ABSTRACT
BACKGROUND: Autoimmune endocrine diseases can be thought of as a case of mistaken identity. The immune system mistakenly attacks one's own cells, as if they were foreign, which typically results in endocrine gland hypofunction and inadequate hormone production. Type 1 diabetes mellitus and autoimmune thyroid disorders (Hashimoto and Graves diseases) are the most common autoimmune endocrine disorders, while conditions such as Addison disease are encountered less frequently. Autoantibody production can precede clinical presentation, and their measurement may aid verification of an autoimmune process and guide appropriate treatment modalities. CONTENT: In this review, we discuss type 1 diabetes mellitus, autoimmune thyroid disorders, and Addison disease, emphasizing their associated autoantibodies and methods for clinical detection. We will also discuss efforts to standardize measurement of autoantibodies. CONCLUSIONS: Autoimmune endocrine disease progression may take months to years and detection of associated autoantibodies may precede clinical onset of disease. Although detection of autoantibodies is not necessary for diagnosis, they may be useful to verify an autoimmune process.
Subject(s)
Autoimmune Diseases , Diabetes Mellitus, Type 1 , Endocrine System Diseases , Graves Disease , Autoantibodies , Autoimmune Diseases/diagnosis , Endocrine System Diseases/diagnosis , Graves Disease/diagnosis , HumansABSTRACT
CXXC5 is a member of the CXXC-type zinc finger epigenetic regulators. Various hematopoietic and nonhematopoietic roles have been assigned to CXXC5. In the present study, the role of Cxxc5 in myelopoiesis was studied using overexpression and short hairpin RNA-mediated knockdown in mouse early stem and progenitor cells defined as Lineage- Sca-1+ c-Kit+ (LSK) cells. Knockdown of Cxxc5 in mouse progenitor cells reduced monocyte and increased granulocyte development in ex vivo culture systems. In addition, ex vivo differentiation and proliferation experiments demonstrated that the expression of Cxxc5 affects the cell cycle in stem/progenitor cells and myeloid cells. Flow cytometry-based analyses revealed that down-regulation of Cxxc5 leads to an increase in the percentage of cells in the S phase, whereas overexpression results in a decrease in the percentage of cells in the S phase. Progenitor cells proliferate more after Cxxc5 knockdown, and RNA sequencing of LSK cells, and single-cell RNA sequencing of differentiating myeloid cells showed up-regulation of genes involved in the regulation of cell cycle after Cxxc5 knockdown. These results provide novel insights into the physiologic function of Cxxc5 during hematopoiesis, and demonstrate for the first time that it plays a role in monocyte development.
Subject(s)
Cell Cycle/genetics , Cell Differentiation/genetics , DNA-Binding Proteins/genetics , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/metabolism , Myelopoiesis , Transcription Factors/genetics , Alleles , Animals , Bone Marrow Cells/cytology , Bone Marrow Cells/metabolism , Flow Cytometry , Gene Expression Profiling , Gene Expression Regulation, Developmental , Gene Knockout Techniques , High-Throughput Nucleotide Sequencing , Mice , Mice, Transgenic , Myeloid Cells/cytology , Myeloid Cells/metabolismABSTRACT
We report a novel variant in IKZF1 associated with IKAROS haploinsufficiency in a patient with familial immune thrombocytopenia (ITP). IKAROS, encoded by the IKZF1 gene, is a hematopoietic zinc-finger transcription factor that can directly bind to DNA. We show that the identified IKZF1 variant (p.His195Arg) alters a completely conserved histidine residue required for the folding of the third zinc-finger of IKAROS protein, leading to a loss of characteristic immunofluorescence nuclear staining pattern. In our case, genetic testing was essential for the diagnosis of IKAROS haploinsufficiency, of which known presentations include infections, aberrant hematopoiesis, leukemia, and age-related decrease in humoral immunity. Our family study underscores that, after infections, ITP is the second most common clinical manifestation of IKAROS haploinsufficiency.
