Complement Deficiencies

Complement is the term used to describe a group of serum proteins that are critically important
in our defense against infection. There are deficiencies of each of the individual components of
complement. Patients with complement deficiencies encounter clinical problems that depend on
the role of the specific complement protein in normal function.

Description of the Complement System and Its Pathways

The complement system consists of more than 30 proteins, present in blood and tissues, as well
as other proteins anchored on the surfaces of cells. The primary functions of the complement
system are to protect from infection, to remove particulate substances, (like damaged or dying
cells, microbes or immune complexes) and to help modulate adaptive immune responses. As part
of the innate immune system, complement acts immediately to start the process of removal and
resolution of the problem. Complement works with the inflammatory cells of the innate immune
system and those of adaptive or acquired immunity. It also interacts with proteins of the
coagulation and kinin generating systems along with others.

Complement activation is tightly regulated and designed to kill invading microbes while
producing minimal “collateral damage” that could result in the destruction of host tissues.
Complement proteins in the circulation are not activated until triggered by an encounter with a
bacterial cell, a virus, an immune complex, damaged tissue or other substance not usually present
in the body.

Complement activation is a cascading event like the falling of a row of dominoes. It must follow
a specific order if the end result is to be achieved. The circulating proteins have been grouped
into three activation pathways, based on the types of substances and proteins that initiate the
activation. If you visualize a trident, the three tines represent the different initiation routes, while
the handle represents the lytic mechanism by which this cascade ultimately destroys the threat,
no matter which activation pathway started the response. The diagram in Figure 1 depicts the
activation pathways.

FIGURE 1
The Classical Pathway (CP) is activated primarily by immunoglobulins (antibodies, including
autoantibodies) that are bound to antigens – either in the fluid phase as soluble immune
complexes, or on cell membrane surfaces or other tissues. Aggregates of immunoglobulins such
as cryoglobulins also activate the CP. Components of the CP are C1q, C1r, C1s, C2 and C4. The
CP was the first to be discovered, but is the most recent in evolutionary terms.

The Lectin Pathway (LP) is similar to the CP except for the first two steps. Mannose binding
lectin (MBL), the Ficolins, and Collectin can initiate the LP. Associated with these are enzymes
referred to as MASPs (MBL-Associated Serine Proteases). C2 and C4 also participate in the LP.
The LP is thought to be the most evolutionarily primitive of the complement pathways and the
first to react before the adaptive immune response occurs.

The Alternative Pathway (AP) is initiated by fragments of the complement component C3.
Other elements of the AP are Factor B, Factor D and properdin. A unique feature of the AP is the
presence of the only positive regulator in the complement system, Properdin. Properdin makes it
possible for the amplification loop of the alternative pathway to set up a very efficient
mechanism for putting lots of C3b onto the surface of the activating cells, protein complexes or
particles in the immediate vicinity of the activation site. Because the ability of the C3b to bind to
these surfaces decays rapidly, the activation is limited to just the region around the C3 cleavage
site. This time-limitation is another control mechanism for the complement pathway.

The Terminal Pathway (TP) is the final set of steps in the complement activation process that
forms a membrane lesion or hole (membrane attack complex or MAC) that kills susceptible
bacteria or other cells that activate complement on their surfaces. The TP is dependent upon at
least one of the other pathways to initiate the process that it then completes. The components of
the TP are C3, C5, C6, C7, C8 and C9. A fluid phase form of the MAC, called the Terminal
Complement Complex (TCC) can be found in the circulation after complement activation occurs
and makes a useful laboratory marker for complement activation.

Control mechanisms to prevent unregulated activity (and tissue damage) are present in each
pathway. C1-esterase inhibitor (C1-inh) is a serine protease inhibitor (SERPIN) that acts by
forming a complex with active enzymes to trap and inactivate them. It is important in controlling
the C1r and C1s activation in the CP, and the MASPs in the LP along with several enzymes in
the coagulation system.

