Biomedical Engineering Reference
In-Depth Information
Ectodysplasin (
tabby
mutation)
X-linked EDA
EdaR (
downless
mutation)
Chr.2-linked EDA
EDARADD (
crinkled
mutation)
Chr.1-linked EDA
NEMO
NF-
κ
B
X-linked EDA-ID
FIGURE 9.2
The EDA/EDAR/EDARADD/NEMO cascade. A simplified version of the sig-
naling cascade is shown, emphasizing the molecules whose mutation leads to EDA. The
names of the mouse mutations are indicated in parentheses. Mutations in the ligand, receptor,
or adaptor lead to EDA, while mutations affecting NEMO lead to EDA-ID, as multiple other
signaling pathways involved in the immune response target the IKK complex.
models of EDAR pathology that this pathway is involved very early during devel-
opment of hair follicle morphogenesis [24], assigning a previously unrecognized
role for NF-
B in this process.
The other symptom affecting EDA-ID patients — immunodeficiency — is less
unexpected based on the well-known function played by NF-
κ
κ
B in both arms of the
immune response (
Chapters 6
,
7
, and
8
). This immunodeficiency is characterized by
unusually severe, life-threatening, and recurrent bacterial infections of the lower
respiratory tract, skin, soft tissues, bones, and gastrointestinal tract, as well as men-
ingitis and septicemia in early childhood
.
The causative pathogens are most often
Gram-positive bacteria (
S. pneumoniae
and
S. aureus
), followed by Gram-negative
bacteria (
Pseudomonas
spp. and
Haemophilus influenzae
) and mycobacteria.
A number of EDA-ID patients have elevated serum IgM levels — the so-called
have an impaired ability to switch in response to the cluster of differentiation 40
(CD40) ligand. In others, immunoglobulin switching is normal, but proliferation and
differentiation are deficient, also resulting in a “hyper-IgM-like” syndrome. A more
consistent feature of EDA-ID pathology is an impaired antibody response to polysac-
charide antigens. In contrast to these B cell anomalies, patients with EDA-ID have
normal T cell proliferation in response to both mitogens and antigens.
In conclusion, both symptoms exhibited by EDA-ID patients can be correlated
with a defect in NF-
B activation. The immunological defect is due to the impair-
ment of a series of important signaling pathways involved in both arms of the immune
response; but the heterogeneity of the symptoms points to some previously unrec-
ognized subtleties in the details of this signaling cascade, unless this heterogeneity
can be assigned to the genetic background. On the other hand, the EDA symptom
is specifically caused by an impairment of the downstream events of the
EDA/EDAR/EDARADD signaling cascade.
κ
