Dataset Information

Common Variable Immunodeficiency, Autoimmune Hemolytic Anemia, and Pancytopenia Associated With a Defect in IKAROS.

ABSTRACT:

Objective

Mutations in IKZF1, which encodes Ikaros family zinc finger 1 (IKAROS) transcription factor, are associated with recurrent infections, cytopenia, autoimmune diseases, and hematologic malignancies. Diverse clinical phenotypes resulting from IKZF1 mutations include pulmonary fungal infections, cytopenia, autoimmune hemolytic anemia (AIHA), and malignancies. In this study, we aimed to assess the DNA-binding ability and pericentromeric (PC) localization of a variant of IKZF discovered in a patient.

Materials and methods

DNA-binding ability of a pathogenic IKZF variant was tested using electrophoretic mobility shift assay and PC localization of the variant was assessed by immunofluorescent microscopy in NIH3T3 cells.

Results

Clinical features of a 3-month-old male infant who underwent hematopoietic stem cell transplantation because of an IKZF1 mutation-associated common variable immunodeficiency, AIHA, and pancytopenia are described. DNA studies revealed a heterozygous missense variant (IKZF1 NM_006060 c.427C>T; p.R143W). Cotransfection studies revealed that mutant R143W has a partial dominant-negative effect over PC targeting and DNA binding.

Conclusions

IKZF1 mutation must be kept in mind if neonatal AIHA, common variable immunodeficiency, and pancytopenia are observed.

SUBMITTER: Yilmaz E

PROVIDER: S-EPMC7987842 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Publications

Common Variable Immunodeficiency, Autoimmune Hemolytic Anemia, and Pancytopenia Associated With a Defect in IKAROS.

Yilmaz Ebru E Kuehn Hye S HS Odakir Eda E Niemela Julie E JE Ozcan Alper A Eken Ahmet A Rohlfs Meino M Cansever Murat M Gok Veysel V Aydin Firdevs F Karakukcu Musa M Hauck Fabian F Klein Christoph C Unal Ekrem E Rosenzweig Sergio D SD Patiroglu Turkan T

Journal of pediatric hematology/oncology 20210401 3

<h4>Objective</h4>Mutations in IKZF1, which encodes Ikaros family zinc finger 1 (IKAROS) transcription factor, are associated with recurrent infections, cytopenia, autoimmune diseases, and hematologic malignancies. Diverse clinical phenotypes resulting from IKZF1 mutations include pulmonary fungal infections, cytopenia, autoimmune hemolytic anemia (AIHA), and malignancies. In this study, we aimed to assess the DNA-binding ability and pericentromeric (PC) localization of a variant of IKZF discove ...[more]

PMID: 33122583

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Project description:Autoimmune hemolytic anemia (AIHA) is an acquired, heterogeneous group of diseases which includes warm AIHA, cold agglutinin disease (CAD), mixed AIHA, paroxysmal cold hemoglobinuria and atypical AIHA. Currently CAD is defined as a chronic, clonal lymphoproliferative disorder, while the presence of cold agglutinins underlying other diseases is known as cold agglutinin syndrome. AIHA is mediated by autoantibodies directed against red blood cells (RBCs) causing premature erythrocyte destruction. The pathogenesis of AIHA is complex and still not fully understood. Recent studies indicate the involvement of T and B cell dysregulation, reduced CD4+ and CD25+ Tregs, increased clonal expansions of CD8 + T cells, imbalance of Th17/Tregs and Tfh/Tfr, and impaired lymphocyte apoptosis. Changes in some RBC membrane structures, under the influence of mechanical stimuli or oxidative stress, may promote autohemolysis. The clinical presentation and treatment of AIHA are influenced by many factors, including the type of AIHA, degree of hemolysis, underlying diseases, presence of concomitant comorbidities, bone marrow compensatory abilities and the presence of fibrosis and dyserthropoiesis. The main treatment for AIHA is based on the inhibition of autoantibody production by mono- or combination therapy using GKS and/or rituximab and, rarely, immunosuppressive drugs or immunomodulators. Reduction of erythrocyte destruction via splenectomy is currently the third line of treatment for warm AIHA. Supportive treatment including vitamin supplementation, recombinant erythropoietin, thrombosis prophylaxis and the prevention and treatment of infections is essential. New groups of drugs that inhibit immune responses at various levels are being developed intensively, including inhibition of antibody-mediated RBCs phagocytosis, inhibition of B cell and plasma cell frequency and activity, inhibition of IgG recycling, immunomodulation of T lymphocytes function, and complement cascade inhibition. Recent studies have brought about changes in classification and progress in understanding the pathogenesis and treatment of AIHA, although there are still many issues to be resolved, particularly concerning the impact of age-associated changes to immunity.

Dataset Information

Common Variable Immunodeficiency, Autoimmune Hemolytic Anemia, and Pancytopenia Associated With a Defect in IKAROS.

Objective

Materials and methods

Results

Conclusions

Publications

Common Variable Immunodeficiency, Autoimmune Hemolytic Anemia, and Pancytopenia Associated With a Defect in IKAROS.

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