Encyclopedia of Medical Immunology

Living Edition
| Editors: Ian MacKay, Noel R. Rose

C1 Deficiency and Associated Disorders

  • Berhane GhebrehiwetEmail author
Living reference work entry
DOI: https://doi.org/10.1007/978-1-4614-9209-2_11-1

Introduction

The complement system is a strictly regulated and highly complex effector system whose major function is to recognize and eliminate pathogens as well as altered self-antigens. Therefore, it constitutes a very powerful arm of the innate and adaptive immune systems with unique ability to discriminate self from nonself and eliminate “danger” through a wide array of processes that include phagocytosis and cytolytic mechanisms. Although there are three interdependent pathways of complement activation – classical, alternative, and lectin – only the role of the classical pathway and the consequences of deficiency in any of the components that initially trigger its activation are discussed here. The first component of complement (Table 1) is a multimolecular complex comprising of one molecule of C1q and the Ca2+-dependent tetramer – C1r-C1s-C1s-C1r – which give rise to the pentameric complex: C1q.C1r2.C1s2 found in plasma. Each molecule within this complex plays a sequential and highly specific role. The role of C1q is to serve as a recognition unit of immune complexes as well as pathogen-associated molecular patterns (bacterial, viral, or parasitic ligands) and modified-self “danger” signals (Cooper 1985; Arlaud et al. 2001). Recognition of any of these signals is then readily translated into a highly specific and orderly intramolecular rearrangement culminating in C1 activation that sequentially sets in motion the classical pathway of complement – the primary mediator of adaptive humoral immunity. Therefore, deficiency in any of the components of C1 results in susceptibility to infections due to failure to activate the classical pathway and eliminate pathogens (Cooper 1985; Arlaud et al. 2001). Not surprisingly therefore, numerous pathogenic microorganisms have evolved an evasive mechanism to avoid destruction by complement using a number of strategies that include molecular mimicry, enzymatic degradation, as well as expression of regulatory proteins that interfere at various steps of complement activation.
Table 1

Components of the C1 complex

Proteins

Mr (kDa)

Chain structure

Mr (kDa) each chain

Plasma concentration (μg/ml)

Chromosomal location

C1q

460

18 (6A,6B,6C)

A = 28 B = 26 C = 24

80–100

1p34–1p36.3

C1ra

86–90

1

86–90

50

12p13

C1sa

80–83

1

80–83

50

12p13

aC1r and C1s circulate in plasma either as a pentamolecular complex with C1q (C1q. C1s-C1r-C1r-C1s) or as a Ca2+ dependent tetramolecular complex – C1s-C1r-C1r-C1s – in the absence of C1q

C1q Structure and Function

Human C1q (460 kDa) is a collagen-like and structurally complex hexameric glycoprotein, which displays a unique “bouquet-of-flowers-like” structure (Fig. 1) when viewed under the electron microscope (Calcott and Muller-Eberhard 1972; Shelton et al. 1972). It is comprised of six globular “heads” or “domains” that are linked via six collagen-like “stalks” to a fibril-like central region resulting in two unique structural and functional domains: the collagen-like region (cC1q) and the globular “head” or domain (gC1q). The C1q molecule (Fig. 1a, b) is made up of three incredibly similar but distinct polypeptide chains – A, B, and C – that are arranged to form six triple helical strands with three peptide chains – A, B, and C – forming one strand (Reid 1985). Within each strand, the A and B chains are linked to each other by a disulfide bond, whereas the C chain – which is associated with the AB chains of a strand through strong non-covalent forces – is disulfide linked to the C chain of an adjacent strand to form a doublet, with three doublets forming an intact C1q molecule (Fig. 1a). Therefore, when analyzed by SDS-PAGE, the typical AB and CC dimers are visualized at approximately 58 and 48 kDa, respectively, and upon reduction, the individual A, B, and C chains fall apart and migrate with an apparent molecular weights of 28, 25, and 24 kDa, respectively (Fig. 1c). The three chains are the product of three distinct genes, which are highly clustered and aligned 5′⇒ 3′, in the same orientation, in the order A-C-B on a 24 kb stretch of DNA on chromosome 1p (Table 1) (Sellar et al. 1991). The assembly of C1q in a 1:1:1 from its three chains therefore requires precisely synchronized transcription of the three C1q genes.
Fig. 1

