Upper two panels: schematic of antibody‑mediated damage to a glomerulus of the kidney. The autoantibody binds to type IV collagen within the basement membrane of the glomerular capillaries, causing complement activation and recruitment and activation of neutrophils and monocytes. Third panel: section of renal glomerulus in biopsy taken from the kidney of a patient with Goodpasture’s syndrome. The glomerulus is stained for IgG deposition by immunofluorescence. Anti‑glomerular basement membrane antibody (stained green) is deposited in a linear fashion along the glomerular basement membrane. Bottom panel: silver staining of a section through a renal glomerulus shows that the glomerulus capillaries (G) are compressed by the formation of a crescent (C), composed of proliferating epithelial cells and an influx of neutrophils (N) and monocytes (M), that have filled the urinary (Bowman's) space surrounding the glomerular capillaries.
monocyte or dendritic cell autoreactive B-cell survival Increased autoantibodies BAFF BAFF-R BCMA TACI dsDNA immune complex ssRNA apoptotic cellnecrotic cell IFN-˜IFN-˜plasmacytoid dendritic cell MyD88TLR-7 TLR-9 Nucleic acid-containing immune complexes generated from dying cells activate plasmacytoid DCs to produce IFN-˜IFN-˜stimulates myeloid cells to produce BAFF, which enhances the survival and autoantibody production of autoreactive B cells
Fig. 15.25 Defective clearance of nucleic acid-containing immune complexes activates overproduction of BAFF and type I interferons that can cause SLE.
of the normal clearance mechanisms, or when there are deficiencies in normal clearance mechanisms. An example of the former is serum sickness (see Section 14-15), which is caused by the injection of large amounts of serum proteins or by small-molecule drugs binding to serum proteins and acting as haptens. Serum sickness is a transient disease, lasting until the immune complexes have been cleared. Similarly, normal clearance mechanisms can be overwhelmed in chronic infections, such as bacterial endocarditis, in which the immune response to bacteria lodged on a cardiac valve is incapable of clearing the infection. The persistent release of bacterial antigens from the valve infection in the presence of a strong antibacterial antibody response causes widespread immune-complex injury to small blood vessels in organs such as the kidney and the skin. Other chronic infections, such as hepatitis C infection, can lead to the production of cryoglobulins and the condition mixed essential cryoglobulinemia, in which immune complexes are deposited in joints and tissues. Alternatively, there can be inherited impairment of mechanisms that contribute to normal clearance of immune complexes; such impairment may be caused by reduced expression of or functional defects in specific components of either complement or its receptors, or in Fc receptors, each of which occurs in subsets of patients with SLE.
Indeed, SLE can result from either the overproduction or the defective clearance of immune complexes, or both, at multiple levels (Fig. 15.25). In this disease, there is chronic IgG antibody production directed at ubiquitous self antigens present in nucleated cells, leading to a wide range of autoantibodies against common cellular constituents. The main antigens are three types of intracellular nucleoprotein particles—the nucleosome subunits of chromatin, the spliceosome, and a small cytoplasmic ribonucleoprotein complex containing two proteins known as Ro and La (named after the first two letters of the surnames of the two patients in whom autoantibodies against these proteins were discovered). For these autoantigens to participate in immune-complex formation, they must become extracellular. The autoantigens of SLE are exposed on dead and dying cells released from injured tissues.