|
Complement plays a vital role in our immune
defence, particularly against bacteria. Although complement
deficiency is rare, it is a potentially fatal condition. This
booklet describes what it means to have a complement deficiency
and outlines the medical facts behind the condition.
Margaret Robinson suffered meningitis three times before
being diagnosed with a complement deficiency. She has not
only survived to tell the tale, but also enjoys an active
family life and raises funds for Meningitis Research.
Meningitis strikes three times
My story begins one sunny Sunday afternoon in April 1977.
I was just 17 and studying for my Scottish Higher grade exams.
I’d just finished a pile of homework when some friends
arrived to invite me for a run to the seaside. Normally I
would have jumped at the chance, but that day I just had to
say "no". My head was beginning to ache and I felt
as though I was going to get the ‘flu.
No-one was more surprised than my Mum at my refusal to go
out. I lay down on the rug in front of the fire and Mum made
me a cup of tea, but it did nothing to stop the shivers that
were coursing through my body. I felt very cold but actually
I had a very high temperature. My legs and arms were hurting
and the pain in my head was becoming much worse.
The next two days passed in a bit of a haze, but by Wednesday
morning I could sit up. I couldn’t move my limbs, my
neck was so stiff I could barely nod, and the pain in my head
was almost unbearable. I couldn’t tolerate even a sip
of water. My Mum phoned our GP, who came almost immediately
and diagnosed meningitis.
An ambulance arrived minutes later and I was stretchered
out, complete with Teddy. A great sense of peace came upon
me and all I wanted to do was drift off to sleep, but an inquisitive
ambulance man plied me with questions to prevent me from slipping
into a coma.
This was my first stay in hospital and the staff were so
nice. I was taken by surprise, though, when I was suddenly
manhandled into a fetal position with one nurse sitting on
my legs, another on my shoulders and a doctor with a needle
saying "This is going to be painful." A lumbar puncture
was performed and it was confirmed that I was suffering from
viral meningitis. Things were not looking good, and when Mum
told the consultant that I was an only child he said "It’s
a pity."
Conscious of the danger I was in, the priest administered
the Sacrament of the Sick. However, after two weeks of drips,
strong painkillers, anti-sickness drugs and penicillin injections
I was allowed home, feeling like a pincushion and looking
very skinny. It was a few months before I really felt well
again, but I went on to make a full recovery.
Two years later, in June, having just sat my final exams
to become a nursery nurse, I began to feel unwell. All the
same symptoms as before began to manifest themselves, but
also present was a strange purple rash all over my body. This
time I had meningococcal septicaemia meningitis and spent
another two weeks in hospital.
I was just beginning to return to normal when in October
of the same year I became unwell yet again. The purple spots
reappeared and an ambulance was called to take me to hospital
for a third time. I had meningococcal septicaemia meningitis
again!
Tests — and at last a diagnosis
On this occasion I spent a month in hospital recovering
and having a series of extensive tests, including a brain
scan. But the staff kept coming up against a brick wall. It
seemed as though my consultant sat up all night thinking of
another test to try. Blood was sent all over the country.
Then a breakthrough came from a Glasgow hospital where it
was discovered that I had a complement 8 deficiency —
which meant that my immune system had little or no defence
against meningitis.
Although this news was scary, it meant that my consultant
now knew what he was dealing with. However, this question
brought with it many questions. Did I always have this problem?
Did my complement 8 stop working suddenly, or was it over
a period of time? Was this a hereditary problem? Here the
doctors hit another stumbling block. Because I was adopted
by my wonderful family as a baby, there were no relatives
whose blood could be tested.
Vaccines and penicillin keep the "bug" at bay
To deal with the immediate problem — the recurrence
of infection — a vaccine which was still in its infancy
was sent from America, and so far as I’m aware I was
the first person in this country to receive it.
Over the next few years I was in and out of hospital on many
occasions. I’ve suffered meningitis five times in all
and have shown signs of meningism at other times. The last
time I was in hospital with this problem was just a few months
after I was married. My husband has known me during all the
times when I was very ill, but it was particularly harrowing
for him to see his young bride whisked away in an ambulance
with its siren blaring.