The intact C1q molecule (b) is assembled from 18 individual chains (6A, 6B, and 6C). The chains are organized to form six individual strands (a), and each strand is comprised of single A, B, and C chains. In each strand, the A chain is disulfide linked to the B chain, whereas the C chain is disulfide linked to the C chain of a neighboring strand to form a doublet (a). The figure in (c) depicts the SDS-PAGE migration profile of C1q purified from serum. The left lane (−DTT) shows the AB (~58 kDa) and CC (~48 kDa) dimers under nonreducing conditions, and the right lane (+DTT) shows individual A (~28 kDa), B (~25 kDa) and C (~24 kDa) chains under reducing conditions

The crystal structure of the trimeric gC1q signature domain reveals a compact jellyroll β-sandwich fold similar to that of the multifunctional tumor necrosis factor (TNF) ligand family (Shapiro and Scherer 1998; Gaboriaud et al. 2007) suggesting that C1q arose by divergence from a primordial recognition molecule of the innate immune system. The evolutionary connection between C1q-like proteins and TNFs, which control many aspects of inflammation, adaptive immunity, apoptosis, and energy homeostasis, not only illuminates the shared diverse functions of these two important groups of molecules but also explains why C1q has retained some of its ancestral “cytokine-like” activities (Shapiro and Scherer 1998).

Although C1q is capable of binding to a plethora of membrane proteins to induce various cellular functions, there are nonetheless two distinct, well-characterized cell surface proteins with affinity for either the collagen domain (cC1qR) or the globular head region (gC1qR/p33) (Ghebrehiwet et al. 2001). However, because subsequent studies have shown that cC1qR shares sequence identity with calreticulin (CR), it is also referred to as cC1qR/CR.

As a classical pattern recognition molecule with unique ability to sense a wide variety of targets, C1q can engage a broad range of repeating molecular patterns via its heterotrimeric gC1q domain including pathogen surfaces and altered self-structures including nascent ligands expressed on apoptotic cells (Gaboriaud et al. 2007; Païdassi et al. 2008). This in turn leads to enhanced phagocytosis, to target cell lysis as well as, to generation of inflammatory signals. Although C1q is able to bind to diverse self and nonself structures with either its cC1q or gC1q domains, it is the multivalence gC1q domains that characterize its unique versatility and diversity (Gaboriaud et al. 2007).

Pathological Disorders Associated with C1q Deficiency

In addition to its traditional role in the classical pathway of complement activation, C1q has also has emerged as a critical catalyst in an expanding list of pathological disorders that includes sepsis, meningitis, pneumonia, as well as autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus (SLE). SLE is a prototype of a systemic autoimmune disease, which affects close to 750,000 individuals in the USA and a much higher number worldwide with a frequency that varies by race and ethnicity with higher rates reported among Black and Hispanic people (Lahita 1999). Although it is a rare multifactorial disease characterized by chronic or episodic inflammation in several organ systems, there is convincing clinical evidence, which shows that homozygous deficiency in any of the classical pathway proteins – C1q, C1r, C1s, as well as C4 and C2 – is a predictor for SLE (Pickering et al. 2000). Among these proteins however, C1q takes center stage in relevance as homozygous deficiency or hereditary deficiency due to mutation in the C1q gene has been shown to be a powerful susceptibility factor for the development of SLE. The most frequent mutation (Table 2) is in the Achain of C1q in which a substitution in the messenger RNA of C at position 2687 by T results in a stop codon (Skattum et al. 2011). In another patient, a loss of Taq I restriction site within the B chain at the position coding for residue 150 also resulted in the termination codon (McAdam et al. 1988). Therefore, on the basis of data accumulated to date, the most probable cause of genetic deficiency in C1q appears to be point mutations in the A, B, or C genes thereby preventing a normal assembly of the C1q molecule. Regardless, the vast majority of the known individuals (≤100 reported to date) with C1q deficiency are known to have developed clinical syndromes closely related to SLE. Although individuals with congenital complement deficiency constitute only a small cohort of all human SLE, this strong association implicates an important role for C1q in the regulation of SLE.
Table 2

