Autoantibody repertoires in inflammatory and autoimmune disease

Team Grönwall

Contact

Caroline Grönwall

Senior research specialist
K2 Department of Medicine, Solna

Visiting adress: CMM L8:04 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: CMM L8:04 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.

Aim

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.

Financing

-The Swedish Research Council (Vetenskapsrådet)

-Reumatikerförbundet

-Konung Gustav V:s 80-års fond

-Stiftelsen Professor Nanna Svartz fond

-Magnus Bergvalls Stiftelse

Group members

Peter Sahlström

PhD student
K2 Department of Medicine, Solna

Selected publications

Differential ACPA Binding to Nuclear Antigens Reveals a PAD-Independent Pathway and a Distinct Subset of Acetylation Cross-Reactive Autoantibodies in Rheumatoid Arthritis.
Lloyd KA, Wigerblad G, Sahlström P, Garimella MG, Chemin K, Steen J, et al
Front Immunol 2018 ;9():3033

 

Variable domain N-linked glycosylation and negative surface charge are key features of monoclonal ACPA: Implications for B-cell selection.
Lloyd KA, Steen J, Amara K, Titcombe PJ, Israelsson L, Lundström SL, et al
Eur J Immunol 2018 06;48(6):1030-1045

Autoimmune reactivity to malondialdehyde adducts in systemic lupus erythematosus is associated with disease activity and nephritis.
Hardt U, Larsson A, Gunnarsson I, Clancy RM, Petri M, Buyon JP, et al
Arthritis Res Ther 2018 02;20(1):36

Autoreactivity to malondialdehyde-modifications in rheumatoid arthritis is linked to disease activity and synovial pathogenesis.
Grönwall C, Amara K, Hardt U, Krishnamurthy A, Steen J, Engström M, et al
J Autoimmun 2017 Nov;84():29-45

Depressed serum IgM levels in SLE are restricted to defined subgroups.
Grönwall C, Hardt U, Gustafsson JT, Elvin K, Jensen-Urstad K, Kvarnström M, et al
Clin Immunol 2017 10;183():304-315

Relation of carotid plaque with natural IgM antibodies in patients with systemic lupus erythematosus.
Grönwall C, Reynolds H, Kim JK, Buyon J, Goldberg JD, Clancy RM, et al
Clin Immunol 2014 Jul;153(1):1-7

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

MAPK phosphatase-1 is required for regulatory natural autoantibody-mediated inhibition of TLR responses.
Grönwall C, Chen Y, Vas J, Khanna S, Thiel S, Corr M, et al
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.
Vas J, Grönwall C, Marshak-Rothstein A, Silverman GJ
Arthritis Rheum 2012 Oct;64(10):3388-98

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