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Structural and functional studies in C1q deficiency
Insights
Two brothers with a severe lupus-like syndrome and a healthy sibling lacked hemolytic complement 1 (C1) activity due to dysfunctional C1q. This genetic disorder impacts complement function and immune response.
Area of Science:
- Immunology
- Biochemistry
- Genetics
Background:
- Complement system dysfunction can lead to immune dysregulation.
- Deficiencies in early complement components are associated with autoimmune diseases.
- Hereditary angioedema and lupus erythematosus are linked to complement component abnormalities.
Observation:
- Two brothers presented with absent hemolytic complement 1 (C1) activity.
- One brother had a severe lupus-like syndrome; the other was healthy.
- Both siblings exhibited depressed levels of C1q, with normal levels of other complement components.
Findings:
- The dysfunctional C1q lacked proper interaction with immunoglobulins and C1r/C1s.
- Addition of normal C1q restored hemolytic activity, ruling out serum inhibitors.
- The abnormal C1q showed partial loss of antigenic determinants and increased molecular weight.
- A genetically linked disorder affecting C1q function was suggested within the family.
Implications:
- This study identifies a novel dysfunctional C1q variant.
- Understanding C1q defects is crucial for diagnosing and managing autoimmune and immune deficiency disorders.
- Further research into C1q structure-function relationships can elucidate complement-mediated disease mechanisms.
Abstract:
The sera of two brothers were found totally lacking hemolytic C activity. One of them, a 16-yr-old male, presented a severe lupus-like syndrome, whereas the other was apparently healthy. Immunochemical quantitation of C components in both sera showed depressed levels of C1q, whereas the levels of C1r, C1s, and C1 inhibitor were elevated. C4, C3, C5, factor B, and beta 1H levels were in the normal range. Hemolytic C1 activity was totally lacking. C4 titers were elevated (150% of normal). C2 hemolytic activity was about one-third of normal, and the titers of the terminal components C3-C9 were also reduced in the two siblings. Double immunodiffusion against anti-C1q antiserum showed a partial loss of C1q antigenic determinants in the two siblings. Furthermore, the C1q of both siblings was unable to interact with immunoglobulins or to associate with C1r and C1s. Addition of purified human C1q to the sera restored their total C and C1 hemolytic activity. The dose response to the C1q addition was linear, indicating that the functional deficiency was not due to the presence of a serum inhibitor. Although antigenically deficient in comparison with normal C1q, the abnormal C1q appeared to have a larger m.w., as determined by gel chromatography. Investigation of other members of this family suggests a genetically linked disorder, because four out of six siblings had the same dysfunctional C1q in their serum.