Download Immunology of the tonsil: a review

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Journal of the Royal Society of Medicine Volume 83 February 1990
Immunology of the tonsil:
Glenis K Scadding MD MRCP
a
review
Royal National Throat, Nose and Ear Hospital, Grays Inn Road WC1
Keywords: tonsils; tonsillectomy; mucosal associated lymphoid tissues (MALT); secretory immunoglobulins; B lymphocytes
Despite the fact that tonsils have been removed for
several hundred years knowledge of their exact
function and of the effects of their removal is
remarkably incomplete. The tonsils undoubtedly form
part of the immune system, participating in its
function of recognition and rejection of foreign
materials and organisms.
Immune system
Innate non-specific immunity involves physical and
chemical barriers, phagocytic cells and humoral
factors, such as complement and interferon. Superimposed on this primitive system in vertebrates is
adaptive immunity, where the response, which is
mediated by lymphocytes and antibodies, improves
on second and subsequent contact with the same
organism, ie it possesses both specificity and memory.
Lymphoid system
Lymphocytes are organized into primary (bone
marrow and thymus) and secondary (spleen, lymph
nodes and mucosal-associated) lymphoid tissues
(Figure 1). The bone marrow is the site of origin of
lymphocytes: T cells migrate from there to the thymus
where they undergo further 'education', becoming
able to recognize antigens only in the context of
self histocompatibility antigens, before becoming
widespread throughout the blood and lymphoid
system. B cells pass from marrow to the secondary
lymphoid organs and blood where they make contact
with antigen and with other lymphocytes. The
immune response is generated and disseminated from
the secondary lymphoid organs.
Figure 1. Section ofhuman tonsil showing MALT. This view
shows the large number ofgerminal centres frequently found
in tonsillar lymphoid tissue (reprinted with kind permission
of Mr C Symes and Gower Medical, London from Roitt,
Brostoff Male, eds. Immunology, 2nd edn, 1989)
The mucosal associated lymphoid tissues (MALT)
are thought of as a special type of secondary lymphoid
organ, concerned with immunity at mucosal surfaces.
The MALT includes Peyer's patches, appendix, and
other gut lymphocytes, known collectively as gutassociated lymphoid tissue (GALT), together with
bronchial-associated lymphoid tissue (BALT), adenoid,
oral, palatinal, lingual and laryngeal tonsils.
The major function of the MALT is the generation
and dissemination of antigen-sensitized B cells which
require second signals for their terminal differentiation to antibody-producing plasma cells in
various secretory tissues.
Paper read to
Section of
Laryngology,
3 March 1989
The tonsils
The tonsils are placed at the gateway of the
respiratory and alimentary tracts where they are
continually directly bombarded by antigen, unlike the
majority of lymph nodes, which receive antigen via
the bloodstream. At the base of the tonsillar crypts
are specialized micropore (M) cells with a tubulovesicular system for antigen transport'. In addition
there are micropores found on the crypt wall, as yet
it is not known whether these are artefactual,
physiological or pathological2.
By analogy with events known to occur in other
parts of the MALT3, the tonsils probably function in
the following way.
Within the tonsil antigen is taken up by antigenprocessing cells, which are of the macrophage lineage,
and presented to T helper cells and B cells. These
latter form the major constituent of the many
germinal centres present in tonsil. (Figures 1 and 2).
Under the correct conditions those B cells bearing
Figure 2. Secondary lymphoid follicle section showing a
germinal centre. The germinal centre contains actively
proliferating B cells. The darker half contains the most
actively proliferating cells, together with macrophages. There
is a mantle of small resting lymphocytes, which have less
cytoplasm and appear more densely packed (reprinted with
kind permission of Dr K McLennan and Gower Medical,
London, from Roitt, Brostoff Male, eds. Immunology,
2nd edn, 1989)
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Journal of the Royal Society of Medicine Volume 83 February 1990
receptors, ie antibodies, capable of combining with
determinants on the antigen will be stimulated to
divide. They then migrate through lymph and blood,
undergoing further differentiation en route, to
colonize various secretory structures,- ,such as gut,
respiratory tract, salivary and mammary glads.
Here they are subjected to 'second signals' which are
only partly defined, but could include antigen, T cell
factors, mitogens or local hormones. These cause
the terminal differentiation of the lymphocytes to
immunoglobulin-secreting plasma cells.
The sites to which lymphocytes 'home' seems to
depend to some extent upon site of origin. There is
evidence to suggest that gut-derived lymphocytes
home selectively to gut, those from the tonsil probably
return to the upper and lower respiratory tract,
including tonsil. Salivary and mammary glands appear
to derive lymphocytes from both sources4. After this
homing process there is still lymphocyte traffic
between the various lymphoid organs via lymphatics
and blood, with about 1-2% of the lymphocyte pool
recirculating each hour. This allows lymphocytes to
come into contact with their appropriate antigen, an
important process since there is a finite number of
lymphocytes capable of recognizing any one antigenic
determinant.
