Incidence of circulating immune complexes in patients with acute poststreptococcal glomerulonephritis and in patients with streptococcal impetigo

In an attempt to further study the possible contribution of circulating immune complexes (CIC) in the pathogenesis of acute poststreptococcal glomerulonephritis, 61 patients with APSGN were studied during the first three weeks of the disease, and 13 patients with noncomplicated streptococcal impetigo as a control group. C1q solid phase ELISA and Conglutinin (K) solid phase ELISA were used to measure the levels of immune complexes. The incidence of CIC in a single serum sample from patients with APSGN was 48%. Elevated levels of immune complexes were found in 46% of the patients with streptococcal impetigo. The absolute levels of CIC were comparable in both groups of patients. No correlation was found among the presence of CIC and the clinical, immunoserological or pathological findings of the disease. Our results do not support the hypothesis that trapping of the circulating immune complexes play an important role on the renal injury poststreptococcal infection. Instead, we suggest that CIC are an epiphenomena present in APSGN, and may represent rather a systemic inflammatory immune response in patients with group A streptococcal infection.     

Humoral immunity to streptococcal antigen in acute and chronic glomerulonephritis

A study was carried out to verify the clinical usefulness of the elaborated method for the measurement of antistreptococcal antibody in revealing the streptococcal etiology of glomerulonephritis.In 158 patients with glomerulonephritis antistreptococcal antibody (ASA), circulating immune complexes (CIC) and haemolytic activity of the complement were measured.On the basis of immune complex formation it has been concluded that streptococcal infection may cause glomerulonephritis. Serial determinations of ASA and CIC are helpful in establishing the streptococcal etiology of glomerulonephritis and in monitoring the course of the disease.     

Extracellular neuraminidase production of streptococci associated with acute nephritis

The possibility that streptococcal neuraminidase has a pathogenic role in acute poststreptococcal glomerulonephritis is reviewed. Experimental and clinical evidence suggesting autologous immune phenomena and anti-Ig reactivity in this disease is discussed. Neuraminidase may also induce sialic acid depletion that would be expected to result in changes of the electrical charge in the immune complex as well as in the glomerular polyanion filtration barrier. The nature of these changes will facilitate penetrability of material with nephritogenic potential. Neuraminidase production was detected in the majority of streptococcal isolates obtained from patients with glomerulonephritis and the best substrate for screening purposes appears to be bovine submaxillary gland mucin. On the basis of available evidence, it is suggested that the development of glomerulonephritis after streptococcal infection probably does not depend on neuraminidase production by the bacteria; however, this enzyme may be responsible for the anti-Ig reactivity demonstrated in some patients and thereby influence the course of the disease.     

Persistent anti-DNA antibodies and DNA-anti-DNA complexes in post-streptococcal glomerulonephritis

Two patients with the typical clinical, serological and pathological features of acute post-streptococcal glomerulonephritis were found to have elevated serum concentrations of DNA-anti-DNA complexes, and, in one case, of anti-DNA antibody, both single and double stranded. The DNA-anti-DNA complexes were found to persist for 15 and 21 months respectively following the initial illness, despite rapid resolution of the clinical features and severe renal dysfunction. It is suggested that the DNA-anti-DNA complexes may have a pathogenetic role in post-streptococcal nephritis, or alternatively act as a marker of those patients who will develop nephritis after a streptococcal infection.     

The role of IgA and IgG immune complexes in IgA nephropathy

The presence of circulating immune complexes in 54 patients with IgA nephropathy has been studied by two different techniques. 64% of the patients had IgG immune complexes and 37% had IgA immune complexes, both determined with the Raji cell assay, and 48% of patients had IgA immune complexes with the anti-IgA inhibition binding assay (anti-IgA Inh BA). In sequential sera from individual patients, immune complexes remained persistently positive or negative in more than 50% of the cases being intermittently in the rest. The immune complexes detected by the Raji cell assay were mostly of 7-13S in size, while those detected by anti-IgA Inh BA were bigger. There was a good correlation between the serum levels of polymeric IgA and the presence of IgA complexes (Raji cell assay). A certain correlation (p less than 0.05) was found between these IgA immune complexes and the clinical activity assessed by the hematuria. A similar correlation (p less than 0.05) was found with specific polymeric IgA immune complexes studied by a method recently described. No relationship was observed between the presence of any HLA antigens and the existence of circulating immune complexes. These results support the contention that IgA immune complexes, especially those composed of polymeric IgA, may have a role in the pathogenesis of IgA nephropathy. Moreover, the high serum levels of polymeric IgA observed in these patients could contribute to the slow clearance and long persistence in the circulation of IgA immune complexes with their subsequent deposition at the glomerular mesangium.     

