Both variants affecting splice sites and those in splicing regulatory elements (SREs) can impair pre-mRNA splicing, eventually leading to severe diseases. Despite the availability of many prediction tools, prognosis of splicing affection is not trivial, especially when SREs are involved. Here, we present data on 92 in silico-/55 minigene-analysed variants detected in genes responsible for the primary immunodeficiencies development (namely BTK, CD40LG, IL2RG, SERPING1, STAT3, and WAS). Of 20 splicing-affecting variants, 16 affected splice site while 4 disrupted potential SRE. The presence or absence of splicing defects was confirmed in 30 of 32 blood-derived patients' RNAs. Testing prediction tools performance, splice site disruptions and creations were reliably predicted in contrast to SRE-affecting variants for which just ESRseq, ΔHZEI-scores and EX-SKIP predictions showed promising results. Next, we found an interesting pattern in cryptic splice site predictions. These results might help PID-diagnosticians and geneticists cope with potential splicing-affecting variants.

• MeSH
• Hep G2 Cells MeSH
• Child MeSH
• Exons MeSH
• HeLa Cells MeSH
• Infant MeSH
• Complement C1 Inactivator Proteins genetics   MeSH
• Humans MeSH
• RNA, Messenger genetics   MeSH
• Mutation MeSH
• Child, Preschool MeSH
• Wiskott-Aldrich Syndrome Protein genetics   MeSH
• Interleukin Receptor Common gamma Subunit genetics   MeSH
• Recombinant Fusion Proteins genetics   MeSH
• RNA Splicing * MeSH
• Immunologic Deficiency Syndromes genetics   MeSH
• STAT3 Transcription Factor genetics   MeSH
• Protein-Tyrosine Kinases genetics   MeSH
• U937 Cells MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Child, Preschool MeSH
• Publication type
• Journal Article MeSH

Xenograft models represent a promising tool to study the pathogenesis of hematological malignancies. To establish a reliable and appropriate in vivo model of aggressive human B-cell leukemia and lymphoma we xenotransplanted four p53-mutated cell lines and one ATM-mutated cell line into immunodeficient NOD/SCID IL2Rγ-null mice. The cell lines MEC-1, SU-DHL-4, JEKO-1, REC-1, and GRANTA-519 were transplanted intraperitoneally or subcutaneously and the engraftment was investigated using immunohistochemistry and flow cytometry. We found significant differences in engraftment efficiency. MEC-1, JEKO-1 and GRANTA-519 cell lines engrafted most efficiently, while SU-DHL-4 cells did not engraft at all. MEC-1 and GRANTA-519 massively infiltrated organs and the whole intraperitoneal cavity showing very aggressive growth. In addition, GRANTA-519 cells massively migrated to the bone marrow regardless of the transplantation route. The MEC-1 and GRANTA-519 cells can be especially recommended for in vivo study of p53-mutated chronic lymphocytic leukemia and ATM-mutated mantle cell lymphoma, respectively.

• MeSH
• Ataxia Telangiectasia Mutated Proteins genetics   MeSH
• Biomarkers MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell genetics   metabolism   pathology   MeSH
• Gene Knockout Techniques MeSH
• Heterografts MeSH
• Humans MeSH
• Lymphoma, Mantle-Cell genetics   pathology   MeSH
• Disease Models, Animal MeSH
• Mutation * MeSH
• Mice, Inbred NOD MeSH
• Mice, Knockout MeSH
• Mice, SCID MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Tumor Suppressor Protein p53 genetics   MeSH
• Interleukin Receptor Common gamma Subunit genetics   MeSH
• Transplantation, Heterologous MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Mantle cell lymphoma (MCL) is an aggressive type of B-cell non-Hodgkin lymphoma (NHL) associated with poor prognosis. Animal models of MCL are scarce. We established and characterized various in vivo models of metastatic human MCL by tail vein injection of either primary cells isolated from patients with MCL or established MCL cell lines (Jeko-1, Mino, Rec-1, Hbl-2, and Granta-519) into immunodeficient NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl)/SzJ mice. MCL infiltration was assessed with immunohistochemistry (tissues) and flow cytometry (peripheral blood). Engraftment of primary MCL cells was observed in 7 out of 12 patient samples. The pattern of engraftment of primary MCL cells varied from isolated involvement of the spleen to multiorgan infiltration. On the other hand, tumor engraftment was achieved in all five MCL cell lines used and lymphoma involvement of murine bone marrow, spleen, liver, and brain was observed. Overall survival of xenografted mice ranged from 22 ± 1 to 54 ± 3 days depending on the cell line used. Subsequently, we compared the gene expression profile (GEP) and phenotype of the engrafted MCL cells compared with the original in vitro growing cell lines (controls). We demonstrated that engrafted MCL cells displayed complex changes of GEP, protein expression, and sensitivity to cytotoxic agents when compared with controls. We further demonstrated that our MCL mouse models could be used to test the therapeutic activity of systemic chemotherapy, monoclonal antibodies, or angiogenesis inhibitors. The characterization of MCL murine models is likely to aid in improving our knowledge in the disease biology and to assist scientists in the preclinical and clinical development of novel agents in relapsed/refractory MCL patients.

