C1q Deficiency and Neuropsychiatric Systemic Lupus Erythematosus

Abstract

C1q deficiency is a rare immunodeficiency, which is strongly associated with the development of systemic lupus erythematosus (SLE). A mutation in one of the C1q genes can either lead to complete deficiency or to low C1q levels with C1q polypeptide in the form of low-molecular weight (LMW) C1q. Patients with C1q deficiency mainly present with cutaneous and renal involvement. Although less frequent, neuropsychiatric (NP) involvement has also been reported in 20% of the C1q-deficient patients. This involvement appears to be absent in other deficiencies of early components of the complement classical pathway (CP) (C1r/C1s, C2, or C4 deficiencies). We describe a new case with C1q deficiency with a homozygous G34R mutation in C1qC-producing LMW-C1q presenting with a severe SLE flare with NP involvement. The serum of this patient contained very low levels of a LMW variant of C1q polypeptides. Cell lysates contained the three chains of C1q, but no intact C1q was detected, consistent with the hypothesis of the existence of a LMW-C1q. Furthermore, we provide a literature overview of NP-SLE in C1q deficiency and hypothesize about the potential role of C1q in the pathogenesis of NP involvement in these patients. The onset of NP-SLE in C1q-deficient individuals is more severe when compared with complement competent NP-SLE patients. An important number of cases present with seizures and the most frequent findings in neuroimaging are changes in basal ganglia and cerebral vasculitis. A defective CP, because of non-functional C1q, does not protect against NP involvement in SLE. The absence of C1q and, subsequently, some of its biological functions may be associated with more severe NP-SLE.

Keywords: C1q deficiency; complement; low molecular weight C1q; mutation; neuropsychiatric systemic lupus erythematosus.

Figure 1

Clinical presentation of the C1q-deficient patient. (A) Malar rash and discoid lupus leading to mild scarring and atrophy. (B) The 3-T magnetic resonance imaging brain (FLAIR image): multifocal diffuse gray matter hyperintensities located in the frontotemporal right lobe and high-intensity area in multiple regions of the right frontal and parietal lobes. (C) Immunofluorescence staining of IgG deposition, C3 deposition, and C1q deposition on the kidney. (D) Electron micrograph of the subendothelial deposition (arrows) of electron dense material. (E) Electron micrograph of mesangial deposition (stars) of electron dense material.

Figure 2

Genetic analysis of the patient and complement activation assays. (A) Data obtained from deep sequencing show a G34R mutation in the C1qC chain. (B) Measurement of the alternative pathway (Wieslab), classical pathway (CP) (Wieslab), C1q, C3, and C4 with nephelometer measurement in the diagnostic laboratory. (C) Reconstitution of the CP by adding different concentrations of purified C1q to the patient serum. As a positive control, normal human serum (NHS) was used, and as a negative control, heat-inactivated NHS (ΔNHS) was used. C4 deposition was used as detection antibody. (D) C5b9 deposition after adding purified C1q to the patient serum and C1q depleted serum. (E) C3c deposition.

Figure 3

Detection of low-molecular weight-C1q in serum. (A) C1q ELISA by using a dilution range of the serum of the C1q-deficient patient (▲), age-matched control (■), and normal human serum (●) as extra control. (B) Western blot analysis of the serum in reduced, non-reduced, and non-reduced/non-denatured conditions. As positive control, an age-matched control is used. Patient serum was diluted 50× and the healthy control 500×. (C) Protein analysis using a BCA protocol and C1q ELISA of different fractions after gel filtration of the serum of a healthy donor. (D) Protein and C1q analysis of the patient.

Figure 4

Analysis of stimulated cells from the C1q-deficient patient on the presence of C1q, (A) Western blot analysis of cell lysates from stimulated PBMCs in reducing conditions, (B) non-reducing and non-denaturing conditions. (C) Western blot analysis of the supernatant of the PBMCs from the patient and the healthy donor (control) after 72 h of culturing in reducing conditions. (D) In non-reducing and non-denatured conditions, the cell lysates and supernatant were added in the same amount. (E) A schematic representation of intact C1q and low molecular weight (LMW)-C1q. In LMW-C1q, positive charges are introduced in the collagen-like tail due the amino acid exchange Gly-Arg at the N-terminal region [modified from Ref. (2)].