Cationic antigens in poststreptococcal glomerulonephritis

Antigen charge is an important factor in the pathogenesis of experimental immune complex glomerulonephritis. Its potential role in man was investigated in post-streptococcal glomerulonephritis, a disease where the causative agent is known. Cationic, extracellular streptococcal antigens were detected in 8 of 18 renal biopsies from patients with acute poststreptococcal glomerulonephritis (APSGN). The antigen was found mainly in earlier biopsies in which both IgG and IgM were present. Patients' sera taken at the time of biopsy contained antibody to cationic, streptococcal antigens. Cationic moieties are known to have affinity for the glomerular basement membrane and it is possible that the type of antigen described here initiates APSGN via in situ immune complex formation.     

IgG, IgA and IgM rheumatoid factors in patients with glomerulonephritis

Rheumatoid factors (RF), autoantibodies to IgG, have been postulated to have some pathogenetic role in the development of some types of glomerulonephritis. A simple and sensitive solid-phase fluorescence immunoassay was employed to determine whether IgG, IgA and IgM RF were detectable in sera from patients with various types of glomerulonephritis, rheumatoid arthritis (RA) and those with various streptococcal infections. IgG, IgA and IgM RF were significantly increased in the majority of patients with RA, lupus nephritis (SLE), acute poststreptococcal glomerulonephritis (APSGN) and various streptococcal infections. The titers of IgG and IgA RF were significantly higher in patients with APSGN than in those with simple pharyngitis. IgM RF was increated in patients with IgA nephropathy (IgA-N) and in those with membranoproliferative glomerulonephritis type I (MPGN). No significantly high RF was observed in membranous nephropathy (MN) or chronic mesangial proliferative glomerulonephritis without IgA deposition (PGN). It is suggested that some autologous immune mechanisms may be involved in the pathogenesis of some types of glomerulonephritis.     

Group A Streptococcus invasive infections: a review

The incidence of group A Streptococcus (GAS) invasive infections has been increasing worldwide, and there is no obvious explanation for this phenomenon. In 1993, a working group on severe GAS infections was established to define accurately what constitutes an invasive infection. Three types of infection are particularly feared: necrotizing fasciitis, myositis and a newly defined entity, named streptococcal toxic shock syndrome (STSS) because of a certain analogy with its staphylococcal counterpart. GAS produces many toxins responsible for its clinical manifestations. Some of them, labelled streptococcal pyrogenic exotoxins, have been characterized as superantigens. These proteins play a key role in initiating the immune response to GAS and are mostly responsible for the precipitous course of invasive infections. Death rates are high in streptococcal invasive infections, ranging from about 20% for necrotizing fasciitis to almost 100% for myositis. Therapy consists mainly of high doses of antibiotic combinations, aggressive surgery, and intravenous administration of immunoglobulins for STSS.     

Localised immune complexes and slipped upper femoral epiphysis

Slipped upper femoral epiphysis remains a disease of unknown aetiology. Recent evidence has bolstered speculation that the immune system may play a role in the aetiology or pathogenesis of slipped epiphysis or of one of its complications, chondrolysis. This study reports the finding of immune complexes in the synovial fluid of all but one hip affected with slipped epiphysis in a consecutive series. In seven patients, immune complexes were detected by both the Raji cell assay and C1q-binding assay; in two, by the C1q-assay only; and in one, by the Raji cell assay only. No patients had immune complexes in the serum. Twenty-one patients with synovitis of the knee or hip caused by a variety of disorders served as the control group. Two of these patients had immune complexes in their synovial fluid. It appears that the immune complexes characterise the synovitis found with slipped upper femoral epiphysis as distinct from most other synovitides.     

Disposition of IgA-containing circulating immune complexes

Two fundamentally different mechanisms may account for the glomerular immune deposits in IgA nephropathy (IgAN): (1) deposition of circulating immune complexes and (2) the in situ formation of immune complexes. In this review the experimental evidence for and against an important role of circulating IgA-containing immune complexes in the pathogenesis of IgAN is summarized. Several physical characteristics, including size, lattice composition, and electrical charge, may influence the deposition of immune complexes in the renal mesangium. Furthermore, the likelihood of deposition of circulating IgA-containing immune complexes in vulnerable locations (such as the kidney) may be increased because of their impaired removal from the circulation by macrophages of the liver and spleen and the erythrocyte-immune complex clearing mechanism. However, the relative contributions of these factors to the pathogenesis of IgAN remain speculative.     

