The autoimmune lymphoproliferative syndrome (ALPS) is a rare disease caused by an impaired CD95-mediated apoptosis. ALPS is divided into 4 subgroups (type 0 to type III) according to the underlying defect of different CD95 pathway genes1 : type 0 disease is caused by homozygous mutations of the CD95 gene,2  type II by mutations of the caspase 10 gene.3  In contrast to the other subgroups, ALPS type III is characterized neither by in vitro resistance to CD95-mediated apoptosis nor by a known genetic defect. The etiology of ALPS type III is still unclear. Collectively, it is known that most ALPS cases are due to heterozygous mutations of the CD95 gene (ALPS type Ia).2,4  In 1996, a heterozygous mutation of the CD95 ligand (CD95L) in a single patient with ALPS and systemic lupus erythematosus (SLE) was detected and classified as ALPS type Ib.5  Very recently, a novel homozygous mutation in the CD95L has been discovered in a second patient with ALPS.6  Due to their findings, Del-Rey et al6  propose expanding the classification to include ALPS type Ic for this gene. However, there are no data on the frequency of this particular mutation.

To test if CD95L mutations in ALPS have a quantitative significance, we recruited a cohort of 20 patients from different countries in central Europe with an impaired apoptosis sensitivity but no mutations in the intracellular CD95 pathway genes CD95, FADD, and caspase 10. All children fulfilled clinical and laboratory criteria of ALPS and were white.

Automatic sequencing of the entire coding region of the CD95L gene (4 exons) was carried out in 20 patients with ALPS and 64 healthy unrelated controls. Although our analysis revealed a novel silent transition (C>T, cDNA nucleotide 366, exon 2, accession number AY858799) in a patient with ALPS, no functional mutation in both patients and controls could be detected (Table 1).

Table 1.

CD95L mutations in lymphoproliferative diseases and healthy controls


Disease

No. of cases

Mutation

Reference
ALPS   20   0   Own data  
T-ALL   24   0   Own data  
B-ALL   21   0   Own data  
Controls   64   0   Own data  
SLE   143   0   Kojima et al7  
Non-Hodgkin lymphoma   111   1   Kim et al8  
Sjörgen syndrome
 
70
 
0
 
Bolstad et al9 
 

Disease

No. of cases

Mutation

Reference
ALPS   20   0   Own data  
T-ALL   24   0   Own data  
B-ALL   21   0   Own data  
Controls   64   0   Own data  
SLE   143   0   Kojima et al7  
Non-Hodgkin lymphoma   111   1   Kim et al8  
Sjörgen syndrome
 
70
 
0
 
Bolstad et al9 
 

As we did not find any relevant CD95L mutation in such a large group, we doubt if the finding by Del-Rey et al6  represents a novel ALPS subgroup beyond their single-case description. Therefore, the definition of 2 ALPS subgroups (Ib and Ic) based on only 2 single cases seems disputable. Moreover, the role of CD95L mutations for the pathogenesis of lymphoproliferative and autoimmune diseases might be overstated.

Although the murine gld phenotype (CD95L mutation)10  might correspond to the report of the ALPS type Ib patient,5  systematic analyses to determine the frequency of CD95L mutations have challenged the impact of such mutations for the pathogenesis of lymphoproliferative and autoimmune diseases. When we analyzed the CD95L gene from 21 children with B-lineage acute lymphocytic leukemia (B-ALL) and 24 children with T-lineage ALL (T-ALL), we did not observe any genomic alteration. Accordingly, other groups did not detect any relevant mutation of the CD95L gene in different lymphoproliferative and autoimmune disorders, such as non-Hodgkin lymphoma, SLE, and Sjogren syndrome7-9  (Table 1). Therefore, we consider the CD95L gene to be of remarkable genomic stability and question its outstanding role in the pathogenesis of the disorders described above.

The A247E mutation in human FASL gene and the classification of autoimmune lymphoproliferative syndrome (ALPS)

Pauly et al question the role of the A247E mutation in FASL gene, recently described by us in a patient with autoimmune lymphoproliferative syndrome (ALPS),1  in the pathogenesis of the disease. The work of Pauly et al includes a valuable search of FASL mutations in groups of ALPS, B-lineage acute lymphocytic leukemia (B-ALL), and T-ALL patients and healthy individuals. As the authors do not find any mutation, they conclude that FASL gene defects are of minor importance in the pathogenesis of ALPS. Besides, they declare that data on the frequency of the A247E mutation are not available.

