Autoimmunity: Twenty Years in the Fas Lane

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DOI: 10.4049/jimmunol.1202833 · Source: PubMed
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Autoimmunity: Twenty Years in the Fas
Madhu Ramaswamy and Richard M. Siegel
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Autoimmunity: Twenty Years in the Fas Lane
Madhu Ramaswamy and Richard M. Siegel
Just over 20 years ago, Shige Nagata and colleagues (1)
forged an important link between defective apoptosis
and autoimmunity when they discovered that loss-of-
function mutations in the gene encoding the TNF family cell
surface receptor Fas/CD95 formed the genetic basis of the
syndrome of lymphoproliferation and autoimmunity in the lpr
mouse strain. Even before the linkage to Fas mutations, lpr mice
had served as a model for human systemic lupus erythematosus
(SLE). However, the discovery of mutations in Fas not only
provided a molecular explanation for the lpr phenotype, it also
inspired investigations that led to the discovery of Fas muta-
tions in human familial autoimmune diseases and spurred
research that discovered the molecular mechanisms underly-
ing Fas-induced apoptosis. Recent findings have expanded the
role of Fas beyond simply inducing apoptosis and prompted
a re-examination of the original premise that autoimmunity
in the context of Fas deficiency results simply from defective
immune cell death.
Homozygous lpr/lpr mutant mice spontaneously produce a
variety of autoantibodies to nuclear Ags with a striking resem-
blance to those found in the sera of patients with SLE (2).
Massive lymphadenopathy and splenomegaly develop in these
mice, hence the name lymphoproliferation (lpr). The primary
cell type accumulating in the lymph nodes and spleen is
abTCR-expressing T cells lacking CD4 and CD8 (termed
“double-negative” T cells [DNT]) and additionally expressing
the CD45 isoform B220. These T cells are oligoclonal but not
malignant; other than being thymus dependent, their origin
remains obscure. DNT are unlikely to be the cells that provide
help for autoreactive B cells because they are anergic to TCR
stimulation and poor producers of cytokines. Reducing the
T cell repertoire with a TCR transgene eliminates production
of DNT but not autoantibody production, showing that DNT
are not required for autoimmunity in lpr mice (3). Conventional
T cells, especially with a memory phenotype, and B cells also
accumulate to greater-than-normal numbers in lpr mice.
Background genes are important modifiers of the lpr phe-
notype, because renal disease and other organ manifestations,
such as arthritis, vasculitis, and salivary gland and skin inflam-
mation, primarily develop in lpr mice back-crossed onto the
MRL genetic background (2, 4).
Once Nagata’s group (5) had cloned the mouse Fas locus,
the identification of Fas mutations in lpr mice using the ge-
netic techniques available at that time was relatively straight-
forward. As described by Nagata in a 2004 interview, he usually
tried to map the loci of genes cloned in the laboratory to see
whether there was any relevance to disease (6). Collaborators
Nancy Jenkins and Neal Copeland at the National Institutes
of Health (NIH) mapped the mouse Fas locus to a location on
chromosome 19, close to where the lpr locus had previously
been mapped (7). Rather than proceeding to positional cloning
and sequencing, which likely would have taken additional years
of effort, the investigators made the leap to directly test for Fas
expression by Northern blotting. They immediately hit the
genetic “jackpot,” finding that cells from lpr/lpr mice expressed
almost no detectable Fas mRNA. Although Watanabe-Fukunaga
et al. (1) found alterations in the Fas genomic locus in lpr
mice by Southern blotting, the exact nature of the genetic
lesion was elucidated by Keith Elkon’s group (8), who showed
that Fas transcription was disrupted in the lpr locus by a retro-
transposon insertion. Watanabe-Fukunaga et al. (1) did solve
the mystery of another Fas allele, lpr
, which turned out to be
a missense mutation in exon 9, which encodes the death
domain. The Fas lpr
mutant protein was nonfunctional
for apoptosis induction. The lpr
allele also had the interest-
ing property of being able to complement the gld (generalized
lymphadenopathy) locus with a similar phenotype. This
suggested that the gld locus was functionally linked to Fas.
