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. 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, to 1 in 20, 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. 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.
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Prophylactic treatments include attenuated androgens and C1 inhibitor. The lectin pathway may be first to react before a traditional immune response occurs. It was thought that deficiency of MBL might explain some cases of increased susceptibility to bacterial infection.
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Unfortunately, the MBL test is occasionally still ordered during an evaluation for immunodeficiency and, when the results show MBL to be low or absent, it is wrongly interpreted as indicating the presence of a primary immunodeficiency disorder. By contrast, expert immunologists experienced in caring for PI patients believe that low or absent components of this lectin system, including low or absent MBL, do not cause immunodeficiency by themselves.
There is no recommended treatment for low or absent MBL, and immunoglobulin replacement therapy is clearly not indicated for that purpose. In such cases the IDF recommends that referral to an experienced immunologist to assist in the diagnostic evaluation be considered.
Complement System and Diseases
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. 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. Deficiencies of the early classical and lectin pathway components are primarily accompanied by upper respiratory infections, otitis media, along with lupus-like symptoms.
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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.
The Human Complement System in Health and Disease
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. This page contains general medical information which cannot be applied safely to any individual case. Medical knowledge and practice can change rapidly. Therefore, this page should not be used as a substitute for professional medical advice. The Immune Deficiency Foundation IDF , founded in , is the national non-profit patient organization dedicated to improving the diagnosis, treatment and quality of life of persons with PI through advocacy, education, and research.
There are approximately , people who are diagnosed with PI in the U. Sign up for action alerts. The small peptide fragment that is released from the activated complement protein is released from the site of the reaction and can act as a soluble mediator. Studies have shown impaired complement activity causes humans to become susceptible to repetitive fulminant or severe infections and may contribute to development of autoimmune disease. In recent years, a number of other diseases and situations where the immune system is compromised have been suggested to be affected by complement activity.
The presence of activated complement proteins and the soluble mediators resulting from their activation can provide information about the nature and extent of inflammation and tissue injury. This is especially true for the small peptide fragment C4d which has a long half-life and the ability to remain at the site of complement activation. This interaction has been exploited as a biomarker in fields where antibodies can cause tissue damage i.
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