The clinical spectrum in a large kindred with autoimmune lymphoproliferative syndrome caused by a Fas mutation that impairs lymphocyte apoptosis

Infante, Anthony J.; Britton, Howard A.; DeNapoli, Thomas; Middelton, Lindsay; Lenardo, Michael J.; Jackson, Christine E.; Wang, Jin; Fleisher, Thomas A.; Straus, Stephen E.; Puck, Jennifer M.

doi:10.1016/s0022-3476(98)70102-7

Cited by 105 publications

(78 citation statements)

References 19 publications

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“…The disease in people is inherited, typically with an autosomal dominant mode of inheritance with variable expression of the clinical signs. 10 The feline disease also appears to have an inherited basis, and although the mode of inheritance is currently uncertain, autosomal recessive inheritance is considered most likely, and further studies to clarify this are in progress.…”

Section: Discussionmentioning

confidence: 99%

A Novel and Likely Inherited Lymphoproliferative Disease in British Shorthair Kittens

Aberdein

Fairley²,

Vernau

et al. 2015

Vet Pathol

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An unusual lymphoproliferative disease was identified in multiple closely related British Shorthair (BSH) kittens, suggesting an inherited predisposition to disease. Affected kittens typically developed rapidly progressive and marked generalized lymphadenopathy, moderate splenomegaly, and regenerative and likely hemolytic anemia from 6 weeks of age. Microscopic findings were suggestive of multicentric T-cell lymphoma, but additional testing revealed a polyclonal population of CD3þ/

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Section: Discussionmentioning

confidence: 99%

A Novel and Likely Inherited Lymphoproliferative Disease in British Shorthair Kittens

Aberdein

Fairley²,

Vernau

et al. 2015

Vet Pathol

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“…All patients showed lymphoproliferations, but the manifestation of the autoimmune features varied. Even siblings or other family members carrying the same mutation (patients 1a and b, patients 10 a, b, and c, and patients 13 a, b, and c) showed differences in the extent of autoimmune features (19,21,23). In lpr and lpr cg mice, FAS mutations result in lymphoproliferations, whereas autoimmunity in these mice is strongly influenced by the genetic background (29).…”

Section: Discussionmentioning

confidence: 99%

Autoimmune Lymphoproliferative Syndrome (ALPS) in a Child from Consanguineous Parents: A Dominant or Recessive Disease?

et al. 2000

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Autoimmune lymphoproliferative syndrome (ALPS) is characterized by autoimmune features and lymphoproliferations and is generally caused by defective Fas-mediated apoptosis. This report describes a child with clinical features of ALPS without detectable Fas expression on freshly isolated blood leukocytes. Detection of FAS transcripts via real-time quantitative PCR made a severe transcriptional defect unlikely. Sequencing of the FAS gene revealed a 20-nucleotide duplication in the last exon affecting the cytoplasmic signaling domain. The patient was homozygous for this mutation, whereas the consanguineous parents and the siblings were heterozygous. The patient reported here is a human homologue of the Fas-null mouse, inasmuch as she carries an autosomal homozygous mutation in the FAS gene and she shows the severe and accelerated ALPS phenotype. The heterozygous family members did not have the ALPS phenotype, indicating that the disease-causing FAS mutation in this family is autosomal recessive. Ϫ TCR␣␤ ϩ T cells, and several autoimmune features, such as autoantibody production and autoimmune hemolytic anemia (1). It is caused by a defect in apoptosis mediated by Fas (also designated CD95, Apo1, or Apt1). ALPS features are highly comparable to the phenotype of mice with lpr or gld mutations, which carry an autosomal recessive mutations in the FAS gene or in the gene encoding Fas ligand (FASL), respectively, causing autoimmunity, lymphoproliferations and accumulation of CD4 Ϫ CD8 Ϫ TCR␣␤ ϩ T cells (2-4). There are three mouse strains carrying different FAS mutations i.e. the lpr, the lpr cg and the Fas-null strains (2,5). Although these mice have a similar phenotype, there are differences in severity and the time of development of the symptoms (6).Both FasL and Fas are transmembrane proteins, which belong to the tumor necrosis factor and tumor necrosis factor receptor family, respectively (7,8). Fas is expressed as a trimer on peripheral activated lymphocytes and also in tissues such as liver, lung, heart, and ovary. The intracellular part of the Fas protein contains a death domain, which is essential for the induction of apoptosis on interaction of Fas and FasL trimers (9). Fas-mediated apoptosis is needed for the elimination of autoreactive T lymphocytes that escaped thymic selection, but seems not to be involved in negative selection of immature cells in the thymus (10 -12). The Fas-FasL interaction also appears to be important in B cell homeostasis and is involved in the control of immune responses (13,14 (1, 19 -24). We herein present a new patient in whom Fas protein expression studies were followed by extensive molecular analysis of the FAS gene of the patient as well as her parents and siblings. The unique genotype and phenotype of this patient are discussed in the context of previously described patients with ALPS and the different mouse strains with distinct FAS gene mutations. METHODSClinical report. The patient is a girl from consanguineous parents. She has three healthy siblings, but two other siblings...

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“…Patients with ALPS type Ia are genetically similar to the lpr mice and possess mutations in TNFRSF6, the gene encoding Fas itself. [9][10][11][12][13][14] Patients with ALPS type Ib, like the gld mice, possess mutations in the gene for the Fas ligand. 15 Patients designated as having ALPS type II have mutations in caspase 10, 16 and patients with ALPS type III have lymphocyte apoptotic defects, but the mutations responsible for their disorder have not yet been identified.…”

Section: Introductionmentioning

confidence: 99%

Increases in circulating and lymphoid tissue interleukin-10 in autoimmune lymphoproliferative syndrome are associated with disease expression

Lopatin

Williams

et al. 2001

Blood

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Autoimmune lymphoproliferative syndrome (ALPS) is an inherited disorder in which genetic defects in proteins that mediate lymphocyte apoptosis, most often Fas, are associated with enlargement of lymph nodes and the spleen and a variety of autoimmune manifestations. Some patients with ALPS have relatives with these same apoptotic defects, however, who are clinically well. This study showed that the circulating levels of interleukin 10 (IL-10) were significantly higher (P < .001) in 21 patients with ALPS than in healthy controls. Moreover, the peripheral blood mononuclear cells (PBMCs) and lymphoid tissues of these patients with ALPS contained significantly higher levels of IL-10 messenger RNA (mRNA; P < .001 and P < .01, respectively).

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The clinical spectrum in a large kindred with autoimmune lymphoproliferative syndrome caused by a Fas mutation that impairs lymphocyte apoptosis

Cited by 105 publications

References 19 publications

A Novel and Likely Inherited Lymphoproliferative Disease in British Shorthair Kittens

A Novel and Likely Inherited Lymphoproliferative Disease in British Shorthair Kittens

Autoimmune Lymphoproliferative Syndrome (ALPS) in a Child from Consanguineous Parents: A Dominant or Recessive Disease?

Increases in circulating and lymphoid tissue interleukin-10 in autoimmune lymphoproliferative syndrome are associated with disease expression

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