CAROLINE GRÖNWALL TEAM

Autoantibodies and their role in inflammatory and autoimmune disease

About

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. RA is for example associated with the presence of circulating autoantibodies recognizing self-proteins post-translationally modified by citrullination. Yet, other types autoreactivities of IgM type may in contrast be very common also in health and play protective roles.

 

Research

Our main research aim is to increase our understanding about how autoantibodies and autoreactive B cells contribute to the pathogenesis of human disease, with the future goal to develop new prognostic and therapeutic strategies. Our studies include investigations of both potentially pathogenic IgG reactivities as well as natural IgM reactivities with potentially immune-homeostatic capacities. We are using antibody engineering and high-throughput methodology to study the immunoglobulin diversity of autoreactive B cells in RA and SLE. We are in addition directly studying the immune activating properties of human monoclonal autoreactive antibody clones isolated from patients, and investigating how to modulate these functions in novel therapeutic approaches. We are especially interested in autoreactivity to post-translational modifications (PTMs) in different classes of autoantibodies.

 

Selected publications

Sahlström P, Hansson M, Steen J, Amara K, Titcombe PJ, Forsström B, Stålesen R, Israelsson L, Piccoli L, Lundberg K, Klareskog L, Mueller DL, Catrina AI, Skriner K, Malmström V, Grönwall C. Different hierarchies of anti-modified protein autoantibody reactivities in rheumatoid arthritis. Arthritis Rheumatol. 2020 Jun 5. doi: 10.1002/art.41385. Online ahead of print

Wang Y, Lloyd KA, Melas I, Zhou D, Thyagarajan R, Lindqvist J, Hansson M, Svärd A, Mathsson-Alm L, Kastbom A, Lundberg K, Klareskog L, Catrina AI, Rapecki S, Malmström V, Grönwall C. Rheumatoid arthritis patients display B-cell dysregulation already in the naïve repertoire consistent with defects in B-cell tolerance. Sci Rep. 2019 Dec 27;9(1):19995. doi: 10.1038/s41598-019-56279-0.

Amara, K., Israelsson, L., Stålesen, R., Sahlström, P., Steen, J., Malmström, V. and Grönwall, C. A Refined Protocol for Identifying Citrulline-specific Monoclonal Antibodies from Single Human B Cells from Rheumatoid Arthritis Patient Material. Bio-protocol. 2019: 9(17): e3347.

Steen J, Forsström B, Sahlström P, Odowd V, Israelsson L, Krishnamurthy A, Badreh S, Mathsson Alm L, Compson J, Ramsköld D, Ndlovu W, Rapecki S, Hansson M, Titcombe PJ, Bang H, Mueller DL, Catrina AI, Grönwall C, Skriner K, Nilsson P, Lightwood D, Klareskog L, Malmström V. Recognition of Amino Acid Motifs, Rather Than Specific Proteins, by Human Plasma Cell-Derived Monoclonal Antibodies to Posttranslationally Modified Proteins in Rheumatoid Arthritis. Arthritis Rheumatol. 2019 Feb;71(2):196-209.

Lloyd KA, Wigerblad G, Sahlström P, Garimella MG, Chemin K, Steen J, Titcombe PJ, Marklein B, Zhou D, Stålesen R, Ossipova E, Lundqvist C, Ekwall O, Rönnelid J, Mueller DL, Karlsson MCI, Kaplan MJ,  Skriner K, Klareskog L, Wermeling F, Malmström V, Grönwall C. Differential ACPA binding to nuclear antigens reveals a PAD-independent pathway and a distinct subset of acetylation cross-reactive autoantibodies in rheumatoid arthritis. Front. Immunol. 2019 Jan 4;9:3033.

Malmström V, Grönwall C. The parallel worlds of ACPA-positive and RF-positive B cells. Nat Rev Rheumatol. 2018 Nov;14(11):626-628. 

Lloyd K, Steen J, Titcombe PJ, Amara K, Israelsson L, Lundström LS, Zhou D, Zubarev RA, Reed E, Piccoli L, Gabay C, Lanzavecchia A, Baeten D, Lundberg K, Mueller DL, Klareskog L, Malmström V, Grönwall C. Variable domain N-linked glycosylation and negative surface charge are key features of monoclonal ACPA: implications for B-cell selection. Eur J Immunol. 2018 Jun;48(6):1030-1045. 

Hardt U, Larsson A, Gunnarsson I, Clancy RM, Petri M, Buyon JP, Silverman GJ, Svenungsson E, Grönwall C. Autoimmune reactivity to malondialdehyde adducts in Systemic Lupus Erythematosus is associated with disease activity and nephritis. Arthritis Res Ther. 2018 Feb 26; 20(1):36. 

Grönwall C, Amara K, Hardt U, Krishnamurthy A, Steen J, Engström M, Sun M, Ytterberg AJ, Zubarev RA, Scheel-Toellner D, Greenberg JD, Klareskog L, Catrina AI, Malmström V, Silverman GJ. Autoreactivity to malondialdehyde-modifications in rheumatoid arthritis is linked to disease activity and synovial pathogenesis. J Autoimmun. 2017 Nov;84:29-45.

Grönwall C, Hardt U, Gustafsson JT, Elvin K, Jensen-Urstad K, Kvarnström M, Grosso G, Rönnelid J, Padyukov L, Gunnarsson I, Silverman GJ, Svenungsson E. Depressed serum IgM levels in SLE are restricted to defined subgroups. Clinical Immunology. 2017 Oct;183:304-315.

Pelzek AJ, Grönwall C, Rosenthal P, Greenberg JD, McGeachy M, Moreland L, Rigby WF, Silverman GJ. Persistance of disease-associated anti-citrullinated protein memory B cells in rheumatoid arthritis persist in clinical remission. Arthritis Rheumatol. 2017 Jun;69(6):1176-

1186.

Grönwall C, Clancy RM, Getu L, Lloyd KA, Siegel DL, Reed JH, Buyon JP, Silverman GJ. Modulation of natural IgM autoantibodies to oxidative stress-related neo-epitopes on apoptotic cells in newborns of mothers with anti-Ro autoimmunity. J Autoimmun. 2016 Sep;73:30-41.

Grönwall C, Charles ED, Dustin LB, Rader C, Silverman GJ. Selection of apoptotic cell specific human antibodies from adult bone marrow. PLoS One. 2014 Apr 23;9(4):e95999.

Silverman GJ, Vas J, Grönwall C. Protective autoantibodies in the rheumatic diseases: lessons for therapy. Nature Reviews Rheumatology. 2013 May;9(5):291-300.

Grönwall C, Chen Y, Vas J, Khanna S, Thiel S, Corr M, Kono DH, Silverman GJ. MAPK phosphatase-1 is required for regulatory natural autoantibody mediated inhibition of TLR responses. Proc. Natl. Acad. Sci. USA. 2012 Nov 27;109(48):19745-50.

Grönwall C, Kosakovsky Pond SL, Young JA, Silverman GJ. In vivo VL-targeted microbial superantigen induced global shifts in the B cell repertoire. Journal of Immunology. 2012 Jul 15;189(2):850-9.

Grönwall C, Vas J, Silverman GJ. Protective roles of natural IgM antibodies. Front Immunol. 2012 Apr 4;3:66.

Grönwall C, Akhter E, Oh C, Burlingame RW, Petri M, Silverman GJ. IgM autoantibodies to distinct apoptosis-associated antigens correlate with protection from cardiovascular events and renal disease in patients with SLE. Clin Immunol. 2012 Mar;142(3):390-8.