Complement: Deficiency Diseases

Abstract

The complement system is crucial for defence against pathogens, removal of unwanted materials such as dying cells or immune complexes as well as for development of adaptive immune responses. Genetically determined deficiencies of components of the complement system are usually relatively rare but they result in many severe diseases such as an increased susceptibility to recurrent, severe infections, autoimmune disorders (systemic lupus erythematosus), glomerulonephritis including membranoproliferative glomerulonephritis type II, paroxysmal nocturnal haemoglobinuria or angioedema. Recently, mutations and polymorphisms in complement proteins, particularly complement inhibitors, have been associated with atypical haemolytic uremic syndrome and age‐related macular degeneration. The elucidation of the pathophysiological basis for the different clinical presentations of complement‐deficient individuals has contributed to a better understanding of the physiological role of complement in normal individuals as well as to the development of emerging therapies. Key Concepts The majority of complement deficiencies are rare but cause severe diseases. Deficiencies of the early components of the classical pathway (C1q/r/s, C4, C2) predispose to systemic lupus erythematosus. The majority of complement deficiencies predispose to infections either with Neisseria species (deficiency of Factor D, Properdin, C5, C6, C7, C8, C9) or Gram‐positive bacteria (C1q/r/s, mannose‐binding lectin, C2, C4, C3, factor I). Mutations in C1q/r/s, C2, C4, C3 and factor I can cause glomerulonephritis. Paroxysmal nocturnal haemoglobinuria is caused by deficiency of complement inhibitors CD55 and CD59. Hereditary angioedema is found in patients with dysfunctional C1‐inhibitor. Atypical haemolytic uremic syndrome is mainly associated with mutations and polymorphisms in complement inhibitors. Age‐related macular degeneration is associated with polymorphisms in complement inhibitor factor H.

Four Aspects of Autoimmunity and How to Regain Tolerance to Self From an Autoimmune Disease Utilizing the Modified Vaccination Technique

“…);  presentation of modified self aags or exogenous self-like ags to dendritic cells prior to antigenic information being processed by T and B cells for plasma cells to produce pathogenic IgG aabs;  regulatory molecules (cytokines, chemokines, etc.) attempting to accelerate or decelerate autoimmune processes;  complement systems or components playing dominant roles in aag and aab reactions during an autoimmune disease (in both pathogenic and non-pathogenic immune responses) (Blom, 2010): a. assisting in the complement-dependent clearance of modified/unmodified self that causes the autoimmune disease (Gaipl et al, 2001;Taylor et al, 2000;Zwart et al, 2004); b. in contributing to the continuously layered aag/aab depositions, e.g. in the glomeruli (Barabas et al, 2003;Barabas et al, 2004b;Barabas et al, 2004c) (pathogenic immune response) causing complement mediated C3, C 5 9 b injury (Barabas et al, 2003;Barabas et al, 2004c) resulting in compromised glomerular filtration;  overwhelming infection by an infectious agent presenting a whole range of potentially antigenic peptides that may initiate autoimmune disease by molecular mimicry;  environmental factors;  potentially self reactive clones of T cells can react with self because of immune regulation failure;  in a few instances self ags can act to initiate and maintain pathogenic autoimmune responses against self, e.g.…”

The odd couple: A fresh look at autoimmunity and immunodeficiency

“…Inherited complement deficiencies predispose to autoimmune rheumatic diseases and angioedema as well to susceptibility to infections (Jerry Winkelstein, Johns Hopkins University, Baltimore, MD) [33]. Since there is linkage disequilibrium of complement genes with MHC genes, there can be coinheritance of genes for immunodeficiency and for autoimmune disease.…”

“…Phenotypes in complement-deficiency states include particularly SLE or other multisystem/vasculitic autoimmune diseases, membranous-proliferative glomerulonephritis type II (MPGM II), and defective host defense against bacterial (often neisserial or pyogenic) infections and to a lesser extent virus infections [33]. Mechanisms for disease in genetically determined C' deficiencies include defective clearance of immune complexes or apoptotic cells, and defective antibody-dependent anti-microbial activities.…”