INSIGHTS | PERSPECTIVES
1560 26 SEPTEMBER 2014 • VOL 345 ISSUE 6204
and a long-term commitment is required to
restore or recover them.
A third implication of the multiple framings concerns the role of valuation. Most environmental decisions are made on the basis
of economic arguments that consider costs
and benefits, usually based on monetary
values. By not having good metrics or by rejecting the idea of valuation in principle (20)
because of its stark formulation in a “nature
for people” framing, conservationists may
cause nature to be excluded from such decisions. If the benefits provided by nature are
assigned no value, they are treated as having
no value, and current trends in the decline
and deterioration of natural systems will
The differences among the framings
are not as stark as they appear. Despite its
strong focus on humans, “people and nature” may actually be very similar to “nature
for itself.” Both framings can include people’s hopes and desires about the environment that they wish to live in and leave to
their descendants. “People and nature” has
traction with other societal needs from the
environment and connects better to policy
because it has a broader focus. Yet there is a
risk that any implementation of “people and
nature” will lack the analytical foundations
that made the earlier framings both deliverable and measurable.
Hopefully the many important features
of “people and nature” will continue to be
the focus for conservation over the coming
decades. By sustaining a coherent and inclusive focus and by developing the relevant
science, tools and decisions should emerge
that can ensure a better future for people
and nature. ■
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Autoimmunity arises from self-reac- tive T and/or B lymphocytes, and underliesa widerangeofconditions, from endocrine disorders to blood cytopenias. Genetic epidemiologi- cal studies have long suggested that
many autoimmune conditions have an inherited component. Autoimmunity is often
described as having polygenic or complex
inheritance. However, both descriptions
are too general to adequately describe the
considerable heterogeneity in patients and
conditions. Spectacular progress in the
genetic dissection of autoimmunity has
come from Mendelian studies of young patients with
rare, distinctive conditions.
Less has been learned from
population-based, genome-wide association studies of
more common, clinically less
The three best-characterized
monogenic autoimmune disorders are autoimmune polyendocrinopathy syndrome
type 1, X-linked immunop-roliferative enteropathy, and
autoimmune lymphoprolierative syndrome
(1). On page 1623 of this issue, Kuehn et al. (2)
add to this list. Patients with only one functional copy of the gene encoding cytotoxic T
lymphocyte antigen 4 (CTLA4) suffer from
severe autoimmunity. These heterozygous
mutations result in a new phenotype, with
infiltration of nonlymphoid organs, such as
the intestine, lungs, and brain, by hyperactive T cells and B cells, along with more classic signs of autoimmunity.
CTLA4 is expressed on the surface of T
cells. It competes with CD28 to bind B7 molecules expressed on antigen-presenting cells
and its activation inhibits the proliferation
of effector T cells and stimulates the suppressive functions of regulatory T cells (3).
These effects help maintain tolerance to self-antigens, as shown by the severe autoimmunity in mice lacking both copies of the Ctla4
gene (4). The physiological importance of
Partial deficiency in the protein CTLA4 underlies severe
autoimmune disease with incomplete penetrance
By Frédéric Rieux-Laucat1,2 and
human CTLA4 was recently highlighted by
the success of treatments based on CTLA4-
blocking antibodies in patients with some
cancers (5). Kuehn et al. report that patients
heterozygous for a loss-of-function CTLA4 allele have a phenotype similar to that of mice
homozygous for a loss-of-function Ctla4 allele, whereas heterozygous mice have no
detectable phenotype (2, 4). Moreover, autosomal dominant CTLA4 deficiency displayed
incomplete penetrance, as some heterozygous individuals were asymptomatic. This
illustrates the similarities and differences
between the small number of inbred mouse
strains studied in experimental conditions
and the large numbers of outbred human
kindreds observed in natural conditions (6).
Since the identification of mutations in
the ADA gene encoding adenine deaminase
as causal for severe combined immunodeficiency in 1985 (7), the genetic basis of more
than 250 inborn errors of immunity has been
determined. Studies initially focused on the
conditions underlying severe infections described in the 1950s, but then shifted to the
analysis of inherited forms and combinations
of infection, allergy, autoinflammation, and
The field of primary immunodeficiencies
has also diversified considerably in terms
of the modes of inheritance. The autosomal
dominant pattern of inheritance is common
to only about 50 immunological conditions,
most of which have been discovered in the
past decade. Even more unusual is the un-
derlying mechanism of haploinsufficiency,
which was first reported in 1989 for a con-
dition called angioedema (9). Haploinsuf- ILLUS