J Clin Pathol: first published as 10.1136/jcp.34.11.1214 on 1 November 1981. Downloaded from J Clin Pathot 1981 ;34:1214-1222 Role of circulating immune complexes in renal diseases ROLAND J LEVINSKY From the Department of Immunology, Institute of Child Health, 30 Guilford Street, London WCJ The elimination of a foreign antigen is a function of induced by repeated antigen administration.7 The the antibody, complement and phagocyte systems. most widely quoted experimental model of immune When an immune complex is formed in the circu- complex injury is serum sickness, in which the lation, clearance is effected by cells of the reticulo- animal develops nephritis and vasculitis due to endothelial system. Macrophages and polymorpho- deposition of immune complexes 8-10 days after the nuclear cells have both IgG Fc and C3b complement injection of antigen. When the antigen is still in receptors so that opsonisation by either the classical excess of antibody within the circulation, the small or the alternative pathway of complement activation immune complexes formed remain in solution but facilitates antigen elimination. This system normally can become trapped in vessel walls at sites of provides a most efficient protection against disease, turbulence or at capillary membranes where filtration since man is continually challenged by a variety of occurs. Tissue damage at these sites results from the inhaled and ingested antigens. biological effects of complexes which activate the Why then does a normally protective system complement system, resulting in immune adherence,copyright. become self-damaging, resulting in immune complex polymorph chemotaxis, release of lysosomal pro- disease? It is unlikely that most immune complex teolytic enzymes and kinins, and platelet aggregation. diseases are due to rare or as yet unidentified The latter causes release of vasoactive amines8 which antigens. It is much more likely that host variation in increase vascular permeability and so further immune response to a common antigen resuits in localise complexes to the site of the injury. effective clearance and health in one individual, but If sections of the kidneys are examined at the persistent circulating antigen and immune complex height of injury, the glomeruli show evidence of of with cell disease in another. Increased concentrations nephritis, endothelial swelling and lifting http://jcp.bmj.com/ circulating soluble immune complexes are found in a of the underlying basement membrane. Immuno- variety of diseases; these include systemic lupus fluorescence shows immunoglobulins of different erythematosus, various forms of glomerulonephritis, classesandvariouscomplementcomponents deposited rheumatoid arthritis, and chronic inflammatory in an irregular granular manner along the capillary bowel diseases.' High concentrations of immune basement membrane.9 A similar distribution of complexes are also found in many forms of dis- electron-dense deposits may be shown by electron seminated malignancy2 where it is thought that they microscopy.10 Despite the similarities between may have an enhancing effect on tumour growth, by animal and human nephritis, there is still controversy on September 30, 2021 by guest. Protected preventing the host from mounting an effective about the role of circulating soluble immune immune response to his own tumour.3 complexes in man; indeed in membranous nephro- Paradoxically, immune complexes are also found, pathy and acute poststreptococcal nephritis it may in low concentrations, in the sera of apparently be difficult to demonstrate immune complexes in the healthy people, particularly after food;4 they have circulation, yet the renal biopsies show the classical also been described in normal pregnancy,5 and in granular deposition of immunoglobulins and com- pre-eclampsia.6 The finding of immune complexes plement components. In animals it is possible to in so many different diseases as well as in normal induce local formation of immune complexes within biological states raises the question whether they do glomeruli by the intravenous injection of bacterial indeed play a crucial role in pathological processes. lipopolysaccharide.1" It is certainly possible that in many forms of glomerulonephritis an extrinsic Evidencefor a damaging role ofimmune complexes antigen provokes the initial injury, possibly releasing Much of the evidence comes from animal studies, in hidden self-antigens which elicit an immune response particular those in which chronic nephritis is resulting in the formation of immune complexes at 1214 J Clin Pathol: first published as 10.1136/jcp.34.11.1214 on 1 November 1981. Downloaded from Role of circulating immune complexes in renal diseases 1215 the site of damage. Local formation of complexes or