Unmethylated CpG motifs are prevalent in bacterial but not vertebrate genomic DNAs. Oligodeoxynucleotides (ODN) containing CpG motifs activate host defense mechanisms leading to innate and acquired immune responses. The recognition of CpG motifs requires Toll-like receptor (TLR) 9, which triggers alterations in cellular redox balance and the induction of cell signaling pathways including the mitogen activated protein kinases (MAPKs) and NF kappa B. Cells that express TLR-9, which include plasmacytoid dendritic cells (PDCs) and B cells, produce Th1-like proinflammatory cytokines, interferons, and chemokines. Certain CpG motifs (CpG-A) are especially potent at activating NK cells and inducing IFN-alpha production by PDCs, while other motifs (CpG-B) are especially potent B cell activators. CpG-induced activation of innate immunity protects against lethal challenge with a wide variety of pathogens, and has therapeutic activity in murine models of cancer and allergy. CpG ODN also enhance the development of acquired immune responses for prophylactic and therapeutic vaccination.

CpG Motifs in Bacterial DNA and Their Immune Effects

The development and widespread use of vaccines against infectious agents have been a great triumph of medical science. One reason for the success of currently available vaccines is that they are capable of inducing long-lived antibody responses, which are the principal agents of immune protection against most viruses and bacteria. Despite these successes, vaccination against intracellular organisms that require cell-mediated immunity, such as the agents of tuberculosis, malaria, leishmaniasis, and human immunodeficiency virus infection, are either not available or not uniformly effective. Owing to the substantial morbidity and mortality associated with these diseases worldwide, an understanding of the mechanisms involved in generating long-lived cellular immune responses has tremendous practical importance. For these reasons, a new form of vaccination, using DNA that contains the gene for the antigen of interest, is under intensive investigation, because it can engender both humoral and cellular immune re...

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DNA vaccines: immunology, application, and optimization*.

Synthetic oligodeoxynucleotides (ODNs) that contain immunostimulatory CpG motifs trigger an immunomodulatory cascade that involves B and T cells, natural killer cells and professional antigen-presenting cells. The response to CpG ODNs skews the host's immune milieu in favour of T helper 1 (TH1)-cell responses and pro-inflammatory cytokine production — an effect that underlies their use as immunoprotective agents, vaccine adjuvants and anti-allergens. Preclinical studies provide evidence that CpG ODNs are effective for each of these uses. Ongoing clinical studies indicate that CpG ODN use is safe in humans, and that they modulate the immune response to co-administered allergens and vaccines.

Immunotherapeutic uses of CpG oligodeoxynucleotides

https://www.ajkd.org/article/S0272-6386(12)80312-X/pdf

Tubulointerstitial changes as a major determinant in the progression of renal damage.

The macrophage theory of depression

In summary, we suggest that the following statements regarding lupus nephritis are best supported by the existing data. 1) Lupus nephritis is an immunologically complex disorder. Autoantibodies directed against multiple epitopes on chromatin, including but not limited to dsDNA, may contribute to nephritis. 2) The presence of charged residues within autoantibody heavy chain CDR regions, particularly CDR3, may be essential to the property of nephritogenicity. 3) Chromatin/antichromatin immune complexes (formed either in the circulation or in situ in the GBM) are likely the proximal cause of lupus nephritis. Cross-reactive autoantibodies or antibodies reacting directly to glomerular antigens are less likely to play a major pathogenic role. 4) The induction of lupus nephritis may relate to the propensity of chromatin or its components to bind to the GBM by virtue of the interactions of histones with type IV collagen and heparan-sulfated glycosaminoglycans. Nonetheless, as indicated above, there are numerous issues that remain to be addressed and clarified with respect to lupus nephritis. Insight into these issues is not only of theoretical interest, but may lead to new approaches to diagnostic testing and more specific therapies to replace currently use nonspecific immunosuppressive drugs, which have substantial toxicities.

