Chemistry Reference
In-Depth Information
death. Uncontrolled infl ammation may also be symptomatic for a large variety of
diseases, most of them induced by allergic or autoimmune dysregulation, such as
rheumatoid arthritis, atherosclerosis, multiple sclerosis, chronic obstructive pul-
monary disease or infl ammatory bowel diseases (IBDs), to name just a few. These
diseases eventually become chronic and have a poor prognosis since treatment
modalities today are still very limited. Chronic infl ammation is often a precancer-
ous stage of tumors such as hepatocellular carcinoma (induced by hepatitis
viruses), lung cancer (as a fi nal stage of a long history of chronic infl ammation
induced, for instance, by heavy tobacco smoking), cervical cancer (induced by
papilloma viruses) and colorectal cancer (possibly as a late stage of IBDs such as
Crohn's disease or colitis ulcerosa). In the following we take a closer look at the
different steps leading to infl ammatory reactions.
27.1
Sequence of Events
Leukocytes circulating in the bloodstream must be directed to, and migrate into,
the infl amed tissue in order to attack the invading microorganisms or to eliminate
the irritating substance. This occurs either by direct contact and subsequent
phagocytosis or by release of an array of cytokines and infl ammatory mediators
that promote cross-talk with other immune cells and maintain the infl ammatory
process, or of enzymes that can damage the infecting organisms. As a rule, granu-
locytes (neutrophils) and monocytes are the predominant immune cells involved
in acute infl ammation, whereas monocytes, T and B lymphocytes prevail in chronic
infl ammations. To reach the site of infl ammation the lymphocytes and other
leukocytes must receive signals from the vascular endothelium adjacent to the
infl amed tissue. These endothelial cells are triggered by soluble factors like hista-
mine or cytokines, such as tumor necrosis factor or interleukin-1
),
to switch into an activation mode and sequentially express receptors that are rec-
ognized by leukocytes. At the molecular level, the fi rst contact between vascular
endothelial cells and leukocytes is mediated via interactions between E-selectin on
endothelial cells (for information on selectins, see Chapter 19 and below) and
distinct oligosaccharides, preferentially of the Lewis
x
( Le
x
) histo - blood group
expressed on the cell surface of leukocytes [the Le carbohydrate sequences are
given below in either the biochemical nomenclature, i.e., sialyl-Le
x
, or the cluster
of differentiation (CD) nomenclature, e.g., CD15s; see also Figure 7.4 for struc-
tures]. For many proteins including lectins and also carbohydrate sequences
known to be involved in immune reactions the CD nomenclature has been estab-
lished based on interactions of these protein and carbohydrate structures with
distinct monoclonal antibodies. Wherever it is possible, we refer here to the CD
nomenclature (Figure 27.1a; for further information, see Info Box.) Due to the low
affi nity of this carbohydrate-protein interaction, contacting leukocytes start to roll
along the endothelial surface until they come to a fi rm halt. This halt is mediated
by protein-protein interactions, i.e., leukocyte integrins binding to endothelial
β
(TNF or IL- 1
β
