Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024312 (lymphopenia)
 4,859 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autoimmune gastritis, a CD4+ T cell-mediated organ-specific autoimmune disease, can be induced by thymectomy of neonatal, but not of older, BALB/c mice. Here we have shown that autoimmune gastritis can also be induced in 6-8-week-old BALB/c mice by thymectomy combined with a single dose of cyclophosphamide (300 mg/kg). This treatment reduced the numbers of splenic T and B cells approximately 25-fold. However, by 8 days after treatment, the number of splenic lymphocytes had returned to normal adult levels. Approximately 50% of treated mice developed autoimmune gastritis after 10-12 weeks. These mice had mononuclear cellular infiltrates within the gastric mucosa and serum autoantibodies to the alpha and beta subunits of the gastric H+/K+ ATPase. Transgenic mice, expressing the gastric H+/K+ ATPase beta-subunit in the thymus (Alderuccio, F., Toh, B. H., Tan, S. S., Gleeson, P. A. and van Driel, I. R., J. Exp. Med. 1993. 178: 419), did not develop autoimmune gastritis after the adult thymectomy/cyclophosphamide treatment. Thus a T cell response to the H+/K+ ATPase beta-subunit is likely to be required for the onset of gastritis. These observations suggest that pathogenic autoreactive T cells exist in the periphery of normal adult mice and that autoimmunity can be induced by the activation of these autoreactive T cells following transient lymphopenia. Cyclophosphamide-treatment of adult mice without thymectomy did not induce autoimmune gastritis, suggesting thymic regulation of these pathogenic T cells.
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PMID:Organ-specific autoimmunity induced by adult thymectomy and cyclophosphamide-induced lymphopenia. 784 36

Thymectomy of BALB/c mice on day 3 of life results in the development of autoimmune gastritis (AIG) due to the absence of CD4(+)CD25(+) regulatory T cells. However, depletion of CD4(+)CD25(+) T cells by treatment with anti-CD25 rarely resulted in AIG. Depletion was efficient, as transfer of splenocytes from depleted mice induced AIG in nu/nu mice. One explanation for this result is that CD4(+)CD25(-) T cells upon transfer to nude recipients undergo lymphopenia-induced proliferation, providing a signal for T cell activation. Cotransfer of CD25(+) T cells did not inhibit initial proliferation but did suppress AIG. Surprisingly, immunization with the AIG target Ag, H/K ATPase, in IFA failed to induce disease in normal animals but induced severe AIG in CD25-depleted mice. These results demonstrate that second signals (nonspecific proliferation, TCR activation, or inflammation) are needed for induction of autoimmunity in the absence of CD25(+) regulatory T cells.
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PMID:Cutting edge: depletion of CD4+CD25+ regulatory T cells is necessary, but not sufficient, for induction of organ-specific autoimmune disease. 1205 2

Although deletion of certain autophagy-related genes has been associated with defects in hematopoiesis, it remains unclear whether hyperactivated mitophagy affects the maintenance and differentiation of hematopoietic stem cells (HSCs) and committed progenitor cells. Here we report that targeted deletion of the gene encoding the AAA+-ATPase Atad3a hyperactivated mitophagy in mouse hematopoietic cells. Affected mice showed reduced survival, severely decreased bone-marrow cellularity, erythroid anemia and B cell lymphopenia. Those phenotypes were associated with skewed differentiation of stem and progenitor cells and an enlarged HSC pool. Mechanistically, Atad3a interacted with the mitochondrial channel components Tom40 and Tim23 and served as a bridging factor to facilitate appropriate transportation and processing of the mitophagy protein Pink1. Loss of Atad3a caused accumulation of Pink1 and activated mitophagy. Notably, deletion of Pink1 in Atad3a-deficient mice significantly 'rescued' the mitophagy defect, which resulted in restoration of the progenitor and HSC pools. Our data indicate that Atad3a suppresses Pink1-dependent mitophagy and thereby serves a key role in hematopoietic homeostasis.
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PMID:Atad3a suppresses Pink1-dependent mitophagy to maintain homeostasis of hematopoietic progenitor cells. 2924 45