Complement deficiencies

Diseases

Overview

Summary

Complement proteins moderate the actions of specific antibodies, aid the processing and removal of immune complexes, and modify T-cell and B-cell responses.

Complement deficiencies can be inherited, or acquired. Acquired complement deficiencies may occur as a result of infection (e.g., recurrent meningococcal or disseminated gonococcal infection) or in conjunction with chronic rheumatologic or autoimmune disease (e.g., systemic lupus erythematosus or cryoglobulinemia).

Diagnosis is based on clinical and/or family history and characteristic serological and molecular findings; only a few specialized laboratories provide comprehensive diagnostics.

Suspicious presentations include meningococcal meningitis in individuals over the age of 5 years, recurrent bacterial infections, angioedema without urticaria, inflammatory disorders of the renal and ophthalmic system, and autoimmune manifestations.

Introduction

Complement plays a key role in host microbial defense. It complements the actions of specific antibodies and aids the processing and removal of immune complexes.[1] [2] [3] [4] It also modifies T-cell and B-cell responses by employing specific receptors found on various immune cells to modulate adaptive immune response.[4] The complement system participates in hematopoiesis, lipid metabolism, reproduction, and tissue regeneration.[3] Multiple interactions connect complement to the clotting, fibrinolysis, and kinin systems.[5] Due to its powerful inflammatory potential, multiple regulatory proteins are necessary to prevent potential tissue damage.

When overactive, the complement system can cause several inflammatory and life-threatening conditions, including sepsis, systemic inflammatory response syndrome, acute respiratory distress syndrome, and multiorgan failure after severe trauma, burns, or infections.[6] It is implicated in severe nephropathies as well as in neurodegenerative disorders, such as Alzheimer disease, Guillain-Barré syndrome, and multiple sclerosis.[7] [8] [9] [10] An overactivated complement system has also been recognized as a significant effector mechanism of reperfusion injury. Organ dysfunction may be caused by the inflammatory response induced by artificial surfaces in hemodialysis and extracorporeal circuits.[11] In these cases, this may lead to transient neutropenia, pulmonary vascular leukostasis, and more rarely, anaphylactic shock.

Disease states occur with deficiencies in complement proteins or defects of factors controlling, focusing, and limiting complement activation.[12] [13] [14] [15] [16] Complement deficiencies can be inherited or acquired (secondary to a complement-consuming disease state). Complement deficiencies may increase the risk of invasive bacterial infections and/or be associated with autoimmune disease.

Complete defects have been described for all complement proteins except serum carboxypeptidase N. Secondary deficiencies result from complement consumption as a result of inflammation, autoantibodies (e.g., C3/C5 nephritic factors; and autoantibodies against C1q, C1-inhibitor, or factor H), decreased synthesis, and/or increased catabolism or protein loss syndromes. Gain-of-function variants of certain complement components (e.g., C3, C2) have been identified and associated with complement overactivation in certain forms of nephropathies.[17] [18]

Complement deficiency states and associated features

Components
- C1q: systemic lupus erythematosus (SLE)-like (occurs in >90% of patients with C1q deficiency), infections
- C1r/s (mostly combined): SLE-like, rheumatoid arthritis (RA), infections
- C4 (C4A, C4B): SLE-like, infections (homozygous: usually clinically apparent; heterozygous: often clinically inapparent)
- C2: SLE-like, RA, infections (pneumonia), vasculitis; often clinically inapparent
- C3: pyogenic infections
- C5: meningitis (Neisseria), SLE
- C6: meningitis (Neisseria), SLE
- C7: meningitis (Neisseria), SLE
- C8 alpha-gamma/C8 beta: meningitis (Neisseria), SLE
- C9: neisserial infections (mostly asymptomatic)
- Factor B: neisserial infections
- Factor D: neisserial infections
- Mannose-binding lectin (MBL): bacterial infections (mostly asymptomatic)
- Ficolin 3 (H-ficolin): respiratory infections, necrotizing enterocolitis
- MBL-associated serine protease 2 (MASP-2): respiratory infections.
Regulators
- C1-inhibitor: hereditary angioedema
- Properdin: meningitis (Neisseria)
- Factor H: infections, atypical hemolytic uremic syndrome (aHUS)/C3 glomerulopathy (C3G), aHUS, C3G/membranoproliferative glomerulonephritis (MPGN)
- FHR1 (FHR3): aHUS, RA, SLE (often associated with antifactor H autoantibodies and deficiency of CFHR [complement factor H-related] proteins, causing susceptibility to autoantibody-mediated aHUS)
- Factor I: infections (sepsis, meningitis, pneumonia), aHUS
- CD46/MCP (membrane cofactor protein): aHUS
- CD55/DAF(decay accelerating factor): severe enteropathy (protein-losing enteropathy), paroxysmal nocturnal hemoglobinuria (somatic mutation of PIGA gene)
- CD59: Guillain-Barré syndrome-like symptoms, hemolysis, paroxysmal nocturnal hemoglobinuria (somatic mutation of PIGA gene).
Receptors
- CR3 (CD18/CD11b): leukocyte adhesion deficiency
- CR4 (CD18/CD11c, LFA-1): leukocyte adhesion deficiency.

