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Skin lesions. (a) multiple scar-like bluish-red lesions on both arms. (b) indurated, erythematous scar-like lesion on the left cheek. (c, d) Skin biopsy showing massive lymphohistiocytic infiltration focally with formation of granulomas (H&E, 100x and 400x, resp.). There was a dominance of CD8+ T-cells and also an increased proportion of CD4/CD8 double-negative T-cells.
Source publication
The nuclease Artemis is essential for the development of T-cell and B-cell receptors and repair of DNA double-strand breaks, and a loss of expression or function will lead to a radiosensitive severe combined immunodeficiency with no functional T-cells or B-cells (T-B-SCID). Hypomorphic mutations in the Artemis gene can lead to a functional, but red...
Similar publications
We report a case of Omenn syndrome due to a novel mutation of the gene DCLRE1C(Artemis). He was referred to our hospital with a complaint of protracted diarrhea, erythematoexfoliative rash, urinary tract infection, pneumonia, and failure to thrive. He was 2 months old. At the first sight, the diagnoses of Omenn syndrome, graft versus host disease (...
Citations
... We reviewed the genetic and clinical features of patients with ARTEMIS deficiency complicated by lymphoma (Table 1). Seven patients, including our patient, have been reported to develop lymphoma, all with hypomorphic DCLRE1C mutations (15)(16)(17)(18). Six patients had EBV-related B-cell lineage lymphoma, and one had Hodgkin lymphoma with EBV reactivation. ...
... Three patients died after anti-B-cell-specific monoclonal antibody treatment. Patient P5 surrendered to respiratory failure before further treatment, while patient P3 succumbed to multiple infections (Pneumocystis jirovecii pneumonia, Herpes simplex virus, Staphylococcus aureus, and Candida albicans) 5 months after HSCT (16). Pavel et al. reported a 14-year-old boy with a radiosensitive defect, normal lymphocyte subpopulations, abnormal lymphocyte phytohemagglutinin A, hypogammaglobulinemia, and a heterozygous loss of exon 11 in DCLRE1C was diagnosed with B-cell non-Hodgkin lymphoma. ...
Introduction
Hypomorphic mutations of DCLRE1C cause an atypical severe combined immunodeficiency (SCID), and Epstein-Barr virus (EBV)-related colon lymphoma is a rare complication.
Case presentation
A teenage boy presented with colon EBV-related colon lymphoma, plantar warts, and a history of recurrent pneumonia. His peripheral blood lymphocyte count and serum level of immunoglobulin (Ig) G were normal, but he exhibited a T⁺B⁻NK⁺ immunophenotype. Genetic analysis by whole exome sequencing revealed compound heterozygous mutations of DCLRE1C (NM_001033855.3), including a novel paternal splicing donor mutation (c.109 + 2T>C) in intron 1, and a maternal c.1147C>T (p.R383X) nonsense mutation in exon 13. Based on his clinical features and genetic results, the diagnosis of atypical SCID with colon lymphoma was established. Our review shows that seven patients, including our patient, have been reported to develop lymphoma, all with hypomorphic DCLRE1C mutations. Among these cases, six had EBV-related B-cell lineage lymphoma, and one had Hodgkin lymphoma with EBV reactivation. Unfortunately, all of the patients died.
Conclusion
Recognizing the radiosensitivity of the disease is critical for the prognosis. Hematopoietic stem cell transplantation before being infected with EBV is an optimal treatment.
... Hypomorphic mutations, resulting in truncation of the last exon, have been described in patients with aggressive Epstein-Barr virus-associated B-cell lymphoma ( Table 1). Although these patients did not show SCID, they showed low diversity in V(D)J junctions [74,75]. These findings were confirmed in mouse models [76]. ...
Although DNA degradation might seem an unwanted event, it is essential in many cellular processes that are key to maintaining genomic stability and cell and organism homeostasis. The capacity to cut out nucleotides one at a time from the end of a DNA chain is present in enzymes called exonucleases. Exonuclease activity might come from enzymes with multiple other functions or specialized enzymes only dedicated to this function. Exonucleases are involved in central pathways of cell biology such as DNA replication, repair, and death, as well as tuning the immune response. Of note, malfunctioning of these enzymes is associated with immune disorders and cancer. In this review, we will dissect the impact of DNA degradation on the DNA damage response and its links with inflammation and cancer.
