Newly Generated DOCK8-Expressing T Follicular Helper Cells Cause Systemic Lupus Erythematosus

Abstract

Pathogens including autoantigens all failed to induce systemic lupus erythematosus (SLE). We studied, instead of pathogen, the integrity of host’s immune response that recognized pathogen. By stimulating TCR with an antigen repeatedly to levels that surpass host’s steady-state response, self-organized criticality, SLE was induced in mice normally not prone to autoimmunity, wherein T follicular helper (Tfh) cells expressing guanine nucleotide exchange factor DOCK8 on the cell surface were newly generated. DOCK8+Tfh cells passed through TCR re-revision and induced varieties of autoantibody and lupus lesions. They existed in splenic red pulp and peripheral blood of active lupus patients, which subsequently declined after therapy. Autoantibodies and lupus lesions were healed by anti-DOCK8 antibody in the mice including (NZBxNZW)F1 and not raised in DOCK8-/- mice. Thus, DOCK8+Tfh cells, generated after repeated TCR stimulation by pathogen, either exogenous or endogenous, in combination with HLA to levels that surpass system’s self-organized criticality, cause SLE.