In 1994, Nagata’s group, which had recently cloned the Fas
ligand (FasL) gene (9), and a team at Immunex and Duke
University identified disabling point mutations in the extra-
cellular domain of FasL as the cause of the gld syndrome (10,
Although Watanabe-Fukunaga et al. (1) speculated that Fas
mutations identified in lpr syndrome may also cause human
autoimmune conditions, no human diseases linked to either
Fas mutations or defective Fas-mediated apoptosis had been
described. However, just at that time, clinical investigators
were evaluating patients who turned out to have an immune
disorder remarkably similar to that seen in lpr mice. The
findings linking the lpr phenotype to Fas mutations undoubt-
edly accelerated the discovery of Fas mutations responsible for
human disease. At the NIH’s Clinical Center in Maryland,
virologist Steven Straus was referred a number of patients with
chronic lymphadenopathy for evaluation of possible EBV in-
fection as a factor in their disease. Characterization of these
patients in collaboration with Mike Sneller, a fellow in War-
ren Strober’s group at NIH, revealed a significant pattern of
Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis
and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda,
MD 20892
This work was supported by the intramural research program of the National Institute
of Arthritis and Musculoskeletal and Skin Diseases.
Address correspondence and reprint requests to Dr. Richard M. Siegel, National
Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of
Health, Building 10, Room 9N238, Bethesda, MD 20892-1820. E-mail address:
Abbreviations used in this article: ALPS, autoimmune lymphoproliferative syn-
drome; DNT, double-negative T cell; FasL, Fas ligand; NIH, National Institutes of
Health; SLE, systemic lupus erythematosus.
by guest on January 7, 2016 from
autoimmunity, primarily autoantibody-mediated hemolytic
anemia, thrombocytopenia, and splenomegaly and lymphade-
nopathy with underlying polyclonal expansion of B cells and
T cells lacking CD4 and CD8 (12). In their article,
the investigators presciently speculated about the similarities
between these patients and lpr and gld mice.
The discovery linking Fas to the lpr mouse phenotype led to
discussions at NIH about the possibility of Fas mutations and
apoptosis defects in this syndrome with immunologist Mike
Lenardo, a discoverer of the phenomenon of TCR-induced
apoptosis, who demonstrated an apoptosis defect in the pa-
tient cells. The team was joined by geneticist and clinical im-
munologist Jennifer Puck, who showed that missense mutations
in Fas-coding sequences clustering in the death domain were
inherited in an autosomal-dominant fashion in five indepen-
dent families with this disorder, which was named autoimmune
lymphoproliferative syndrome (ALPS) (13). Expression of the
mutant protein blocked Fas-induced apoptosis in normal cells,
and T cells from ALPS patients also failed to undergo death as
the result of restimulation through the TCR (restimulation-
induced cell death) (13). These data confirmed findings about
the role of Fas in restimulation-induced cell death in CD4
T cells made around the same time (14–16). Independently,
Frederic Rieux-Laucat and colleagues (17) in Paris and Keith
Elkon’s group (18) in New York identified Fas mutations in
similar groups of patients, some of whom had been described
in the 1960s as having Canale–Smith syndrome, with many
of the same clinical features as what became known as ALPS.
Cohorts of patients with ALPS were subsequently described
around the world (19–21). Today, there are likely to be $500
families, z80% of whom have Fas mutations, with the clin-
ical syndrome of ALPS fitting recently revised diagnostic cri-
teria (22). Although most Fas mutations in ALPS are inherited,
some patients with a similar clinical syndrome, but without
germline Fas mutations, were found to have somatic point
mutations in Fas that likely underlie their disease (23). Muta-
tions found in other non-Fas–related genes in ALPS patients
have further shed light on apoptosis-signaling pathways (22).
Ironically, despite lpr mice serving as a model for systemic
lupus in humans, investigation of mutations or polymorphisms
in Fas in patients with SLE and unbiased whole-genome asso-
ciation studies of SLE susceptibility loci have not yielded evi-
dence of common or rare genetic variants in Fas that drive sus-
ceptibility to lupus. Although its usefulness as a single-gene
model of autoimmunity was not diminished, these findings
made it clear that lpr is a mouse model for ALPS, rather than
The discoveries that Fas mutations can cause genetic auto-
immune disease in both mouse and man triggered intensive
study of this receptor and the molecular basis of transmem-
brane signaling initiated by Fas. Within the next 4 years, the
essential components of the death-inducing signaling complex
that are recruited to the Fas death domain (24) were eluci-
dated. The adaptor protein FADD and the cysteinyl aspartic
protease, caspase-8, were found to be essential components for
Fas-induced apoptosis (25–27). Aggregation in the Fas death–
inducing signaling complex activates caspase-8, which, in turn,
catalyzes the cleavage of downstream or “effector” caspase-3,
whose activation results in irreversible cell death. In some cells,
amplification of the cell death signal through the mitochon-
dria is also required (28). Fas and FasL can form homotrimers,
but a number of lines of evidence suggest that formation of
receptor oligomers beyond the 3:3 complex of Fas with FasL
is critical for effective activation of Fas apoptotic signaling. Only
membrane-bound FasL is capable of triggering active down-
stream receptor complexes, and soluble FasL cannot induce
Fas-induced apoptosis in vitro or in vivo (29, 30). The crystal
structure of Fas and FADD consists of five receptor oligomers,
suggesting at least a dimer of Fas trimers as the minimal active
signaling complex (31), and microscopically visible clusters of
receptors are seen after receptor ligation (32, 33). Fas cluster-
ing and efficient signaling are supported by receptor localiza-
tion in lipid rafts, which is mediated by palmitoylation of a
membrane-proximal cysteine (34–36), and preassociation of
receptor chains is mediated by a separate domain from ligand
binding (37).
