What role do cells of the innate and adaptive immune

response play in chronic inflammation?

Intro: Chronic inflammation is an inflammatory response of prolonged duration, that

is to say the prolonged local response of a tissue to damage or infection. It is a
common and varied condition, often occupying a grey area between serving an
important healing function, and possibly causing deleterious collateral damage to
surrounding tissue. Macrophages, plasma cells, lymphocytes, dendritic cells and in
certain conditions eosinophils all have a role to play. Study of their functions could
possibly lead to ways to control and modify them, and thus the potential benefits of
such work are enormous.

Draw: schematic diagram showing typical features of chronic inflammation, with

particular emphasis on the cells. For example, show macrophages, perhaps releasing
cytokines and/or noxious substances. Token pathogen perhaps? Show Th1 cells, with
macrophages being activated and recruited. Maybe a plasma cell with the odd
antibody? Depending on the nature of the pathogen, one could show eosinophils
(parasite) or even granuloma (Mycobacterium).

Background info: The essential idea of chronic inflammation is quite simple1.

Initially, neutrophils are the first cell to respond to the damaging event, leading to
acute inflammation. If they are unable to deal with the damage, they die and in so
doing release chemokines and cytokines, attracting in monocytes and other cells. And
as a precautionary measure, almost, lymphocytes also enter so that if the
macrophages alone are unable to eliminate the noxious stimulus, the lymphocytes can
activate them still further to do so. But if these laudable mechanisms fail, and the
stimulus is not eliminated, chronic inflammation is the result. Recent molecular work
on chronic inflammation has focused on the transcription factor NFκB, which has
been associated with endotoxin, cytokines, and viruses, and regulates the expression
of adhesion molecules, E-selectin and many chemotactic cytokines.

Macrophages2 are the major cell type of chronic inflammation, and are present
throughout its duration. If unable to destroy the noxious agent, they can sequester it in
their cytoplasm indefinitely3. They are recruited as monocytes, initially by neutrophils
and then by further macrophages. They don’t arrive at the site until after about 48hr,
and then differentiate to macrophages under the influence of IFNγ and other
cytokines. Here, they are often immobilised, and undergo local proliferation. They are

1
This isn’t an essay about chronic inflammation per se, so this is grossly oversimplified! For more
detail, refer to another set of notes in this series. I try to avoid overlap, particularly in the clinical
examples, but there inevitably is some, so apologies.
2
As for their relation to innate and adaptive immunity, they are sometimes characterised as
“limbocytes”, straddling the two, (perhaps in the same way as chronic inflammation does). They have
also been described as the “prima donna” cells of chronic inflammation.
3
As long as it doesn’t kill them. Again see the earlier notes.
activated4. They secrete many substances, serving to orchestrate the response,
including both the reparative and immune aspects:
• cytokines (IL1, TNFα), which stimulate fibroblast proliferation and collagen
synthesis, which are important for repair. TNFα also stimulates macrophages
in vitro, contributing to a positive feedback mechanism, and allowing for
faster activation than waiting for the lymphocytes to do it.
• Substances such as VEGF stimulating angiogenesis.
• chemokines (IL8, MCP1), attracting other cells such as lymphocytes (which
can then attract more macrophages).
• Mediators of acute inflammation, including PAF (platelet activating factor
and arachidonic acid metabolites
• Oxygen metabolites, proteases and hydrolytic enzymes. For destruction of
pathogen, but cause much of the collateral damage to body’s own tissue.

There are several “special cases” of macrophage involvement:

• Epithelioid cells: a form of activated macrophage, specialised for protein
secretion with voluminous cytoplasm.
• Giant cells: Both these and epithelioid cells are found in granulomata. TB.
• Foam cells: they get stuffed with excess oxidized and altered lipoproteins and
are the villains of artherosclerosis. Macrophages dominate compared to T
cells. Secrete TNFα and proteinases that influence composition and fate of
plaques. Produce Apolipoprotein E, which protects against artherosclerosis in
murine models.
• They may also make the round trip back to the secondary lymph tissue to act
as APC’s

Lymphocytes are another major cell type5. Activated lymphocytes will tend to start
arriving at roughly the same time as macrophages, although it may take longer for
CD8+ T cells and small numbers of B cells to arrive. Presence of lymphocytes in
tissue that normally wouldn’t have them implies a local immune response.
• Th1 cells6 drive macrophage response7 (two main signals, via IFNγ and
CD40L (on T cell) interacting with CD40 on Mφ. Furthermore, stimulate Mφ
proliferation via GM-CSF and IL3. Other signals include TNFα8.) Attracts Mφ
via CCL29.
Modulate antibody production (particularly any isotype switching, again via

