Download Immune defence in the lymphatic system of the skin

118
Review Article
Immune defence in the lymphatic
system of the skin
K. Schmolke
Dept. for lab. medicine (DRK-Kliniken), Berlin, Germany
Keywords
Schlüsselwörter
Epidermis, Langerhans dendritic cells, lymphatic system, antigen-presenting cell
Epidermis, Langerhans-Dendriten, Lymphbahn, antigenpräsentierende Zelle
Summary
Zusammenfassung
As the interface organ between the body and
the external environment, the skin is predestined to have frequent and intensive contact
with pathogens and therefore possesses a
particularly well-developed immunological
defence. The immune system protects the
body’s integrity with innate components
such as the skin’s physicochemical barrier
function, the phagocytic cells and the complement system. The network of Langerhans
dendritic cells in the epidermis allows immediate detection and rapid transport of
antigen material to the regional lymph nodes
and the triggering of a specific immune response by T and B cells. For immunological
processes, the passage through the lymphatic system is decisive, as diverse interactions occur between cells and the lymphatic
system. On the one hand, the interaction of
dendritic receptors with antigenic structures
triggers intracellular signals, allowing migration through the lymphatic system to the
lymph node via chemokines and chemokine
receptors. On the other hand, the Langerhans
dendritic cells alter their own phenotype during migration through the lymphatic system:
they lose their ability to phagocytise in favour of the increased synthesis of MHC molecules and become antigen-presenting cells.
Als Grenzorgan zwischen Außen und Innen
ist die Haut prädestiniert für häufigen und intensiven Kontakt mit Pathogenen und ist daher immunologisch besonders gerüstet. Das
Immunsystem schützt die Integrität des Organismus mit angeborenen Komponenten
wie der physikalisch-chemischen Barrierefunktion der Haut, den Phagozytosezellen
und dem Komplementsystem. Das Netzwerk
der Langerhans-Dendriten in der Epidermis
ermöglicht sofortiges Aufspüren und zügigen
Transport von Antigenmaterial in den regionären Lymphknoten und Auslösung einer
spezifischen Immunantwort durch T- und
B-Zellen. Für immunologische Vorgänge ist
die Passage durch die Lymphbahnen entscheidend, da Zellen und Lymphbahnen vielfältig wechselwirken. Einerseits werden
durch die Interaktion von dendritischen Rezeptoren mit antigenen Strukturen intrazelluläre Signale getriggert, die die Wanderung
durch die Lymphbahn zum Lymphknoten
über Chemokine und Chemokinrezeptoren
ermöglichen. Die Langerhans-Dendriten andererseits verändern sich auch selbst phänotypisch während der Wanderung durch die
Lymphbahnen: sie verlieren die Phagozytosefähigkeit zugunsten der verstärkten Synthese
von MHC-Molekülen und werden zu antigenpräsentierenden Zellen.
Correspondence to
Dr. med. Kathrin Schmolke
Oberärztin der zentralen Abteilung für Labormedizin
DRK-Kliniken Berlin, Standort Westend
Spandauer Damm 130, D-14050 Berlin, Germany
E-mail: [email protected]
Immunabwehr im Lymphsystem der Haut
Phlebologie 2015; 44: 118–120
DOI: http://dx.doi.org/10.12687/phleb2262-3-2015
Received: March 18, 2015
Accepted: March 19, 2015
Lymphatic system
The lymphatic system regulates tissue
pressure through the return flow of interstitial fluid into the blood. This fluid, the
lymph, is returned to the venous system via
the venous angles. In addition to its
homoeostatic function in fluid balance, the
lymphatic system also performs transport
functions in the upper gastrointestinal region for high-molecular, hydrophobic chylomicrons from the digestive tract. The
lymphatics are also used by another system
for transporting its components: the immune system. Immune cells migrate via the
lymphatic vessels from the periphery into
the regional lymph nodes. En route to the
lymphatic organs, lymphatic vessels and
immune cells interact with each other in a
variety of ways.
Functions of the immune
system
The function of the immune system is to
defend the body against infectious pathogens and to monitor the tissue integrity
of the body as a whole. An essential precondition for this is the ability to distinguish between the body’s own components
(“self ” = harmless) and non-self components (“foreign” = potentially dangerous).
This is enabled via the expression of MHC
molecules (MHC – major histocompatibility complex) on the cell surface of nucleated cells, which present cellular peptides externally, thus signalling an intact
self to the immune system: they are not attacked.
Apoptotic cells and tumour cells are on
the border between self and foreign: As
originally endogenous cells that have
undergone mutagenic changes, tumour
cells can potentially present mutagenically
altered peptides via their surface MHC,
© Schattauer 2015
Phlebologie 3/2015
Downloaded from www.phlebologieonline.de on 2017-06-16 | IP: 88.99.165.207
For personal or educational use only. No other uses without permission. All rights reserved.
