T-cell receptor–HLA-DRB1 associations suggest specific antigens in pulmonary sarcoidosis

Abstract

In pulmonary sarcoidosis, CD4+ T-cells expressing T-cell receptor Vα2.3 accumulate in the lungs of HLA-DRB1*03 + patients. To investigate T-cell receptor-HLA-DRB1*03 interactions underlying recognition of hitherto unknown antigens, we performed detailed analyses of T-cell receptor expression on bronchoalveolar lavage fluid CD4 + T-cells from sarcoidosis patients. Pulmonary sarcoidosis patients (n=43) underwent bronchoscopy with bronchoalveolar lavage. T-cell receptor α and β chains of CD4 + T-cells were analysed by flow cytometry, DNA-sequenced, and threedimensional molecular models of T-cell receptor-HLA-DRB1*03 complexes generated.Simultaneous expression of Vα2.3 with the Vβ22 chain was identified in the lungs of all HLA-DRB1*03 + patients. Accumulated Vα2.3/Vβ22-expressing T-cells were highly clonal, with identical or near-identical Vα2.3 chain sequences and inter-patient similarities in Vβ22 chain amino acid distribution. Molecular modelling revealed specific T-cell receptor-HLA-DRB1*03-peptide interactions, with a previously identified, sarcoidosis-associated vimentin peptide, (Vim)429-443 DSLPLVDTHSKRTLL, matching both the HLA peptide-binding cleft and distinct T-cell receptor features perfectly.We demonstrate, for the first time, the accumulation of large clonal populations of specific Vα2.3/Vβ22 T-cell receptor-expressing CD4 + T-cells in the lungs of HLA-DRB1*03 + sarcoidosis patients. Several distinct contact points between Vα2.3/Vβ22 receptors and HLA-DRB1*03 molecules suggest presentation of prototypic vimentin-derived peptides. @ERSpublications Clonal CD4 + lung T-cells associating with HLA-DRB1*03 molecules indicate specific antigens in pulmonary sarcoidosis

Association of HLA antigens with the clinical course of sarcoidosis and familial disease

“…Initial chest x-ray revealed more advanced disease in HLA-DRB1*014 and HLA-DRB1*015 positive patients. Previous studies revealed that HLA-DRB allels played a crucial role for many aspects of sarcoidosis [9,10,[17][18][19][20]. Prognosis and outcome of sarcoidosis predominantly depends upon the specific HLA profile of the patient.…”

Beryllium disease and sarcoidosis: still besties after all these years?

“…GRUNEWALD et al [20] demonstrated clonal expansion of a T-cell subset that binds to a specific Type II HLA molecule (DRB01*03) in a cohort of Löfgren's patients. Modelling of the peptide-binding groove predicted that a self-antigen, probably derived from vimentin, could be the inciting antigen [20].…”

“…GRUNEWALD et al [20] demonstrated clonal expansion of a T-cell subset that binds to a specific Type II HLA molecule (DRB01*03) in a cohort of Löfgren's patients. Modelling of the peptide-binding groove predicted that a self-antigen, probably derived from vimentin, could be the inciting antigen [20]. In prior work, the same group had demonstrated the presence of multiple self-peptides, including vimentin, bound to HLA molecules from sarcoidosis bronchoalveolar lavage cells [21].…”

Specific antigen(s) in sarcoidosis: a link to autoimmunity?

“…In summary, the study presented by GRUNEWALD et al [10] introduces a new concept in sarcoidosis research and may pave the way for an understanding of sarcoidosis as a mimicry-driven autoaggressive disorder.…”

“…In this issue of the European Respiratory Journal, GRUNEWALD et al [10] from Sweden add a new immunopathogenetic concept of sarcoidosis: they present evidence that the major histocompatibility complex (MHC) class II molecules on antigen-presenting cells contain an autoantigen that is recognised by the T-cell receptor (TCR) of the responding T-cells of sarcoidosis patients leading to their clonal expansion. This observation is a result of the long-lasting work of this group at the Karolinska Institut (Stockholm, Sweden) on the role of interactions between MHC-II and TCR in sarcoidosis.…”