The Role of Immune Complexes in the Pathogenesis of Disease

Summary: The role of immune complexes in the pathogenesis of disease. B. S. Andrews and R. Penny, Aust. N.Z. J. Med., 1976, 6, pp. 591–602.
Circulating antigen-antibody complexes are incriminated in the pathogenesis of autoimmune and inflammatory disease, and more recently malignancy.
Extensive knowledge of the immuno-pathological reactions has evolved from the study of experimental serum sickness in animals and of the potential aetiological agents (e.g. viruses) from spontaneous immune complex diseases in animals.
Numerous techniques, both direct and indirect, have now been described to identify immune complexes in serum, though no single technique will identify regularly immune complexes in all clinical situations, nor will it demonstrate the pathogenicity of the immune complex in a given patient.
Human disorders with a definite immune complex basis (glomerulonephritis, systemic lupus erythematosus, rheumatoid arthritis) and others with a possible immune complex basis (e.g. cutaneous vasculitis) are presented.
Management of immune complex disorders is based on removal of the initiating agent if known (e.g. infection, drug, malignancy) or the use of non-specific antiinflammatory therapy. Specific immunotherapy, in practice and theory, is discussed.     

肝硬化 肝癌患者血清循环免疫复合物的研究

采用一种简单、敏感的放射免疫法测定了101例肝病患者(25例肝癌,17例肝硬化,26例慢迁肝,33例乙肝病毒携带着)的血清循环免疫复合物,并观察了各组肝功能的变化以及HBV标志.结果表明:肝癌组的IgG-CIC含量及γ-GT含量明显高于其它各组.IgG-CIC 5.21(PHC),3.43(LC),2.41(CPH)及1.92(ASC),P<0.01.γ-GT 262(PHC).63.1(LC),44.7(CPH)以及18.7(ASC),P<0.01.伴有HBV感染的肝癌组中有80%可检出IgG-CIC,而CPH及ASC组中仅有50%可检出IgG-CIC.研究结果还表明:肝癌组中,IgG-CIC含量随着AFP含量的升高而上升.但在AFP过度升高时,IgG-GIC反而降低.这可能提示:随着肿瘤的生长,IgG-CIC升高,AFP值随肿瘤恶化逐渐上升,致使IgG-CIC从结合补体转变成非结合补体,导致IgG-CIC的下降.根据结果提示:HBV感染与肝癌发生有着密切关系.     

Immune Complexes in Acute Pancreatitis

Abstract: Immune complexes were detected in the sera of ten of 22 patients with acute pancreatitis using a Clq deviation assay. Five of these were positive using a second technique. There was no correlation between immune complexes and clinical or aetiological features of the pancreatitis. Two patients with immune complexes developed a benign and transient pancreatic polyarthritis. Immune complexes may provide one common path in the sequence of pathogenic events that lead to pancreatitis .     

Immune Complexes in Diabetes Mellitus

Summary: Immune complexes in diabetes mellitus. J. A. Charlesworth, L. V. Campbell, J. Quin, L. Lazarus and G. J. Macdonald, Aust. N.Z. J. Med., 1979, 9, pp. 370–373.
Sera from 86 well controlled diabetics were examined for the presence of immune complexes. Thirty-six patients were receiving standard insulins, 19 monocomponent preparations, 24 oral hypoglycaemic agents and seven dietary restriction alone. Three methods were used to detect complexes: measurement of complement components, a Clq binding assay (BA) and the Raji cell radioimmunoassay (RIA). Complement components were normal in all patients. Eleven (31%) of the group on standard insulins had a positive Raji cell RIA; none had an abnormal Clq-BA. One patient on monocomponent therapy had a mildly positive Raji cell RIA; Clq-BA was negative in each patient of this group. Thirteen (54%) of the patients on oral hypoglycaemic agents were positive on one or both assays while one patient on diet alone was abnormal on both assays. These data show that immune complex production is common in both insulin-requiring and non-insulin-requiring diabetics and that this phenomenon is strikingly less frequent in patients on mono-component insulins. Such observations could bear relevance to the pathogenesis of microvascular complications in diabetes.     

