Blood vessels are naturally protected from immune attack, a protection that is lost in autoimmune vasculitis. Vasculitides are a heterogeneous group of diseases and are classified into three major categories based on the size of affected blood vessels [1]. Large vessel vasculitides giant cell arteritis (GCA) and Takayasu arteritis exclusively target the aorta and large arteries [2]. Polyarteritis nodosa and Kawasaki disease are recognized as medium vessel vasculitides [3,4], they manifest mostly in the main visceral arteries and the coronary arteries, respectively. Small blood vessels, including capillaries and arterioles, are other preferred targets of a variety of vasculitides, most prominently, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and IgA vasculitis [5,6].

Like other autoimmune diseases, pathogenic concepts in vasculitis have followed the classical paradigm that faulty immune responses are directed against an autoantigen. Classical paradigm predicts that tolerance against self is broken, that auto-reactive T cells expand to provide help to auto-reactive B cells. Autoantibodies and cytokines are believed to be the major effector molecules driving tissue inflammation. Paradigmal shifts in cancer immunology have made it clear that this classical paradigm is far from correct and that autoantigen-independent pathways are equally, or even more, important than auto-antigen recognition. The discovery of immune checkpoints (IC) as the ultimate controllers of the strengths and duration of immune responses has opened new avenues to readdress the immunopathology of autoimmune disease. ICs are engaged when receptors on T cells bind to ligands on partner cells to receive co-stimulatory (“on”) or co-inhibitory (“off”) signals. These immune checkpoints determine the kinetics, duration and intensity of immune responses and inhibitory immune checkpoints have become the prime target of cancer immunotherapy [7,8]. Stop signal-providing inhibitory ICs are utilized by tumor cells to paralyze anti-tumor T-cell immunity and can be unleashed through IC inhibitors (ICI). It is obvious that ICs play a critical role in setting the threshold of responsiveness in the immune system and are therefore of particular interest in autoimmune disease [9].

Here, we will review current knowledge of IC function in vasculitis, exemplified in GCA. Little information is available for other vasculitides, but recent work has highlighted that two inhibitory checkpoints are broken in GCA and that these failed checkpoints contribute significantly to inappropriate T cell immunity. A clustering of immune checkpoint failure in GCA has given rise to the “lost inhibition concept”, a concept that obviously affects diagnostic and therapeutic approaches in this vasculitis.