Immunopathogenetic mechanisms in renal disease

This review deals with various immunopathogenetic mechanisms of renal diseases. Although immune-complex nephritis was long thought to be the result of deposition of circulating immune complexes, recent studies have revealed the importance of in situ formation. In experimental Heymann nephritis, an antigen (gp 330) has been localized on glomerular epithelial cells, and antibodies reactive with gp 330 have been eluted from glomeruli; deposits appear to result from shedding of complexes from the podocyte surface into the basement membrane. In human disease, it seems likely that mesangial and subendothelial deposits most often result from deposition of circulating immune complexes, whereas subepithelial deposits are formed mainly in situ. Cell-mediated immune mechanisms are capable of producing glomerular injury, as shown in experimental models. In humans, Wegener's granulomatosis and idiopathic crescentic glomerulonephritis may involve such mechanisms. In certain forms of experimental and human tubulointerstitial nephritis, cell-mediated immunity also seems to play an important role.     

FcgammaRIIa polymorphism in systemic lupus erythematosus

FcgammaRIIs are the most widely distributed of the Fcgamma receptor family and play an important role in the clearance of immune complexes. Evidence that the FcgammaRIIa-R131 allotype is less able to process and clear immune complexes effectively suggests that this may be a disease susceptibility factor for systemic lupus erythematosus (SLE). Data from studies published thus far do not agree on the potential role of FcgammaRIIa polymorphism in the genetics of SLE. Most studies in fact show no evidence for any correlation between polymorphism of FcgammaRIIa and risk for SLE. However, it remains to be determined whether FcgammaRIIa polymorphism may play a critical role in certain groups of patients, especially in those of differing ethnic background. Polymorphism of FcgammaRIIa may also be important in determining disease phenotype, and identification of this influence may have important implications in patient care and in identifying patients for more aggressive therapy.     

Reticuloendothelial System Fc Receptor Function and Plasmapheresis in Systemic Lupus Erythematosus: A Preliminary Report

Reticuloendothelial System (RES) Fc receptor-mediated immune clearance and levels of immune complexes were measured in patients with systemic lupus erythematosus undergoing plasmapheresis. RES clearance defects improved and disease manifestations and levels of circulating immune complexes decreased after plasmapheresis. Patients with initially abnormal reticuloendothelial system function, elevated levels of circulating immune complexes, and active acute illness appeared to respond to plasmapheresis. One patient with normal immune clearance, lacking measureable immune complexes, and manifesting chronic disease remained unchanged.
Improvements seen following plasmapheresis were best maintained in patients receiving parenteral cyclophosphamide in the post-pheresis period. The correlation of clinical response, improved RES function, and decreased levels of immune complexes suggests the interaction of the latter two parameters in disease pathogenesis. Plasmapheresis has an important role as a research tool, and may be of clinical usefulness in a small number of patients with serious complications of systemic lupus erythematosus.     

IgA nephropathy and idiopathic thrombocytopenic purpura with splenectomy: a case report

A 14-year-old boy who had had a splenectomy at the age of 2 years for idiopathic thrombocytopenic purpura, suffered from IgA nephropathy. Serum IgA and IgE levels were elevated and low levels of circulating immune complexes were detected. Splenectomy may play a role in the pathogenesis or susceptibility to IgA nephropathy by means of decreased clearance of circulating immune complexes or impaired immune regulation, such as increased IgA synthesis.     

The pathogenetic potential of environmental antigens in IgA nephropathy

Patients with IgA nephropathy (IgAN) can be considered high responders for IgA production; data which indicate a generalized hyperreactivity of the immune system include autoantibody production, increased response to viral vaccination, and high titers of antibodies to various common respiratory and gastrointestinal microbes. From clinical and experimental observations, two types of antigen seem to be most involved in the pathogenesis of IgAN, ie, environmental respiratory or gastrointestinal infectious agents and dietary antigens. A role played by microbes has been suggested because macroscopic hematuria shortly follows a pharyngitis or a gastrointestinal disturbance. Antibodies to a wide spectrum of viral and bacterial infectious agents have been detected in sera from patients with IgAN. The possible role of dietary antigens has been demonstrated experimentally in animal models. In human IgAN, antibodies to various dietary antigens have been detected in sera; antibodies have also been found in IgA immune complexes and renal eluates. In human IgAN, a significant decrease in serum levels of IgA-containing circulating immune complexes after a gluten-free diet has been observed. The present experience accounts for 27 IgAN patients followed for 6 months to 3 years on a gluten-free diet. A decrease in serum levels of IgA-containing circulating immune complexes was observed in 64% of the patients whose initial levels were high during a period of unrestricted diet. Patients with basal high levels also had significantly high levels of IgA antibodies to dietary antigens, including bovine serum albumin, ovalbumin, and various gluten fractions. After 1 year of gluten-free diet the levels significantly decreased. A disappearance of antigliadin IgA, observed in 80% of the cases, was paralleled by a decrease in titers of the other antibodies to dietary components. These data support the hypothesis that in patients with IgAN, gluten may act as a toxic lectin, increasing the permeability of the intestinal mucosa to various dietary antigens.     

