The autoimmunity paradigm pertains to aberrant adaptive immune responses, dependent on classical major histocompatability complex (MHC) based antigen-dependent T cell responses. These involve CD4-mediated activation of other effector cells, including macrophages, via interferon gamma production, as well as tissue destruction, mediated by cytotoxic CD8 T cells, in addition to T cell dependent B cell autoantibody production. This autoimmunity paradigm has dominated immunology to the extent that concepts of many disorders, including Crohn’s Disease, have been moulded to fit the prevailing dogma. However, in the past decade this autoimmune-centric view of immune-mediated disease has undergone a fundamental shift that was ushered in by an improved understanding of a range of monogenic human inflammatory disorders. Specifically, mutations in proteins associated with innate immune cells, such as monocytes/macrophages and neutrophils, have implicated innate immune dysregulation in the pathogenesis of many of these disorders, which have been collectively termed the autoinflammatory diseases (1). The term autoinflammation is now used interchangeably with the term innate immune-mediated inflammation, and is becoming the accepted term to describe innate immune mediated disease (2).
Originally, the autoinflammatory diseases were designated as being quite distinct from MHC and autoantibody-associated disorders that were clearly linked, both genetically and immunologically, to adaptive immunity. This approach tended towards a two-tiered classification of inflammation against self and failed to explain obvious overlaps between these two types of inflammation, especially concerning MHC class I-associated disorders. We have proposed an immunological disease continuum (IDC) (3), whereby diseases are classified as being driven by adaptive or innate immune responses, with the majority involving variable degrees of interaction between these two systems.
The classification of MHC class I associated diseases as autoimmune is contentious, given that these conditions lack specific autoantibody associations. The present classification places MHC class I associated diseases as intermediates between autoinflammation and autoimmunity. The formal recognition of autoinflammation has implications for a better clinical understanding for targeted therapy of the immunological diseases. For example, anti-cytokine therapy is especially effective in autoinflammatory disease with, anakinra, the interleukin-1 receptor antagonist, showing good efficacy in some monogenic autoinflammatory disorders (4). On the other hand strategies to target lymphocytes are especially effective in autoimmune diseases, such as lupus. In some cases both anti-cytokine and anti-lymphocyte strategies are effective in disorders that lie somewhere along the autoimmune-autoinflammatory disease continuum. Finally, cytokine blockade of diseases with a strong autoinflammatory basis may aggravate or precipitate autoimmune diseases such as systemic lupus erythematosus. Placing inflammatory disease along a continuum, therefore, may have relevance for therapy development, since disorders with a prominent autoinflammatory component could be targeted via innate immune pathway blockade.
Masters SL, Simon A, Aksentijevich I, Kastner DL. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annu Rev Immunol 2009;27:621-68
Beutler B, Hoffmann J. What infections actually are. J Innate Immun. 2009;1:2-3
McGonagle D, McDermott MF. A proposed classification of the immunological diseases. PLoS Med 2006; 3:e297
Savic S, Dickie LJ, Battellino M, Familial Mediterranean fever and related Periodic Fever Syndromes/Autoinflammatory diseases. Curr Opin Rheumatol 24:103-112, 2012
Disclosure of Interest None Declared
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.