The majority of MALT lymphocytes secrete immuno
globulin A (IgA) which acts as a 'mucosal antiseptic
paint'. It exists as a dimer, the two molecules being
joined by a J chain, also secreted by the plasma cell.
Dimeric IgA passes through epithelial cells to reach
the mucosal surface, during this process it becomes
coated with secretory piece which- protects the
molecule from enzymic digestion (Figure 3). IgA
combines with pathogens or other molecules, either
preventing their attachment. and absorption or
rendering them harmless, so that they are absorbed,
transported as an immune complex and dealt with by
the reticulo-endothelial system.
Tonsillar imunoglobulin secretion differs from the
usual MALT pattern. Immunoglobulin G-producing
cells predominate in palatine and nasopharyngeal
Figure 3. Transport of IgA across the mucosal epithelium.
IgA dimers secreted by plasma cells bind to membrane
receptors on the internal surface ofepithelial cells. They are
endocytosed and transported across the cell to the luminal
surface where the vesicle fuses with the plasma membrane,
releasing dimeric IgA and a secretory component derived
from cleavage of the receptor. This probably protects the
immunoglobulin from enzymic digestion (reprinted with kind
permission of Gower Medical, London from Roitt, Brostoff
Male, eds. Immunology, 2nd edn, 1989)
Figure 4. Natural killer cell in human tonsil. Two natural
killer cells, stained with monoclonal antibody HNK-1
conjugated with horseradish peroxidase, are seen close to
blood vessels. These cells, which form part of the innate
immune system, can kill cells with surface alterations due
to viral infection or neoplasia (courtesy Ms H Wang)
tonsils5, with IgA immunocytes representing about
30-35%. Unlike the adenoids there is -no tonsillar
production of secretory piece, so both IgA and IgG pass
out directly into the pharyngeal secretions by leaking
between epithelial cells, this is enhanced when there
is inflammation. IgD-producing cells are far more
plentiful than in GALT, although they represent only
1-3% of the tonsillar immunocyte population6. IgEproducing cells can also be found in tonsil, occurring
more frequently in tonsillectomy specimens than does
atopy in the population, suggesting that allergic
children are more likely to come to tonsillectomy.
These differences probably reflect an adaptation to
the unique situation of the tonsil. Bacteria that
inhabit the upper respiratory tract (but not those in
gut) have receptors for IgD, these probably- stimulate
IgD-bearing B cells to divide, hence increasing the
numbers present in tonsil7.
Immunological functions other
than antibody production
A tonsil contains up to 109 lymphoid cells, up to
50% of which are T cells. Many of these will be
involved in the regulation of the antibody response,
either promoting it (helper T cells) or preventing it
(suppressor T cells). Other T cells are responsible for
delayed type hypersensitivity reactions to large
organisms, such as fungi. Another type can kill virally
infected cells. Recognition in both cases is by the
T cell antigen receptor, which is similar to the antigen
combining site of antibody. Cytokines, such as
interferon gamma, are produced by tonsillar T cells.
Natural killer cells are also present in tonsil, closely
apposed to blood vessels (Figure 4). These form part
of the innate immune system and can kill virusinfected and tumour cells, but their method of
recognizing such cells is as yet unknown.
Immune deficiency
Selective deficiency of IgA is the commonest humoral
immune deficiency, affecting about 1 in 700 of the
population. In children IgA deficiency is often
transient, levels increasing to normal by about
7 years. There is an association between this and
allergy.
In some patients with selective IgA deficiency
secretory IgA is lacking, but may be replaced
by secretory IgM, which is also protective. In others
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Journal of the Royal Society of Medicine Volume 83 February 1990
immunoregulatory compensation gives rise to a large
number of IgD-producing cells in respiratory mucosa.
This cannot act as secretory antibody, hence these
individuals tend to have recurrent respiratory tract
infections8. IgD-bearing cells are increased in tonsillectomy specimens.
Inflammation of the tonsils
Antigens are continuously present on the crypt
epithelium giving rise to lymphocyte activation, thus
a certain amount of inflammation is physiological.
Recurrent or chronic inflammation
Histologically, chronically inflamed tonsils differ little
from 'normal' ones, which have been relatively little
studied. There is a decrease in activated lymphoid celLs
and immiunoglobulin containing cells9, which could
be primary, or the result of infections. The relative
increase in IgD-bearing cells as noted earlier may be
due to bacterial stimulation. Epithelial changes also
occur, with an initial increase in reticulated epithelium
to cover the interfollicular areas as well as the
follicles. Later the follicles become covered in squamous
epithelium, which lacks M cells, thus antigen entry
is likely to be reduced10.
