How underappreciated autoinflammatory (innate immunity) mechanisms dominate disparate autoimmune disorders

Abstract

Historically inflammation against self was considered autoimmune which stems back to the seminal observations by Ehrlich who described serum factors, now known to be autoantibodies produced by B lineage cells that mediate "horror autotoxicus". The 20^th century elucidation of B- and T-cell adaptive immune responses cemented the understanding of the key role of adaptive immune responses in mediating pathology against self. However, Mechnikov shared the Nobel Prize for the discovery of phagocytosis, the most rudimentary aspect of innate immunity. Fast forward some 100 years and an immunogenetic understanding of innate immunity led to the categorising of innate immunopathology under the umbrella term 'auto inflammation' and terminology such as "horror autoinflammaticus" to highlight the schism from the classical adaptive immune understanding of autoimmunity. These concepts lead to calls for a two-tiered classification of inflammation against self, but just as innate and adaptive immunity are functionally integrated, so is immunopathology in many settings and the concept of an autoimmune to autoinflammation continuum emerged with overlaps between both. Herein we describe several historically designated disorders of adaptive immunity where innate immunity is key, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD) where the immunopathology phenotype is strongly linked to major histocompatibility complex (MHC) class II associations and responds to drugs that target T-cells. We also consider MHC-I-opathies including psoriasis and Behcet's disease(BD) that are increasingly viewed as archetype CD8 T-cell related disorders. We also briefly review the key role of barrier dysfunction in eczema and ulcerative colitis (UC) where innate tissue permeability barrier dysfunction and microbial dysbiosis contributes to prominent adaptive immune pathological mechanisms. We also highlight the emerging roles of intermediate populations of lymphocytes including gamma delta (γδ) and mucosal-associated invariant T (MAIT) cells that represent a blend of adaptive immune plasticity and innate immune rapid responders that may also determine site specific patterns of inflammation.

Keywords: MHC-I antigen presentation; autoantibodies; autoimmunity; autoinflammatory diseases; immune cells; neutrophil.

Figure 1

Citrullination occurs via the enzyme peptidyl arginine deiminase-4 (PADI4) and likely predates autoimmunity and occurs at sites of non-specific inflammation such as the gums and lungs where macrophages and neutrophils contribute to such citrullination processes. Afterwards, this innate immune phase leads citrullinated peptides presentation to CD4 Tmphocytes via MHC-II peptide presentation. ACPA production is induced after T and B lymphocyte interactis With citrullinated proteins immune complex formation and FcR binding on macrophages, TNF and other cytokine release occurs. In effect autoimmunity is sandwiched between Innate immune Initiation events and innate immunity terminal effector events. This is likely why RA does not cross the placenta and mediated neonatal autoimmunity.

Figure 2

Type I IFNs are released from keratinocytes under the influence of ultraviolet light. They enable the development of autoantibodies from B-lymphocytes, which is the most important step in the pathogenesis of SLE, either directly or by stimulating the release of Blyss from monocytes. In addition to this autoantibody development, type I IFNs also increase NET formation and release nucleic acids from neutrophils. NETosis, which is one of the most important defence mechanisms of neutrophils, is an extracellular web-like fibre network consisting of nucleic acids that can bind to microorganisms including pathogens. The most important contribution of NET formation to the SLE pathogenesis is that free DNA structures that induce autoantibody formation assume the necessary autoantigen role.

Figure 3

In the MHC-I-opathies, the ultimate aim of CD8 T-cell adaptive immunity is to facilitate neutrophil migration and activation at sites of Inflammation. Initially innate cells including DCs, macrophages and even neutrophils in tissues can produce IL-23. Such IL-23 release stimulates tissue resident lymphoid cells including ILC3 cells and other innate lymphocytes to produce IL-17. In parallel, APC activation of conventional T-cells in the usual MHC-1 driven adaptive pathway dramatically amplifies the release of IL-17, CXCLS and GM-CSF from CD8 T-lymphocytes to which antigen is presented by dendritic cells. This further increases neutrophil recruitment and inflammation. There the IL-23/17 axis is both a key part of both innate and adaptive immune responses at certain tissue specific sites including the skin the gut the enthesis and the uveal tract.