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Deficiency of the effector mechanisms of the immune response and autoimmunity.

Authors
Type
Published Article
Journal
Ciba Foundation symposium
0300-5208
Publication Date
Volume
129
Pages
149–171
Identifiers
PMID: 2960501
Source
Medline
License
Unknown

Abstract

It has long been the conventional wisdom that most autoimmune responses represent a pathological aberration of the immune system and a great deal of effort has been devoted to investigating how such abnormal responses may be induced. It seems likely, however, particularly in the form of autoimmunity seen in diseases like systemic lupus erythematosus (LE) and associated with immune complex disease, that it is not the induction of the autoimmune response that is primarily abnormal, but its persistence, and that this abnormal persistence is a consequence of a failure of the proper functioning of the effector mechanisms of the immune response. The strongest reason for so believing is the striking incidence of these diseases in subjects with deficiencies of the early components of the classical complement pathway. Total, homozygous deficiencies are rare and account for only a small proportion of patients with systemic LE. However, partial, heterozygous deficiency of these components is much commoner and also carries an increased susceptibility to these diseases. An explanation for this association is given. In the presence of an adequately functioning complement system immune complexes remain soluble and of relatively small size. It is proposed that this is a result of the incorporation of C4 and C3 into the antigen-antibody lattice leading to a reduction in the effective valency of antigen and antibody. The Goldberg theory of immune precipitation predicts that a reduction in valency would inhibit precipitation and the formation of large complexes. In the absence of adequate complement function this mechanism will fail and large, potentially insoluble complexes with little C4 and C3 on them will be formed. These large immune complexes without sufficient C4 and C3 bound on them will also not be bound normally to erythrocyte CR1 and will therefore be transported in the (peripheral) plasma stream rather than in the (central) erythrocyte stream. It is proposed that this will result in the deposition of immune complexes in peripheral small blood vessels rather than in the sinusoids of the liver and spleen; and that this peripheral deposition gives rise to inflammation, with the release of autoantigens and the formation of further autoantibodies. The importance of CR1 in relation to these diseases is emphasized by the reduction in CR1 numbers that accompanies their active phase. This appears to be due to proteolysis of the receptor while the immune complex-bearing erythrocyte is sequestered in the reticuloendothelial system.

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