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The Immunopathology of Complement Proteins and Innate Immunity in Autoimmune Disease

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Abstract

The complement is a powerful cascade of the innate immunity and also acts as a bridge between innate and acquired immune defence. Complement activation can occur via three distinct pathways, the classical, alternative and lectin pathways, each resulting in the common terminal pathway. Complement activation results in the release of a range of biologically active molecules that significantly contribute to immune surveillance and tissue homeostasis. Several soluble and membrane-bound regulatory proteins restrict complement activation in order to prevent complement-mediated autologous damage, consumption and exacerbated inflammation. The crucial role of complement in the host homeostasis is illustrated by association of both complement deficiency and overactivation with severe and life-threatening diseases. Autoantibodies targeting complement components have been described to alter expression and/or function of target protein resulting in a dysregulation of the delicate equilibrium between activation and inhibition of complement. The spectrum of diseases associated with complement autoantibodies depends on which complement protein and activation pathway are targeted, ranging from autoimmune disorders to kidney and vascular diseases. Nevertheless, these autoantibodies have been identified as differential biomarkers for diagnosis or follow-up of disease only in a small number of clinical conditions. For some autoantibodies, a clear relationship with clinical manifestations has been identified, such as anti-C1q, anti-Factor H, anti-C1 Inhibitor antibodies and C3 nephritic factor. For other autoantibodies, the origin and the functional consequences still remain to be elucidated, questioning about the pathophysiological significance of these autoantibodies, such as anti-mannose binding lectin, anti-Factor I, anti-Factor B and anti-C3b antibodies. The detection of autoantibodies targeting complement components is performed in specialized laboratories; however, there is no consensus on detection methods and standardization of the assays is a real challenge. This review summarizes the current panorama of autoantibodies targeting complement recognition proteins of the classical and lectin pathways, associated proteases, convertases, regulators and terminal components, with an emphasis on autoantibodies clearly involved in clinical conditions.

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Abbreviations

AAE:

Acquired angioedema

Abs:

Antibodies

AE:

Angioedema

AP:

Alternative pathway

APS:

Anti-phospholipid syndrome

BD:

Behçet’s disease

C3GN:

C3 glomerulonephritis

C3GP:

C3 glomerulopathy

CP:

Classical pathway

CS:

Complement system

DDD:

Dense deposit disease

aHUS:

Atypical haemolytic uremic syndrome

HAE:

Hereditary angioedema

HCV:

Hepatitis C virus

HIV:

Human immunodeficiency virus

HUV:

Hypocomplementemic urticarial vasculitis

HUVS:

Hypocomplementemic urticarial vasculitis syndrome

LN:

Lupus nephritis

LP:

Lectin pathway

MAC:

Membrane attack complex

MASP:

MBL-associated serine protease

MBL:

Mannose-binding lectin

MPGN:

Membranoproliferative glomerulonephritis

RA:

Rheumatoid arthritis

SLE:

Systemic lupus erythematosus

SS:

Sjögren syndrome

TP:

Terminal pathway

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Authors and Affiliations

  1. Laboratoire d’Immunologie, Pôle de Biologie, CHU Grenoble Alpes, 10217, Cedex 9, 38043, Grenoble, CS, France

    Federica Defendi, Giovanna Clavarino, Jean-Yves Cesbron & Chantal Dumestre-Pérard

  2. Université Grenoble Alpes, CNRS, CEA, IBS, F-38000, Grenoble, France

    Nicole M. Thielens

  3. Université Grenoble Alpes, BNI TIMC-IMAG, UMR5525, CNRS , BP170, Cedex 9, 38042, Grenoble, France

    Giovanna Clavarino, Jean-Yves Cesbron & Chantal Dumestre-Pérard

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Correspondence to Federica Defendi.

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Defendi, F., Thielens, N.M., Clavarino, G. et al. The Immunopathology of Complement Proteins and Innate Immunity in Autoimmune Disease. Clinic Rev Allerg Immunol 58, 229–251 (2020). https://doi.org/10.1007/s12016-019-08774-5

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