This wasn’t one of the worst bouts, because I had of
course had the vaccine by then. However, since February 1983
I have taken penicillin in tablet form every day to keep the
dreaded bug at bay. I have also had another vaccine, and the
combined treatments seem to work.
Good management makes a normal life possible
I don’t allow the shadow of meningitis to control
my everyday life, although I’m always aware that if I
develop a pain in my head I mustn’t put myself at any
risk. I know too that I can telephone the hospital at any
time.
My husband and I are now blessed with a family of our own.
We have a daughter aged eleven and a son of nine, both of
whom have had their blood tested, and so far so good. Both
children are old enough to understand about Mummy’s meningitis
and they, along with other family members and friends, are
periodically roped into fund-raising for Meningitis Research.
I do this fund-raising to say a heartfelt thanks to the hospital
staff, particularly to my consultant Dr A K R Chaudhuri, who
worked tirelessly to find a solution to my problem. I am forever
in his debt.
Dr Jonathan North and Profesor Keith Whaley explain how the
complement system works, and how complement deficiency is
caused and managed.
How the Body Deals with Bacteria
The body’s immune system protects us from invasion
by micro-organisms (germs) which would otherwise take full
advantage of the free meal of nutrients with which we would
provide them. To see how effective the immune system is at
preventing infection, just look at what happens to meat when
it is exposed to air.
Bacteria are one type of micro-organism and are ultimately
dealt with by a type of white blood cell known as neutrophils.
Neutrophils engulf and digest bacteria in a process called
phagocytosis. Neutrophils deal with some types of bacteria
without any other component of the immune system being involved.
However, other types of bacteria have a coating which makes
it difficult for neutrophils to engulf them. This is one of
the main areas in which complement plays a vital role. Along
with antibody, complement coats these bacteria and allows
neutrophils to phagocytose them. In some cases this coating
process damages the cell wall of the bacterium and kills it.
The complement pathways: classical and alternative
The complement system consists of a group of proteins
found in the blood. They can be activated in two different
ways.
The classical pathway is triggered by antibody. The first
complement component (C1) binds with antibody on the surface
of micro-organisms and, as a result, is converted to its active
form. Activated C1 then acts on the fourth (C4) and second
(C2) components of complement and induces them to form a complex,
C42, which is able to activate the major complement component
(C3).
The alternative pathway involves other components of complement:
factors B, D and properdin. As in the classical pathway, these
components form a complex which also activates C3. This activation
process occurs spontaneously, but in normal individuals is
tightly regulated. However, in the presence of certain micro-organisms,
activated C3 binds to their surfaces and amplifies the whole
process so that the organism becomes heavily coated with C3.
This pathway of complement activation does not therefore need
to be triggered by antibody and forms part of our built-in
immunity.
The alternative pathway is less efficient than the classical
pathway, but it is vitally important in the early stages of
infection, before the infected person has been able to produce
antibodies against the infecting bacteria.
The crucial role of C3
The process of coating micro-organisms with C3 is known
as opsonisation. People who lack antibody cannot activate
the classical pathway, and so certain bacteria are not opsonised.
(This is why people with antibody deficiency experience recurrent,
prolonged and often severe bacterial infections. Intravenous
immunoglobulin provides the antibacterial antibodies needed
to trigger the classical complement pathway.)
Neutrophils have receptors on their surface and these receptors
bind very strongly to activated C3 if it is present on bacteria.
Thus, opsonised bacteria are taken up and killed more readily
than unopsonised ones.
The Membrane Attack Complex
When C3 is bound to the surface of micro-organisms (and
other cells), binding of further complement proteins can occur.
These proteins (C5 to C9) form a complex known as the membrane
attack complex (MAC), which disrupts the membranes of some
micro-organisms — resulting in their death.
Complement and inflammation
In addition to opsonising bacteria and producing the MAC,
complement has several other functions. Small fragments of
the main proteins are released during activation and some
of these, most notably those from C3 and C5, are very potent
at producing inflammation.
Inflammation is one of the body’s primitive responses
designed for protection against infection. It is seen around
an area of infection and is often the only means of telling
that an infection is present. During inflammation the small
blood vessels dilate and become leaky. This allows antibodies
and complement to leak into the infected area and attack the
invading micro-organisms. Directed by these complement fragments,
neutrophils and other white blood cells also migrate out of
the blood vessels to phagocytose the opsonised bacteria.
