26 IG Living | December-January 2015 | IGLiving.com

Missing or reduced elements of thecomplement system, a complex andessential part of the innate immunesystem, cause recurrent bacterialinfections and predispose individuals

to autoimmune disorders.

Defects of theComplement System

By Bob Geng, MD

THE COMPLEMENT SYSTEM is an essential part of ourbody’s defense against infections.  It helps the cells in ourimmune system to better recognize and capture bacteria, andcan also lead to direct elimination of bacteria by destroying itscell membrane. There are many components to the comple-ment system, and three distinct pathways in which it can be acti-vated.  In addition to its components, many regulatory pro-teins are involved in ensuring the normal functioning of thecomplement system.

Complement proteins are made in the liver and circulate in thebloodstream.  They can be activated spontaneously (alternativepathway), by the molecules on the surfaces of pathogens directly(lectin pathway) or by the antibodies generated against specificpathogens (classical pathway). The nine main proteins involvedin the classical pathway of activation are C1, C2, C3, C4, C5,C6, C7, C8 and C9. In the alternative pathway, factor B, factorD and properdin are involved in addition to components C3 andC5 through C9. In the lectin pathway, mannose-binding lectin(MBL) and mannan-binding lectin-associated protease 2 (MASP-2) are involved in addition to components C2 through C9. 

Defects of the complement system are rare, but they canoccur at crucial steps in each of the

pathways of activation, as well asamong the regulatory pro-

teins. These deficiencies incomplement componentscan be either inheritedor acquired. This articlewill focus mainly onthe inherited disorders,the way they may pres-

ent, the method of diag-nosis and treatment

strategies, but it will alsobriefly touch on the essential

aspects of acquired complementdeficiencies. 

Inherited DisordersInherited disorders are deficient in components of the comple-

ment system. The clinical features of inherited disorders generallypresent as recurrent infections and/or autoimmunedisorders. Infections include respiratory tract illnesses (sinusitis,bronchitis, pneumonia), meningitis and, in severe cases, sepsis. Thebacteria involved are generally Streptococcus pneumonia,

Haemophilus influenza type B andNeisseria meningitidis.  The mainautoimmune syndrome associated withinherited disorders is systemic lupus erythe-matosus (lupus).  Lupus symptoms includejoint pains, rash, fevers and various organ dysfunctions (lung,kidney, central nervous system, etc.).

Disorders in the classical pathway can include defects in theproduction of any component of the complementsystem. Deficiencies of components C1 through C4 can presentwith autoimmune complications and/or recurrent bacterialinfections. The most common C1 disorder is C1q deficiency. C1qis one of the subcomponents of C1. C2 deficiency can be eitherpartial or complete. Complete C2 deficiency is sometimes seenwith IgG subclass deficiencies, as well as in conjunction withother autoimmune disorders. Partial C2 deficiency does notappear to have any clinical significance in most people. CompleteC3 deficiency can lead to severe recurrent infections, as well asautoimmunity, but partial C3 deficiency does not appear to haveany clinical significance. Deficiencies in the regulatory proteinsfactor H and/or factor I can lead to a secondary C3deficiency. Total C4 deficiency often presents with early-onsetlupus, and partial C4 deficiency can also predispose patients tothe development of lupus. Often in cases of lupus, it can be dif-ficult to discern whether a low C4 level is due to inherent defi-ciency in C4 or to increased amount of consumption secondaryto the buildup of immune complexes as part of the diseaseprocess of lupus. 

The components C5 through C9 form the membrane attackcomplex (MAC) that leads to direct destruction ofbacteria. Deficiencies in any one of these components can pre-dispose individuals to develop recurrent infections to Neisseriaspecies.  In the U.S., C5, C6 and C8 deficiencies are the mostcommon among all MAC defects. C9 deficiency is most oftenseen in Japanese patients, and tends to be less severe thandeficiencies in any of the other elements of the MACbecause bacteria can still be destroyed by thecomponents C5 through C8. 

Assessment of the classical pathwayfunction should always begin with anassay of the CH50 (total hemolyticcomplement), which measuresthe ability of a patient’sserum to destroy sheepred blood cells.  The

27IG Living | December-January 2015 | IGLiving.com

28 IG Living | December-January 2015 | IGLiving.com

value reported indicates the degree of dilution of the patient’sserum that can still destroy 50 percent of the sheep red bloodcells.  An elevated CH50 indicates high level of activity of theclassical pathway of the complement system, but does not haveany specific clinical meaning except suggesting the presence ofactive inflammation and immune activation.  An undetectableCH50 can indicate the complete deficiency of any component ofthe system. However, given the fact that cell lysis (a process inwhich a cell is broken down or destroyed as a result of someexternal force or condition) can still occur without C9, even acomplete deficiency of C9 may yield only a low but stilldetectable CH50 measurement. If the CH50 is low, then meas-urements of specific components can be performed. If the initialCH50 is low, the first thing to do is to repeat the test to rule outthe possibility of an error from poor handling of the serum spec-imen since the CH50 can be reduced after prolonged exposureto room temperature. 