Genetic C1 deficiency and disease association

Protein

Inherited deficiency

Frequently found mutation

Disease association

C1q

Autosomal recessive

g2687C to T➔ stop codon

SLE, recurrent bacterial infections, pneumonia, sepsis, and cancer

C1r

Autosomal recessive

Not known

SLE, bacterial infections, rhinobronchitis, impaired immune adherence

C1s

Autosomal recessive

Mutation in exon 6 at position 938

SLE, bacterial infection, impaired immune adherence

Recent studies also reveal that C1q can enhance chemotaxis, modulate angiogenesis, and regulate trophoblast migration (Ghebrehiwet et al. 2012). Deficiency in C1q therefore would result in pathological disorders in which these functions are relevant. These include preeclampsia (Hong et al. 2009), Alzheimer’s disease (Stephan et al. 2013) and cancer (Singh et al. 2011). For example, pregnant C1q-/-mice have been shown to reproduce the key features of human preeclampsia that correlate with increased fetal death. Treatment of the C1q-/- mice with the cholesterol-lowering drug, pravastatin, prevented the onset of preeclampsia by apparently restoring trophoblast invasiveness, placental blood flow, and angiogenic balance (Hong et al. 2009). Another disease in which the role of C1q has been slowly taking center stage is Alzheimer’s disease. Age-related cognitive decline is caused by an impacted neuronal circuitry. Recent studies, which show that C1q levels increase by as much as 300-fold in the normal aging mouse and human brain, would suggest that C1q is involved in triggering an immune attack against the synapses (Stephan et al. 2013). Most significantly, the concentration of C1q was predominantly localized in close proximity to synapses in regions of the brain such as the hippocampus, substantia nigra, and piriform cortex, which have been identified to be vulnerable in neurodegenerative diseases. In contrast, aged C1q-deficient mice exhibited significantly less cognitive and memory decline as evidenced by certain hippocampus-dependent behavior tests compared with their wild-type littermates (Stephan et al. 2013).

Previous experimental data have also suggested that C1q plays a role in suppression of tumor cell proliferation (Ghebrehiwet et al. 2012). The mechanistic underpinning of this function was intimated by recent observations, which showed that C1q induces apoptosis of prostate cancer cells by activating the tumor suppressor molecule WW domain containing oxidoreductase (WWOX or WOX1) and destabilizing cell adhesion. Conversely, downregulation of C1q enhanced prostate hyperplasia and cancer formation due to failure of WOX1 activation (Hong et al. 2009). These are only few examples of a long list of disorders in which C1q is directly or indirectly involved in triggering or contributing to the pathology.

