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.
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.
Image & Media Gallery
Studies Seeking Patients
Carlucci PM, Purmalek MM, Dey AK, Temesgen-Oyelakin Y, Sakhardande S, Joshi AA, Lerman JB, Fike A, Davis M, Chung JH, Playford MP, Naqi M, Mistry P, Gutierrez-Cruz G, Dell'Orso S, Naz F, Salahuddin T, Natarajan B, Manna Z, Tsai WL, Gupta S, Grayson P, Teague H, Chen MY, Sun HW, Hasni S, Mehta NN, Kaplan MJ. Neutrophil subsets and their gene signature associate with vascular inflammation and coronary atherosclerosis in lupus. JCI Insight. 2018 Apr 19;3(8).
Carmona-Rivera C, Carlucci PM, Moore E, Lingampalli N, Uchtenhagen H, James E, Liu Y, Bicker KL, Wahamaa H, Hoffmann V, Catrina AI, Thompson P, Buckner JH, Robinson WH, Fox DA, Kaplan MJ. Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis. Sci Immunol. 2017;2(10).
Faridi MH, Khan SQ, Zhao W, Lee HW, Altintas MM, Zhang K, Kumar V, Armstrong AR, Carmona-Rivera C, Dorschner JM, Schnaith AM, Li X, Ghodke-Puranik Y, Moore E, Purmalek M, Irizarry-Caro J, Zhang T, Day R, Stoub D, Hoffmann V, Khaliqdina SJ, Bhargava P, Santander AM, Torroella-Kouri M, Issac B, Cimbaluk DJ, Zloza A, Prabhakar R, Deep S, Jolly M, Koh KH, Reichner JS, Bradshaw EM, Chen J, Moita LF, Yuen PS, Li Tsai W, Singh B, Reiser J, Nath SK, Niewold TB, Vazquez-Padron RI, Kaplan MJ, Gupta V. CD11b activation suppresses TLR-dependent inflammation and autoimmunity in systemic lupus erythematosus. J Clin Invest. 2017 Apr 3;127(4).
Smith CK, Seto NL, Vivekanandan-Giri A, Yuan W, Playford MP, Manna Z, Hasni SA, Kuai R, Mehta NN, Schwendeman A, Pennathur S, Kaplan MJ. Lupus high-density lipoprotein induces proinflammatory responses in macrophages by binding lectin-like oxidised low-density lipoprotein receptor 1 and failing to promote activating transcription factor 3 activity. Ann Rheum Dis. 2017;76(3):602-611.
Carmona-Rivera C, Purmalek MM, Moore E, Waldman M, Walter PJ, Garraffo HM, Phillips KA, Preston KL, Graf J, Kaplan MJ, Grayson PC. A role for muscarinic receptors in neutrophil extracellular trap formation and levamisole-induced autoimmunity. JCI Insight. 2017;2(3):e89780.
Lood C, Blanco LP, Purmalek MM, Carmona-Rivera C, De Ravin SS, Smith CK, Malech HL, Ledbetter JA, Elkon KB, Kaplan MJ. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat Med. 2016 Jan 18. doi: 10.1038/nm.4027. [Epub ahead of print]
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 PC, Carmona-Rivera C, Xu L, Lim N, Gao Z, 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.
Khandpur R, Carmona-Rivera C, Vivekanandan-Giri A, Gizinski A, Yalavarthi S, Knight JS, Friday S, Li S, Patel RM, Subramanian V, Thompson P, Chen P, Fox DA, Pennathur S, Kaplan MJ. NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci Transl Med. 2013 Mar 27;5(178).