... In PIDs in which T cell development is severely impaired (such as SCID with B cells but no T cells (SCID T-B+), resulting from mutations in IL2RG, JAK3, IL7RA or CD3 subunits) or combined immunodeficiency (CID) caused by mutations in ZAP70 (characterized by the almost total absence of CD8 T cells), few cases of severe EBV infections have been documented.[32][33][34][35][36] Patients who carry hypomorphic mutations in genes causing SCID T-B-(such as RAG1/2, LIG4 and DCLRE1C) may also experience severe B-cell lymphoproliferative disorders in which B-cell development is preserved to some extent.[37][38][39][40][41] The fact that severe EBV infections are so rare in these conditions is somewhat surprising, given the sever-ity of the T-cell defects. ...
Primary immunodeficiencies (PIDs) provide researchers with unique models to understand in vivo immune responses in general and immunity to infections in particular. In humans, impaired immune control of Epstein‐Barr virus (EBV) infection is associated with the occurrence of several different immunopathologic conditions; these include non‐malignant and malignant B‐cell lymphoproliferative disorders, hemophagocytic lymphohistiocytosis (HLH), a severe inflammatory condition, and a chronic acute EBV infection of T cells. Studies of PIDs associated with a predisposition to develop severe, chronic EBV infections have led to the identification of key components of immunity to EBV – notably the central role of T‐cell expansion and its regulation in the pathophysiology of EBV‐associated diseases. On one hand, the defective expansion of EBV‐specific CD8 T cells results from mutations in genes involved in T‐cell activation (such as RASGRP1, MAGT1, and ITK), DNA metabolism (CTPS1) or co‐stimulatory pathways (CD70, CD27, and TNFSFR9 (also known as CD137/4‐1BB)) leads to impaired elimination of proliferating EBV‐infected B cells and the occurrence of lymphoma. On the other hand, protracted T‐cell expansion and activation after the defective killing of EBV‐infected B cells is caused by genetic defects in the components of the lytic granule exocytosis pathway or in the small adapter protein SH2D1A (also known as SAP), a key activator of T‐ and NK cell‐cytotoxicity. In this setting, the persistence of EBV‐infected cells results in HLH, a condition characterized by unleashed T‐cell and macrophage activation. Moreover, genetic defects causing selective vulnerability to EBV infection have highlighted the role of co‐receptor molecules (CD27, CD137, and SLAM‐R) selectively involved in immune responses against infected B cells via specific T‐B cell interactions.
Objective:
In this study, we explored the expression of transcription factors, cytokines, and co-stimulatory molecules within the helper T (Th) cell subsets (Th1, Th2, Th17 and Treg) of patients with hypomorphic DCLRE1C gene mutations.
Methods:
The study comprised eight patients and five controls. Transcription factor and cytokine expressions of Th subsets and co-stimulatory molecules were investigated by qPCR and flow cytometric following T cell stimulation. The findings were compared between patients (non-HSCT) and with hematopoietic stem cell transplantation (HSCT).
Results:
Flow cytometric analyses; while the Treg rate was significantly lower in non-HSCT than in controls (p = 0.010), the IFN-γ rate was significantly higher in patients than in the control and HSCT groups (p = 0.016, p = 0.022 respectively). Co-stimulatory molecule expressions were significantly lower in non-HSCT than in control (p < 0.001), and there was a significant improvement after HSCT. Post-stimulation qPCR analysis, significant changes were detected in non-HSCT/control, non-HSCT/HSCT and HSCT/control comparisons.
Conclusions:
Our study is the first study to molecularly investigate Th cell subsets in hypomorphic DCLRE1C patients. It was determined that abnormalities in Th cell subsets still persisted despite HSCT. There are still many conditions to be explained in these patients, and we believe that our study may shed light on future studies.
Leukemias and lymphomas are the dominant malignancies in childhood, comprising over one third of all pediatric cancer cases. They are also prevalent in adulthood, each being among the ten most common cancer types. Inherited immunodeficiencies and immune dysregulatory syndromes, on the other hand, are quite rare, with nearly all of these conditions affecting few patients. Due to their rarity, they are undoubtedly under-recognized, and many have only recently been described, further complicating their diagnosis. Nonetheless, it is increasingly evident that many of the same genetic lesions that cause immune dysfunction also carry predilection to developing specific, or in some cases several, types of hematologic cancer. This chapter briefly summarizes the molecular and cellular pathophysiology and clinical features for many of these entities, including the leukemias and lymphomas associated with them. A table consisting of several additional immunodeficiency syndromes linked to hematologic malignancies is provided at its conclusion.
