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Systemic Autoimmunity Branch
Systemic autoimmune diseases are a group of disorders characterized by a failure in self-tolerance to a wide variety of autoantigens, and include conditions like systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and anti-neutrophil cytoplasmic antibody associated-vasculitis (AAV). These disorders are very heterogeneous, but they have some commonalities. For instance, all appear to manifest after multi-step processes where genetic and environmental factors play key roles in predisposing individuals to a higher risk of establishing abnormal innate and adaptive immune responses. Subclinical immune dysregulation eventually leads to a pre-clinical phase of variable duration (sometimes decades), during which autoantibodies to specific antigens are synthesized. It is believed that exposure to a variety of additional environmental hits may be required to trigger the acute clinical manifestations that are characteristic of these specific conditions.
NET formation in low density granulocytes detected by laser confocal
microscopy immunofluorescence using human anti neutrophil elastase
antibody and Hoechst. A color-coded depth analysis of the
immunofluorescence of netting LDGs is displayed.
As treatments to suppress aberrant immune responses have improved and patients are able to survive for longer periods of time, the prevalence of end-stage complications, such as development of accelerated atherosclerosis not explained by traditional cardiovascular risk factors, has increased. We need to identify the susceptibility triggers that lead to a break in tolerance, as well as enhance our understanding of the innate and adaptive immune pathways crucial to initiate and perpetuate these autoimmune responses. In addition, we need to better identify the mechanisms that lead to specific clinical phenotypes and promotion of end-organ damage.
The broad and long-term objectives of the Systemic Autoimmunity Branch are to further the understanding of the clinical spectrum and pathophysiology of systemic autoimmune diseases, and to translate this knowledge into better therapies that improve outcomes for patients with these conditions. A major goal of the Systemic Autoimmunity Branch is to combine natural history or treatment studies with basic investigations into the etiology and/or pathophysiology of rheumatic diseases, with an emphasis on SLE, AAV, RA and other systemic autoimmune diseases affecting adults. Additionally, the branch works to train the next generation of scientists and physician scientists focused on the understanding of the pathogenesis and advancement in the treatments of patient afflicted by systemic autoimmune diseases.
Current areas of interest of the branch include:
- The role of neutrophils and neutrophil extracellular traps (NETs) in induction of loss of immunologic tolerance and acceleration of organ and vascular damage;
- How type I Interferons (IFNs) contribute to the development of premature atherogenesis and vasculopathy in SLE and other connective tissue diseases;
- Identification of novel biomarkers and therapeutic targets to mitigate CV damage and induce immunomodulation in SLE and other systemic rheumatic diseases.
Domingo-Gonzalez R, Martínez-Colón GJ, Smith AJ, Smith CK, Ballinger MN, Xia M, Murray S, Kaplan MJ, Yanik GA, Moore BB. Prostaglandin E2 Inhibits Neutrophil Extracellular Trap Formation Post-stem Cell Transplant. Am J Respir Crit Care Med. 2015 Sep 29. [Epub ahead of print]
Grayson PC1, Carmona-Rivera C1, Xu L2, Lim N2, Gao Z2, Asare AL, Specks U, Stone JH, Seo P, Spiera RF, Langford CA, Hoffman GS, Kallenberg CG, St Clair EW, Tchao NK, Ytterberg SR, Phippard DJ, Merkel PA, Kaplan MJ, Monach PA; Rituximab in ANCA-Associated Vasculitis-Immune Tolerance Network Research Group. Neutrophil-Related Gene Expression and Low-Density Granulocytes Associated With Disease Activity and Response to Treatment in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. Arthritis Rheumatol. 2015 Jul;67(7):1922-32. doi: 10.1002/art.39153.
Knight JS, Subramanian V, O'Dell AA, Yalavarthi S, Zhao W, Smith CK, Hodgin JB, Thompson PR, Kaplan MJ. Peptidylarginine deiminase inhibition disrupts NET formation and protects against kidney, skin and vascular disease in lupus-prone MRL/lpr mice. Ann Rheum Dis. 2014 Aug 7.
Smith CK, Vivekanandan-Giri A, Tang C, Knight JS, Mathew A, Padilla RL, Gillespie BW, Carmona-Rivera C, Liu X, Subramanian V, Hasni S, Thompson PR, Heinecke JW, Saran R, Pennathur S, Kaplan MJ. Neutrophil extracellular trap-derived enzymes oxidize high-density lipoprotein: An additional proatherogenic mechanism in systemic lupus erythematosus. Arthritis Rheumatol. 2014 May 16.
Carmona-Rivera C1, Zhao W, Yalavarthi S, Kaplan MJ. Neutrophil extracellular traps induce endothelial dysfunction in systemic lupus erythematosus through the activation of matrix metalloproteinase-2. Ann Rheum Dis. 2014 Feb 25. doi: 10.1136/annrheumdis-2013-204837
Palanichamy A, Bauer JW, Yalavarthi S, Meednu N, Barnard J, Owen T, Cistrone C, Bird A, Rabinovich A, Nevarez S, Knight JS, Dedrick R, Rosenberg A, Wei C, Rangel-Moreno J, Liesveld J, Sanz I, Baechler E, Kaplan MJ, Anolik JH. Neutrophil-mediated IFN activation in the bone marrow alters B cell development in human and murine systemic lupus erythematosus. J Immunol. 2014 Feb 1;192(3):906-18. doi: 10.4049/jimmunol.1302112. Epub 2013 Dec 30.
Knight JS, Luo W, O'Dell AA, Yalavarthi S, Zhao W, Subramanian V, Guo C, Grenn RC, Thompson PR, Eitzman DT, Kaplan MJ. Peptidylarginine Deiminase Inhibition Reduces Vascular Damage and Modulates Innate Immune Responses in Murine Models of Atherosclerosis. Circ Res. 2014 Jan 14. [Epub ahead of print]
Kahlenberg JM, Yalavarthi S, Zhao W, Hodgin JB, Reed TJ, Tsuji NM, Kaplan MJ.An essential role of caspase 1 in the induction of murine lupus and its associated vascular damage. Arthritis Rheumatol. 2014 Jan;66(1):152-62. doi: 10.1002/art.38225.
Marder W, Khalatbari S, Myles JD, Hench R, Lustig S, Yalavarthi S, Parameswaran A, Brook RD, Kaplan MJ. The Peroxisome Proliferator Activated Receptor-γ Pioglitazone Improves Vascular Function and Decreases Disease Activity in Patients With Rheumatoid Arthritis. J Am Heart Assoc. 2013 Nov 19;2(6):e000441. doi: 10.1161/JAHA.113.000441.See extended list of publications
Updated August 12, 2015