C1QB

The complement system is a crucial component of the innate immune response, composed of over 30 proteins that act in concert to defend the body against infections, promote inflammation, and clear apoptotic cells. It is divided into three major pathways: the classical pathway, the alternative pathway, and the lectin pathway, all of which converge on a common terminal pathway leading to the formation of the membrane attack complex (MAC). Central to the classical pathway is the C1 complex, which consists of three subunits: C1q, C1r and C1s. Of these, C1q is a key molecule because it initiates the classical pathway by binding to antibodies or pathogen-associated molecular patterns (PAMPs). C1q is composed of three distinct chains: C1qA, C1qB and C1qC. Each chain plays a critical role in the functionality of C1q, and their molecular interactions are essential for the initiation of immune responses. The C1QB gene encodes the B chain of C1q, and its unique structural and functional properties position it as a promising target for drug development, particularly in the context of immune modulation and autoimmune diseases.

NCBI Gene ID: 713

UniProtKB ID: P02746

Structure and Function of C1QB

The C1q complex is a crucial initiator of the classical complement pathway, and its structure has been extensively studied. C1q is composed of six subunits, arranged in three heterotrimers, each containing one A, one B, and one C chain. These chains are characterized by a long, collagen-like region and a globular head domain. The C1qB chain, in particular, is integral to the function of C1q, as it contributes to the recognition of antigen-antibody complexes, which is a key event in the initiation of the classical complement cascade.

The C1qB chain consists of approximately 200 amino acids and is characterized by an extended triple helix in the collagen-like region and a globular head at the C-terminal end. The globular head contains the binding sites for C1r and C1s, the serine proteases that, upon activation, cleave and activate subsequent complement proteins. This structural organization is critical for target recognition and subsequent activation of the complement cascade.

Figure 1. Structural organization of the C1q molecule. C1q (460 kDa) is composed of 18 polypeptide chains. (a) The A, B and C chains each have a short N-terminal region, followed by a collagen region (CLR) of w81 residues and a C-terminal globular region (gC1q domain) of w135 residues. (b) The interchain disulfide bonding yields 6A–B dimer subunits and 3C-C dimer subunits. The triple-helical collagen region in the A and B chains of an A–B subunit, together with one of the C-chains present in a C–C subunit, form a structural unit (ABC–CBA), which is held together by both covalent and non-covalent bonds (c). Three of these structural units associate, via strong non-covalent bonds in the fibril-like central portion, to yield the hexameric C1q molecule that has a tulip-like structure (d). The crystal structure of the gC1q domain of human C1q (Protein Data Bank code 1PK6, depicted as a ribbon diagram of ghA in blue, ghB in green, ghC in red, with the calcium ion shown as a yellow ball), has revealed a compact, spherical, heterotrimeric assembly (50 A diameter), held together predominantly by non-polar interactions, with non-crystallographic pseudo-threefold symmetry (e). The three gC1q modules show clear differences in their electrostatic surface potentials, which in part explains modularity in terms of ligand recognition. (Kishore et al., 2004)

Functionally, the primary role of C1qB is to facilitate recognition of immune complexes formed when antibodies bind to antigens on the surface of pathogens or damaged cells. Upon binding, C1q activates C1r and C1s, leading to the cleavage of C4 and C2 proteins. This process ultimately leads to the formation of the enzyme C3 convertase, which cleaves C3 into C3a and C3b. C3b is a central component of the complement system, mediating opsonization of pathogens and formation of MAC, which induces lysis of the target cell. Thus, the function of C1qB, through its role in activating the classical pathway, is essential for both innate immune defense and immune regulation.

The Role of C1QB in Immune Responses

C1q, and by extension C1qB, is critical for the immune response to a wide range of pathogens, including bacteria, viruses and fungi. It also plays an important role in clearing apoptotic cells and maintaining immune tolerance. However, dysregulation of C1q function has been implicated in a variety of autoimmune and inflammatory diseases.

• Immune Defense and Pathogen Clearance: The classical complement pathway, activated by C1q, is essential for the recognition and neutralization of pathogens. Upon binding to pathogen-associated molecular patterns (PAMPs) or immune complexes, C1q facilitates activation of the downstream complement cascade, leading to generation of C3b and formation of MAC. This promotes opsonization of the pathogen and subsequent phagocytosis by immune cells. In addition, the MAC induces direct lysis of target cells, further contributing to pathogen clearance.
• Clearance of Apoptotic Cells: One of the critical roles of C1q is the clearance of apoptotic and necrotic cells. C1q binds to specific markers on dying cells and promotes their recognition by macrophages and dendritic cells. This process is essential for maintaining tissue homeostasis and preventing the accumulation of cellular debris that can lead to chronic inflammation and autoimmune responses. Impaired clearance of apoptotic cells has been implicated in the development of autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).
• Regulation of Immune Tolerance: In addition to its pro-inflammatory functions, C1q also plays a regulatory role in maintaining immune tolerance. By clearing apoptotic cells, C1q prevents the release of intracellular autoantigens that could otherwise trigger autoimmune responses. In addition, C1q has been shown to modulate the function of dendritic cells and T lymphocytes, promoting the development of regulatory T cells (Tregs) and inhibiting excessive inflammatory responses.