Complement physiology

The complement system comprises more than 50 complement proteins, including individual components of the cascade system, regulatory factors (many of which are cell-surface restricted), and receptors. They are present in plasma and other body fluids, and may also exert essential intracellular immune modulatory functions.[19]

Complement genes are distributed across different chromosomes.[20]

Most complement proteins are secreted by the liver and form part of the acute phase response. Other tissues (e.g., kidney, brain) are also able to produce complement proteins, such as fatty cells for factor D (adipsin). Certain complement components are proteases, which, on activation, cleave the next complement protein in the cascade sequence. The sequence of amplification steps shows similarities to that of the blood coagulation cascade.

The complement cascade can be activated by 3 main routes: the classical pathway (CP), the alternative pathway (AP), and the lectin pathway (LP).[1]Image

The CP serves as a key effector function of specific antibody responses, whereas the AP and LP, as part of the innate immune system, are important in first-line antibody-independent defense against bacterial infection. The terminology of the complement system components relates to the sequence in which they were discovered, which explains why the cascade is not arranged in a logical numeric order. Component proteins and regulators of the AP are called factors (e.g., factor B, factor H).

CP activation is primarily initiated by antibody (immunoglobulin)-derived mechanisms. The fragment crystallizable (Fc) regions of IgM and IgG antibodies (but not IgA) become structurally altered (e.g., when bound to a specific antigen within an immune complex or within a cryoglobulin). The CP is activated when C1 binds to the Fc region via its C1q moiety.

In the absence of antibodies, target-bound C-reactive protein (CRP) can also bind to C1q and activate the CP. The LP is initiated by the binding of ficolins and mannose-binding lectin (MBL, a well known opsonin and an acute phase reactant with structural similarities to C1q) to carbohydrate residues on pathogens and altered tissues. Similar to the C1 complex, MBL-carbohydrate binding leads to the activation of MBL-associated serine proteases (MASPs) that, like C1s, are able to cleave C4 and C2, thereby connecting the LP to the CP. By contrast with the CP, the AP is activated mainly by non-antibody (non-immunoglobulin) mechanisms. Permanent low-grade hydrolysis of C3 (C3[H₂O]) leads - upon binding of factor B and subsequent cleavage by factor D - to the generation of a fluid phase C3-convertase (C3b[H₂O]Bb), which is stabilized by properdin. In healthy states this activity is self-limited; however, if newly-cleaved C3 binds to pathogens or altered tissue, the AP response is amplified. The regulatory potential of the targeted cells determines whether a C3 convertase is formed on the surface, opsonization occurs, and the cascade reaction is continued.

Once complement is activated by any of these pathways, enzyme complexes (C3 convertases) are generated that cleave C3 into 2 fragments (C3a and C3b). C3a is the smaller fragment. Like C5a, which is generated later, C3a is a pro-inflammatory signaling molecule (anaphylatoxin). Anaphylatoxins are chemoattractants. They recruit and activate multiple inflammatory cells, including neutrophils and mast cells. Receptors for C3b and its metabolic product iC3b on phagocytic cells allow removal of the opsonized targets. Potentially pathologic immune complexes (containing antibody complexed with viral, bacterial, or autoantigens) activate the CP and C3b, which flags them for removal from the circulation by C3b-receptor-carrying erythrocytes and disposal by phagocytic cells in the reticuloendothelial system. Upon C3b binding to the C3 convertase, a C5 convertase is generated that cleaves C5 into C5a and C5b. C5b together with C6, C7, C8, and multiple C9 molecules generate the lipophilic membrane attack complex (MAC), C5b-9, causing target cell death by cell membrane lysis.

