Autoantibody repertoires in inflammatory and autoimmune disease
Visiting adress: L5:02 Karolinska Universitetssjukhuset Solna, 17176 Stockholm
Postal adress: Institutionen för medicin, Solna (MedS), K2, Forskargrupp L Klareskog, L8:04, Karolinska Universitetssjukhuset, Solna 171 76 Stockholm
Shipping adress: L5:02 Karolinska Universitetssjukhuset Solna, 17176 Stockholm
B-cells and antibodies are an essential part of the adaptive immune system and play important roles in protecting us from infectious threats. Yet, with the adaptive immune system comes also the risk of developing autoimmune disease and self-reactive IgG autoantibodies. In autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), the host immune system for unknown reasons recognize self-biomolecules as foreign, causing if untreated, devastating disease. Different diseases are characterized by different distinct disease-associated autoreactivities. Yet, other types of IgM autoreactivities may in contrast be very common and play protective roles.
Disease associated IgG autoantibodies in rheumatoid arthritis
Rheumatoid arthritis is associated with the presence of circulating autoantibodies recognizing self-proteins post-translationally modified by citrullination. These anti-citrullinated protein antibodies (ACPA) can recognize a range of different modified proteins with patient-unique profiles and while antibodies can be present long before onset of disease, the number of IgG reactivates seem to increase over time until the disease enters a chronic phase. Although it has been hypothesized that the ACPA IgG and the ACPA positive B-cells contributes to disease pathogenesis and that different reactivities may drive different disease pathways, the mechanism(s) still remain to be elucidated. In addition, the phenotype, immunogenetics, and clonal diversity of the autoreactive B-cells have not yet been well established.
Protective IgM in homeostasis and immune regulation
Natural IgM are present in the circulation already from birth and these autoreactive antibodies have been postulated to have innate-like properties and play roles in apoptotic cell clearance and homeostasis. Previous studies have shown that higher serum levels of IgM antibodies recognizing oxidation-modified determinants on apoptotic cells are associated with less disease activity and protection from cardiovascular disease in patients with SLE. Murine studies have shown that the same IgM reactivities can induce potent anti-inflammatory signaling pathways in innate immune cells and mediate phagocytosis of apoptotic cells.
Our research aim is to use antibody engineering and high-throughput technology for surveys of B-cell repertoires in autoimmune patients. The overall goal is to increase our knowledge about disease pathogenesis to develop better diagnostic, prognostic and therapeutic approaches.
Work plan and methods
The current investigations are using protein engineering and next generation sequencing techniques for surveys of self-reactive B-cell repertoires in patients with autoimmune disease. We are also performing serum biomarker assays with a focus on different subsets of autoreactive antibodies. In addition, we directly study the immune activating properties of monoclonal autoreactive antibodies and how to modify these functions for development of new therapies.
-The Swedish Research Council (Vetenskapsrådet)
-Konung Gustav V:s 80-års fond
-Stiftelsen Professor Nanna Svartz fond
-Magnus Bergvalls Stiftelse
Five selected publications
Relation of carotid plaque with natural IgM antibodies in patients with systemic lupus erythematosus.
Clin. Immunol. 2014 Jul;153(1):1-7
Protective autoantibodies in the rheumatic diseases: lessons for therapy.
Nat Rev Rheumatol 2013 May;9(5):291-300
MAPK phosphatase-1 is required for regulatory natural autoantibody-mediated inhibition of TLR responses.
Proc. Natl. Acad. Sci. U.S.A. 2012 Nov;109(48):19745-50
Natural antibody to apoptotic cell membranes inhibits the proinflammatory properties of lupus autoantibody immune complexes.
Arthritis Rheum. 2012 Oct;64(10):3388-98
In vivo VL-targeted microbial superantigen induced global shifts in the B cell repertoire.
J. Immunol. 2012 Jul;189(2):850-9