Rosanne Van Schaarenburg

In this thesis we report on the production of C1q by immune cells and non-immune cells. Deficiency of C1q as a consequence of a genetic mutation is strongly associated with the development of Systemic Lupus Erythematosus (SLE). In chapter 2 we describe a not previously reported genetic mutation in one of the C1q genes. The patient is currently a teenager and has suffered from infectious problems but did so far not develop SLE. When patients are diagnosed with C1q deficiency due to a genetic mutation the risk to develop SLE is high, but there is high degree of variation between the patients in clinical manifestations. In chapter 3, we used questionnaires to get an overview of C1q deficient patients worldwide, revealing that once the C1q deficient patients reach adulthood that then the chance of fatal infections is reduced. This overview highlighted the importance of a personal approach for therapy, especially in young children.

A mutation in of the genes of C1q can also lead to a non-functional structure of C1q, Low Molecular Weight-C1q (LMW-C1q). In chapter 4 we described a C1q deficient patient who has low levels of LMW-C1q. This patient demonstrates a severe form of SLE and neuropsychiatric SLE (NPSLE). Our data indicate that the classical pathway activity is not required for NP involvement in SLE, but the absence of C1q and the biological consequences may have a role in the pathogenesis of NPSLE. When we investigated other NPSLE patients we see many different clinical manifestations. To investigate if complement activation and components play a role in NPSLE we performed data analyses and serum analyses. The NPSLE patients have a high degree of complement activation and the levels of anti-C1q and C1q circulating immune complexes are increased compared to healthy controls. The association NPSLE and the levels of anti-C1q, C3/APSO and C4 are probably due to the disease activity and the presence of anti-phospholipid antibodies (discussed in chapter 5).

In the second part of this thesis we described the production of C1q by different cells. We demonstrate that mast cells, which are originating from the same myeloid progenitor cells as the already known C1q producing cells; macrophages and dendritic cells, are able to produce functional active C1q (chapter 6). We were able to detect C1q secreted from chondrocytes. This was surprising as these cells are originating from mesenchymal stem cells, which is different from haematopoietic stem cells. The main role of chondrocytes is to produce cartilage and maintain the homeostasis of the cartilage (chapter 7). Overall, all these studies demonstrate the involvement of C1q in disease and the production of C1q by immune cells and non-immune cells.

In our institute we have identified a C1q deficient patient with a previously unknown mutation in the C1qB chain of C1q resulting in a complete C1q deficiency. Several studies have already shown the association between the absences of C1q in disease like SLE [1-3]. However, this patient did demonstrate several infections but no signs of autoimmunity. Currently, he is receiving prophylactic antibiotics to protect the patient from bacterial infections. If and when patients with a C1q deficiency will develop lupus is unpredictable and it is therefore important to keep him under close control to detect any signs of autoimmunity as early as possible.

Because C1q deficiency is often reported in literature as case reports describing only the initial presentation and no follow-up, we investigated the clinical manifestations of C1q deficient patients around the world. Our data shows that even during follow up the clinical presentation and severity of symptoms in persons that are deficient for C1q is very divers. Even though this case series comprised 45 individuals (comprising the majority of cases known to date) there is no clear algorithm to describe how to manage C1q deficiency clinically. Also differences in clinical presentation are seen within families with the same mutation in one of the C1q genes. Indicating, that other factors like environmental factors or epi-(genetic) changes can influence the different outcome of clinical presentations [4, 5]. From this study we can conclude that the manifestation of the disease in C1q deficient patients is unfortunately not predictable. Especially in young children, where the risk of developing a fatal infectious disease is high. In future studies C1q deficient patients should be monitored regularly from a young age if possible. Together with the familial history and clinical manifestations of the C1q deficient patient, the clinician can decide which treatment will be applied, like FFP or HSCT.

Patients with established SLE have a wide diversity in clinical presentations. Patients can e.g. demonstrate cutaneous lupus or glomerulonephritis, but can also demonstrate symptoms involving the nervous system resulting in neuropsychiatric SLE (NPSLE). In the literature neuropsychiatric involvement in patients with a deficiency in the early components of the classical pathway is only described for patients with a C1q deficiency. We have had the opportunity to investigate in detail a C1q deficient patient demonstrating NPSLE. With this study together with