Figure 2. The interaction of macrophages with complement. Innate immune pattern recognition receptors C1q, MBL, and ficolins recognize a number of structures including immune complexes, damaged-self molecules expressing damage associated molecular patterns (DAMPS), apoptotic cells (ACAMPs), and pathogens (PAMPs), leading to activation of classical and lectin pathways, respectively, and amplification via the alternative pathway. (Bohlson et al., 2014)

C1QB and Disease Pathogenesis

The involvement of C1q and its components in disease pathogenesis has been well-documented in various autoimmune, inflammatory, and infectious diseases. The C1qB chain, as part of the C1q complex, plays a critical role in these processes.

• Autoimmune Diseases: One of the most well-established links between C1q and disease is in the context of autoimmune diseases, particularly systemic lupus erythematosus (SLE). SLE is characterized by the formation of autoantibodies against nuclear antigens, which form immune complexes that can be deposited in tissues and induce inflammation. In individuals with C1q deficiency, clearance of these immune complexes is impaired, leading to accumulation of autoantibodies and development of tissue damage. In addition, C1q deficiency has been associated with an increased risk of developing other autoimmune diseases, such as rheumatoid arthritis and vasculitis.
• Age-Related Diseases: The role of C1q in immune regulation is also important in the context of aging. As individuals age, there is a decline in the efficiency of immune clearance, including the clearance of apoptotic cells. This decline has been linked to the development of age-related diseases such as Alzheimer's disease and cardiovascular disease. The accumulation of apoptotic cells and immune complexes in tissues can lead to chronic inflammation, which contributes to the pathogenesis of these diseases.
• Infectious Diseases: C1q also plays a protective role in infectious diseases, where its ability to recognize and bind to pathogens is critical for immune defense. However, some pathogens have evolved mechanisms to evade complement activation, which can lead to persistent infections. For example, in certain viral infections, C1q has been shown to interact with viral particles and contribute to their neutralization. Deficiency of C1q or other components of the complement system may impair the immune response to these pathogens.

C1QB as a Drug Target

Given its central role in the immune response and disease pathogenesis, C1q, particularly C1qB, represents a promising therapeutic target. Targeting C1q offers several potential strategies to modulate the complement system in a range of diseases, from autoimmune to infectious diseases.

• Inhibition of C1q in Autoimmune Diseases: One of the most compelling therapeutic applications of C1q inhibition is in the treatment of autoimmune diseases. In diseases such as lupus, excessive complement activation contributes to tissue damage, and inhibition of C1q could reduce inflammation and prevent tissue injury. Strategies to inhibit C1q function could include the use of monoclonal antibodies or small molecules that disrupt the interaction between C1q and immune complexes. Clinical trials evaluating the efficacy of complement inhibitors, such as eculizumab (a monoclonal antibody that inhibits C5), have shown promise in treating conditions such as paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome, which are characterized by excessive complement activation.
• Targeting C1q in Age-Related Diseases: In age-related diseases such as Alzheimer's and cardiovascular disease, the accumulation of apoptotic cells and immune complexes contributes to chronic inflammation. Modulation of C1q activity could reduce this inflammation and slow the progression of these diseases. The development of small molecules or biologics that inhibit C1q binding to apoptotic cells may provide a novel therapeutic avenue for these diseases.
• Enhancement of C1q Activity in Infectious Diseases: Conversely, in the context of infectious diseases, enhancing C1q function could enhance the immune response to pathogens. This could be achieved by developing therapies that promote the binding of C1q to pathogens or immune complexes, thereby enhancing complement-mediated pathogen clearance. However, such therapies would need to be carefully regulated to avoid excessive inflammation and tissue damage.

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References

1. Bohlson SS, O'Conner SD, Hulsebus HJ, Ho MM, Fraser DA. Complement, c1q, and c1q-related molecules regulate macrophage polarization. Front Immunol. 2014;5.
2. Chen LH, Liu JF, Lu Y, He XY, Zhang C, Zhou HH. Complement C1q (C1qA, C1qB, and C1qC) may be a potential prognostic factor and an index of tumor microenvironment remodeling in osteosarcoma. Front Oncol. 2021;11.
3. Kishore U, Gaboriaud C, Waters P, et al. C1q and tumor necrosis factor superfamily: modularity and versatility. Trends in Immunology. 2004;25(10):551-561.