There is now abundant evidence that brain microglia, when activated, have the lineage, receptors, and synthetic capacity to participate in both potentially neurotoxic inflammatory responses and potentially beneficial phagocytic responses. Amyloid beta peptide (Abeta) forms highly insoluble, beta-pleated aggregates that are widely deposited in the Alzheimer's disease (AD) cortex and limbic system. Aggregated Abeta also activates the classical and alternative complement cascades. These properties make Abeta an excellent target for microglial phagocytosis, a view supported by multiple reports, through well established mechanisms of phagocyte clearance.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/glia.10153

Microglia and inflammatory mechanisms in the clearance of amyloid β peptide

Complement is a humoral effector system composed of 21 plasma proteins that was identified initially because of its cytolytic effects. In addition to cytolysis, complement has a number of different functions related to inflammatory and other host defense processes. The description of the reaction mechanism includes: (1) activation of the classical pathway through recognition of IgG and IgM antibodies by C1q, (2) activation of the alternative pathway which is usually achieved without participation of immunoglobulins, (3) generation of proteolytic enzymes composed of heteropolymers that cleave certain precursor proteins, (4) formation of the membrane attack complex (MAC), and (5) participation of control mechanisms. Methodologies for studying protein concentration and functional activities of complement components include not only the classical hemolytic techniques but also the extremely sensitive new radioimmunoassays and enzyme immunoassays for measuring the products of complement activation that are generated in vivo. Examples of genetically controlled complement deficiencies have been published for most complement components. The symptomatology of some of these patients serves to emphasize the protective role of complement. Acquired deficiencies are significant not only as laboratory aids in diagnosis and to evaluate the course of certain diseases, but also to indicate possible pathogenic disease mechanisms. Recently, it has been recognized that the complement proteins with genes located in the HLA region are polymorphic. Certain variants of proteins C2, C4, and factor B occur with higher frequencies in certain diseases than in the general population, which appears to be of great practical importance in laboratory medicine.

Complement in the pathophysiology and diagnosis of human diseases.

Erythema nodosum leprosum (ENL) is a painful inflammatory complication of leprosy occurring in 50% of lepromatous leprosy patients and 5-10% of borderline lepromatous patients. It is a significant cause of economic hardship, morbidity and mortality in leprosy patients. Our understanding of the causes of ENL is limited. We performed a systematic review of the published literature and critically evaluated the evidence for the role of neutrophils, immune complexes (ICs), T-cells, cytokines, and other immunological factors that could contribute to the development of ENL. Searches of the literature were performed in PubMed. Studies, independent of published date, using samples from patients with ENL were included. The search revealed more than 20,000 articles of which 146 eligible studies were included in this systematic review. The studies demonstrate that ENL may be associated with a neutrophilic infiltrate, but it is not clear whether it is an IC-mediated process or that the presence of ICs is an epiphenomenon. Increased levels of tumor necrosis factor-α and other pro-inflammatory cytokines support the role of this cytokine in the inflammatory phase of ENL but not necessarily the initiation. T-cell subsets appear to be important in ENL since multiple studies report an increased CD4+/CD8+ ratio in both skin and peripheral blood of patients with ENL. Microarray data have identified new molecules and whole pathophysiological pathways associated with ENL and provides new insights into the pathogenesis of ENL. Studies of ENL are often difficult to compare due to a lack of case definitions, treatment status, and timing of sampling as well as the use of different laboratory techniques. A standardized approach to some of these issues would be useful. ENL appears to be a complex interaction of various aspects of the immune system. Rigorous clinical descriptions of well-defined cohorts of patients and a systems biology approach using available technologies such as genomics, epigenomics, transcriptomics, and proteomics could yield greater understanding of the condition.

/pdf/a-systematic-review-of-immunological-studies-of-erythema-3jb2r5ewt4.pdf

A Systematic Review of Immunological Studies of Erythema Nodosum Leprosum.

Identification of virus components in circulating immune complexes isolated during hepatitis A virus infection.

