Chapter 16

Traffic of White Blood Cells

Inflammation and leukocytes

The first sightings of white cells adhering to the walls of the finer vessels and then emigrating into the tissues under conditions of inflammation were recorded more than 150 years ago (Figure 16.1).1–3 Cohnheim’s detailed

histological description of 18824,5 remained the basis of most textbook accounts of inflammation for a further 80 years. Later, the first electron microscopic investigation of leukocyte adherence and migration provided much-needed detail but failed to reveal how cells adhere to the inflamed endothelium.6 Nor were any ideas forthcoming about how the cells penetrate an apparently coherent endothelial cell layer.

Inflammatory mediators

It is essential that migratory cells such as leukocytes can tolerate changes in their environments. They must be able to move from the bone marrow (where they are attached) into the blood (where they float free) and then

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Fig 16.1  Augustus Waller’s microscopic examination of cell adherence and extravasation from the vessels of an inflamed frog tongue.

‘The blood, as we are aware, consists of a transparent fluid holding in suspension numerous particles, most of which are red and of a flattened shape, while a few others are colourless, and spherical in form … The peculiar manner in which the lymph-globules, or corpuscles, conduct themselves when in the capillaries, when in an organ in a state of irritation, has of late engaged much attention. The experiments of Mr W. Addison of Malvern, have greatly contributed to show these important functions in inflammation. In the tongue of the frog and toad they may be frequently seen circulating with the red particles in the vessels, down to the minutest capillaries. As it has already been pointed out, these spherules are generally found, when they come into contact with the parieties of the vessels, to retain their adherence with greater force than is manifested by the red particles in the like circumstances; as in the figure, where the current was observed to continue for many minutes without displacing the globules near the sides of the vessel. Thus we frequently see a lymph-globule remain in the same place, notwithstanding the current of red particles sweeping and pushing by it. The appearance in the larger vessels of these spherules, adherent to their inner surface, has been very aptly compared to so many pebbles or marbles over which a stream runs without disturbing them … The corpuscles, which are transparent, are occasionally seen to be granulated … Let us now examine the admirable manner in which nature has solved the apparent paradox, of eliminating, from a fluid circulating in closed tubes, certain particles floating in it, without causing any rupture

or perforation in the tubes, or allowing the escape of the red particles, which are frequently the smaller of the two, or that of the fluid part of the blood itself … After the observation had continued for half an hour, numerous corpuscles were seen outside the vessels, together with a very few blood discs in the proportion of about one to ten of the former. No appearance of rupture could be seen in any of the vessels. The corpuscles were generally distant about

0mm 03 from their parieties. After the experiment had lasted about two hours, thousands of these corpuscles were seen scattered over the membrane, with scarcely any blood discs … No trace of the corpuscular extravasation could be seen, except the presence of the corpuscles themselves……. I consider therefore as established, 1st , the passage of these corpuscles ‘de toute pièce’ through the capillaries; 2ndly, the restorative power in the blood, which immediately closes the aperture thus formed … In endeavouring to account for the fact of the passage of the corpuscles through the vessels we find considerable difficulties. It cannot be referred to the influence of vitality, as it is observed likewise to take place after death. It may be surmised, either that the corpuscle, after remaining a certain time in contact with the vessel, gives off by exudation from within itself some substance possessing a solvent power over the vessel, or that the solution of the vessel takes place in virtue of some of those molecular actions which arise from the contact of two bodies; actions which are now known as exerting such extensive influence in digestion, and are referred to what is termed the catalytic power’. Paraphrased from Waller.2,3

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Traffic of White Blood Cells

Fig 16.2  Generation of inflammatory mediators at sites of infection.

Tissue damage and bacterial infection induce the release of inflammatory mediators from various cell types. Bacterial protein A binds and activates the TNFreceptor. Bacterial lipopolysaccharide (LPS), which acts on local fibroblasts, dendritic cells, vascular endothelial cells, mast cells and resident leukocytes induces release of Gro, histamine, IFN- , IL-1 , IL-6, IL-8, MCP-1, RANTES, and TNF- . Collectively, these mediators are responsible for the up-regulation of

adhesion molecules on vascular endothelial cells and the activation of integrins on leukocytes. This results in their extravasation followed by migration to sites of damage/infection. Formylmethionyl peptides released from bacteria (as well as from the damaged mitochondria of host cells) facilitate the migratory response (chemotaxis). These processes allow the rapid accumulation of leukocytes, in particular neutrophils, at sites of infection as a first line of defence. It also initiates the process of tissue remodelling and repair (wound healing).

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Protein A. Derived from Staphylococcus aureus, protein A binds with very high affinity to both the constant (Fc ) and variable (Fab) regions of IgG and IgM antibodies.9 Protein A contributes to the pathology of Staphylococcus aureus by directly binding to TNFreceptors on the respiratory epithelium. This plays an important role in the onset of inflammation of the lower respiratory tract, leading to severe pneumonia associated with tissue damage and sometimes sepsis.10 Protein A can also bind some membrane-associated B cell antigen receptors and promote antibody production.11 This plays a role in the defence against the pathogens but is also associated with autoimmune disorders such as rheumatoid arthritis.

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Traffic of White Blood Cells

‘Die öfters beobachtete Thatsache, dass Neubildungen, namentlich malingner Natur, durch ein interkurrentes Erysipel zur Verkleinerung oder zum Verschwinden gebracht werden, ist von hervorragendem theoretischem und praktischem Interesse. In ersterer Hinsicht verdient diese Thatsache gerade gegenwärtig besondere Beachtung, wo die Untersuchung der Aetiologie der malignen Neubildungen auf der Tagesordnung steht, deren Ergebnisse vielleicht geeignet sind, auch über die Art und Weise der salutären Wirkung des Erysipels Licht zu verbreiten. In praktischer Beziehung haben jene Beobachtungen zu Versuchen mit der kunstlichen Erzeugung eines kurativen Erysipels Veranlassung gegeben, um inoperable bösartige Neubildungen zur Heilung zu bringen.

Allein die Zulässichkeit.solcher Versuche ist noch eine offene Frage …’:

‘The frequently observable fact that new formations, particularly those of a malign nature may be caused to regress or to disappear by a concurrent

erysipelas is of very great interest both in theory and practice. In respect of the former this fact merits particular attention, especially at the present time, given the current preoccupation with the study of the aetiology of new formations, the results of which may well be capable of shedding new light upon the beneficial effects of erysipelas. On the practical front these observations have given rise to experiments in which curative erysipelas is artificially induced in order to bring about the healing of inoperable new formations. However the admissibility of such experiments remains an open question …’

Table 16.1  Sources of inflammatory mediators

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