119
K. Schmolke: Immune defence in the lymphatic system of the skin
Immune System
Differentiation
Tolerance
Self
Foreign
Self
Altered self
Intact
cell
Dead cell
Tumour cell
Elimination
Foreign
Pathogen
Foreign body
Transplant
Fig. 1 The task of the immune system is to maintain the integrity of the whole body and all its cells.
This requires the ability to distinguish between the body’s own structures (self) and non-self structures
(foreign). The immune system must tolerate the body’s own structures and recognise (and eliminate)
foreign structures.
thus revealing themselves to the immune
system. Tumour cells accordingly downregulate MHC on their cell surface (1).
This is a specific mechanism, to avoid destruction by the immune system (immune
escape). Apoptotic cells, on the other hand,
lose MHC during the membrane degradation of induced cell death. Apoptosis is a
targeted process and does not trigger any
concerted inflammatory reaction (2).
The immune system is not alerted, as
the cells die according to a plan, disintegrating from the inside, and cell residues
are phagocytised. Pathogens, on the other
hand, express completely different molecular structures on their surfaces compared
with body cells. They are thus clearly recognisable to the immune system and
trigger an immune reaction. The picture is
similar for allogeneic transplants; although
they possess human MHC, it is that of another individual. Both are identified as
foreign and are attacked by the immune
system (▶Fig. 1).
The cellular and particulate components of the immune system are subdivided
into innate and adaptive. The innate part
reacts rapidly, uniformly and unchangingly
to a wide variety of stimuli (non-specific
reaction).
The carriers of the non-specific immunity are widely disseminated in the body and
react conservatively and ubiquitously (“the
more the merrier”). In addition to the
physicochemical barriers, the innate immune system also includes the phagocytes
and the complement system. The adaptive
part reacts with a temporal delay and
requires highly differentiated stimuli,
which are recognised via specialised receptors (specific reaction). The cells of the specific immunity, however, can adapt and remember and they differ from each other.
On initial contact with a pathogen, only a
few T and B cells react; on second contact,
many cells react rapidly and with highly
avid receptors.
Immunity of the skin
As it forms an interface organ, the skin is
predestined to have particularly frequent
and intensive contact with pathogens. Al-
Fig. 2 The lymphatic vessels of the skin form a
horizontal, polygonal capillary network below the
epidermis. They do not contain smooth-muscle
cells but are attached to the surrounding matrix
through anchoring filaments. Murine epidermis
after fluorescence lymphangiography; © with the
kind permission of G. Randolph; reproduced with
the permission of Macmillan Publishers Ltd: Nature Reviews Immunology (Randolph et al. 2005)
though the epidermis itself is one of the few
lymph-free body tissues (3, 4), the borderline between the body and the external environment has a particularly well-developed immunological defence. If pathogens
succeed in overcoming the physicochemical barriers, the innate immune defence is
initially activated. Controlled by chemokines, neutrophils migrate from the vessels
into the tissue, where they phagocytise at
the site of the primary reaction.
Complement components are activated
by binding of C3b to bacterial lipopolysaccharide (LPS) and precipitate a cascade,
leading to the formation of pore complexes
that destroy the bacterial cell wall. Individual complement components additionally
exert an opsonising effect (i.e. marking for
phagocytosis). Repetitive molecular surface
structures, such as the LPS of the Gramnegative bacterial cell wall, are identified by
tissue macrophages via specific receptors.
As these structures, which have become
highly conserved through evolution, are
not expressed on human cells, they allow
the macrophages rapid and reliable identification of the invading pathogens.
The network of the Langerhans dendritic cells in the skin triggers transfer of
the pathogenic structures to the specific
immune system. Langerhans cells are dendritic cells of the monocytic line, which
branch out between the epidermal cells
using their elongated cellular processes.
They continuously phagocytise extracellular material in their surroundings. After
absorbing pathogenic material, they migrate via the dermal lymphatic system to
the nearest locoregional lymph node (5, 6).
During their migration through the
lymphatic system, the Langerhans dendritic cells undergo phenotypical and functional changes and mature to their actual
function as antigen-presenting cells (APC).
They lose their ability to phagocytise in favour of greater synthesis of MHC molecules. Via MHC, they present antigenic
peptides to T cells in the nodular T-cell regions. If a naive or memory T cell with its
T-cell receptor fits exactly to the antigenic
peptide presented, this results in the
formation of an immunological synapse,
leading to the initiation of a specific immune response (7) with destruction of the
antigen.
Phlebologie 3/2015
© Schattauer 2015
Downloaded from www.phlebologieonline.de on 2017-06-16 | IP: 88.99.165.207
For personal or educational use only. No other uses without permission. All rights reserved.
