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Title: Abnormalities of immune complex processing in systemic lupus erythematosus
Author: Hammond, Anthony
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1992
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Heterozygous deficiency of C4A is a common inherited abnormality in patients with SLE who also acquire a reduction of erythrocyte (E) complement receptor type 1 (CR1) numbers. These factors could contribute to disease expression by reducing the efficiency of complement and ECR1 mediated mechanisms for the physiological disposal of circulating immune complexes (CIC). I therefore studied aspects of the physiology of C4A and C4B, the isotypes of the fourth complement component and the mechanisms of reduced ECR1 expression. C4A binds preferentially to amino groups, while C4B is more efficient in forming ester bonds with hydroxyl moieties. I therefore examined the differential binding of C4A and C4B to SLE erythrocytes in vivo and to heat aggregated IgG ICs in vitro. My results demonstrate an excess of C4B associated with erythrocytes and a stronger correlation of serum C4A levels with immune complex deposition. These findings reflect factors which may be of importance during periods of disease activity and high CIC levels in SLE. The twin C4 loci are highly polymorphic including null and duplicated alleles. I have studied the serum levels of C4A and C4B amongst carefully genotyped normal subjects and have confirmed observations of the extensive phenotypic overlap between subjects with differing C4 gene numbers. Factors contributing to phenotypic overlap including age, gender, acute phase responses and abnormal serological reactivity were also studied. I also found that the C4B deficient extended haplotype associated with Felty's syndrome encodes expressed homoduplicated C4A alleles, making impairment of CIC clearance an unlikely pathophysiological mechanism for this association.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available