Review: Nephritogenic autoantibodies in lupus: Current concepts and continuing controversies

Paradoxical conservation of cardiac and renal arachidonate content in essential fatty acid deficiency.

Preautoimmune New Zealand Black/White (NZB/NZW) mice immunized with Escherichia coli (EC) double standard (ds) DNA produce antibodies that bind mammalian dsDNA and display specificities similar to spontaneous lupus anti-DNA. Since calf thymus (CT) dsDNA fails to induce these antibodies, these results suggest a special potency of foreign DNA in inducing serological manifestations of lupus in a susceptible host. To assess the effects of DNA immunization on clinical manifestations in NZB/NZW mice, we measured renal disease and survival of mice immunized with either (a) EC dsDNA as complexes with methylated bovine serum albumin (mBSA) in adjuvant; (b) CT dsDNA with mBSA in adjuvant; (c)mBSA alone in adjuvant; or (d) unimmunized. After immunization with EC dsDNA, NZB/NZW mice developed significant levels of anti-dsDNA antibodies. Nevertheless, these mice had less proteinuria, nitrate/nitrite excretion, and glomerular pathology than mice immunized with either mBSA alone, CT dsDNA/mBSA complexes, or unimmunized mice. Survival of the EC dsDNA immunized mice was significantly increased compared with the other mice. Furthermore, immunization of mice after the onset of anti-DNA production and proteinuria stabilized nephritis and prolonged survival. The improvement in renal disease occurred despite the expression of autoantibodies that bound mammalian dsDNA as well as glomerular antigens. These results suggest that bacterial DNA has immunological properties that attenuate murine lupus despite the induction of pathogenic antibodies.

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Modulation of renal disease in autoimmune NZB/NZW mice by immunization with bacterial DNA.

To clarify the pathogenesis of lupus nephritis, we developed an assay that defines a glomerular binding activity (GBA) in both murine and human lupus sera highly correlated with nephritis. In the current study, we used a cross-adsorption strategy to establish that the GBA in MRL lpr serum binds to the glomerular basement membrane (GBM). We subsequently observed that this binding to the GBM was competitively inhibited by either exogenous DNA or histone, abrogated by pretreatment of the GBM with DNAse, and restored after DNase treatment with DNA/histone in a synergistic fashion. GBM binding was also completely inhibited by pretreatment of GBM with collagenase but not heparatinase. The effect of collagenase was not reversed by the subsequent addition of DNA, but was restored by the sequential re-addition of type IV collagen and DNA. By using purified basement membrane components, we found that MRL lpr serum bound avidly to DNA coated on type I collagen but less well (or not at all) to DNA coated on type IV collagen, laminin, or fibronectin. Histone pretreatment of type IV collagen before DNA addition, however, synergistically enhanced binding in a fashion similar to that seen with native GBM. Thus, the GBA in MRL lpr serum seems to be comprised of autoantibodies that bind to histones and/or DNA that adhere to type IV collagen within the GBM. These data support the planted Ag hypothesis as the principal pathogenic mechanism in lupus nephritis and suggest that multiple autoantibodies may contribute to this disorder.

Glomerular binding activity in MRL lpr serum consists of antibodies that bind to a DNA/histone/type IV collagen complex.

Glucose-induced phospholipid hydrolysis in isolated pancreatic islets: quantitative effects on the phospholipid content of arachidonate and other fatty acids

James B. Lefkowith

Papers

Review: Nephritogenic autoantibodies in lupus: Current concepts and continuing controversies

Paradoxical conservation of cardiac and renal arachidonate content in essential fatty acid deficiency.

Modulation of renal disease in autoimmune NZB/NZW mice by immunization with bacterial DNA.

Glomerular binding activity in MRL lpr serum consists of antibodies that bind to a DNA/histone/type IV collagen complex.

Glucose-induced phospholipid hydrolysis in isolated pancreatic islets: quantitative effects on the phospholipid content of arachidonate and other fatty acids