Immune Complexes in Aplastic Anaemia

S ummary . Immune complexes (IC) have been detected in nine out of 15 patients presenting with idiopathic aplastic anaemia using the polymorphonuclear neutrophil immunohistochemical technique. Immunosuppressive treatment undertaken in one patient produced a gradual recovery, the bone marrow repopulation being paralleled by the disappearance of IC. The significance of IC in aplastic anaemia and the relationship with possible pathogenesis and therapy of the disease are discussed.     

Platelet Transfusion Therapy and Circulating Immune Complexes

Abstract: 30 platelet transfusions were administered to 9 thrombocytopenic patients with acute leukemias. Using the Raji cell radioimmunoassay, the serum concentration for circulating immune complexes (CIC) were determined immediately before and 10–12 h after each transfusion therapy. Elevated serum concentrations for CIC were present in 14 of the pretransfusion samples. After platelet transfusion therapy, a significant (p<0.02) decrease in the values of CIC occurred. In these 14 transfusion studies the mean percent platelet increment was considerably lower (0.10>p>0.05) than the mean for the 16 transfusion studies in which the pretransfusion values for CIC were normal. These results show that CIC probably play an important role in removing transfused platelets from the circulation. Conversely, platelets are able to remove CIC from the circulation.     

应用单克隆抗体ELISA检测包虫病人循环免疫复合物的研究

应用抗包虫单克隆抗体F1建立了检测包虫病人循环免疫复合物和解离抗原的ELISA法。102例包虫病人中CIC阳性率为50％(51/102),其中手术前检出率为62.62％(33/53),手术后检出率为36.73％(18/49)。二者差异显著(P<0.005)。用PEG沉淀的免疫复合物经尿素解离后检测包虫抗原的阳性率为58.82％(60/102)。CIC与解离抗原二者累积阳性率达到86.27％(88/102)。表明在包虫病人中CIC的存在是普遍的。F1单克隆抗体ELISA法在检测包虫病人CIC和解离抗原上有极高的敏感性,因而证明F1单克隆抗体所识别的抗原表位是形成CIC的主要抗原成分。在IgG型CIC阳性的血清中解离抗原的检出率仅为48.1％(23/51)。可能是由于IgG抗体的高度亲和力,由其形成的CIC解离效率低。在IgG-CIC阴性血清中,检出解离抗原的阳性率高达72.5％(37/51),证明了在相当部分包虫病人血清中可能存在着IgE和IgM型CIC。解离抗原阳性率高表明这类CIC容易解离。在17例特异性IgG抗体阴性的包虫病人中CIC阳性者10例(58.82％),解离抗原阳性者9例(52.94％),二者累积阳性率为76.47％(13/17)。说明CIC与解离抗原的检测在IgG抗体阴性的包虫病人诊断上有实际意义。     

包虫病人特异性IgM型和IgE型循环免疫复合物的初步研究

应用ABC-捕获ELISA法研究了包虫病人血清中特异性IgM型和IgE型循环免疫复合物(IgM-CIC,IgE-CIC)。IgM-CIC的检出率为47.6％,IgE-CIC为64.3％。肺包虫病人中CIC的检出率略高于肝包虫病,但无显著性差异。特异性IgE抗体阴性的包虫病人中,IgE-CIC检出率达89.5％,而抗体阳性者中为57.7％。在5例特异性IgM抗体阴性的肺包虫病人中,有4例IgM-CIC阳性,而4例IgM抗体阳性者中仅1例CIC阳性。表明由于CIC的形成可造成特异性IgM和IgE游离抗体的“耗竭”。用8M尿素处理后,三种特异性CIC均可被解离。用单克隆抗体检测解离抗原的阳性率在IgG-CIC中为51.3％,在IgM-CIC中为75.0％,在IgE-CIC中为75.9％,证明解离效率与相应抗体的亲和力呈反比。作者认为,包虫病人特异性抗体的检出,不能反映抗体应答的真正水平,抗体阳性加上抗体阴性而CIC阳性者,才能完全反映抗体应答的频率:在IgG为95.2％,IgM为85.1％,IgE为95.6％。提示包虫病人IgM-CIC和IgE-CIC的检测可大大提高免疫诊断的价值,有实际意义。     

