J. Michelle Kahlenberg,
Assistant Professor of Internal Medicine,
Division of Rheumatology
Systemic Lupus Erythematosus (SLE) is an autoimmune disease with pleiotropic manifestations, including renal failure, hematologic abnormalities and severe skin disease in up to 70% of patients1. While progress is being made, much remains unknown about disease pathogenesis. As a result, many treatments are globally immunosuppressive and result in severe side effects such as sterility and increased risk of infection and malignancy.
Recently, the innate immune system, particularly the role of type I IFNs, has been demonstrated to play an important role in disease development. IFN-α levels correlate with disease severity2, and in murine models of lupus, including (NZB/NZW)F1, IFN-α signaling is required for B-cell activation, formation of autoantibodies and induction of proteinuria3. Type I IFNs also play a role in development of cutaneous lesions in SLE, correlate with rash severity and are induced by stimuli such as UV light at increased levels over healthy controls4,5 . Our work has suggested that type I IFNs can regulate the inflammasome6,7 , so we are searching to understand how and the impact this has on disease development using murine models as well as primary tissue from patients.
1. Mikita, N., Ikeda, T., Ishiguro, M. & Furukawa, F. Recent advances in cytokines in cutaneous and systemic lupus erythematosus. J Dermatol 38, 839-849, doi:10.1111/j.1346-8138.2011.01237.x (2011).
2. Baechler, E. et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proceedings of the National Academy of Sciences of the United States of America 100, 2610-2615 (2003).
3. Thibault, D. et al. Type I interferon receptor controls B-cell expression of nucleic acid-sensing Toll-like receptors and autoantibody production in a murine model of lupus. Arthritis research & therapy 11, R112-R112 (2009).
4. Braunstein, I., Klein, R., Okawa, J. & Werth, V. P. The IFN-regulated gene signature is elevated in SCLE and DLE and correlates with CLASI score. British Journal of Dermatology, no-no, doi:10.1111/j.1365-2133.2012.10825.x (2012).
5. Reefman, E., Kuiper, H., Limburg, P. C., Kallenberg, C. G. M. & Bijl, M. Type I interferons are involved in the development of ultraviolet B- induced inflammatory skin lesions in systemic lupus erythaematosus patients. Annals of the Rheumatic Diseases 67, 11-18, doi:10.1136/ard.2007.070359 (2008).
6. Kahlenberg, J. M., Carmona-Rivera, C., Smith, C. K. & Kaplan, M. J. Neutrophil Extracellular Trap–Associated Protein Activation of the NLRP3 Inflammasome Is Enhanced in Lupus Macrophages. The journal of immunology 190, 1217-1226, doi:10.4049/jimmunol.1202388 (2013).
7. Kahlenberg, J. M. et al. Inflammasome activation of IL-18 results in endothelial progenitor cell dysfunction in systemic lupus erythematosus. J Immunol 187, 6143-6156, doi:jimmunol.1101284 [pii]
Kahlenberg JM, Carmona-Rivera C, Smith CK, and Kaplan MJ. Neutrophil Extracellular Trap-Associated Protein Activation of the NLRP3 Inflammasome Is Enhanced in Lupus Macrophages. Journal of Immunology 2013; 190:1217-1226.
Kahlenberg JM, Kaplan MJ. Mechanisms of premature atherosclerosis in rheumatoid arthritis and lupus. Annu Rev Med. 2013;64:249-63.
Kahlenberg JM, Thacker SG, Berthier CC, Cohen CD, Kretzler M, Kaplan MJ. Inflammasome activation of IL-18 results in endothelial progenitor cell dysfunction in systemic lupus erythematosus. J Immunol. 2011 Dec 1;187(11):6143-56.
Kahlenberg JM, Kaplan MJ. The interplay of inflammation and cardiovascular disease in systemic lupus erythematosus. Arthritis Res Ther. 2011 Feb 28;13(1):203.
Kahlenberg JM, Fox DA. Advances in the medical treatment of rheumatoid arthritis. Hand Clin. 2011 Feb;27(1):11-20.
Kahlenberg JM. Neuromyelitis optica spectrum disorder as an initial presentation of primary Sjögren's syndrome. Semin Arthritis Rheum. 2011 Feb;40(4):343-8.
Verhoef PA, Kertesy SB, Lundberg K, Kahlenberg JM, Dubyak GR. Inhibitory effects of chloride on the activation of caspase-1, IL-1beta secretion, and cytolysis by the P2X7 receptor. J Immunol. 2005 Dec 1;175(11):7623-34.
Kahlenberg JM, Lundberg KC, Kertesy SB, Qu Y, Dubyak GR. Differing caspase-1 activation states in monocyte versus macrophage models of IL-1beta processing and release. J Leukoc Biol. 2004 Sep;76(3):676-84. Epub 2004 Jul 7.
Kahlenberg JM, Dubyak GR. Mechanisms of caspase-1 activation by P2X7 receptor-mediated K+ release. Am J Physiol Cell Physiol. 2004 May;286(5):C1100-8.
Peña CE, Kahlenberg JM, Hatfull GF. Protein-DNA complexes in mycobacteriophage L5 integrative recombination. J Bacteriol. 1999 Jan;181(2):454-61.
Peña CE, Kahlenberg JM, Hatfull GF. The role of supercoiling in mycobacteriophage L5 integrative recombination. Nucleic Acids Res. 1998 Sep 1;26(17):4012-8.