The dynamic interplay among the different complement pathways and their control processes
involves other plasma protein systems such as enzymes of the coagulation system, enzymes from
inflammatory cells, and substances such as histamine released from cells in the local
environment. All of these participants affect the outcome of an activation event. Most of the
time, the outcome is favorable to the host, with the danger met and the situation returned rapidly
to normal. The diseases that accompany uncontrolled activation or inadequate performance of
complement’s functions are often the result of inherited deficiency or subtle impairment of one
or more of the components.
Complement Deficiencies and Their Diagnosis

Clinical indications for possible complement deficiencies include recurrent mild or serious
bacterial infections, autoimmune disease, or episodes of angioedema (a painless, but often
dramatic, swelling under the skin, or swelling in the intestines, which can be extremely painful).
Very rarely angioedema in the brain can be fatal. This swelling does not respond to
antihistamines or epinephrine. The list of potential complement-related problems includes renal
disease, vasculitis (blood vessel inflammation) and age-related macular degeneration. A history
of family members having the same presentation should increase the suspicion of an inherited
complement deficiency, most of which are inherited as autosomal co-dominant conditions. All
genes, except for those in the Male sex chromosome Y, come in pairs, one inherited from mom
and one from dad.

Co-dominance occurs when the contributions of both alleles are visible in the phenotype. In the
ABO blood group example, the A and B allele classes are co-dominant in producing the AB
blood group phenotype, in which both A-type and B-type antigens are made. By contrast, with
traditional dominant–recessive gene combination like eye color, a single brown allele is
dominant and if the other parent contributed a blue color allele, the eyes will be brown rather
than a mix of brown and blue. In this context it means both the normal and mutant complement
proteins are produced in the affected individuals. There is an exception in the case of Properdin,
the gene for which is on the X chromosome and is inherited as an x-linked disease.

The initial tests done to evaluate a patient’s complement system are critical because they can
often identify an inherited defect and indicate what further testing must be done to make the
diagnosis. The aim of the evaluation process is to clearly define the complement component
deficiency with as few tests as possible, while ruling out acquired causes of low complement
values. Several screening tests are available that make it easier to find the answers. It is
important to know as much as possible about the reason(s) for low or absent complement so that
decisions regarding appropriate treatment can be made, including when to use antibiotics and
immunizations as well as genetic counseling for inherited deficiencies.

Therapeutics specific for complement deficiencies are still in the developmental stage for most
components, but in some cases, such as C1-Inh deficiency, there are currently several drugs
available. For uncontrolled complement activation as in PNH or due to dysfunctional FH, there
are a few drugs available to treat acute episodes or to prevent recurrence. Therapeutics for
complement-derived diseases is in its infancy at this time, but more treatments should become
available in the near future.

Deficiencies in the Classical Pathway: C1q, C1r, C1s, C4, C2, C1-Inh

Rapid clearance of immune complexes, dying cells and debris from damaged tissues is a job that
is performed efficiently by a normal CP.  Primary deficiency of C1q, C1r, C1s or C4 is closely
linked to development of systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA),
thought to be due in part to the inability of complement to clear immune complexes and dying
cells. Small complexes are cleared from the circulation when they bind to complement receptors
on macrophages in the spleen and liver.

Without complement, the complexes can grow too large to be easily cleared. The resulting
aggregates can activate the alternative pathway, allowing C3 to be deposited into the matrix,
with re-solubilized complexes that can be dealt with by the clearance through the liver and
spleen. Failing this, these large complexes are no longer soluble, and form deposits in the tissues
and become a site of inflammation. Dying cells, if not cleared by non-inflammatory CP activity,
may serve as sources of altered self-antigens with the potential for inducing autoantibodies.

C2 deficiency is the most common complement deficiency in Caucasian populations, with

frequency estimates between 1 in 10,000 to 1 in 20,000 for homozygous C2-deficient patients.
C2 deficiency is found in a slightly higher proportion of SLE patients compared to healthy
controls. In primary immunodeficiency, C2 deficiency is found in young children who have
recurrent infections, primarily upper respiratory infections with Streptococcus pneumoniae or
similar organisms. These children often have frequent ear infections and colds.