Circulating Immune Complexes in Human Acute Leukaemia

S ummary . Circulating immune complexes (CIC) in the sera of 60 newly diagnosed leukaemic patients were investigated by two methods, ¹²⁵I-C1q binding test (C1q-BA) and conglutinin binding assay (KgB-SP). Positivity percentages were respectively 20.0% (C1q-BA) and 28.3% (KgB-SP). The small overlap between the results of the two methods suggests the occurrence of different types of CIC. The presence of CIC was found to be related only to clinical haemorrhage and thrombocytopenia; it did not prove to affect the prognosis and the survival of leukaemic patients.     

Immune Complexes in Rheumatoid Arthritis Sera and Synovial Fluids

Sera and synovial fluids from 88 patients with rheumatoid arthritis were examined for circulating immune complexes by three assays: monoclonal rheumatoid factor radioimmunoassay, Clq binding assay, and Raji cell radioassay. Paired samples were available for 82 patients. Immune complexes were detected with high frequency in the synovial fluid by each assay (75% by the monoclonal rheumatoid factor radioimmunoassay, 95% by the Clq binding assay, and 61% by the Raji cell radioassay). In rheumatoid arthritis sera, immune complexes were detected with high frequency by the Clq binding assay (85%) and the monoclonal rheumatoid factor radioimmunoassay (70%) but infrequently by the Raji cell radioassay (26%). The presence of immune complexes in serum was most frequently accompanied by the presence of complexes in fluid, regardless of the method of detection; moreover, the levels of immune complexes in synovial fluid were generally higher than in paired serum. Further, the levels of immune complexes as measured by the Clq binding assay correlated with certain parameters of clinical activity, while the monoclonal rheumatoid factor radioimmunoassay and Raji cell radioassay correlated with extraarticular features (excluding nodules) of rheumatoid arthritis.     

Intravenous Immune Serum Globulin in Immunodeficiency

This study was undertaken to compare intravenous gamma-globulin (IVGG) for 1 year in patients with primary immune defects who had previously been treated with intramuscular gamma-globulin (IMGG). Forty-three patients were available for analysis. After administration of 300 mg/kg of IVGG every 3 weeks, blood immunoglobulin levels increased to within 1 SD of normal for the patient's ages. In 5 patients, this dosage regimen did not raise the immunoglobulin levels satisfactorily, although they were still better than those achieved with IMGG. In 18 patients, treatment benefits became apparent after 5–6 months of treatment. Substantial improvement was observed in 70% of these patients. Sixteen reactions occurred with 638 infusions, an incidence rate of 2.5%. If 2 patients with an IgM macroglobulin and 1 patient with an anti-IgA antibody were excluded, the reaction incidence would probably have been 1%.     

Prion Disease and the Innate Immune System

Prion diseases or transmissible spongiform encephalopathies are a unique category of infectious protein-misfolding neurodegenerative disorders. Hypothesized to be caused by misfolding of the cellular prion protein these disorders possess an infectious quality that thrives in immune-competent hosts. While much has been discovered about the routing and critical components involved in the peripheral pathogenesis of these agents there are still many aspects to be discovered. Research into this area has been extensive as it represents a major target for therapeutic intervention within this group of diseases. The main focus of pathological damage in these diseases occurs within the central nervous system. Cells of the innate immune system have been proven to be critical players in the initial pathogenesis of prion disease, and may have a role in the pathological progression of disease. Understanding how prions interact with the host innate immune system may provide us with natural pathways and mechanisms to combat these diseases prior to their neuroinvasive stage. We present here a review of the current knowledge regarding the role of the innate immune system in prion pathogenesis.     

