It is well known that the biggest genetic risk factor for the autoimmune disease systemic lupus erythematosus (SLE) is major histocompatibility complex class II (MHC-II). What remains unclear is the identity of the self-antigens that trigger autoimmunity. As such, the disease is difficult to treat.
In a recent study, researchers from Osaka University revealed that the body’s own proteins—neoself-antigens—are the primary target for autoreactive T cells clonally expanded in SLE. In addition, they found that the neoself antigens are presented on MHC-II in the absence of the invariant chain, which is essential for peptide presentation.
This work is published in Cell in the paper, “Neoself-antigens are the primary target for autoreactive T cells in human lupus.”
Autoimmune diseases are widespread and notoriously difficult to treat. The underlying causes of why the immune system attacks its own tissues in patients with these conditions remain poorly understood. The immune system has many checks and balances to make sure that it only reacts to “non-self” triggers.
“T cells have been thought to discriminate between small fragments of protein derived from self and non-self proteins presented on the major histocompatibility complex II (MHC-II), and ‘trained’ not to respond self-antigens,” explained Hisashi Arase, MD, from the Laboratory of Immunochemistry, World Premier International Immunology Frontier Research Centre, Osaka University. “However, when the MHC-II is missing a crucial piece called the invariant chain, it can present larger, misfolded self antigens, called neoself-antigens, to T cells.”
Given that autoantibodies to neoself-antigens are frequently found in patients with autoimmune diseases, the researchers explored T cell reactivity in patients with lupus and in mice, in which the invariant chain was depleted from adults.
They found that “when neoself-antigen presentation was induced by deleting the invariant chain in adult mice, neoself-reactive T cells were clonally expanded, leading to the development of lupus-like disease.” The findings also suggest that “neoself-reactive CD4+ T cells were significantly expanded in SLE patients.”
“The results were striking,” said Shunsuke Mori, PhD, also from the Laboratory of Immunochemistry, World Premier International Immunology Frontier Research Centre, Osaka University. “We found that approximately 10% of clonally expanded T cell repertoire in lupus patients recognized neoself-antigens. Furthermore, induction of neoself-antigens induced lupus-like disease in mice, meaning that they mounted an immune response to the body’s own tissues, thereby causing autoimmune disease.”
They also investigated the effect of Epstein–Barr virus (EBV) infection, a risk factor for lupus, on T cell reactivity to neoself-antigens. They found that reactivation of EBV, which most people are infected with but is usually dormant, increases the presentation of neoself-antigens on MHC-II through downregulating the expression of the invariant chain, triggering the activation of T cells directed against the body. This could explain why EBV reactivation is linked to the onset or exacerbation of lupus.
“Our findings demonstrate that T cells discriminate self- and neoself-antigens and do not recognize neoself-antigens as self antigens, thus leading to the development of autoimmunity when neoself-antigens are presented on MHC-II,” said Arase.
