ T cells could not prevent a life-threatening course of viral and bacterial infections, the development of an EBV-induced lymphoma, and immune dysregulation reflected by severe autoimmune cytopenia. Impaired generation of immune diversity under conditions of limited LigIV activity can cause a human SCID variant with a characteristic immunological phenotype.

Unravelling the association of partial T-cell immunodeficiency and immune dysregulation

“…The reason why identical RAG1 or RAG2 mutations can result in either the severe or partial form of immunodeficiency is currently unknown; it might be due to the stochastic effects of recombinase activity in individual thymocytes on the composition of the oligoclonal TCR repertoire, an alteration of recombinase activity by additional genetic factors or the influence of environmental factors (such as viral infections) on the T-cell clones that manage to expand 15,16 . ligase Iv is also required for v(d)J recombination and LIG4 mutations can manifest as complete immunodeficiency 17 ; however, the majority of individuals with LIG4 mutations have partial immunodeficiency and include autoimmune components such as autoimmune thrombocytopaenia 18,19 . IL2RG and IL7RA have essential roles in Il-7-dependent thymocyte survival, and mutations in these genes have been associated with both omennlike syndrome 10,11 and severe T-cell deficiency [20][21][22][23] .…”

V(D)J and immunoglobulin class switch recombinations: a paradigm to study the regulation of DNA end-joining

“…In contrast to RS-SCIDs, these patients are not completely devoid of B and T lymphocytes, although their numbers can be drastically reduced. Several other reports of DNA-LigaseIV deficiency further demonstrated the high heterogeneity of this syndrome for its impact on immunodeficiency (from no deficiency to SCID) as well as on its developmental consequences (with or without microcephaly) and cancer incidence (Ben-Omran et al, 2005;Enders et al, 2006;van der Burg et al, 2006;Buck et al, 2006b). In the more severe forms, the V(D)J recombination is strongly affected both quantitatively and qualitatively as a consequence of the DNA rejoining deficiency.…”

DNA repair and the immune system: From V(D)J recombination to aging lymphocytes

“…In contrast to RS-SCID patients, these patients are not devoid of B and T lymphocytes, although their numbers can be drastically reduced. Several other reports of DNA-ligase IV deficiency further demonstrated the high heterogeneity of this syndrome for its impact on immunodeficiency (from no deficiency to SCID) as well as on its developmental consequences (with or without microcephaly) and cancer incidence [22,[29][30][31]. In the more severe forms, the V(D)J recombination is strongly affected both quantitatively and qualitatively as a consequence of the DNA rejoining deficiency.…”