• MeSH
• Immunophenotyping MeSH
• Immunohistochemistry MeSH
• Liver metabolism   MeSH
• Kaplan-Meier Estimate MeSH
• Bone Marrow metabolism   MeSH
• Middle Aged MeSH
• Humans MeSH
• Lymphoma, Mantle-Cell drug therapy   genetics   metabolism   MeSH
• Disease Models, Animal * MeSH
• Brain metabolism   MeSH
• Mice, Inbred NOD MeSH
• Mice, Knockout MeSH
• Mice, SCID MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Tumor Cells, Cultured MeSH
• Interleukin Receptor Common gamma Subunit deficiency   genetics   MeSH
• Gene Expression Regulation, Neoplastic * MeSH
• Aged MeSH
• Spleen metabolism   MeSH
• Transcriptome genetics   MeSH
• Transplantation, Heterologous MeSH
• Animals MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Mice MeSH
• Aged MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Altered immune response, including low-grade inflammatory processes, is involved in the pathogenesis of schizophrenia, a chronic psychiatric disorder with complex etiology. Distinct gene variants of a number of pro-inflammatory and chemotactic cytokines together with their receptors associate with this disorder. Interleukin-2 receptor gamma (IL-2RG) represents an important signaling component of many interleukin receptors and so far, no data on the functional state of this receptor in schizophrenia have been reported. The aim of this study was to investigate mRNA expression of the IL2RG gene (IL2RG) in schizophrenia patients in comparison with healthy subjects (controls). Total RNA was isolated from peripheral blood of 66 schizophrenia patients and 99 healthy subjects of Armenian population. The mRNA expression was determined by quantitative real-time polymerase chain reaction (RT-PCR) using PSMB2 as housekeeping gene. IL2RG mRNA expression was upregulated in peripheral blood of patients in comparison with controls (patients vs. controls, median [interquartile range]: 2.080 [3.428-1.046] vs. 0.324 [0.856-0.000], p<0.0001). In conclusion, our findings suggest that over-expression of the IL2RG gene may be implicated in altered immune response in schizophrenia and contribute to the pathomechanisms of this disorder.

• MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• RNA, Messenger blood   genetics   MeSH
• Interleukin Receptor Common gamma Subunit genetics   MeSH
• Receptors, Interleukin-2 genetics   MeSH
• Schizophrenia genetics   immunology   physiopathology   MeSH
• Case-Control Studies MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

IL-2 and IL-15 are structurally relative cytokines that share two receptor subunits, CD132 (γ(c) chain) and CD122 (β chain). However, the expression pattern and physiological role of IL-2 and IL-15 private receptor α chains CD25 and IL-15Rα, respectively, are strikingly different. CD25, together with CD122 and CD132, forms a trimeric high affinity IL-2 receptor that is expressed and functions on cells acquiring an IL-2 signal. Conversely, IL-15Rα is expressed and binds IL-15 with high affinity per se already in the endoplasmic reticulum of the IL-15 producing cells and it presents IL-15 to cells expressing CD122/CD132 dimeric receptor in trans. Thus, while IL-2 is secreted almost exclusively by activated T cells and acts as a free molecule, IL-15 is expressed mostly by myeloid cells and works as a cell surface-associated cytokine. Interestingly, the in vivo biological activity of IL-2 can be dramatically increased through complexing with certain anti-IL-2 mAbs; such IL-2/anti-IL-2 mAbs immunocomplexes selectively stimulate the proliferation of a distinct population of immune cells, depending on the clone of the anti-IL-2 mAb used. IL-2/S4B6 mAb immunocomplexes are highly stimulatory for CD122(high) populations (memory CD8(+) T and NK cells) and intermediately also for CD25(high) populations (Treg and activated T cells), while IL-2/JES6-1 mAb immunocomplexes enormously expand only CD25(high) cells. Although IL-2 immunocomplexes are much more potent than IL-2 in vivo, they show comparable to slightly lower activity in vitro. The in vivo biological activity of IL-15 can be dramatically increased through complexing with recombinant IL-15Rα-Fc chimera; however, IL-15/IL-15Rα-Fc complexes are significantly more potent than IL-15 both in vivo and in vitro. In this review we summarize and discuss the features and biological relevance of IL-2/anti-IL-2 mAbs and IL-15/IL-15Rα-Fc complexes, and try to foreshadow their potential in immunological research and immunotherapy.

• MeSH
• Killer Cells, Natural cytology   drug effects   immunology   MeSH
• CD8-Positive T-Lymphocytes cytology   drug effects   immunology   MeSH
• Immunoglobulin Fc Fragments chemistry   MeSH
• Antigen-Antibody Complex genetics   immunology   pharmacology   MeSH
• Interleukin-15 genetics   immunology   pharmacology   MeSH
• Interleukin-2 genetics   immunology   pharmacology   MeSH
• Humans MeSH
• Antibodies, Monoclonal chemistry   MeSH
• Mice MeSH
• Interleukin-15 Receptor alpha Subunit genetics   immunology   MeSH
• Interleukin-2 Receptor alpha Subunit genetics   immunology   MeSH
• Interleukin Receptor Common gamma Subunit genetics   immunology   MeSH
• Gene Expression Regulation MeSH
• T-Lymphocytes, Regulatory cytology   drug effects   immunology   MeSH
• Signal Transduction MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH