Human disease Mouse mutant or knockoutGene Single-gene traits associated with autoimmunity APECED (APS-1) Knockout Mechanism of autoimmunity Decreased expression of self antigens in the thymus, resulting in defective negative selection of self-reactive T cells AIRE IPEX Knockout and mutation (scurfy) Decreased function of CD4 CD25 regulatory T cells FOXP3 ALPS lpr/lpr; gld/gld mutants Failure of apoptotic death of self-reactive B and T cells FAS SLE Knockout Defective clearance of immune complexes and apoptotic cellsC1q IBD Hypomorph Defective autophagy/clearance of bacteria by innate cells in intestines ATG16L1 IBD Knockout Defective IL-10 signaling; impaired anti-infammatory responseIL10RA, IL10RB Type 1 diabetes None Decreased expression of insulin in thymus; impaired negative selectionINS Association with Graves’ disease, type 1 diabetes, and others Knockout Failure of T-cell anergy and reduced activation threshold of self-reactive T cells CTLA4
Fig. 15.36 Single-gene traits associated with autoimmunity. APS‑1, autoimmune polyglandular syndrome 1; IPEX, immune Listed are examples of monogenic disorders that cause dysregulation, polyendocrinopathy, enteropathy, X‑linked syndrome; autoimmunity in humans. Mice with targeted deletions (knockout) ALPS, autoimmune lymphoproliferative syndrome. The lpr mutation or spontaneous mutations (for example, lpr/lpr) in homologous in mice affects the gene for Fas, whereas the gld mutation affects genes have similar disease characteristics and are useful models the gene for FasL. Adapted from J.D. Rioux and A.K. Abbas: Nature for the study of the pathogenic basis for these disorders. APECED, 435:584–589. With permission from Macmillan Publishers Ltd. autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy; suppressive function normally displayed by these cells is impaired. A spontaneous frameshift mutation in the mouse Foxp3 gene (the scurfy mutation) that results in loss of the DNA-binding domain of FoxP3 or complete knockout of Foxp3 leads to an analogous systemic autoimmune disease, in this case associated with the absence of FoxP3+ Treg cells.
Autoimmunity caused by defective development and survival of Treg cells also results from mutation of CD25, the high-affinity chain of the IL-2 receptor complex that is constitutively expressed by Treg cells (see Section 9-16). Because deficiency of CD25 affects the development and function of effector T cells as well, in addition to autoimmunity, patients affected by this mutation suffer multiple immunological deficiencies and susceptibility to infections. These findings further confirm the importance of Treg cells in the regulation of the immune system.