Skin infiltration of CD56^bright CD16^‐ natural killer cells in a case of X‐SCID with Omenn syndrome‐like manifestations

Abstract

We observed a patient with X-linked severe combined immunodeficiency (X-SCID) with Omenn syndrome-like manifestations. X-linked inheritance, absence of CD132 expression and impaired response to interleukin-2 (IL-2) indicated that the case is typical of X-SCID due to gamma(c) defect. However, this case was unusual in that circulating natural killer (NK) cells were increased and nearly half of these NK cells exhibited the CD56(bright) CD16(-) phenotype. A missense mutation was found within exon 5 of the IL2RG gene. The identical mutation was detected within NK, CD4(+) T and B cells. Engraftment of maternally derived NK cells or gene reversion was ruled out. The erythroderma-like skin lesion was characterized by infiltration of the dermis by CD56(bright) NK cells admixed with CD1a(+) dendritic cells (DC). Expression of mRNA for inflammatory cytokines was significantly enhanced within the skin. This may be the first human case to demonstrate that close cell-to-cell contact between DC and NK cells provides an effective alternative pathway for NK cell differentiation/activation in vivo.

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

“…one example of this is omenn syndrome, which is characterized by a combination of immunodeficiency and graft-versus-hostdisease-like autoimmunity and immune dysregulation with elevated IgE production. Partial loss-of-function variants of the genes RAG1 (recombination-activating gene 1), RAG2, DCLRE1C (dNA crosslink repair 1C; also known as ARTEMIS), IL2RG (Il-2 receptor γ-chain), IL7RA and RMRP are known to cause omenn syndrome [6][7][8][9][10][11] . other related conditions arise from defects in the genes ADA (AdA deficiency), LIG4 (ligase Iv deficiency), ZAP70 (ζ-chain-associated protein kinase of 70 kda; ZAP70 deficiency) and STAT5B (signal transducer and activator of transcription 5b; growth-hormone insensitivity with immunodeficiency).…”

“…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] . In the case of IL2RG, identical alleles have been identified in both diseases 11,24 .…”

“…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] . In the case of IL2RG, identical alleles have been identified in both diseases 11,24 . A similar effect may be responsible for the variations in the clinical manifestation of deficiency of STAT5B, a component of the receptor signalling pathway for growth hormones and key haematopoietic-cell cytokines (including Il-7).…”

Detection of T lymphocytes with a second-site mutation in skin lesions of atypical X-linked severe combined immunodeficiency mimicking Omenn syndrome

“…9,10 In addition, we have recently reported an X-linked SCID (XSCID) patient with massive skin infiltration of natural killer (NK) cells, resulting in OS-like manifestations. 11 Here, we describe another case of XSCID mimicking OS. The patient carried a splice site mutation that allowed development of peripheral T and NK cells, and showed revertant T-cell mosaicism caused by a second-site mutation predominately in the skin.…”

“…[11][12][13][14][15] The purity of the sorted CD4 ϩ T, CD8 ϩ T, CD19 ϩ B, and CD56 ϩ NK cells was 98.1%, 99.3%, 86.4%, and 98.3%, respectively. T-cell and B-cell lines from the patient were established by transformation with Herpes virus saimiri and Epstein-Barr virus, respectively.…”