The spectrum of apoptotic defects and clinical manifestations, including systemic lupus erythematosus, in humans with CD95 (Fas/APO-1) mutations
✍ Scribed by Akshay K. Vaishnaw; Elias Toubi; Satomi Ohsako; Jorn Drappa; Saundra Buys; Jaime Estrada; Anneliese Sitarz; Larry Zemel; Jia-Li Chu; Keith B. Elkon
- Publisher
- John Wiley and Sons
- Year
- 1999
- Tongue
- English
- Weight
- 300 KB
- Volume
- 42
- Category
- Article
- ISSN
- 0004-3591
No coin nor oath required. For personal study only.
✦ Synopsis
Objective:
To determine the clinical spectrum of disease in humans with mutations in the cd95 (fas/ apo-1) receptor and to obtain mechanistic insight into the different clinical phenotypes observed.
Methods:
Clinical information for each of the index cases, first-degree relatives, and any family members reported to have canale-smith syndrome (or another autoimmune disease) was gathered by direct interview, chart review, and verification of data by the physician or pathologist concerned. apoptosis of activated t or b lymphocytes was induced by agonistic anti-cd95 antibodies and quantified by a cell death assay (propidium iodide staining in the subdiploid peak) or cell viability assay (alamar blue or 3h-thymidine incorporation).
Results:
Evaluation of an additional 8 probands with novel heterozygous cd95 mutations revealed hypergammaglobulinemia and immune-mediated cytopenias in all patients, as well as urticarial rash, oral ulceration, lymphopenia, and peripheral neuropathy in some individuals. one patient (p4) had systemic lupus erythematosus (sle) characterized by a world health organization class v lupus nephropathy, a recurrent, reversible multifocal central nervous system disorder, high-titer antiphospholipid autoantibodies, and autoimmune cytopenias. in the p4 pedigree, the father had reduced t and b cell apoptosis associated with a cd95 mutation, whereas an independent b cell apoptotic defect was demonstrated in maternal family members who did not have a cd95 mutation. three cases of b cell lymphoma occurred in carriers of the cd95 mutation.
Conclusions:
Cd95 mutations are associated with loss of regulation of b lymphocytes, which predisposes to systemic autoimmunity including sle. the p4 family provides a model of the complex genetic and functional interactions that are required for the development of a lupus-like syndrome.