The spectrum of apoptotic defects and clinical manifestations, including systemic lupus erythematosus, in humans with CD95 (Fas/APO-1) mutations.
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.
Vaishnaw
A K
AK
Hospital for Special Surgery-Cornell University Medical Center, New York, New York 10021, USA.
Toubi
E
E
Ohsako
S
S
Drappa
J
J
Buys
S
S
Estrada
J
J
Sitarz
A
A
Zemel
L
L
Chu
J L
JL
Elkon
K B
KB
D017209:Apoptosis; D001327:Autoimmune Diseases / Q000235:genetics; D001402:B-Lymphocytes / Q000166:cytology; D002675:Child, Preschool; D005192:Family Health; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008206:Lymphatic Diseases / Q000235:genetics / Q000276:immunology; D008297:Male; D009154:Mutation; D010375:Pedigree; D013577:Syndrome; D013601:T-Lymphocytes / Q000166:cytology; D019014:fas Receptor / Q000235:genetics*
D019014:fas Receptor