Lymph nodes as gatekeepers of autoimmune diseases

Secondary lymphoid organs such as lymph nodes (LNs) are the home of peripheral tolerance mechanisms which control autoreactive T cells and prevent immune responses to self-antigen. In systemic autoimmunity, there is a clear failure of these peripheral tolerance mechanisms that leads to chronic inflammation and tissue destruction, highlighting the role for LNs as possible gatekeepers of autoimmunity. In recent years there has been a shift in research focus towards tissue sites in autoimmune diseases ranging from type 1 diabetes to rheumatoid arthritis in an effort to better characterise pathogenesis and guide diagnostic and therapeutic decisions. Although this has yielded great insight, it fails to tackle the initial break in tolerance that initiates disease progression which is most likely originating in peripheral LNs. In the majority of autoimmune diseases a preclinical phase is recognised. This is characterised by the presence of autoantibodies, which is indicative of a break in immune tolerance, and the absence of clinically apparent inflammation or tissue destruction. This review explores how our current knowledge of LNs in the preclinical and established phases of autoimmune diseases provides insight into possibly shared pathological mechanisms that drive disease progression and highlight the gaps in our knowledge that may help uncover new therapeutic avenues for intervention and prevention.