Specific autoimmunity in rheumatoid arthritis : T cells, antibodies and genetic regulation

Complex interactions between genes and environmental factors may result in destruction of the body’s own cells and tissues by the immune system, i.e. autoimmunity. Rheumatoid arthritis (RA) is a chronic joint inflammation mediated by all arms of the immune system that can lead to tissue destruction and functional disabilities. Many genetic variants and environmental factors that affect the immune system in RA have been revealed in recent years, however it is still not known precisely how they regulate and control autoimmunity. In this work I studied the function and specificity of adaptive immunity in RA, and also addressed influences from known genetic variants that predispose for disease.

First, autoantibody responses to several RA-associated citrullinated autoantigens were studied in a cohort of patients with established RA. Antibody responses and their interrelationships were examined, both in the whole study cohort and following stratification to HLA-DRB1 types, since HLA-DRB1 alleles are the strongest genetic risk factors known for RA. The autoantibodies were found to be highly specific for RA and displayed only limited cross reactivity. HLA-DRB1*04 alleles strongly associated with the presence of these autoantibodies both in sera and synovial fluid.

T cells are believed to be central mediators of RA pathogenesis, however studying T cell specificity has been proven difficult. The stinking HLA-DRB1*04 association with different anti-citrulline antibody responses encouraged us to revisit T cell recognition and responses to citrullinated proteins. We identified an epitope from vimentin that binds HLA-DRB1*0401 in its citrullinated but not in its native form and T cell recognition and function were investigated. CD4 T cells from both HLADRB1* 0401 RA patients and healthy donors recognized citrullinated vimentin.

However, T cells derived from RA patients secreted higher levels of cytokines, suggesting previous activation and/or cytokine dysregulation in RA. This study required a development of an assay sensitive enough to allow detection of rare antigen-specific CD4 T cells. Having such a tool, we further applied the same method to functionally examine type-II collagen (CII)-reactive CD4 T cells from peripheral blood and synovial fluid from HLA-DR*04 RA patients. T cells indeed recognized different variants of the immunodominant T cell epitope of CII and displayed epitope spreading throughout the disease. Synovial fluid derived T cells produced higher levels of inflammatory cytokines as compared to blood suggesting local reactivation.

Many more RA predisposing genetic variants have been identified outside the HLA-DRB1 locus in recent years. We therefore continued to study the association with autoantibody specificities in two independent cohorts of RA patients. Several genetic variants were found to control autoantibodies formation; some associated with several autoantibodies whereas others exclusively linked with a single fine specificity.

In summary, our data suggest that both B and T cells selectively respond to autoantigens in RA and are controlled by HLA and additional RA-predisposing genes. This work emphasizes the importance of multidisciplinary investigation for the understanding of interaction between genes and immunity in order to functionally explain epidemiological findings. We further hope that our findings regarding T and B cell specificities will encourage others to continue in this direction, which may pave the road towards specific therapy in patients following precise gene-immune investigation.

List of scientific papers

I. Multiple antibody reactivities to citrullinated antigens in sera from patients with rheumatoid arthritis: association with HLA-DRB1 alleles. Omri Snir*, Mona Widhe*, Caroline von Spee, Johan Lindberg, Leonid Padyukov, Karin Lundberg, Åke Engström, Patrick J Venables, Joakim Lundeberg, Rikard Holmdahl, Lars Klareskog, Vivianne Malmström. Ann Rheum Dis. 2009; 68:736-743.
https://doi.org/10.1136/ard.2008.091355

II. Antibodies to several citrullinated antigens are enriched in the joints of RA patients. Omri Snir, Mona Widhe, Monika Hermansson, Caroline von Spee, Johan Lindberg, Sanne Hensen, Karin Lundberg, Åke Engström, Patrick J. W. Venables, René E. M. Toes, Rikard Holmdahl, Lars Klareskog, Vivianne Malmström. Arthritis & Rheumatism. 2010; 62:44-52.
https://doi.org/10.1002/art.25036

III. Identification and functional characterization of T cells reactive to citrullinatedvimentin in HLA-DRB1*0401 humanized mice and RA patients. Omri Snir*, Mary Rieck*, John A. Gebe, Betty B. Yue, Crystal A. Rawlings, Gerald Nepom, Vivianne Malmström, and Jane H. Buckner. Arthritis & Rheumatism. [Accepted]
https://pubmed.ncbi.nlm.nih.gov/21567378

IV. Multifunctional T cell reactivity to native and glycosylated type-II collagen in rheumatoid arthritis. Omri Snir, Johan Bäcklund, Julia Boström, Ida Andersson, Jan Kihlberg, Lars Klareskog, Rikard Holmdahl and Vivianne Malmström. [Submitted]

V. Common variants in non-HLA-DRB1 alleles associate with distinct ACPA fine specificities in RA patients. Omri Snir, David Gomez-Cabrero, Maria Seddighzadeh, Katharina Ute Klich, Lena Israelsson, Anca I Catrina, Jesper Tegner, Lars Klareskog, Vivianne Malmström and Leonid Padyukov. [Manuscript]