Complement Receptor Deficiency Clinical Presentation

Updated: May 28, 2019
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Dirk M Elston, MD  more...
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Presentation

History

In 1980, Fearon [14] originally identified and determined the molecular structure of the human CR1 receptor on red blood cells. This finding was followed by the discovery of 3 other cellular receptors for C3b and its degradation products: iC3b, C3dg, and C3d.

Genetic and acquired deficiencies of complement receptors were described only recently; they are associated with autoimmune disorders and infections. Deficiencies in CR1 and CR2 are mainly associated with SLE and other autoimmune dysfunctions. Human CR2, a B-cell membrane glycoprotein that plays a central role in autoimmunity, is reduced in SLE; a complete deficiency of CR2 and CR1 promotes the development of anti-DNA antibodies in mouse models of SLE. [15]

No complete deficiency is described, but reduced expression has been reported in humans. Whether they represent an inherited or acquired phenomenon is unclear, but findings tend to support the acquired phenomenon theory. Deficiencies in CR3 and CR4 have been observed in the leukocyte adhesion syndrome, which is inherited in an autosomal recessive fashion. C3aR and C5aR receptor deficiencies have been studied mainly in complement knockout mice and guinea pigs.

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Physical Examination

Reduction in the number of complement receptors and immature host defenses in preterm newborns

Host defenses in neonates are not fully developed, and defective chemotaxis is believed to play a role. Neutrophils in preterm newborns have significantly fewer receptors for complement factors C3b (CR1/CD35) and iC3b (CR3) than neonates born at term or in adults. Also, C5aR receptor expression is reduced in preterm neonates.

CR1 and/or CR2 receptor deficiency in SLE and other conditions

SLE in humans is associated with abnormal B-cell functions and circulating autoantibodies probably caused by a dysregulation in B-cell tolerance. A rare acquired form of CR1 deficiency was documented in systemic lupus erythematosus associated with autoantibodies against CR1. [16]

In patients with severe SLE, expression of CR1/CD35 on erythrocytes is reduced to about one half of that of healthy individuals. This finding is correlated with disease activity. CR1 receptors are absent on the glomerular podocytes of patients with proliferative glomerulonephritis.

Mice with a deficiency in CD35/21 develop severe SLE with glomerulonephritis and have high amounts of double-stranded DNA (dsDNA) and antinuclear antibodies.

Fluctuating levels of CR1 are not unique to SLE. Decreased numbers of CR1 receptors on erythrocytes is also reported in other autoimmune disorders or diseases with complement activation, such as lepromatous leprosy, autoimmune hemolytic anemias, juvenile rheumatoid arthritis, and Sjögren syndrome.

Low numbers of CR1 receptors on red blood cells, as well as decreased expression of CR1 on erythrocytes and neutrophils, are also found in patients with AIDS. Their presence is correlated with more advanced disease.

Complement is implicated in the pathogenesis of not only autoimmune disorders but also organ failure due to sepsis, trauma, and burns. Under physiological conditions, regulatory proteins and cellular receptors such as CR1/CD35 prevent uncontrolled activation of complement. In numerous animal models, recombinant soluble CR1 significantly reduced complement-mediated tissue damage and prolonged the survival of heart and kidney transplants in pretreated recipients. Recombinant soluble CR1 is well tolerated in humans, and its therapeutic potential has been evaluated in adults with respiratory distress syndrome and myocardial infarction.

Leukocyte adhesion deficiency and CR3 and/or CR4 receptor deficiency

An autosomal recessive inherited deficiency of the leukocyte beta2 integrin receptor CD11/18 is known as the leukocyte adhesion deficiency syndrome. It is associated with recurrent cutaneous infections and gingivitis. Leukocyte adhesion deficiency I was described in a patient with painful recurrent leg ulcers resembling pyoderma gangrenosum. [17] The syndrome is characterized by absent or reduced expression of leukocyte antigens CR3, LFA1 and CR4, or P150,95 and impaired neutrophil adhesive functions (eg, margination, chemotaxis, iC3b-mediated opsonization, phagocytosis). The defect is heterogeneous in that the severity of the disease parallels the degree of deficiency. The more severe forms are due to defects in gene encoding the common beta chain. Heterozygote individuals do not have a predisposition to infections, and their neutrophilic function is normal.

The following conditions are associated with newborns who are affected: delayed separation of the umbilical cord and secondary omphalitis, severe recurrent Staphylococcus aureus and gram-negative bacterial infections, periodontitis, impaired wound healing, lack of pus formation, and leukocytosis.

C3aR and C5aR receptor deficiency

To the author's knowledge, only animal studies have been performed at this time.

C3a has been implicated in the development of adult respiratory distress syndrome or multisystem failure in patients with toxic shock syndrome. The protective role of receptor C3aR in septic shock has been shown in mice with targeted homozygous gene deficiency for C3aR (C3aR-/-). An increased susceptibility to shock was observed in these mice and associated with increased levels of tumor necrosis factor-alpha and interleukin 6.

C3a and its receptor C3aR also have a pivotal role in the pathogenesis of allergy-induced responses, such as bronchoconstriction in asthma, as demonstrated in guinea pigs with a natural C3aR defect or in genetically engineered C3aR knockout mice. [18]

In C5aR-deficient mice, the inflammatory response is decreased in skin, lung, and peritoneum.

Blocking the C5a receptor may be a good alternative to high-dose corticosteroids in treating ANCA-associated vasculitis. [19]

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Complications

Complications may be life threatening in severe cases. Complications include problems associated with underlying autoimmune disorders and life-threatening systemic bacterial infections in some patients with the leukocyte adhesion deficiency syndrome.

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