4
Activation is not an all or nothing process. There are at least two types: quick (i.e. stimulation) and
slow. Stimulation is the burst of activity usually caused by phagocytosis, lasting seconds or minute,
rather like the behaviour of neutrophils. For chronic inflammation we are more interested in the slow
activation, which is akin to hypertrophy. Even this is a step by step process.
5
There are a lot of functions that these lymphocytes could have. Among them, homing to an inflamed
area, processing antigen, secreting cytokines (thereby recruiting further lymphocytes and affecting
other cells), secreting antibody and killing a cell. While all these are of interest to the immunologists,
and covered here, down the microscope, without immunostaining the pathologists can only recognise
the last two (Majno and Joris).
6
If not the prima donna, then the éminence grise?
7
Macrophage activation is their main role. This activation takes hours in itself, as all these substances
are synthesized de novo. Which is different from the immediate secretion of the CD8 T cells, for
example.
8
Antibodies against this can inhibit macrophage activation.
9
Thus completing the macrophage  Th1  macrophage feedback loop mentioned above.
 CD40L and various cytokines depending on the exact isotype).
Modulate cell mediated cytotoxicity – CD8 T cells – via IL2 amongst others.
• B cells differentiate into plasma cells, produce antibodies against pathogen or
against the body’s own tissue. Against pathogen: antigen neutralization,
clearance of foreign antigens and particles, and antibody dependent cell
mediated cytotoxicity. Against body’s own tissue: cell mediated cytotoxicity
becomes more of a problem!

Dendritic cells: phagocytose antigen, migrate to lymph nodes, trap antigen specific
T-cells, encourage lymphocyte cloning. Essential for adaptive immune response. It is
said that they migrate to the site of chronic inflammation and thereby maintain the
inflammatory response “on site”, though the evidence for this is sparse. While they
normally derive from bone marrow, with the appropriate cytokine mixture they can be
grown from monocytes, which could be of importance.

Neutrophils are occasionally observed in chronic inflammation, but this is rare.

They will have similar phagocytosing and chemotactic functions to macrophages, and
are often eventually phagocytosed by them.

Eosinophils: Sometimes a readily observable feature of chronic inflammation,

examples are in allergic type reactions10 and response to parasites. They share many
functional features with the neutrophil11, and similarly their basic granules contain
molecules that are harmful to both parasites and host cells. They respond to mast
cells, and differentiate under influence of IL5. Interestingly, they contain enzymes
which should be useful for ending the inflammatory response: examples include
histaminase, arylsulphatase (inactivates leukotrienes) and a phospholipase that can
inactivate PAF. But physiological role of these not yet understood. Certainly, when
misdirected as in asthma, eosinophils can cause a lot of damage in certain types of
chronic inflammation.

Clincal Examples: Four good examples, at least, in the other set of notes. Here:
schistosomiasis (billharziasis. The most important helminthic disease of humans.
Covered for role of eosinophils and PMN’s) and rheumatoid arthritis12 (role of B
cells):
The schistosomule13, having entered the human, is carried to the liver. Pathology due
to immune response: chronic inflammation characterized by granuloma or large
numbers of neutrophils and eosinophils around egg. Thousands of eggs, every day. S.
mansoni and S. japonicum: liver disease. S. haematobium: eggs in bladder. We
mentioned how the macrophages release mediators promoting repair. In this case, the
uncontrolled division can lead to bladder cancer.

10
Eosinophils: a frustrated cell in a worm free world? In the west, now that we don’t get so many
worms, there is a real question as to whether eosinophils are an asset or a liability.
11
That said, there are important differences. Eosinophils have a longer life span, have Major Basic
Protein (hence eosinophils) in granules that binds to negatively charged molecules on parasite surface.
But not as good at phagocytosing and killing bacteria as the neutrophil. The very fact that they
accumulate in certain disease conditions should tell us something about their function.
12
Apologies if this is seems somewhat decadent.
13
Schistosome egg
Rheumatoid arthritis: Type III hypersensitivity: immune complex disease. Role of
Epstein Barr virus? Since the immune complexes can be deposited anywhere, disease
symptoms are systemic.

Conclusion: Clinical practice and research have yet to fully engage chronic
inflammation, yet this must surely be one of the priorities of modern medicine.
Chronic inflammation includes a whole host of different cell types, as befits a disorder
with such varied manifestations. Many of these cells interact with each other via a
number of different chemicals, as discussed above. These represent obvious targets
for therapy. And this approach is starting to bear some fruit. For example, anti-TNFα
antibodies such as infliximab are now licensed for use in the UK for treatment
rheumatoid arthritis, Crohn’s disease and psoriasis. Hopefully these are the first of
what will turn out to be many such therapies.

APPENDIX

So far we have discussed the various cell types in very general terms. But there
important differences between the cell types in different parts of the body. In
particular: macrophages, the orchestrators of chronic inflammation, vary between
different sites in the body. Their differences go some way to explaining the variety
seen in chronic inflammation.

e.g. in the CNS, the parenchyma, the neuropil, exerts a powerful anti-inflammatory
effect, and blocks the initial migration of PMN’s in acute inflammation. But after
some time, if stimulus persists, the microglia are activated and there is chronic
inflammation. In the liver, Kuppfer cells have limited antimicrobial activity, and
resistance to infections such as Listeria requires migration of further macrophages.
Alveolar macrophages are potent downregulators of the T cell response via NO. Low
CR3 and high SRA: different to recruited macrophages. They however readily form
granulomata (TB), and antigen challenge via airways can cause massive type IV
hypersensitivity, local tissue destruction and extensive cell death. Regional
differences have also been invoked to describe artherosclerosis.