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The evolutionarily ancient innate immune system provides immediate responses to pathogen‐associated molecular patterns(PAMPs) and damage‐associated molecular patterns (DAMPs) associated with microbes and injured or dying cells, respectively [3]. In contrast, the adaptive immune system responds to specific peptide antigens through antigen‐specific T‐cell responses and B‐cell production of antigen‐specific antibodies [4]. It is now clear that cytokines produced by an innate immune response dictate both the type and magnitude of adaptive responses and that both innate and adaptive immunity play important roles in the immunopathogenesis of all autoimmune diseases (Table 2.2 and Figure 2.2).

Table 2.1 Comparison of classic autoimmunity with AIH, PBC or PSC.

Classic autoimmunity	AIH	PBC	PSC
Disease‐specific autoantigens	Yesa	Yes	Yesb
Disease‐specific autoantibodies	Yes, types 1 and 2	Definite	Yes
Epitope determinant spreading	Unclear	No	Unclear
Female predilection	Yes	Yes	No
Occurrence in children and adults	Yes	No, adults only	Yes
Polygenetic predisposition	Yes	Yes	Yes
HLA immunogenetic associations	Yes	Yes	Yes
Non‐HLA genetic associations	Yes	Yes	Yes
Environmental triggers	Yes	Yes	Yes
Tissue/organ‐specific pathology	Yes	Yes	Yes
Associated extrahepatic autoimmune diseases	Yes	Yes	Yes
Associated IBD	Yes (weak)	No	Yes (strong)
Response to immunosuppression	Yes	Yes	No
Autoantigen‐specific animal models	Yes for type 2 No for type 1	Yes	No

^a T and B cell epitopes defined in type 2, not type 1 AIH.

^b β‐Tubulin isoform 5, not rigorously tested to determine prevalence, sensitivity or specificity.

AIH, autoimmune hepatitis; IBD, inflammatory bowel disease; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis.

Innate immune inflammasome responses, especially those mediated by nucleotide‐binding oligomerization domain (NOD)‐like receptor P3 (NLRP3), occur in both innate immune cells and non‐immune cells, including hepatocytes, cholangiocytes, and hepatic stellate cells (HSCs) [5]. Thus, clinicians must embrace a new paradigm: cells or tissues are not passive “targets” of autoimmune diseases (including AILDs), but instead are active participants in the immunopathogenesis of their own injury and demise.