Structure and Pathological Disorders Associated with C1r and C1s Deficiency

As described above, C1r and C1s are the first proteases responsible for setting in motion the downstream events that occur during activation of the classical pathway. The two proteins, which are modular serine proteases located on human chromosome 12p13 (Tables 1 and 2), form a calcium-dependent tetramer, C1s-C1r-C1r-C1s, and circulate in plasma either as a pentameric complex in association with C1q or as an independent tetramer in the absence of C1q. Both C1r and C1s display remarkably similar structural organization in that both are single-chain zymogens (Fig. 2) of approximately 83–90 kDa and upon activation – which involves cleavage of a single Arg-Ile bond – each is converted to a single chain comprised of a non-catalytic A chain of approximately 56–60 kDa single-chain protease disulfide-bonded to a catalytic B chain of approximately 27–30 kDa. Starting from the N-terminus, the structural organization of the two proteases is identical and comprises of several distinct modules that include CUB, EGF, and CCP modules (Fig. 2). Within macromolecular C1, the C1s-C1r-C1r-C1s tetramer is located between the collagen-like arms of C1q and adopts a “figure 8”-type configuration in a manner that allows contact of the catalytic domains of C1r and C1s (Fig. 3). Such configuration facilitates cleavage of C1s by C1r (Arlaud et al. 2001). The conversion of C1r to an active protease is the first step in the initiation of the classical pathway. Although the mechanism is not well known, it is believed that recognition of an activator by C1q induces a conformational change within the pentameric C1 that allows autocatalytic activation of C1r, and activated C1r then cleaves proenzyme C1s into a disulfide-linked single-chain enzyme (Fig. 2). The natural substrates of C1s are C4 and C2, which are sequentially cleaved into C4a and C4b and C2a and C2b, respectively, with the larger fragments forming the major C3-converting enzyme – C4b-C2a – that sets in motion the classical pathway of complement.
Fig. 2

The structure of C1r and C1s is almost identical and consists of two CUB (C1r/C1s, Uegf and bone morphogenetic protein-1 type protein), EGF (epidermal growth factor), and CCP (complement control protein) modules, in the order depicted (a). In both cases, enzymatic activation involves cleavage of a single Arg-Ile bond (b) with the catalytic domain located in the C-terminal fragment of the disulfide-linked single chain (Adapted from Arlaud et al. 2001)

Fig. 3

The C1 complex is made up of C1q and the C1s-C1r-C1r-C1s tetramer positioned between the arms of the C1q molecule in a manner that allows contact of the catalytic domains of C1r and C1s to each other. This positioning is presumed to facilitate cleavage of C1s by C1r

Although the primary site of synthesis for both C1r and C1s is the liver, both are also synthesized by a vast array of tissues and cell types (Ghebrehiwet et al. 2012). Deficiency in either C1r (Day et al. 1971) or C1s (Amano et al. 2008) is relatively rare with fewer than 20 cases reported to date, and because of their shared chromosomal localization, deficiency of C1r will almost certainly result in deficiency in C1s. A mutation at position 938 in exon 6 of the C1s cDNA has been shown to create a premature stop codon generating splice variants of C1s mRNA transcripts in normal human cells (Amano et al. 2008). The splice variants are derived from the skipping of exon 3 and from the use of an alternative 3′ splice site within intron 1 which increases the size of exon 2 by 87 nucleotides (Amano et al. 2008). Because of their close association and interdependent function within the C1 complex, deficiency in C1q or in either of the proteases will result in susceptibility to infections including sepsis, meningitis pneumonia, defective immune responsiveness, and increased risk of autoimmune disorders including SLE.

Diagnosis and Treatment of Diseases Associated with C1 Deficiency

Routine screening for complement deficiency by measurement of CH50 – which measures functional activity of complement – should provide an initial indication of whether an individual has normal, low, or absent CH50. While low levels of CH50 may indicate ongoing consumption due to infection, the absence of CH50 would almost invariably indicate complete deficiency in any of the components shared by all the pathways, i.e., classical, alternative, or lectin. Therefore, further screening should be tailored on the basis of the disease that the patient is suspected of having. For example, a patient while suspected SLE or rheumatoid arthritis could be screened for C1 deficiency, meningitis or sepsis could be due to deficiency in C3 or C9.

Because deficiency in the early complement components would almost invariably predispose one to upper respiratory infections or autoimmune diseases, and there is no treatment for C1 deficiency to date, prophylactic treatment with antibiotics or vaccinations against associated infections (e.g., meningococcal or H. influenza) is recommended for C1 deficient individuals.

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© Springer Science+Business Media LLC 2016

Authors and Affiliations

  1. 1.The Department of MedicineStony Brook UniversityNew YorkUSA
  2. 2.Health Sciences CenterStony Brook University School of MedicineNew YorkUSA

Section editors and affiliations

  • Kathleen Sullivan
    • 1
  1. 1.University of PennsylvaniaPhiladelphiaUSA