of viruses, bacteria, parasites, moulds and ingested deposition of circulating immune complexes are not food antigens, but some are intrinsic such as DNA, mutually exclusive mechanisms of tissue damage, RNA, immunoglobulins and other proteins. The but it must be emphasised that the mere demonstra- portal of entry for the antigen may be important in tion of soluble immune complexes in the circulation the type of immune response elicited; entry via the does not necessarily mean that they are directly gastrointestinal tract may be morelikely to producean responsible for the disease. IgA antibody response than entry by respiratory or parenteral routes. If the antigen is a virus or a Host factors contributing to variation in susceptibility parasite, its mode of replication within the host and to immune complex disease the subsequent release of reproductive antigenic In human poststreptococcal glomerulonephritis, as material may be important in producing different in serum sickness, the majority of individuals types of immune complexes. recover from the disease rapidly and completely. The different immunoglobulin classes and sub- Only a very small minority develop chronic glom- classes of antibodies impart different biological erulonephritis with ensuing renal failure. Such properties to the immune complexes. Theoretically, variation in immune response to an antigen may be immune complexes may be produced by all the demonstrated in experimental nephritis in rabbits immunoglobulin classes, and some evidence has where only those animals producing non-precipit- been provided for complexes involving IgM, IgG, ating (poor quality) antibody develop chronic IgA and also IgE.22-24 The complement-binding disease; those producing precipitating antibody get characteristic of the immune complex is determined acute nephritis and recover.'2 Oldstone and Dixon'3 by the class of immunoglobulin involved, and the demonstrated that only certain strains of mice were size of the complex depends on factors such as the susceptible to chronic nephritis when infected with antibody :antigen ratio, strength of antibody lymphocytic choriomeningitis virus in the neonatal binding and whether secondary interaction has period. In response to antigen injected in saline, the occurred with rheumatoid factors or immuno- strains of mice to chronic nephritis a human susceptible conglutinin, naturally occurring 1gM copyright. produced lower-affinity antibody-that is, with antibody to activated C3bi. Another factor is the weaker antigen-antibody binding than the nephritis- action of complement in solubilising membrane- resistant animals,'4 suggesting that susceptibility was bound immune complexes.25 genetically determined. Low affinity antibody is poor Thus immune complexes vary not only in the at antigen elimination'5 and is one example of a antigen but also in the immunoglobulin class and defective rather than an overactive immune system subclass, in size, in complement-binding capacity and failing to eliminate antigen and so predisposing to in the antigen:antibody ratio (Fig. 1). All these chronic immune complex disease. There are many features may be important in the localisation of examples in man of immune complex disease with complexes in one organ rather than another, and in http://jcp.bmj.com/ underlying primary immune deficiency-for example, the different syndromes and diseases which result. the higher incidence of juvenile chronic polyarthritis in children with selective IgA deficiency,'6 the (Site of entry ) (Quantity) arthritis complicating hypogammaglobulinaemia,'7 Antgen (Rate of release) (Affinity) Antiby and the increased incidence of diseases such as sys- (Replication) (Subclass) temic lupus erythematosus in people with inherited (Structure ) (Duration) deficiencies of the complement system, in particular on September 30, 2021 by guest. Protected homozygous C2 deficiency.'8 The genetic differences in susceptibility to immune Immune complexes Varying in antigen, antibody class and subclass, size, complex disease in animals is antigen non-specific. It complement binding capacity as well as Ag/Ab ratio is likely that this is true also for man since a common antigen such as hepatitis B can occur in the healthy Solubilisation Local anatomy. carrier state, yet has been incriminated in such dif- by complement permeability factors. ferent diseases as chronic active hepatitis,'9 mem- cell receptors branous nephropathy,20 and polyarteritis nodosa.21 Reticuloendothelial system Tissue deposition capacity and funct ion Factors affecting immune-complexformation, deposition and elimination There are many variables involved in the formation Removal by BES.- of immune complexes. There is the wide variety of Fig. 1 Factors affecting immune complex formation