Autoantibodies and Immune Complexes

SLE is characterized by the production of a large list of antibodies against an array of non-organ-specific self-antigens present in the nucleus, cytoplasm, cell membrane, and serum. An immune response against self is commonly part of the normal immune response and is strictly regulated. Immune cells with autoreactive potential are present in large numbers in healthy individuals, and germline genes encoding for antigen receptors of autoreactive T and B cells are part of the normal gene repertoire. Autoreactive cells are positively selected in an antigen-driven manner (Nemazee 2000, Tonegawa 1983).

IgM antibodies to DNA are frequently produced in the normal host and bind to single-stranded (ss)DNA; they have low affinity for DNA and broad cross-reactivity with a variety of other self-antigens. The production of these natural anti-DNA antibodies is tightly regulated, and they usually do not undergo isotype switching and are encoded by germline genes; affinity maturation by the process of somatic mutation does not occur. On the contrary, anti-DNA antibodies in the serum of patients with SLE have quite different features in that they have undergone isotype switching to IgG of various subclasses, and germline genes usually do not encode them because new amino acids are introduced into their variable regions to enhance affinity (somatic mutations and hypermutations). Continuous receptor editing in lupus B cells may provide an additional impetus toward production of more "pathogenic" autoantibodies. Because DNA is a highly anionic macromolecule, positively charged amino acids, particularly arginine, are introduced into the autoantibody-variable regions to enhance DNA binding. Lupus anti-DNA antibodies are thus usually charged, IgG, relatively low cross-reactive and have high affinity towards double-stranded (ds)DNA.

T cells from patients with LE, activated by nucleosomes, provide help to lupus B cells to produce anti-dsDNA of the IgG class. DNA, nucleosomes, and other intracel-lular autoantigens that are common targets for the lupus immune system are made accessible to immune cells during apoptosis. These autoantigens can be found in surface blebs of dying apoptotic keratinocytes after ultraviolet (UV) light exposure. It is possible that exposure of a genetically susceptible individual to environmental factors causing apoptosis may serve as the trigger to form anti-DNA and other autoantibodies. The ability of an individual to produce anti-DNA antibodies is, to some degree, genetically determined (see Chap. 15).

Several lines of evidence have led to the classification of lupus as an immune complex disease. Immune complexes have been documented in the serum of patients with LE, and both immunoglobulin and complement factors or split products have been detected in several tissues, including kidneys and skin. In addition, hypocom-plementemia and increased levels of complement split factors are found in the serum and urine of patients with LE.

Cells expressing Fc and complement receptors, such as monocytes, phagocytes, and neutrophils, mediate clearance of immune complexes. Immune complex clearance is decreased in patients with LE, perhaps owing to abnormal Fc receptor function, resulting from the expression of alleles that bind IgG with lesser affinity or decreased numbers or altered allele expression of complement receptor 1.

The number of involved antigen and antibody molecules defines the lattice of an immune complex. The size and extent of lattice formation determine the rate of clearance and tissue deposition of immune complexes, and the number of Fc molecules in each immune complex defines its ability to bind to Fc receptors and trigger Fc-mediated cell functions. Large immune complexes (>Ag2Ab2) are quickly cleared by the reticuloendothelial system, and, when saturated, they deposit to tissues. Large immune complexes tend to activate complement more efficiently. Small immune complexes have a lesser tendency to deposit to tissues. The initial interaction may involve the charge of the antibody, as with deposition to kidneys, binding to an Fc or complement receptor or by specific or nonspecific binding of the F(ab')2 fragment of the involved antibody.

Immune complexes in the serum of patients with LE have distinct reasons to deposit to tissues in that those containing cationic anti-DNA antibodies facilitate binding to the kidney basement membrane. These antibodies are of IgG1, IgG2, and IgG3 subclasses and can activate complement effectively. In addition to anti-DNA antibodies, other nephrophilic antibodies can bind to the kidneys and instigate the formation of immune complexes and disease (Davidson and Diamond 2001).

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