Complement deficiencies and their diagnosis
Over 50% of people who have a deficiency in complement proteins develop infections. An even higher percentage of individuals with a deficiency in the CP develop autoimmunity, primarily systemic lupus erythematosus (SLE). A deficiency of C3, the most abundant complement protein, results in severe, recurrent infections (especially those of the respiratory tract) that begin soon after birth. As the age increases, infections are primarily due to a bacterial species, Neisseria, which can cause meningitis. Hence, the typical clinical symptoms of complement deficiencies include recurrent mild or serious bacterial infections and autoimmune disease. In C1 inhibitor deficiency, episodes of angioedema (a swelling under the skin or in the intestines) occur. The list of potential complement-related health 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.
The initial tests done to evaluate an individual’s complement system can identify an inherited defect and indicate what further testing must be done to make the diagnosis. The aim of the evaluation process is to define the complement component deficiency, while ruling out acquired causes of low complement values. Several screening blood tests are available that make it easier to find the answers. These include CH50, which is a useful tool to screen for classical pathway deficiencies, and AH50, which is used to screen for alternative pathway deficiencies. Individual complement levels can also be tested. 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 for decisions about genetic counseling for inherited deficiencies.
Therapies 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 a number of medications available. For poorly controlled complement activation, especially that occurring due to deficiencies in regulatory proteins as in aHUS or PNH, there are certain drugs available to treat acute episodes or to prevent recurrence. Additionally, a monoclonal antibody to C5 (eculizumab) is used to block complement-induced damage. Additional therapeutic agents may become available in the next decade.
Deficiencies in the alternative pathway: C3, factors D, B, and properdin
Inherited C3 deficiency results in repeated, severe infections starting from birth, especially those of the respiratory tract. Organisms such as Streptococcus pneumoniae and Hemophilus influenzae are the most frequent causes of infection. These infections have decreased in frequency and severity due to use of antibiotics and vaccines.
Properdin is the only complement protein that is X-linked, so its deficiency only affects males. The protein is synthesized by immune cells such as monocytes, granulocytes, and T cells. Properdin deficiency increases the susceptibility to bacterial infections of the Neisseria family of organisms. The most prominent in the group is Neisseria meningitidis, which can cause a serious form of meningitis. Typical family histories include male relatives who have had or died from Neisserial infections.
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.
Deficiencies in the classical pathway: C1, C4, C2, C1-INH
Rapid clearance of immune complexes, dying cells, and debris from damaged tissues is a job that is efficiently performed by a normal classical pathway. The C1 protein is made up of C1q, C1r, and C1s. Complete deficiency of C1, C2, or C4 is closely linked to the development of systemic lupus erythematosus (SLE). This is thought to be due in part to the inability of complement to clear immune complexes and debris from dying cells, especially DNA and RNA.
C2 deficiency is the most common complement deficiency in populations of European descent, with frequency estimates between 1 in 10,000 to 1 in 20,000 individuals are hom*ozygous C2-deficient. In primary immunodeficiencies (PI), C2 deficiency is found in young children who have recurrent infections, mainly upper respiratory tract or ear infections due to Streptococcus pneumoniae and Hemophilus influenzae. Many adults with C2- deficiency also have SLE.
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 moderate to severe swelling in the extremities, face, lips, larynx (vocal cords), and gastrointestinal tract (intestines) that is frequently painful and debilitating. Intestinal swelling can cause acute severe abdominal pain, and the acute intestinal swelling can result in obstruction, which may need acute surgical intervention. Swelling the vocal cords can be concerning because of the possibility of airway obstruction leading to suffocation. These episodes typically last 3-5 days if not treated with effective medication.
Acute treatments for HAE include C1 inhibitor, a replacement therapy [both plasma-derived (concentrate) and recombinant products are available]; ecallantide, a kallikrein inhibitor (available in the U.S. only) and icatibant, a bradykinin-2 receptor antagonist. Note that steroids and antihistamines are not effective to treat HAE or prevent attacks. Prophylactic treatments include androgens, C1 inhibitor concentrates, and lanadelumab.
Deficiencies in the lectin pathway: MBL, M-ficolin, L-ficolin, H-ficolin, CL-11, MASPs
Deficiencies in the lectin pathway are fairly common, affecting approximately 5-30% of individuals. There is some controversy over the importance of the lectins to overall immunity. Most experts agree that the lectin pathway is important to fight bacterial infections during the early months of a baby’s life when maternal antibodies decrease, and the child’s own antibody production is not fully functional. In certain cases, the deficiency may be severe. [For example, a hom*ozygous mutation in the ficolin-3 gene leads to severe, recurrent pulmonary infections in children that can result in severe lung disease, including bronchiectasis (damage to the lungs), later in life. Other studies have shown increased susceptibility to HSV-2 (herpes simplex virus-2), influenza A, Pseudomonas aeruginosa, and Staphylococcus aureus. hom*ozygous mutations in either the collectin-11 gene or MASP-1 gene can result in developmental abnormalities (including facial irregularities, cleft lip and palate, and cognitive defects).
Mannose binding lectin deficiency
Mannose binding lectin deficiency (MBL) is a part of the lectin pathway of the complement system, one of several different components of our immune defense. The lectin pathway may be the 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. However, when a test was developed to measure MBL in the blood, it was determined that low or absent MBL is very common, affecting approximately 5-30% of all individuals. Therefore, its absence alone cannot be a cause of serious immunodeficiency, or a large portion of the world’s population would suffer from frequent major recurrent and potentially fatal infections. 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 PI. By contrast, expert immunologists experienced in caring for people with PI 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. It is important to stress that the finding of low or absent MBL does not indicate that the cause for an individual’s infections has been found and that the diagnostic process must continue until the correct diagnosis is determined.
Deficiencies in the regulatory proteins: Factor H, factor I, CD46, CD55, and CD59
Complete deficiency of factor H leads to uncontrolled activation of the alternative pathway and C3 consumption. Recent data has been published that demonstrates how critical the role of this complement control protein is in maintaining health in a number of tissues. In addition to bacterial infections, deficiency or dysfunction of factor H is associated with various forms of kidney disease, including atypical hemolytic uremic syndrome (aHUS), as well as age-related macular degeneration (AMD). Heterozygous variants in factor I and CD46 can also result in aHUS. These diseases are examples of control processes gone awry on the surfaces of the organs affected. An acquired deficiency of CD59 is seen in paroxysmal nocturnal hemoglobinuria, which is associated with hemolytic anemia and renal failure. More recently, genetic sequencing has identified mutations in CD55 that are associated with CHAPLE syndrome (complement hyperactivation, angiopathic thrombosis, and protein-losing enteropathy), which often presents as abdominal pain or diarrhea, recurrent infections, and thromboembolic disease (blood clots).