Hereditary angioedema (HAE) is a disease caused by deficiency of the CP control protein, C1-
Inh. Symptoms generally begin around puberty but can occur earlier. These individuals have
recurrent swelling in the extremities, face, lips, larynx or GI tract. The patients describe a
sensation of fullness but not pain or itching in the affected area except for those with abdominal
swellings who often experience acute abdominal pain. The latter two presentations are of the
most concern because suffocation can occur if the airways are obstructed, and the acute swelling
of the abdominal region produces intense pain often resulting in exploratory surgery.

The mechanism for production of the swelling involves not the complement enzymes, but the
kinin-generating pathway. It is the production of Bradykinin through this pathway that is
responsible for the tissue permeability changes that cause the swelling. Acute treatments include
C1 inhibitor, a replacement therapy (both plasma derived and recombinant products are
available); ecallantide, a kallikrein inhibitor; and icatibant, a bradykinin-2 receptor antagonist.
Prophylactic treatments include attenuated androgens and C1 inhibitor.

Deficiencies of the Lectin Pathway Components

MBL, M-ficolin, L-ficolin, H-ficolin, CL-11, MASPs

MBL deficiency is fairly common, affecting approximately 5-30% of individuals. There is some
controversy over the importance of the lectins to overall immunity, but most authors agree that
the early months of a baby’s life are dependent on the ability of the lectin pathway to fight
bacterial infections during the period when maternal antibodies decrease and the child’s own
antibody production is not fully functional. Other studies have shown increased susceptibility to
herpes simplex virus-2, influenza A, Pseudomonas aeruginosa and Staphylococcus aureus.

Deficiencies of the Alternative Pathway

Factors D, B and Properdin

Factor D deficiency is very rare and has only been described in two families. Both of these
families had multiple members with a history of serious infections. Factor B is an acute phase
protein and increases during inflammation. There is only one unconfirmed report of this
deficiency in humans.

Properdin is the only complement protein that is X-linked. The protein is synthesized by
monocytes, granulocytic cells and T-cells. Several mutant forms of the protein have been
identified that result in decreased AP function. Properdin deficiency increases the susceptibility
to bacterial infections of the Neisseria family of organisms. The most prominent in the group is
N. Meningitis, the cause of a serious form of meningitis. Typical family histories include male
relatives who have had or died from Neisserial infections.

Alternative Pathway Control Proteins

Deficiencies of factor H are linked with a wide variety of symptoms. Complete deficiency of H
leads to uncontrolled activation of the AP and depletion of C3 occurs. This form of factor H
deficiency is similar in presentation to the late component deficiencies due to the low or absent
levels of C3. Recent data has been published that demonstrates how critical the role for this
complement control protein is in maintaining health in a number of tissues. In addition to
bacterial infections, deficiency or dysfunction of factor H and the resulting dysregulation of the
AP is associated with various forms of kidney disease including atypical Hemolytic Uremic
Syndrome (aHUS), as well as age-related macular degeneration (AMD). These diseases are
examples of control processes gone awry on the surfaces of the organs affected.

Treatment of Complement Deficiencies

Deficiencies of the early classical and lectin pathway components are primarily accompanied by
upper respiratory infections, otitis media, along with lupus-like symptoms. Any complement
deficiency should be treated as an immune deficiency, and the patient should be immunized
against the likely candidate microbes for their deficiency. Antibody responses should be checked
after vaccination, since the inability to activate complement impairs the immune response to
some extent. Currently, there are no specific treatments for complement deficiencies. Infection
prevention and appropriate treatment of infections (usually with antibiotics), when they do occur
is key in the care of patients with these deficiencies. Fresh frozen plasma has been tried in some
cases, but carries the risk that the patient may make antibody to the missing complement
component, so prolonged use is not advised. Prophylactic antibiotics can be used if the patient
experiences repeated infections, and increased vigilance with rapid treatment of problems is
another option. Most of these patients eventually make antibodies against the offending bacteria
and do not get sick as often.

Boys with Properdin deficiency (X-linked) should be immunized against Neisseria meningitidis,
in addition to the usual vaccinations of childhood. Often there is a family history of an uncle or
other relative who died from Neisserial infection at an early age. Deficiencies of the other
alternative pathway components and the terminal pathway proteins are also susceptible to
Neisseria meningitidis and should be immunized. The vaccine titers should be verified in these
individuals as well.