Which clinical history findings are characteristic of opsonization-caused complement deficiencies?

Updated: Apr 28, 2021
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Michael A Kaliner, MD  more...
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Answer

Opsonization is the process of coating a pathogenic organism so that it is more easily ingested by the macrophage system. The complement protein C3b, along with its cleavage product C3bi, is a potent agent of opsonization in the complement cascade. Any defect that causes decreased production of C3b results in inadequate opsonization ability. Such opsonization defects can be caused by deficiencies in components of the classic, alternative, or MBL pathways, or defects may be caused by deficiencies of the C3b component itself.

The clinical history of patients with classic pathway deficiencies varies slightly from other complement-deficient patients. In the small number of patients studied, patients with classic pathway deficiencies (ie, deficiency of C1qrs, C2, or C4) are similar in presentation to patients with primary immunoglobulin deficiencies. For example, patients tend to have frequent sinopulmonary infections with organisms such as Streptococcus pneumoniae. More commonly, these patients develop autoimmune syndromes.

In order to generate an antibody response, an antigen must bind to the complement receptor (CR2) on B cells and the complement protein C3d. A deficiency of C1-C4 proteins leads to an inadequate humoral response in these patients. Patients also have a decrease in classic pathway production of the opsonin C3b, but the alternative and MBL pathways seem to compensate for this defect because opsonin is not completely absent.

Opsonization defects can also be caused by alternative pathway deficiencies. In the alternative pathway, a deficiency of factor B, factor D, or properdin can result in a decreased amount of C3b. Deficiencies in properdin have been described in some detail. Properdin is a protein encoded on the X chromosome. Properdin stabilizes the C3 convertase (C3bBb) of the alternative pathway. Stabilization of C3 convertase increases the half-life of the complex from 5 minutes to 30 minutes, exponentially increasing the amount of C3b that can be deposited on a microbial surface. The role of C3b as an opsonin is essential in defense against neisserial infection, and the risk of overwhelming neisserial infection increases in the absence of properdin.

The third pathway whose deficiencies can result in opsonization defects is the MBL pathway. MBL is one of the collectin proteins. These proteins share specific structural characteristics, namely the presence of a collagenlike region and a Ca2+ -dependent lectin domain. Of all the lectin proteins, only MBL has been shown to have the ability to activate the complement system. The MBL protein can activate the C4 and C2 components of complement by forming a complex with serine proteases known as MASP1 and MASP2. MASP1 and MASP2 activation results in the protein products C3 and C3b. The MBL protein is versatile because it can bind to a variety of substrates, prompting some to describe the MBL as a kind of universal antibody. Clinically, MBL deficiencies increase risk of infection with the yeast Saccharomyces cerevisiae and encapsulated bacteria such as Neisseria meningitides and S pneumoniae. [14]

Finally, absolute deficiencies of C3 itself also result in defective opsonization. The C3 component occupies an important place at the junction of both the classic and alternative pathways. As such, C3 deficiency results in severe opsonization dysfunction. C3 deficiency also causes deficient leukocyte chemotaxis because of decreased C3a concentrations and decreased bactericidal killing secondary to decreased formation of MAC. Clinically, patients present at an early age with overwhelming infections from encapsulated bacteria. In addition to opsonization problems, C3 deficiency also impairs adequate clearance of circulating immune complexes, and 79% of patients with C3 deficiency develop some form of collagen vascular disease.

Deficiencies of the inhibitory proteins of the classic and alternative pathways can also result in a functional C3 deficiency through uncontrolled consumption of C3. Factors H and I are proteins that inhibit C3 formation in the alternative and classic pathways, respectively. Deficiencies in either of these C3 inhibitors can result in an overactivation of C3 and subsequent C3 depletion. Clinically, these patients are similar to patients with absolute C3 deficiency.

While deficiencies in complement proteins can predispose patients to infections such as the clinical conditions described above, a deficiency in regulation of complement can also lead to disease. Deficiencies or defective regulation of the alternative complement pathway can occur because of genetic mutations or deficiencies in the regulatory protein Factor H. This defective regulation of the alternative pathway can be associated with diseases such as an atypical form of hemolytic uremic syndrome, membranoproliferative glomerulonephritis (type I and II), and age-related macular degeneration.


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