Classical Pathway Deficiencies

Classical Pathway Deficiency Background

Homozygous deficiencies in the classical pathway proteins are associated with an increased susceptibility to systemic lupus erythematosus/SLE. This pathophysiological association is not due either to ascertainment artefact (that is complement deficiency is not found in patients with SLE simply because more tests of complement activity are performed among this group of subjects), or to linked disease susceptibility genes. The argument against ascertainment artefact follows two major studies of the prevalence of complement deficiency in Swiss Army recruitss and in Japanese blood donors, among whom no examples of inherited homozygous classical pathway component deficiencies were identified. The argument against the association being explained by linked disease susceptibility genes may be countered in the following manner: there is an identical pattern of disease susceptibility found in association with deficiencies of proteins that share physiological activities but are not genetically linked to each other. This argument is strengthened by the increased prevalence of SLE among subjects with acquired deficiencies of complement activity, for example that associated with deficiency of the control protein, C1 inhibitor.

Deficiency of any of the three subcomponents of C1 will block classical pathway activation. Hereditary C1q deficiency is caused either by a failure to synthesize C1q (about 60% of cases) or by the synthesis of a dysfunctional molecule (40%). At least 40 cases of homozygous deficiency of C1q have been reported. C1q is composed of six copies of each of three chains, A, B and C and preliminary data suggest that deficiency is often the result of a defect in synthesis of the B chain.

The classical pathway of complement C3 plays a role in the generation of antibody responses, which has been partially clarified by study of humans and other animals with complementdeficiency. Antigen-presenting cells (APCs) and B cells bear complement receptors; in particular, the specialized APC, the follicular dendritic cell, has complement receptors 1, 2 and 3. Binding of immune complexes to follicular dendritic cells in the germinal centres of lymph nodes is important in the generation of memory B cells, and depletion of C3 in experimental animals impairs antigen localization to germinal centres. Impaired primary responses and a reduced secondary response to low doses of T-celldependent antigens were measured in humans and guinea-pigs with deficiencies of complement proteins. It was recently found that levels of the lgG subclass, IgG4, were markedly reduced in patients with hereditary deficiency of classical pathway proteins and C3.

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Classical Pathway Deficiency References

1. Pettigrew H D, et al. (2009). Clinical significance of complement deficiencies. Annals of the New York Academy of Sciences, 1173(1), 108-123.
2. Morgan B P, et al. (1991). Complement deficiency and disease. Immunology today, 12(9), 301-306.
3. Botto M. (1999). C1q knock-out mice for the study of complement deficiency in autoimmune disease. Experimental and clinical immunogenetics, 15(4), 231-234.