Associated with Immune Complexes

We selected various diseases for discussion. Rather than a litany, the list is somewhat eclectic. We summarize findings in those diseases in which considerable clinical experience with laboratory tests has accumulated and in which immune complex testing has been shown to bear some clinical relevance to the disease (as defined in the introduction). Our emphasis is on those diseases in which immune complexes appear to have a definite pathologic role, the antigen-antibody system has been well defined, or testing for immune complexes is of some value in clinical management. 

Rheumatoid factors of the IgM and IgG classes have been shown to form immune complexes in serum or joint fluid either by self-association (K17, M4, M26, P13, Sll, W21) or by reaction with native IgG (C4, K17, M4, N5, Sll, W21, W22), and these appear to be the predominant immune complex material in rheumatoid arthritis (C4, Gl, K17, M4, M26, N5, Sll, W21, W22). The primary cause of rheumatoid factor production in rheumatoid arthritis is unknown. However, rheumatoid factors are known to be present in other diseases associated with chronic antigenic stimulation (C14, M14) and can be induced in vitro by stimulation with antigens, autologous aggregated IgG, anti-idiotype reagents, and polyclonal B cell activators such as lipopolysaccharide and Epstein-Barr virus (C4, Dll, F6, F7, Gil, 16, P10, S24). Rheumatoid factors, including IgG rheumatoid factors which form selfassociating intermediate-sized (11-19 S) complexes, play a major role in 

Although most of these immune complex materials appear to be combinations of IgG-IgG rheumatoid factor or IgG-IgM rheumatoid factor, other antigen-antibody systems may be important as well. The majority of patients with seropositive rheumatoid arthritis have antibodies to nuclear antigens present in Epstein-Barr virus-infected human cell lines (All, C6, N4, T4). Indeed, some rheumatoid factors appear to have dual specificity for both autologous IgG and these nuclear antigens (A13). Other, as yet unknown, types of complexes may be important as well (L3). 

In spite of the strong evidence for the role of DNA/anti-DNA complexes in causing the kidney lesions of systemic lupus (A6, K13, K15, W19), it is not certain that the material assayed in serum as immune complexes is actually composed of DNA linked to specific antibody. Several groups have demonstrated DNA (D2) or anti-DNA (H10) in immune complex material from sera, but careful studies by others have failed to repeat these findings (A7, H27, 18). DNA, by itself, does not persist in the circulation (G10, 17). Because of the multiplicity of autoantibodies found in lupus, any of a number of antigen-antibody systems may be involved (T4). Based on direct examination and the reactivity patterns with various immune complex assays, the immune complex material found in systemic lupus tends to be macromole-cular ( 19 S) and complement fixing (A5, A7, C5, D2, El, F12, Gl, L2, M10, N6, T15). 

Immune complex measurements have been widely used in patients with systemic lupus because of the strong evidence that this disease is mediated by immune complex injury. In general, a good correlation has been found between levels of immune complexes, anti-DNA titers, depressed comple- 

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Scharfstein, J., Correa, E. B., Gallo, G. R., and Nussenzweig, V., Human C4-binding protein. Association with immune complexes in vitro and in vivo. J. Clin. Invest. 63, 437-442 (1979). 

Qiacko et al, 1996). Cell growth is arrested when the type II Fey receptor bl (FcyRIIbl) associates with the B ceU receptor (BCR) by the interaction of their extracellular domains with immune complexes. Clustering FcyRIIbl with BCR induces the phosphorylation of the immimoreceptor tyrosine-based inhibitory motif (ITIM) within the FcyRIIb intracellular tail, which then allows SHIP to bind through its SH2 domain. Recruitment of SHIP to the cell membrane by FcyRIIb p-ITIM is believed to block extracellular uptake and cell growth via the inositol 5-phosphatase activity of SHIP. 

As seen in Table 3.3, many diverse traits are associated with the complex. However, it may be observed that two general classes of traits predominate (1) those involving polymorphic cell-surface structures, i.e. alloantigens (2) those involving mechanisms of immune response or recognition. Of course, these classes need not be mutually exclusive. Many or all of the immunological traits may reflect functions of cell-membrane molecules. 

The first component of complement is Cl. This is a complex of three molecules designated Clq, Clr and Cls. The classical pathway is only initiated by an immune complex (antibody bound to antigen) when Clq binds to the Fc portion of the complexed antibody (IgM or IgG). The binding of Clq activates the Clr and Cls molecules associated with it to yield activated Cl which now cleaves C4 and then C2 (subunits of... 

Cyanidin is the most common anthocyanin in foods. In addition, anthocyanins are stabilized by the formation of complexes with other flavonoids (co-pigmentation). In the United States, the daily anthocyanin consumption is estimated at about 200 mg. Several promising studies have reported that consumption of anthocyanin-rich foods is associated with reductions of the risks of cancers - and atherosclerosis and with preventive effects against age-related neuronal and behavioral declines. These beneficial effects of anthocyanins might be related to their reported biological actions such as modulators of immune response and as antioxidants. Knowledge of anthocyanin bioavailability and metabolism is thus essential to better understand their positive health effects. 

Paraneoplastic syndromes are clinical syndromes owing to nonmetastatic systemic effects of cancer. Tumors make and secrete biologically active products that can stimulate or inhibit hormone production, autoimmunity, immune complex production, or immune suppression. Lung cancer, particularly small cell lung cancer, is associated with a high rate of paraneoplastic... 

Homo sapiens (compared to Drosophila melanogaster) Large-scale gene duplications with substantial expansion of genes involved in acquired immune response (B cells, T cells, major histocompatibility complex genes, cytokines, chemokines and their receptors), plasma proteases (complement and hemostatic proteins), proteins associated with apoptotic regulation and proteins related to neuronal network formation and electrical coupling... 

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