The role of Fc receptors and complement in autoimmunity

Autoantibodies interact with the innate immune system, including the complement network and Fc receptors (FcRs) bearing effector cells, resulting in the induction of tissue injury. It was suggested that these two pro-inflammatory pathways might mediate distinct effector responses, and that only one or the other effector arm may usually dominate an inflammatory response. Recent studies, however, support the notion that autoantibody-induced tissue injury may depend on both, FcRs and selected pathways of the complement network. This review summarizes our current knowledge on the interactions between autoantibodies, FcRs and complement components as essential triggers of tissue injury in autoimmune diseases like rheumatoid arthritis, anti-glomerular basement membrane glomerulonephritis and subepidermal blistering diseases. Manipulation of these connective pathways might be of therapeutic use to control antibody-mediated autoimmune diseases.     

The role of Fc:Fc interactions in insoluble immune complex formation and complement activation

The initial rate of formation of insoluble immune complexes from rabbit IgG and ovalbumin was approximately 12 times that for formation of F(ab')₂-ovalbumin complexes. At low IgG concns, in the range 0.7–2.7 nM, the formation of insoluble immune complexes was characterised by a lag phase, especially for complexes formed in low antigen excess, compared to antibody excess. Guanidine HC1 (at concns up to 0.5 M) and urea (at concns up to 1 M) decreased the initial rates of formation of IgG immune complexes more than F(ab')₂ immune complexes. Pre-formed IgG immune complexes were solubilised at lower guanidine HC1 concns than were F(ab')₂ immune complexes. Clq enhanced the initial rate of formation of IgG immune complexes at Clq:IgG ratios up to 1:1. Higher Clq concns decreased the initial rate of formation of the complexes. Urea (1 M) blocked the Clq mediated enhancement of immune complex formation.     

Histamine metabolism in the Arthus reaction

Histamine metabolism, i.e., concentration of histamine and activities of histamine-degrading enzymes, histamine-N-methyltransferase (HMT), and diamine oxidase (DAO), were examined in the Arthus reaction induced in guinea pig skin. The specific activity of HMT was 44.12 +/- 3.80 pmole/min/mg protein and was about 15 times greater than that of DAO in control specimens. However, HMT activity decreased time dependently to 35% of the control at 3 hr and to 10% 48 hr after the initiation of the reaction. DAO activity increased to 150% till 1 hr followed by a linear decrease to 35% at 6 hr and to 10% at 48 hr. Histamine concentration showed a prominent linear decrease to 15% of the control at 2 hr followed by an increase to about 85% at 6 hr. This biphasic change seemed to be well explained by the dynamic changes in the activities of histamine-degrading enzymes. Such decrease in enzyme activities were not observed in other experimentally induced inflammations including dinitrochlorobenzene allergic and croton oil dermatitis. The addition of tissue extract from the Arthus reaction sites resulted in about 30% inhibition in both of two enzyme activities, suggesting the presence of some inhibitory factor(s) in the reaction sites.     

Biogenic amines in the Arthus reaction

The concentrations of serotonin, tryptamine, dopamine, and tyramine were quantitatively determined in the Arthus reaction, since the activity of histamine-N-methyltransferase (HMT), a major histamine-metabolizing enzyme that had been demonstrated to be inhibited by such biogenic amines in vitro, decreased significantly in the reaction site. The concentrations of serotonin, tryptamine, and dopamine were unchanged in dinitrochlorobenzene allergic and croton oil dermatitis except for a slight increase of tryptamine in the latter. Tyramine was unable to be demonstrated quantitatively in all specimens tested. The concentration of serotonin decreased to about 30% that of the control level until 1 hr, followed by a prominent increase to about two-fold at 6 hr after the initiation of the Arthus reaction accompanying with a concomitant decrease in HMT activity. However, the concentrations of tryptamine and dopamine were rather decreased in the reaction site, and the net decrease of two amines was far greater than the increased amount of serotonin. The decrease in HMT activity is not stoichiometrically well elucidated from these results, and therefore, the presence of other hypothetic inhibitory factors that are increased in the Arthus reaction should be suspected.     