Intravenous Immune Serum Globulin in Immune Thrombocytopenia: Clinical Results and Biochemical Evaluation

Intravenous gamma-globulin of the pH 4-treated Swiss Red Cross (SRC) preparation is an effective therapy for acute and chronic immune thrombocytopenia (ITP) of childhood and chronic ITP in adults. Patients who may respond satisfactorily to treatment include those without detectable immune complexes and those with poor response to pre-treatment. Results are especially good in children, half of whom with chronic conditions are able to discontinue therapy.     

Patterns of Proteinuria and Circulating Immune Complexes in Febrile Patients

ABSTRACT. Circulating immune complexes (CIC) were detected in 8 of 15 patients with fever due to non-renal infections. Elevated urinary albumin and β-2-microglobulin excretion rates were found during the febrile period compared to the levels two days after normalization of the temperature. No relationship could be demonstrated between CIC and the excretion rates of albumin and β-2-microglobulin or the albumin/β-2-microgIobulin ratio. Thus we have not been able to confirm the hypothesis that the glomerular type of proteinuria is caused by immune complexes.     

Plasma Exchange and Immune Complex Diseases: The Predictability of Immune Complexes Removal to Clinical Response

58 patients were treated by discontinuous flow plasma exchange because of an immune complex (IC) disease. 41 patients who had a high level of circulating IC prior to plasmapheresis showed both clinical and immunochemical evidence of improvement with plasma exchange. Only 2 patients with a high level of IC did not improve after therapy: these patients suffered from multiple sclerosis and idiopathic thrombocytopenic purpura, respectively. Prior to PE therapy the level of circulating IC in 15 patients was within the normal range, when measured according to Manca et al. In this group none of the patients worsened after therapy, whereas 8 patients showed an objective improvement. The positive correlation between IC removal and clinical results suggests that patients with a high level of circulating IC are most likely to benefit from apheretic treatment.     

Portal Hypertension as Immune Mediate Disease

Context:

Portal Hypertension (PH) is a progressive complication due to chronic liver disease. In addition to pathophysiologic changes in the micro-circulation, in PH are established fibrous tissue (periportal fibrous septal) and regenerative hyperplastic nodules (from micro- to macro-nodules) promoting hepatic architectural distortion.

Evidence Acquisition:

A literature search of electronic databases was undertaken for the major studies published from 1981 to today. The databases searched were: PubMed, EMBASE, Orphanet, Midline and Cochrane Library. We used the keywords: "portal hypertension, children, immune system, endocrine system, liver fibrosis".

Results:

It is believed that PH results from three “phenotype”: ischemia-reperfusion, involving nervous system (NS); edema and oxidative damage, involving immune system; inflammation and angiogenesis, involving endocrine system. However, its exact cause still underdiagnosed and unknown.

Conclusions:

PH is a dynamic and potentially reversible process. Researchers have tried to demonstrate mechanisms underlying PH and its related-complications. This review focuses on the current knowledge regarding the pathogenesis, and immune, endocrine-metabolic factors of disease. The strong positive association between immune system and development of PH could be efficient to identify non-invasive markers of disease, to modify prognosis of PH, and to development and application of specific and individual anti-inflammatory therapy.     

Evaluation of Intravenous Immune Serum Globulin in Immune Thrombocytopenia: Preliminary Results

Due to difficult clinical problems caused or aggravated by the presence of severe thrombocytopenia, 4 patients with immune thrombocytopenia (ITP) refractory to conventional regimens were treated with intravenous gamma-globulin. One patient had a lasting remission, 2 others had a partial or brief response, and 1 patient had no improvement in platelet count.