K. Schmolke: Immune defence in the lymphatic system of the skin
The functions of the lymphatic system of the skin
As a transport network, the lymphatic system forms part of the immune system. It
forms a network in the skin that lies parallel to the avascular epidermis in the cutis
(▶Fig. 2). Lymph flow is unidirectional
from the periphery to the centre and is secured by means of valvular structures. The
confluence of the thoracic duct and the
vena cava in the venous angle unites the
lymph and blood flow. As T cells can circulate between the blood and the lymph and
dendritic cells from the periphery migrate
to the lymph nodes, the likelihood of them
meeting in the lymph node is particularly
high (▶Fig. 3).
The dendritic cells form an interface between the innate and the specific immune
system and process a broad spectrum of
antigens from dermatological pathogens.
Immature dendrites in the surface epithelia
phagocytise antigens similar to macrophages. They can absorb extracellular material (e.g. from bacteria, fungi and parasites) or are directly infected by viruses and
absorb intracellular viral proteins. The interaction of dendritic receptors with antigenic structures triggers intracellular signals, allowing migration through the lymphatic system to the lymph node via chemokines and chemokine receptors.
The interplay of CCR7 (chemokine receptor type 7) on the dendrites and the corresponding ligands CCL19 (chemokine ligand 19) in the lymphatic system appears to
allow migration to the lymph node along a
directional gradient (8). CCL19-deficient
mice show a marked defect in dendritic cell
migration to the lymph nodes (9, 10). Concurrently, more MHC is expressed, leading
to an increased antigen presentation,
further reinforced by inflammatory mediators (leukotrienes, prostaglandins). During its passage through the lymphatic system, therefore, the Langerhans dendritic
Tissue cell
Interstitium
Lymphocapillary
vessel
Fig. 3
T cells migrate back
and forth between the
blood and lymphatic
system. (Image source:
National Cancer Institute website
http://www.cancer.gov)
Tissue fluid
Arterioles
cell changes from a sedentary phagocyte
into a migratory cell, which effectively
presents its absorbed antigen load to the
corresponding immune cell partner at the
correct location.
In skin sections experimentally separated from the lymph, no specific immune
response can be precipitated, despite the
fact that the blood flow continues to function without interruption (7), as T cells can
never be sensitised to antigenic material directly in the tissue. Passage of the epidermal dendrites through the lymphatic system is essential in order to trigger an adaptive immune response.
Moreover, a destroyed lymphatic system
can no longer perform this task. Risk factors are infections, particularly by staphylococci and streptococci (erysipelas), but
also parasitic disease, trauma, irradiation
or chemotherapy drugs. This leads to oedema with atrophy of the lymph nodes above
areas of prolonged stagnation (11).
Treatment approaches such as the manual lymphatic drainage restore the dendritic cell transport by reactivating the
lymph flow. This promotes the antigen
presentation in the lymph node and therefore the innitiation of an immune response.
Venule
Lymphatic
system
Literatur
1. Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity 2004; 137–148.
2. Bossi G et al. The secretory synapse: the secrets of
a serial killer. Immunol Rev 2002; 189:152–160.
3. Mumprecht V, Detmar M. Lymphangiogenesis and
cancer metastasis. J Cell Mol Med 2009;
1405–1416.
4. Cueni LN, Detmar M. The lymphatic system in
health and disease. Lymphat Res Biol 2008; 6:
109–122.
5. Randolph GJ, Angeli V, Swartz MA. Dendritic-cell
trafficking to lymph nodes through lymphatic
vessels. Nature Immunology 2005; 5: 617–628.
6. Mártin-Fontecha A et al. Regulation of Dendritic
Cell Migration to the Draining Lymph Node: Impact on T Lymphocyte Traffic and Priming. J Exp
Med 2003; 198(4): 615–621.
7. Murphy KP, Walport M. Janeway Immunology.
Spektrum Verlag Heidelberg 2009.
8. Förster R et al. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell
1999; 99: 23–33.
9. Gunn MD et al. Mice lacking expression of secondary lymphoid organ chemokine have defects in
lymphocyte homing and dendritic cell localization. J Exp Med 1999; 189: 451–460.
10. Luther SA et al. Coexpression of the chemokines
ELC and SLC by T zone stromal cells and deletion
of the ELC gene in the plt/plt mouse. Proc Natl
Acad Sci 2000; 97: 12694–12699.
11. Olszewski WL et al. Topography of Accumulation
of Stagnant Lymph and Tissue Fluid in Soft Tissues of Human Lymphedematous Lower Limbs.
Lymphat Res Biol 2009; 4: 239–245.
© Schattauer 2015
Phlebologie 3/2015
Downloaded from www.phlebologieonline.de on 2017-06-16 | IP: 88.99.165.207
For personal or educational use only. No other uses without permission. All rights reserved.
120