Class I, II, and III MHC gene products were examined in 248 Central European SLE patients. The previously reported association with HLA-A1, -B8 and -DR3, and C4AQ0 alleles was confirmed. The frequency of HLA-DR2 was also slightly elevated in SLE patients, while no increase in C4BQ0 alleles was observed. Additional findings were a significantly increased frequency of HLA-B13 and a significant decrease of HLA-B44.

Association of class I, II, and III MHC gene products with systemic lupus erythematosus. Results of a Central European multicenter study.

Some of the molecular events in the complement (C)-mediated solubilization of immune complexes (IC) have been clarified in recent years The solubilization is primarily mediated by alternative C pathway proteins whereas factors in the classical pathway accelerate the process Components of the membrane attack complex do not participate in the reaction Besides affecting the size and solubility of circulating IC the interaction with C factors influences the reactivities of the complexes towards fluid phase reactants and mediates the reversible binding of IC to cellular C3 receptors Our knowledge of the cellular localization, expression and structure of the C3 receptors, especially the C3b (CR1) receptor, has been considerably extended in the last few years, whereas our understanding of the physiological role of these receptors is still fragmentary However, it is becoming increasingly evident that impaired solubilization of IC in patients with compromised C function may permit the complexes to deviate from their normal pattern of interaction with C3 receptors probably influencing both the organ distribution and clearance of IC and thereby also their phlogistic potentials

Complement-mediated solubilization of immune complexes and their interaction with complement C3 receptors.

Thirty-two of 36 serum samples from 19 SLE patients showed reduced capacity to mediate complement-dependent solubilization of immune complexes (IC). SLE patients with nephritis exerted the lowest complement-mediated solubilization capacity (CMSC) whereas sera from patients with inactive disease gave the highest CMSC values, with three out of four samples within the normal reference range. Thirty-five of the 36 serum samples showed inhibition of CMSC in a newly developed CMSC inhibition assay. The strongest CMSC inhibition was exerted by sera from newly discovered cases of SLE who received no medical treatment and the lowest inhibition by sera from patients with inactive disease. There was a significant negative correlation between CMSC and CMSC inhibition (r = -0.67, P less than 0.001). Sera with low concentrations of C1q, C3, factor B or high C3d levels showed markedly reduced CMSC values. Pronounced CMSC inhibition was observed only in samples with normal or high factor H values. No significant correlation was found between CMSC or CMSC inhibition and circulating IC levels, but pronounced CMSC inhibition was registered only in strongly IC positive sera.

Complement-mediated solubilization of immune complexes. Solubilization inhibition and complement factor levels in SLE patients.

The complement-mediated solubilization (CMS) of immune complexes (IC) and the initial kinetics (IKS) of this reaction in human sera depleted of or deficient in C2, C3, C8, factors B, P and I were investigated. Sera depleted of B or P and those lacking native C3 or factor I showed virtually no CMS whereas the IKS and CMS capacity of a C8-deficient serum were within the reference range. The IKS of a C2-deficient serum was markedly retarded while the CMS capacity was normal. Addition of C2 normalized the kinetics of the reaction. There was a good correlation between the kinetics of CMS determined by a radioassay and kinetic data for the binding of C3b to preformed immune complexes. The CMS capacity reached maximum at 39-41 degrees C and at an ionic strength of approximately 0.20 mu. Selective chelation of Mg2+ completely abolished the CMS of IC. Maximal CMS was observed at Mg2+ concentration of about 2mM. Chelation of Ca2+ in serum by Mg2+-ethylene glycol tetraacetic acid reduced the CMS capacity by up to 50% and the IKS was markedly retarded. Varying the Zn2+ or Mn2+ ion concentrations in serum influenced neither the IKS nor the CMS capacity.

Solubilization of immune complexes in complement factor deficient sera and the influence of temperature, ionic strength and divalent cations on the solubilization reaction.

Svend-Erik Svehag

Papers

Complement-mediated solubilization of immune complexes and their interaction with complement C3 receptors.

Complement-mediated solubilization of immune complexes. Solubilization inhibition and complement factor levels in SLE patients.

Solubilization of immune complexes in complement factor deficient sera and the influence of temperature, ionic strength and divalent cations on the solubilization reaction.