Biomedical Engineering Reference
In-Depth Information
Chemokines
VCAM-1
Hematopoietic
cell
α
41
LT
β
R
LT
α
1
β
2
RANK
RANKL
Local stromal
cell
FIGURE 7.1
NF-κB in early events of lymphoid organogenesis. The early events of lymphoid
organogenesis involve the association of hematopoietic lineage cells and VCAM1 expressing
stromal cell. This interaction initiates an NF-κB-dependent signaling loop whereby LTα
1
β
2
ligates LTβR on stromal cells. Activation of LTβR induces NF-κB-dependent upregulation
of organogenic chemokines and VCAM1, which results in increased recruitment of hemato-
poietic cells. Increasing expression of RANKL results in NF-κB activation via RANK, which
is also expressed on hematopoietic cells. The resulting differentiation of these hematopoietic
cells, which includes increased expression of LTα
1
β
2
, initiates a positive feedback loop leading
to organogenesis. Large arrows indicate NF-κB-dependent gene regulation.
R is crucial during secondary
lymphoid organogenesis. Indeed, the alymphoplasia (
aly
) mouse, which lacks mul-
tiple secondary lymphoid organs, has an inactivating point mutation in NIK
[23,24,25]. RelB/p52 heterodimers, liberated by processing of p100 to p52, are
thought to be the primary transcriptional mediator of several key organogenic factors
- CXCL12, CXCL13, CCL19, CCL21, and MadCAM-1 [26]. The p52 knockout
lacks normal B cell follicles, germinal centers, and Peyer's patch development [27,
28, 29]; RelB is also required for Peyer's patch development [26]. Although lymph
node development occurs in RelB knockouts, the nodes are small at birth and are
resorbed perinatally. Many of these defects are shared in Lymphotoxin, NIK, and
IKK
Alternative pathway signaling downstream of LT
β
R, knockouts of RANK also
lack peripheral lymph nodes, suggesting that more than one alternative pathway
stimulus may be involved in LN development [7].
The spleen is a particularly important secondary lymphoid organ because it has
a vital role in the final steps of B cell development as well as the initiation and
maturation of B cell responses. Splenic architecture must, therefore, be maintained
to mount a normal adaptive response. The spleen is divided histologically into areas
of white and red pulp. The red pulp is the site where erythrocytes that have reached
the end of their lifespan are phagocytosed by macrophages. The white pulp is
populated by splenic lymphocytes and consists of B cell follicles and T cell zones.
Splenic architecture allows for dynamic changes, most notably the formation of
α
knockout animals [20,30]. In addition to LT
β