Defects of the alternative pathway are extraordinarily rare.The most common defect of the alternative pathway isProperdin deficiency, which is an X-linked disorder (the geneonly occurs on the X chromosome) that affects onlymales. Fewer than five cases have been reported for deficiency infactor D, and there is one reported case of factor Bdeficiency.  Alternative pathway defects present with recurrentrespiratory tract infections, meningitis and/or sepsis secondary toStreptococcus pneumonia or Neisserial species.  Unlike theassessment of the classical pathway, the alternative pathway canbe assessed by an assay called the AH50, which is not commonlyavailable. If the AH50 is very low, then possibility of Properdin,factor B and factor D deficiency should be considered. 

Management of patients with classical and alternative pathway

defects requires persistent vigilance for infections, early initiationof antibiotics and adequate vaccinations.  Patients should betaught to recognize early warning signs of severe infection suchas stiff neck, rash, fevers, severe respiratory tract symptoms,etc. They need to seek medical attention right away from profes-sionals who understand the significance of these disorders. Patientsshould receive all necessary vaccines, and are not at higher risk ofdeveloping adverse reactions from live viral vaccines. Complementdeficient patients need to be vaccinated against the encapsulatedbacteria such as Streptococcus pneumonia, Haemophilusinfluenza B and Neisseria meningitidis because they are at ahigher risk of developing recurrent infections to these organ-isms. However, when these patients receive vaccines, they shouldbe given protein-conjugated (i.e., Prevnar) rather than purelypolysaccharide vaccines (i.e., Pneumovax) in order to mount amore robust immune response.  Plasma replacement therapy israrely done for complement deficient patients mainly because itis not practical and carries an increased risk of transmitting blood-borne illnesses. There is very limited experience or evidence ofsuccess, and it is currently not part of the standard of care. 

The most common defect in the lectin pathway of comple-ment activation is deficiency in  MBL, a protein that attachesonto the surface of bacteria and triggers the activation of thecomplement cascade. MBL levels can be directly measured andare generally defined as being deficient when the level in theblood is lower than 500ng/ml. In many individuals, MBL defi-ciency is asymptomatic (since the other pathways of complementactivation are still intact), but in some people, it can lead torecurrent bacterial infections. However, deficiency in MBL canpredispose individuals to develop more severe symptoms if theyhave chronic inflammatory conditions. In addition, MBL defi-ciency in addition to another known defect of the immune systemcan lead to more severe and frequent bacterial infections. Bothrecombinant (synthetically made) and plasma-derived MBLproducts are commercially available, but are still currently underresearch investigation as a form of replacement therapy. Themost likely indication for this investigational therapy may bepatients diagnosed with MBL deficiency plus another knowndefect of the immune system who are suffering from severe acutebacterial infections.

Acquired DisordersSome patients acquire complement deficiency as a conse-

quence of another illness. There are a series of conditions thatcan lead to acquired disorders of the complement system. The

The clinical features of inherited complement

disorders generally present asrecurrent infections and/or

autoimmune disorders.

most common cause of acquired complement deficiency islupus, which in half of all cases will result in a reduced level ofC2, C3 and C4. Lupus is a disease associated with an increasedamount of immune complex formation (antibody-antigencomplexes), which accelerates the consumption of complementfactors. Another condition associated with an increased amountof immune complex buildup is cryoglobulinemia. Cryoglobulinsare proteins in the blood that will precipitate (separate out)at temperatures cooler than normal body temperature.Cryoglobulinemia can be a result of chronic viral hepatitisinfection or can occur without any identifiable cause. Complementdeficiency from cryoglobulinemia generally present withlow C2 and C4 levels without a significant decrease in C3levels. 

Another acquired condition that leads to complement defi-ciency is the development of an autoantibody (an abnormalantibody that recognizes and targets normal elements in the

body) called C3 nephritic factor, which leads to an overactiva-tion and excessive consumption of C3. This condition leads tolow C3, low factor B and low AH50, all of which indicate analternative pathway defect. Since the classical pathway is notaffected, the C4 level is usually normal. The presence of C3nephritic factor often leads to the development of membra-noproliferative glomerulonephritis (a severe form of kidneydisease) during childhood, as well as an increased number ofbacterial infections.  

Since all complement proteins are made in the liver, severeliver disease can lead to a decreased production of those comple-ment proteins resulting in lower levels in the blood. In patientswith alcoholic liver disease, C3 and C4 levels may bereduced. However, liver disease would have to be quite advancedbefore seeing appreciably lower complement levels in the blood,so other conditions need to be considered for significantly lowlevels in patients with mild liver dysfunction. 

st sticks W

e during her infusion!y onct cr’didnt her dauears tha�rst time in 5 y

a t it ws mom said tha’ttienthe pae changed the needleser wty afthe daT

tient Aaor/Patdinaoroegional IG CRea ndr- A

y noticeabldle harer wq need-our subt if yWha

! usion!ert ugh

as the, edles

etacaodv Asaexa., Te O.

le? dle

olo toying HIgH-Fl vider about troour proAsk yo

or sufeenceerebig di�e maker needlebette

HIgH-Fith W

oday!

