Hanno B. Richards

15 – ORIGINS OF ANTINUCLEAR ANTIBODIES

Publisher Summary The production of antinuclear antibodies (ANAs) is one of the defining features of systemic lupus erythematosus (SLE). This chapter reviews what has been learned about antinuclear antibodies and their molecular targets and pathogenesis. Interferons, cytokines with antiviral and antiproliferative effects, as well as important effects on the activation of immune effector cells, are likely to be involved in the pathogenesis of SLE. They are classified into type I and type II IFNs based on sequence homology, receptor usage, and the cellular origin. There is strong evidence that T cells are involved in autoantibody production, including indirect evidence from characteristics of the autoantibody response, the inability of tetramethylpentadecane (TMPD) to induce autoantibodies in T-cell-deficient mice, the likely involvement of TH17 and TFH cells in the induction of lupus autoantibodies, and the diminished autoantibody production following CTLA4-Ig treatment. However, there also is evidence that autoantibodies can arise independently of T cells via extrafollicular activation of autoreactive B cells. Most studies suggest that B-1 cells produce polyreactive antibodies, exhibit only limited somatic mutation, develop independently of T cells, and are prone to make low-affinity autoantibodies against repetitive epitopes such as pneumococcal polysaccharide (TI-2 antigens). In contrast, conventional (B-2) B cells require cognate T cell help and produce high-affinity, somatically mutated antibodies. Further studies are needed to define to what degree autoantibody production in SLE patients results from cognate T–B interactions and post-germinal center memory/plasma cells and vs. extrafollicular, T-cell-independent (TLR-mediated) responses.

Induction of B Cell Autoimmunity by Pristane

Plasmacytomas are induced in BALB/cAn and certain other strains of mice after intraperitoneal injection of 2, 6, 10, 14 tetramethylpentadecane (pristane) (1). The pathogenesis of these tumors remains incompletely understood despite intensive study. Chromosomal translocations involving the immunoglobulin and c-myc loci are generated and may be important for malignant transformation. Production of IL-6 and prostaglandin intermediates within the peritoneal oil granulomas developing in pristane-treated mice also appears to play a critical role. Indomethacin inhibits both IL-6 production and the development of plasmacytomas (2,3). The lack of plasmacytoma development in IL-6 knockout mice further underscores the importance of this cytokine in the neoplastic process (4). The reduced frequency of plasmacytomas in specific pathogen free (SPF) vs. conventionally housed mice (5) argues that antigenic stimulation also may contribute to the pathogenesis of these plasma cell tumors.

Pathogenesis of Autoantibody Production and Glomerulonephritis in Pristane-Treated Mice

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease of uncertain etiology that is influenced by both genetic and environmental factors. Although lupus is usually considered to be primarily a genetic disorder, environmental triggers, such as ultraviolet light and certain medications (1), can trigger the disease in genetically susceptible hosts. The isoprenoid alkane pristane (2,6,10,14-tetramethypentadecane), a component of mineral oil, has recently been shown to be a powerful environmental trigger that induces a lupus-like syndrome in nonautoimmune strains of mice (2,3). Pristane-treated mice develop autoantibodies associated with SLE, including the marker antibodies anti-Sm, double-stranded DNA (dsDNA), and ribosomal P, as well as less disease-specific autoantibodies (anti-nRNP, Su, single-stranded DNA [ssDANA], and histone) at titers as high as 1:250,000 (4). They also develop immune complex—mediated glomerulonephritis closely resembling human lupus nephritis with glomerular IgG, IgM and complement deposition, and mesangial hypercellularity (2,3). These similarities with human lupus and the fact that disease can be induced in virtually all normal strains of mice, regardless of genetic background, suggest that this new inducible lupus model may be useful for defining the immunologic defects causing SLE.