Functional cooperation of C3b-acceptors, Fc gamma-receptors and cell-surface proteases on macrophages

Macrophages are FcR-positive cells, synthetize complement components and express proteolytic enzymes on their surface. In this paper a functional cooperation of C3b acceptor (C3bA) sites, which bind covalently nascent C3b molecules via their metastable binding site, IgG FcRs and cell surface proteases are described and the possible importance of this cooperation in regulation of immune response is discussed. It was found that isolated monocytes did not express C3bA in contrast to cultured macrophages which showed immune adherence positivity. Stimulation of macrophages resulted in enhanced expression of C3bA. C3 synthetized by macrophages was shown to be cleaved by cellular proteases which resulted in the binding of nascent C3b to C3bA. C3bA-nascent C3b interaction inhibited FcR-dependent effector functions, such as immune complex phagocytosis and antibody-dependent cellular cytotoxicity.     

Polymorphisms of Fc gamma-receptors RIIa, RIIIa, and RIIIb in patients with adult periodontal diseases

Polymorphisms influencing the binding affinity between the Fcgamma receptors and IgG of different subclasses are thought to be of importance in the individual susceptibility to infections with Gram-negative bacteria contributing to periodontal disease. One hundred and fifty-four Caucasian subjects were clinically and radiographically examined for their periodontal status and genotyped for their allelic pattern of FcgammaRIIa, FcgammaRIIIa, and FcgammaIIIb polymorphism. In assessing periodontitis according to mean probing depth and attachment loss, no differences were found in allele frequencies or combined allotypes between the subjects with mild or moderate and those with severe signs of periodontitis. However, the extent and severity of bone loss were significantly associated with the genotype of the receptor FcgammaRIIIa. An increased risk of severe bone destruction was observed in individuals carrying the FcgammaRIIIa-VV genotype (OR = 5.3; 95% CI 1.4-26.2). FcgammaRIIIb is in linkage disequilibrium with FcgammaRIIIa. Hence it is also related to periodontal disease. There is no indication of an association between the polymorphism of FcgammaRIIa and periodontitis. The results are evidence that the FcgammaRIIIa genotype coding for the high affinity receptor imposes an additional risk of bone loss as does the FcgammaRIIIb genotype coding for the low affinity receptor.     

Pathology of reversed passive Arthus reaction in the chicken

Sequential study of gross and microscopic changes in the chicken skin revealed that it was possible to induce a reversed passive Arthus reaction in 14- to 20-week-old chickens, using bovine serum albumin and anti-bovine serum albumin. However, high doses of immune reactants were required to elicit lesions of optimal intensity. The lesions were characterised by erythema, oedema, and the formation of thrombi in the vessels of the superficial dermis. Thrombosis, caused by the adherence of thrombocytes to vascular endothelium, induced widespread necrosis and haemorrhage. The inflammatory changes, which were confined to the deep dermis, included a necrotising vasculitis with infiltration of heterophils, monocytes and basophils. Phagocytosis of carbon particles by heterophils and basophils appeared to be sensitisation-dependent. The reaction was also characterised by the development of perivascular lymphoid foci. The findings indicate that in chickens the thrombocyte appears to be the principal cell involved in the induction of tissue damage.     

The requirement for platelets in the active Arthus reaction

The active Arthus reaction was completely inhibited in rabbits made thrombocytopenic with platelet antiserum. Platelets or some platelet factor is necessary for the development of immune vasculitis in this model. Since the classic Arthus reaction depends on the union of extravascular antigen with intravascular antibody, it is probable that the missing platelet factor is an agent that alters vascular permeability.     

Light and immunofluorescent study of the Arthus reaction in the rabbit lung

A localized Arthus reaction was produced in the lung of sensitized rabbits by delivery of antigen into a lower lobe bronchus using a method of selective bronchial catheterization under fluoroscopy. The rabbits were sensitized with bovine immunoglobulin G (B-IgG) in incomplete Freund's adjuvant (IFA) to produce precipitating antibody without classic delayed hypersensitivity. Pulmonary histopathology was studied at intervals following antigen challenge, using light and immunofluorescent microscopy. Gross lesions peripheral to the lower lobe bronchus receiving antigen were found within 12 hr. Subsequent necrosis resulted in a dense scar by 6 wk. Microscopically, early lesions were typified by localized bronchitis, bronchiolitis, alveolitis, and vasculitis with exuberant exudates containing predominantly polymorphonuclear leukocytes. Extensive focal necrosis was present by 72 hr. Immunofluorescent studies revealed the presence of B-IgG, rabbit IgG, and complement (C3) in and around bronchi, bronchioles, alveoli, and vessels. No granulomatous lesions were found, and proliferation of alveolar lining cells was not detected in these studies. Thus, the lung can participate in an acute Arthus reaction following local antigen challenge in systemically sensitized animals. The pathology more closely resembles a necrotizing bacterial pneumonia than an interstitial or hypersensitivity pneumonitis under the conditions of this experimental system. Implications for human disease are speculative.     