Despite their essential role in Fas apoptotic signaling, analysis
of the in vivo role of FADD and caspase-8 revealed additional
unexpected functions. FADD- and caspase-8–deficient mice
were found to be embryonically lethal and revealed that these
molecules were also required for efficient hematopoietic and
T cell development (38–40). Patients homozygous for a hypo-
morphic mutation in caspase-8 had reduced Fas-induced apo-
ptosis in their T cells, as well as significant immunodeficiency
and T cell activation defects distinct from those of Fas-
deficient ALPS patients (41). A role for FADD and caspase-8
in preventing programmed necrosis recently provided an expla-
nation for these apparently paradoxical functions (42–45),
because FADD- or caspase-8–deficient cells may default into
programmed necrosis and become eliminated more easily when
Fas or other activating stimuli are given.
In addition to preventing programmed necrosis, Fas can
deliver signals that oppose cell death in a number of contexts
(46). Fas can costimulate T cell activation (47, 48), and non-
apoptotic Fas signaling contributes to liver regeneration in
partial hepatectomy models (49, 50). Fas is expressed on most
primary T cells after activation, but only a small fraction of
T cells, primarily those with an effector memory phenotype, is
highly susceptible to Fas-induced apoptosis (51, 52). It has
become clear that the intrinsic cell death machinery, regulated
primarily by the bcl-2 family of proteins, particularly the
proapoptotic BH3 domain–containing protein bim, controls
apoptosis independently of Fas during thymic negative selec-
tion and the clonal contraction of T cells after acute antigenic
stimulation (53, 54). Fas–FasL interactions are only required
for the elimination of T cells responding to repeatedly admin-
istered Ags, such as occurs during chronic infections (14, 55,
56). The nonapoptotic pathway may be the dominant func-
tion in Fas-expressing tumor cells where Fas is highly expressed,
and loss of Fas in hepatic and ovarian tumors can result in
tumor regression in mouse models (57). These findings brought
the understanding of Fas and apoptosis signaling full circle from
its initial discovery as a receptor for Abs that induce apoptosis
in tumor cells (58).
Even with all these advances over the past two decades, a
number of fundamental questions about how Fas prevents
autoimmunity still remain to be addressed. Although the
apoptotic defect in Fas-deficient cells is easy to demonstrate in
vitro in activated T cells, it is not clear that this defect is respon-
sible for the loss of self-tolerance that results in autoimmunity
in Fas deficiency. Experiments with mice lacking Fas expres-
sion specifically in T cells, B cells, or dendritic cells revealed
by guest on January 7, 2016 from
that autoimmunity can result from deletion of Fas in any of
these compartments (59, 60), although deletion of Fas in
any single cell lineage could not reproduce the syndrome of
complete Fas deficiency. Less is known about how Fas sig-
naling is regulated in B cells and other cell types. In another
of their many contributions to the understanding of the
biology of Fas/CD95, Nagata’s group (61) discovered that
anti-Fas Abs cause lethal hepatic necrosis due to engagement of
Fas on hepatocytes, limiting the therapeutic use of anti-Fas
Abs to eliminate autoreactive immune cells. Thus, under-
standing how cells control whether they die, survive, or
proliferate after Fas engagement, as well as what other signals
influence this cell fate decision, remains important for the
design of immunotherapies that target this remarkable receptor
We thank Mike Lenardo and Mike Sneller for discussions about the history
of the discovery of ALPS and Fas mutations in humans and Vera Siegel for
proofreading the manuscript.
The authors have no financial conflicts of interest.
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