.q- ubes a k

a, loF

03-6043

om.ctsoducmsmedicalprr 9600 •624 • 800

30 IG Living | December-January 2015 | IGLiving.com

Disorders of Regulatory ProteinsRegulatory proteins help activate and control the complement

system. Defects in C1 inhibitor, factor H, factor I, CD55 (decayaccelerating factor) and CD59 have been associated with humandisease.

The deficiency of C1 inhibitor level or function leads to thedevelopment of hereditary angioedema (HAE).  The extensivereview of HAE, including its diagnosis, pathogenesis and treat-ment is beyond the scope of this article.  In addition to C1inhibitor being involved in the complement system, it is alsoinvolved in the kinin pathway that regulates the production of apotent vasodilator called bradykinin. Deficient level or functionof C1 inhibitor ultimately leads to an excessive amount ofproduction of bradykinin, which in turn leads to severeswelling. The swelling can occur in the extremities, on the face,the lips, tongue, throat or abdomen.  A bradykinin-mediatedangioedema is not associated with any hives, and does notrespond to antihistamines, steroids or epinephrine. HAE can betreated either acutely or prophylactically by plasma-derivedC1 inhibitor replacement therapy (Berinert or Cinryze, respec-tively).  Antifibrinolytics and androgens were used more com-monly for HAE in the past, but due to the rise of newer andmore efficacious drugs, they are less commonly used today. Foracute treatment of attacks, direct bradykinin receptor blockers(Icatibant) and kallikrein inhibitor (Ecallantide) have beenshown to be efficacious in the treatment of HAE. 

Factor H and I are elements that control and regulate theactivation of C3.  Therefore, if there is a complete deficiency(homozygous deficiency) in either one of these factors, an exces-sive amount of C3 would be consumed via the alternativepathway, and those patients would present similar to patientswho have a C3 deficiency.  The most common symptoms arerecurrent bacterial infections.  Partial deficiency (heterozygousdeficiency) would predispose individuals to develop nondiar-rheal hemolytic uremic syndrome, the HELLP syndrome (apregnancy-related condition that is associated with kidneyinjury, anemia, low platelets and high liver enzymes) and age-related macular degeneration. 

The cell surface proteins CD55 and CD59 protect our ownblood cells from being damaged by the complementsystem. They block the activation of C3 and prevent the assem-bly of the C5 to C9 membrane attack complex from injuringour own cells.  However, when someone is deficient in eitherone of those cell surface proteins, the complement system is nolonger inhibited, which results in the destruction of the

cell. Red blood cells are particularly vulnerable to this deficiency,which is why the main disease that results from this conditionis paroxysmal nocturnal hemoglobinuria (PNH).  In PNH,episodes of uncontrolled destruction of red blood cell occursleading to significant anemia and to the presence of hemoglobin(the oxygen binding molecule in red cells) in theurine.  Furthermore, PNH can predispose individuals to thedevelopment of low platelet counts and blood clots in theveins. Blood transfusions are important to prevent the anemiafrom becoming dangerous for patients, and oral steroids can beeffective on an episodic basis to decrease the amount of red celldestruction, but long-term use of steroids is not advised due tothe significant amount of side effects.  In addition to bloodtransfusions and close monitoring of the blood cell counts, thereis a targeted treatment medication called Eculizumab that hasbeen shown to be effective. Eculizumab is a monoclonal anti-body that targets C5 and prevents the initiation of the mem-brane attack complex, therefore preventing the destruction ofthe cell. Clinical studies of Eculizumab have shown that it is asafe treatment, and that it has significantly decreased theamount of red cell destruction and prevents the development ofvenous blood clots. 

An Essential Part of the Immune SystemThe complement system is an essential part of the innate

immune system that protects against recurrent infections.  Anormal complement system also regulates the process of inflam-mation in the body. It is a complex system that can malfunctionwhen any particular component of the system is missing orreduced. When it malfunctions, individuals become vulnerableto not only bacterial infections, but also become predisposed tothe development of autoimmune diseases. Complement disor-ders are rare and complex.  Improving education about themwill help increase awareness, as well as result in better care forpatients.

BOB GENG, MD, MA, studied medicine at Washington University School ofMedicine in St. Louis, where he also completed his residency training in internalmedicine. He is currently a third-year fellow in allergy and immunology at UCLAMedical Center. Dr. Geng received his bachelor and master of arts in GeorgetownUniversity’s School of Foreign Service.

References1. Wen, L, Atkinson, JP, Giclas, PC. Clinical and laboratory evaluation of complement deficiency. J Allergy Clin Immunol,2004;113(4):585.

2. Liszewski, MK, Atkinson, JP. Inherited disorders of the complement system. Uptodate, August 2014.3. Sullivan, KE, Winkelstein, JA. Chapter 21: “Deficiencies of the Complement System.” Editors Stiehm, ER, Ochs, HD,Winkelstein, JA. Immunologic Disorders in Infants & Children 5th Edition. Elsevier. Philadephia, 2004; pages 652-683.