Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0409974 (
lupus
)
22,386
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Mutations in a number of signaling components in mice can lead to strong autoimmune phenotypes. In some cases, these mutations likely compromise important feedback inhibitory pathways that downregulate antigen receptor signaling. For example, a deficiency of Lyn leads to a severe
lupus
-like autoimmunity. This autoimmunity may result from loss of a feedback inhibitory pathway in which Lyn phosphorylates CD22, triggering recruitment of the tyrosine phosphatase SHP-1 to the plasma membrane, which then dampens BCR signaling. Loss of Lyn also compromises an inhibitory pathway involving Fc gamma RIIb and SHIP, an
inositol phosphatase
. Mutation of Fyn exacerbates the autoimmunity caused by loss of Lyn. This may be due in part to a nonimmunological compromise in the integrity of the podocytes in the kidney, which may make the kidneys more susceptible to immune complex-induced damage. Fyn-deficient mice exhibit a number of immunological abnormalities and also exhibit some autoimmunity, although this is less severe than what is seen in Lyn-deficient mice. Recently a gain of function mutation in CD45 that may enhance activity of Src family tyrosine kinases has also been found to cause autoimmune disease, suggesting that the level of Src family tyrosine kinase activity is an important determinant of immune tolerance. Finally, several studies suggest that there is a significant interaction between Src family tyrosine kinases and the Fas pathway that is important for self-tolerance. Although these studies are still at an early stage, it seems clear that alterations in regulators of antigen receptor signaling can contribute to autoimmunity.
...
PMID:Signaling mutations and autoimmunity. 1240 47
Unlike conventional B cells, regulatory B cells exhibit immunosuppressive functions to downregulate inflammation via IL-10 production. However, the molecular mechanism regulating the production of IL-10 is not fully understood. In this study, we report the finding that activation-induced cytidine deaminase (AID) is highly upregulated in the IL-10-competent B cell (B10) cell from Innp5d
fl/fl
Aicda
Cre/+
mice, whereas the 5'
inositol phosphatase
SHIP-1 is downregulated. Notably, SHIP-1 deficiency in AID
+
B cells leads to a reduction in cell count and impaired IL-10 production by B10 cells. Furthermore, the Innp5d
fl/fl
Aicda
Cre/+
mouse model shows B cell-dependent autoimmune
lupus
-like phenotypes, such as elevated IgG serum Abs, formation of spontaneous germinal centers, production of anti-dsDNA and anti-nuclear Abs, and the obvious deposition of IgG immune complexes in the kidney with age. We observe that these
lupus
-like phenotypes can be reversed by the adoptive transfer of B10 cells from control Innp5d
fl/fl
mice, but not from the Innp5d
fl/fl
Aicda
Cre/+
mice. This finding highlights the importance of defective B10 cells in Innp5d
fl/fl
Aicda
Cre/+
mice. Whereas p-Akt is significantly upregulated, MAPK and AP-1 activation is impaired in B10 cells from Innp5d
fl/fl
Aicda
Cre/+
mice, resulting in the reduced production of IL-10. These results show that SHIP-1 is required for the maintenance of B10 cells and production of IL-10, and collectively suggests that SHIP-1 could be a new potential therapeutic target for the treatment of autoimmune diseases.
...
PMID:SHIP-1 Deficiency in AID
+
B Cells Leads to the Impaired Function of B10 Cells with Spontaneous Autoimmunity. 2897 92