Complement Deficiency and Its Effects
Deficiency in a complement component can arise in two
ways: if the component is used up, or through a genetic cause.
Conditions that can use up complement components include
infection itself and autoimmune diseases (in which the immune
system turns against the body and attacks it). In these cases,
the low levels of complement are temporary and seldom lead
to serious health problems.
In genetic complement deficiency, complement proteins are
not made at all or are made at reduced concentrations. There
is often a history of problems affecting other family members.
Disorders of the complement system account for about 2% of
people with primary immunodeficiency.
Deficiencies involving the classical pathway
People who lack C1, C4 or C2 cannot activate C3 through
the classical pathway and therefore can experience infections
with certain bacteria which have to be opsonised before they
can be killed, such as pneumococcus, haemophilus and meningococcus.
Some people with a deficiency involving the classical pathway
can experience a group of conditions which are characterised
by inflammation caused by immune complexes. This can be in
addition to, or instead of, bacterial infection.
Immune complexes are formed when antibody binds to soluble
targets rather than to the surface of a cell such as a micro-organism.
They cause inflammation if they are not removed. Complement
plays a major role in clearing immune complexes by forming
a link between an immune complex and cells that circulate
through the blood. These cells can be loaded up with immune
complexes and then carry the harmful mixture away to be dealt
with in the spleen and other places. Without the classical
pathway, immune complexes are left in place. This is manifested
by disorders (such as lupus) that affect the kidney, joints,
skin and other organs.
Interestingly, approximately 20% of patients with a deficiency
involving the classical pathway are free from both types of
problems.
Deficiencies involving the alternative pathway
Deficiencies of alternative pathway components are the
rarest of the complement deficiencies. Properdin deficiency
is an X-linked disorder and therefore only occurs in males.
Deficiencies of properdin and Factor D are most often associated
with infections of the meningococcus. Infections are usually
not seen until the mid to late teens. Protection against other
organisms is provided by the classical pathway — which
demonstrates the importance of a combined antibody and complement
attack against most bacteria.
Deficiencies of other complement components
The vital role of C3 in the immune response is clearly
illustrated by individuals who lack this protein. They experience
recurrent infections of the respiratory tract, as well as
meningitis and septicaemias. Like people who are deficient
in classical pathway components, they also suffer immune complex
disease, often affecting the kidneys.
People who are deficient in components of the MAC (like Margaret
Robinson) characteristically experience meningococcal infections,
although those who are deficient in C9 have a lower incidence
of these infections. As in properdin deficiency, the infections
are commonly first seen in the mid to late teens.
The Treatment of Complement Deficiency
It is not possible to replace components which are lacking
in people who have a genetic deficiency of complement. The
first stage in managing patients is to identify those affected,
and this is done by screening all patients with recurrent
or severe bacterial infections.
The next stage in management is to make the person fully
aware of the implications of his or her deficiency, so that
any infections are taken seriously and treated with antibiotics
promptly (GPs often need this information as well). As well
as using antibiotics to treat infections that may initially
seem trivial, it is also important to use these drugs correctly
to treat more serious infections — i.e. to know which
antibiotics are most effective at treating the types of bacteria
that are likely to cause problems.
In patients in whom recurrent infections are a particular
problem the use of prophylactic antibiotics should be considered.
Finally, if a particular component of the immune system is
lacking, the rest of the system needs to be on top form. Therefore,
a full assessment of the patient’s immune system is required.
Since patients with a deficiency in the alternative pathway
rarely suffer recurrent infections, the implication is that
specific antibody (generated after the first infection) plays
a major role in protection. Therefore, we ensure that complement
deficient patients have good specific antibodies by measuring
the levels of these antibodies and boosting any low ones by
vaccines such as Pneumovax, Hib and Tetravalent Meningococcal
vaccine.
Professor Whaley is Head of the Department of Immunology
at Leicester Royal Infirmary. Dr North is Consultant Immunologist
at the Birmingham City Hospital NHS Trust.
Medical information published by the PiA
is approved by our Medical Advisory Panel. However, it is
intended for general guidance only, and should not be used
in place of the personal consultation needed with your physician.
|
