The production and secretion of complement component C1q by human mast cells.

C1q is the initiation molecule of the classical pathway of the complement system and is produced by macrophages and immature dendritic cells. As mast cells share the same myeloid progenitor cells, we have studied whether also mast cells can produce and secrete C1q. Mast cells were generated in vitro from CD34+ progenitor cells from buffy coats or cord blood. Fully differentiated mast cells were shown by both RNA sequencing and qPCR to express C1QA, C1QB and C1QC. C1q produced by mast cells has a similar molecular make-up as serum C1q. Reconstituting C1q depleted serum with mast cell supernatant in haemolytic assays, indicated that C1q secreted by mast cells is functionally active. The level of C1q in supernatants produced under basal conditions was considerably enhanced upon stimulation with LPS, dexamethasone in combination with IFN- γ or via FcεRI triggering. Mast cells in human tissues stained positive for C1q in both healthy and in inflamed tissue. Moreover, mast cells in healthy and diseased skin appear to be the predominant C1q positive cells. Together, our data reveal that mast cells are able to produce and secrete functional active C1q and indicate mast cells as a local source of C1q in human tissue.

C1q Deficiency and Neuropsychiatric Systemic Lupus Erythematosus.

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.

Marked variability in clinical presentation and outcome of patients with C1q immunodeficiency.

OBJECTIVE: Globally approximately 60 cases of C1q deficiency have been described with a high prevalence of Systemic Lupus Erythematosus (SLE). So far treatment has been guided by the clinical presentation rather than the underlying C1q deficiency. Recently, it was shown that C1q production can be restored by allogeneic hematopoietic stem cell transplantation. Current literature lacks information on disease progression and quality of life of C1q deficient persons which is of major importance to guide clinicians taking care of patients with this rare disease. METHODS: We performed an international survey, of clinicians treating C1q deficient patients. A high response rate of >70% of the contacted clinicians yielded information on 45 patients with C1q deficiency of which 25 are published. RESULTS: Follow-up data of 45 patients from 31 families was obtained for a median of 11 years after diagnosis. Of these patients 36 (80%) suffer from SLE, of which 16 suffer from SLE and infections, 5 (11%) suffer from infections only and 4 (9%) have no symptoms. In total 9 (20%) of the C1q deficient individuals had died. All except for one died before the age of 20 years. Estimated survival times suggest 20% case-fatality before the age of 20, and at least 50% of patients are expected to reach their middle ages. CONCLUSION: Here we report the largest phenotypic data set on C1q deficiency to date, revealing high variance; with high mortality but also a subset of patients with an excellent prognosis. Management of C1q deficiency requires a personalized approach.

C1q, antibodies and anti-C1q autoantibodies.

The complement system has long been known for its role in combating infections. More recently the complement system is becoming increasingly appreciated for its role in processes that range from waste transport, immune tolerance and shaping of the adaptive immune response. Antibodies represent the humoral part of the adaptive immune response and the complement system interacts with antibodies in several ways. Activated complement fragments impact on the production of antibodies, the complement system gets activated by antibodies and complement proteins can be the target of (auto)antibodies. In this review, written to celebrate the contributions of Prof. Dr. M.R. Daha to the field of immunology and especially complement, we will focus on C1q and its various interactions with antibodies. We will specifically focus on the mechanisms by which C1q will interact with monomeric IgG versus polymerized IgG and fluid-phase IgM versus solid-phase IgM. In addition in this review we will discuss in detail how C1q itself is targeted by autoantibodies and how these autoantibodies are currently considered to play a role in human disease.

Identification of a novel non-coding mutation in C1qB in a Dutch child with C1q deficiency associated with recurrent infections.

INTRODUCTION: C1q deficiency is a rare genetic disorder that is strongly associated with development of systemic lupus erythematosus (SLE). Several mutations in the coding regions of the C1q genes have been described that result in stop-codons or other genetic abnormalities ultimately leading to C1q deficiency. Here we report on a Dutch boy suffering from recurrent infections with a complete C1q deficiency, without any SLE symptoms. METHODS: The presence of C1q in serum was assessed using ELISA and hemolytic assay. By western blot we examined the different C1q chains in cell lysates. We identified the mutation using deep-sequencing. By qPCR we studied the mRNA expression of C1qA, C1qB and C1qC in the PBMCs of the patient. RESULTS: Deep-sequencing revealed a homozygous mutation in the non-coding region of C1qB in the patient, whereas both parents were heterozygous. The mutation is located two nucleotides before the splice site of the second exon. In-silico analyses predict a complete abrogation of this natural splice site. Analyses of in vitro cultured cells from the patient revealed a lack of production of C1q and intracellular absence of C1qB in the presence of C1qA and C1qC peptides. Quantitative PCR analysis revealed total absence of C1qB mRNA, a reduced level of C1qA mRNA and normal levels of C1qC mRNA. CONCLUSION: In this study we report a new mutation in the non-coding region of C1qB that is associated with C1q deficiency.

Autoantibodies against complement components and functional consequences.

The complement system represents a major component of our innate immune defense. Although the physiological contribution of the complement system is beneficial, it can cause tissue damage when inappropriately activated or when it is a target of an autoantibody response. Autoantibodies directed against a variety of individual complement components, convertases, regulators and receptors have been described. For several autoantibodies the functional consequences are well documented and clear associations exist with clinical presentation, whereas for other autoantibodies targeting complement components this relation is currently insufficiently clear. Several anti-complement autoantibodies can also be detected in healthy controls, indicating that a second hit is required for such autoantibodies to induce or participate in pathology or alternatively that these antibodies are part of the natural antibody repertoire. In the present review, we describe autoantibodies against complement components and their functional consequences and discuss about their clinical relevance.

Anti-C1q autoantibodies, novel tests, and clinical consequences.

Although anti-C1q autoantibodies have been described more than four decades ago a constant stream of papers describing clinical associations or functional consequences highlights that anti-C1q antibodies are still hot and happening. By far the largest set of studies focus on anti-C1q antibodies is systemic lupus erythematosus (SLE). In SLE anti-C1q antibodies associate with involvement of lupus nephritis in such a way that in the absence of anti-C1q antibodies it is unlikely that a flare in nephritis will occur. Anti-C1q antibodies occur in several autoimmune conditions but also in healthy individuals. Although considerable progress has been made in the understanding of how anti-C1q antibodies may contribute to tissue injury there is still a lot to learn about the processes involved in the breaking of tolerance to this protein. There has been considerable improvement in the assays employed to test for the presence of anti-C1q antibodies. Hopefully with these new and standardized assays at hand larger clinical association studies will be conducted with independent replication. Such large-scale studies will reveal the true value of clinical testing for anti-C1q autoantibodies in several clinical conditions.