The absence of FASL mutations in the group of 20 ALPS patients does not necessarily imply that defects in that gene do not participate in the pathogenesis of the disease. To clarify the question, it would be essential to analyze a broad series of patients who completely fulfill the ALPS criteria as well as those with milder or related phenotypes. Patients with different genetic backgrounds should be studied, since some genetic defects arise and accumulate in human groups with a common ethnic origin, whereas they are undetectable in other populations.

Regarding frequency of the A247E mutation, in our paper1  we analyzed a total of 155 individuals: 104 race-matched healthy donors and 51 race-matched patients with systemic lupus erythematosus (SLE), as SLE was the clinical phenotype associated with the first human FASL mutation described. We did not find the A247E mutation in the FASL gene in any of the individuals tested, and in the “Abstract” we stated that “FASL abnormalities cause an uncommon apoptosis defect.”1 

It should also be taken into account that, at present, unidentified genes, not only the genes that Pauly et al's group has tested (CD95, FASL, FADD, and CASP10), code for proteins that participate in a cascade of events that finally result in apoptosis. Consequently, while the causative genetic defect for the ALPS patients studied remains unknown, they should be classified as ALPS type III.

Finally, ALPS categorization takes into account the genes mutated as well as homozygosity or heterozygosity (type 0, homozygous FAS mutation; type Ia, heterozygous FAS mutation; type Ib, heterozygous FASL deletion; etc). In this sense, the new homozygous FASL mutation found by Del-Rey et al1  together with the indistinguishable clinical ALPS phenotype in comparison with ALPS type Ia patients argue for this case to be included as a new ALPS type Ic subgroup. Other primary immunodeficiencies referred to in a single reported case, such as CD8 deficiency,2  are included as individual conditions in the Classification of Primary Immunodeficiency Diseases.3 

The authors declare no competing financial interests.

Correspondence: Luis M. Allende, Servicio de Inmunología, Hospital Universitario 12 de Octubre, 28041-Madrid, Spain; e-mail: lallende.hdoc@salud.madrid.org.

1
Del-Rey M, Ruiz-Contreras J, Bosque A, et al. A homozygous FASL gene mutation in a patient causes a new type of autoimmune lymphoproliferative syndrome.
Blood
.
2006
;
108
:
1306
-1312.
2
De la Calle-Martin O, Hernández M, Ordi J, et al. Familial CD8 deficiency due to a mutation in the CD8 alpha gene.
J Clin Invest
.
2001
;
108
:
117
-123.
3
Notarangelo L, Casanova JL, Conley ME, et al. Primary immunodeficiencies diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee Meeting in Budapest, 2005.
J Allergy Clin Immunol
.
2006
;
117
:
883
-896.

The authors declare no competing financial interests.

Supported by the Deutsche José Carreras Leukämie Stiftung (DJCLS) München and the Deutsche Leukämie Forschungs-Hilfe (DLFH) Heidelberg.

E.P. and B.F. contributed equally to this work.

1
Rieux-Laucat F, Fischer A, Deist FL. Cell-death signaling and human disease.
Curr Opin Immunol
.
2003
;
15
:
325
-331.
2
Rieux-Laucat F, Le Deist F, Hivroz C, et al. Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity.
Science
.
1995
;
268
:
1347
-1349.
3
Wang J, Zheng L, Lobito A, et al. Inherited human caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II.
Cell
.
1999
;
98
:
47
-58.
4
Fisher GH, Rosenberg FJ, Straus SE, et al. Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome.
Cell
.
1995
;
81
:
935
-946.
5
Wu J, Wilson J, He J, et al. Fas ligand mutation in a patient with systemic lupus erythematosus and lymphoproliferative disease.
J Clin Invest
.
1996
;
98
:
1107
-1113.
6
Del-Rey M, Ruiz-Contreras J, Bosque A, et al. A homozygous Fas ligand gene mutation in a patient causes a new type of autoimmune lymphoproliferative syndrome.
Blood
.
2006
;
108
:
1306
-1312.
7
Kojima T, Horiuchi T, Nishizaka H, et al. Analysis of Fas ligand gene mutation in patients with systemic lupus erythematosus.
Arthritis Rheum
.
2000
;
43
:
135
-139.
8
Kim HS, Lee SH, Lee JW, et al. Mutational analysis of Fas ligand gene in human non-Hodgkin lymphoma.
APMIS
.
2003
;
111
:
490
-496.
9
Bolstad AI, Wargelius A, Nakken B, et al. Fas and Fas ligand gene polymorphisms in primary Sjogren's syndrome.
J Rheumatol
.
2000
;
27
:
2397
-2405.
10
Takahashi T, Tanaka M, Brannan CI, et al. Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand.
Cell
.
1994
;
76
:
969
-976.