Multiple regulatory proteins are necessary to ensure that potential complement-mediated tissue damage is prevented or at least limited.[21] Factor H and factor I regulate the AP, whereas C1-inhibitor (C1-INH) and C4 binding protein (C4bp) control the CP and LP.

C3 convertases are inherently unstable, with short half-lives, which helps limit and control complement activation. Membrane cofactor protein, also known as MCP or CD46, and decay accelerating factor, also known as DAF or CD55, control C3 activation on the cell surface. Excess MAC-mediated complement lysis is prevented by the soluble inhibitors clusterin and vitronectin, and the membrane-associated MAC-inhibitory protein (CD59).Image

Inherited complement deficiencies

There are a number of inherited complement deficiencies:

Classical pathway: C1q, C2, C4 deficiency
Alternative pathway: factor B, factor D deficiency
Lectin pathway: MBL, MASP2 deficiency
C3 deficiency
C5, C6, C7, C8, C9 deficiency
Regulators: C1-inhibitor, factor H, factor I, properdin, CD46, CD55, CD59 deficiency.

Epidemiology

Complement deficiencies represent approximately 3% to 5% of all primary immunodeficiencies, but may be as high as 10%.[22] European Society for Immunodeficiencies (ESID) reporting website and interactive reporting tool Inherited complement deficiency has been calculated to have a prevalence of about 0.03%, excluding mannose-binding lectin (MBL) deficiency, which is estimated to occur in about 5% of the general white population.[22] However, as with all inborn errors of immunity/primary immunodeficiencies, a significant number of patients with complement deficiency probably remain undiagnosed due to limited clinical and laboratory experience of the conditions. The most frequent complement deficiencies affect C2 and MBL, which most often remain clinically silent.

The incidence of hereditary angioedema (Quincke edema) with C1-inhibitor deficiency (C1-INH-HAE) is estimated as approximately 1:50,000.[23] [24] However, complement protein deficiencies are significantly more common in people with specific diseases. In systemic lupus erythematosus, 30% of patients have a pre-existing complement deficiency and in individuals with disseminated Neisseria infections it is thought to be around 20%.[25] [26] [27] [28] [29]

Images

Complement cascade: activation and regulation. Complement is activated via three pathways, the classical, the alternative, and the lectin pathways. This results in: (1) the generation of various pro-inflammatory peptides, which bind to specific receptors on multiple immune cells, as well as (2) the assembly of the membrane attack complex, C5b-9 (MAC). On each level of the cascade reaction, complement is tightly regulated by soluble and membrane-associated inhibitors. Key: C1-INH = C1 inhibitor; C4bp = C4 binding protein; CPN = carboxypeptidase N; DAF = decay accelerating factor; MAC = membrane attack complex; MASP = MBL-associated serine protease; MBL = mannose-binding lectin; MCP = mebrane cofactor protein

Citations

Key Articles

Schröder-Braunstein J, Kirschfink M. Complement deficiencies and dysregulation: Pathophysiological consequences, modern analysis, and clinical management. Mol Immunol. 2019 Oct;114:299-311.[Abstract]
Grumach AS, Kirschfink M. Are complement deficiencies really rare? Overview on prevalence, clinical importance and modern diagnostic approach. Mol Immunol. 2014 Oct;61(2):110-7.[Abstract]
Maurer M, Magerl M, Betschel S, et al. The international WAO/EAACI guideline for the management of hereditary angioedema-The 2021 revision and update. Allergy. 2022 Jul;77(7):1961-90.[Abstract][Full Text]
Brodszki N, Frazer-Abel A, Grumach AS, et al. European Society for Immunodeficiencies (ESID) and European Reference Network on Rare Primary Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN RITA) complement guideline: deficiencies, diagnosis, and management. J Clin Immunol. 2020 May;40(4):576-91.[Abstract][Full Text]

Other Online Resources

European Society for Immunodeficiencies (ESID) reporting website and interactive reporting tool
European diagnostic complement labs

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