Is hemophagocytic lymphohistiocytosis an autoimmune disease?

Arkwright et al recently reviewed the association of autoimmunity with several inherited immunodeficiency diseases.1 It has been suggested that most if not all autoimmune diseases are initiated by response to a single self-antigen.2 Mackay and Rosen3 defined an autoimmune disease as a clinical syndrome caused by the activation of T and/or B cells in the absence of an ongoing infection or other discernible cause. In many cases of autoimmune diseases, autoantibodies are produced and may serve as markers of the antigen-specific B- and T-cell response.2 

In the context of X-linked lymphoproliferative disease (XLP) and other inherited immunodeficiency diseases, Arkwright et al for the first time included also the immunologic disorder “hemophagocytic lymphohistiocytosis (HLH)” as an autoimmune phenomenon.1HLH is characterized by uncontrolled T-lymphocyte and macrophage activation. Unrestricted release of inflammatory cytokines, such as interferon and tumor necrosis factor, is a prominent feature of primary and secondary HLH, including the Epstein-Barr virus–related form.4 5 

According to common classifications, HLH does not fulfill the criteria of an autoimmune disease (ie, an immune reaction to a more or less defined self-antigen).

We wonder, that Arkwright et al defines autoimmunity only as a bystander tissue damage due to suboptimal, chronic immune response to persisting opportunistic infection.1 Due to this definition, all chronic infectious disease in immune-deficient subjects would be classified as autoimmune phenomena.