Tonsillitis occurs when trapped organisms multiply
within and on the tonsil. Such infections are
frequently polymicrobial. There are likely to be
predisposing factors to this, including failure of
host defence and virulence of the organism itself.
Local production of B-lactamase by other bacteria
within the tonsil has been shown to occur11. This can
prevent penicillin antibiotics from destroying otherwise sensitive organisms. Bacteria can also release
histamine from tonsillar mast cells'2, contributing to
the inflammation. Viral infection is itself a cause
of tonsillar inflammation; chronic infection with
Epstein-Barr virus also reduces host resistance to
other organisms by stimulating the production of
T suppressor cells.
It is conceivable that some episodes of upper
respiratory tract infection and tonsillitis are allergic
rather than infective in origin. It is now known that
the late phase of the allergic reaction, which involves
infiltration by inflammatory cells, mucosal oedema
and hyperreactivity, can last from hours to weeks
following allergen contact, and is probably responsible
for much of the morbidity associated with allergy13.
With chronic exposure to allergens such as house dust
mite or animal dander the initial immediate reaction
is not always apparent, so that careful history taking
and skin prick testing are necessary. Symptoms may
be caused by allergy alone, or by infection subsequent
to mucosal oedema and blockage. Treatment of the
underlying allergy should reduce the frequency of
episodes of 'tonsillitis'.
Tonsillectomy
The human tonsils are most active in childhood, with
some involution after puberty. However considerable
B-cell activity is seen in clinically healthy adult
tonsils, even at 80 years of age.
The indications for, and the therapeutic effects of,
tonsillectomy for recurrent infections remain the
subject of debate. There is no evidence for benefit
from the operation in preventing the recurrence of
streptococcal hypersensitivity disorders, such as
rheumatic fever.
The practice of tonsillectomy and/or adenoidectomy
has decreased over the past decade, since the
operations have little influence on the natural history
of upper respiratory tract infections. A recent unique
controlled studyl4 involving 12 authors over 11 years
showed that the benefit from tonsillectomy in patients
selected on rigorous criteria with recurrent severe
tonsillitis was modest. The advantage of the operated
over the non-operated group was present for two
years, but most of the non-operated group had less
than three infections a year, mostly mild, compared
with a 14% incidence of surgery-related complications.
A similar earlier study15 showed a decrease in sore
throats for the first two postoperative years only,
probably insufficient benefit to justify the risks of
operation.
Children with perennial allergic rhinitis were found
in a recent study'6 to be four times more likely to
have undergone an ENT operation than those with
orthopaedic problems. Only 40% improved following
operation, whereas 90% improved with medical
treatment of their allergies.
Immunological effects of tonsillectomy
These have not been extensively studied and investigations are hampered by the fact that any immune
defect could have been present preoperatively, since
sequential studies are few. However, there is evidence
for a decrease in the activated B cell population, with
a decrease in secretory IgA and a fall in other
immunoglobulins, but only to the lower end of the
normal range'7.
There is no evidence of a general increase in
infections postoperatively compared to an age-matched
control group. Resistance to polioviruses is however
reduced'8. Children who were previously immunized
orally with live poliovirus vaccine dropped their
titres three-fold to four-fold after tonsillectomy and
adenoidectomy. Attempts to vaccinate seronegative
children who had been subjected to tonsillectomy and
adenoidectomy resulted in delayed and lowered
nasopharyngeal secretory immune responses as
measured by IgA antibodies to poliovirus.
It was thought that the increased meningococcal
carrier state after tonsillectomy could increase the
risk of meningococcal meningitis several months
later. However this has occurred only in Russia (five
reports since 1959).
An increase in Hodgkin's disease in tonsillectomized
children in New York was reported in 197119 Since
then several other studies have investigated this with
conflicting results20. In fact the association could be
with tonsillitis, rather than tonsillectomy.
Although the effects reported are slight the role of
Waldeyer's ring in reinforcing immunity of the whole
upper respiratory tract should be considered before
a child is subjected to tonsillectomy, as well as the
possibility that some underlying disorder such as
allergy or IgA deficiency is responsible for his or her
symptoms.
References
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2 Howie AJ. Scanning and transmission electronmicroscopy
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3 Elson CO. Induction and control of the gastrointestinal
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4 Brandtzaeg P. Immunobarriers of the mucosa of the
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(Accepted 22 August 1989. Correspondence to Dr Glenis
Scadding, 143 Chevening Road, London NW6 6DZ)
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