Focal segmental membranous glomerulonephropathy associated with other glomerular diseases

In four patients with the nephrotic syndrome, renal biopsy revealed focal segmental membranous glomerulonephropathy (FSMGN) associated with the histologic patterns of "nil" disease (two cases), hereditary nephritis and diffuse diabetic glomerulosclerosis. The occurrence of FSMGN in association with other glomerular diseases, presumably unrelated to immune complex deposition, is infrequent in our experience. Rather than necessarily representing an early stage or milder form of membranous glomerulonephropathy, it may be an epiphenomenon. This interpretation has prognostic and therapeutic implications and raises important pathogenetic questions. In particular, this study suggests that in some instances, preexisting functional and structural abnormalities may play a role either in the deposition of preformed circulating immune complexes or in the local formation of immune complexes.     

Extracorporeal Immunomodulation Relevant to Organ Substitutions

Abstract: Multiple administration of the generally called immunosuppressing agents is the usual fashion for suppressing/ameliorating the rejection reaction that inevitably occurs after organ allotransplantation. Although a definite mechanism of the rejection reaction has not been elucidated, evidence has accumulated that cellular components, such as T- and B-lymphocytes, and humoral factors, such as antibodies and immune complexes, play a certain role. There also is a possibility that direct removal or functional revolution of those components and/or factors utilizing an extracorporeal procedure influence an immune mechanism of the rejection reaction. Some of the extracorporeal procedures, which have been developed from blood purification techniques, have been evidenced to modify an immune mechanism and, as a result, bring about better graft function to a considerable extent that may not be otherwise achieved by traditional immunosuppressant treatment. The term "extracorporeal immunomodulation" was given to such extracorporeal procedures.     

Immunoglobulin-antiimmunoglobulin interactions and immune complexes in IgA nephropathy

IgA nephropathy (IgAN) is characterized by mesangial co-deposition of IgA and C3. Elevated levels of circulating immune complexes containing these components in significant numbers of patients have been found in several studies; IgAN is therefore assumed by many investigators to be an immune complex-mediated disease. Our studies have shown that IgG is often co-complexed with IgA within circulating immune complexes, and we have begun to examine the potential mechanisms for these observations. In this regard, elevated levels of IgA rheumatoid factor and of IgG anti-IgA antibodies were found in some patients. Nevertheless, we were unable to correlate levels of circulating immune complexes with any clinical index of disease. Furthermore, many individuals with the acquired immune deficiency syndrome (AIDS) also have elevated levels of circulating immune complexes containing IgG and IgA, IgA rheumatoid factor, and IgG anti-IgA antibodies, although these patients apparently do not have mesangial IgA deposits. Therefore, the role of circulating IgA-containing immune complexes in the pathogenesis of IgAN requires further evaluation.     

Glomerular Deposition Diseases: Insights into Mechanisms

Recent experimental studies demonstrate that glomerular basement membrane immune deposits may be formed locally or by deposition of intact complexes from the circulation. Electrostatic interactions may play a role in both of these mechanisms and may account, at least in part, for differences in patterns of localization in the various deposition diseases.     

Composition of IgA-containing circulating immune complexes in IgA nephropathy

Macromolecular IgA is found with a relatively high frequency in the sera of patients with IgA nephropathy (IgAN). This macromolecular IgA consists of polymeric IgA, IgA-containing immune complexes, or both. The presence of polymeric IgA antibodies reflects a recent IgA response. Vaccination data in patients with IgAN suggest that these patients respond more vigorously with their mucosal immune system than do controls. The association of exacerbations with upper respiratory tract infections suggests that the immunogenic stimuli probably are of microbial origin and are presented to mucosal surfaces. Analysis by sucrose density ultracentrifugation has shown that the macromolecular IgA may contain IgG, IgA rheumatoid factor, and C3. The search for the antigen or antigens specifically responsible for IgAN has been unsuccessful. Although IgG and IgA rheumatoid factor may contribute, they do not account for the pathogenesis of the disease in all patients. Alternative mechanisms have to be assumed for patients who do not have detectable levels of IgA-containing immune complexes. They could have polymeric IgA or IgA-containing immune complexes intermittently, as has been shown in children with relapsing IgAN. The binding of circulating IgA antibodies to antigens present in the mesangium can lead to the local formation of deposits in the absence of circulating IgA complexes.