Fc receptors and their interaction with complement in autoimmunity

Genetic studies in mice indicate a crucial role for Fc receptors (FcR) in antibody-mediated autoimmune diseases. Like other immune regulatory receptor pairs, the FcR system is constituted by activating and inhibitory receptors that bind the same ligand, the Fc portion of Ig. Analyses of animal models have shown that the inhibitory Fc receptor, FcgammaRIIB can suppress antibody-mediated autoimmunity, whereas activating-type FcR, such as FcgammaRIII promote disease development. This review summarizes recent advances of FcR, as obtained from gene deletion studies in mice, and highlights the importance of factors that interact with FcR in autoimmunity. There is emerging evidence for an indispensable role of the complement component C5a in the regulation of FcR and the sensing of FcR-dependent effector cell responses. On the other hand, FcR might be alternatives to serum complement in the generation of C5a at sites of inflammation. Thus, FcR and complement interact with each other at the level of C5a by linking regulatory events with effector cell activities in autoimmunity. This connecting pathway is now proposed to be a promising new therapeutic target for the treatment of inflammation and autoimmune disease in both mice and humans.     

In vivo modulation of human lymphocyte Fc gamma-receptors in response to oral antigen (cows' milk) challenge

Following consumption of 1.2 litres of cows' milk by normal human adults there was a rapid fall in the proportion of peripheral blood lymphocytes bearing receptors for the reacted Fc of IgG (Fc gamma-receptors). This phenomenon was transient and apparently confined to the lymphocyte Fc gamma-receptor+ve subpopulation. Similar observations were made in rats but only in those animals pre-exposed to cows' milk suggesting that an immunological mechanism is involved. In man it was found that Fc gamma-receptors could only be re-expressed following incubation of post-milk lymphocytes in normal human serum. It is proposed that rapid in vivo modulation of lymphocyte Fc gamma-receptors occurs following oral antigen (cows' milk) challenge probably mediated by soluble food antigen-antibody complexes. The subsequent recovery of these receptors in vivo and in vitro may be due to the binding of 'fluid-phase' Fc gamma-receptors found in normal human serum.     

P-selectin requirement for neutrophil accumulation and injury in the direct passive Arthus reaction

The aim of this study was to investigate the role of P-selectin in the accumulation of neutrophils in the direct passive Arthus reaction in rat skin. Direct passive Arthus dermal reaction was induced in male Sprague-Dawley (SD) rats by a single i.v. injection of rat anti-sheep globulin (SG) 1 h before i.d. injection of SG antigen. Anti-P-selectin or irrelevant control antibody was given 1 h before rat anti-SG injection. Complement depletion was also performed in a separate group by pretreatment with cobra venom factor (CVF). In all groups dermal swelling was assessed 4 h after antigen challenge. Four hours after antigen challenge, rats treated with control antibody developed skin swelling (2.29 ± 0.47 mm), prominent complement deposition and neutrophil accumulation. This response was associated with local up-regulation of endothelial P-selectin. Pre-treatment with anti-P-selectin antibody 1 h before passive Arthus induction prevented skin swelling (0.29 ± 0.06 mm, P < 0.05, cf with control antibody treatment), neutrophil accumulation and up-regulation of endothelial P-selectin despite complement deposition. CVF treatment prevented complement deposition, neutrophil accumulation and skin swelling (0.13 ± 0.07 mm, P < 0.05, cf with saline treatment). However, endothelial P-selectin expression was still present. Inhibition of skin swelling and neutrophil accumulation in direct passive Arthus by functional inhibition of P-selectin suggest a pivotal role for this adhesion molecule in this inflammatory process. These results also suggest that multiple steps are involved in the evolution of direct passive Arthus, including both P-selectin expression and complement activation. However, while complement activation is essential for neutrophil accumulation and expression of dermal injury, P-selectin up-regulation initiated by antibody/antigen deposition occurs independently of complement activation.