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SNPs within enhancers, especially SEs, play dominant roles in autoimmune pathogenesis (see section Epigenetics) [16]. The theoretical fear that targeting epigenetic regulatory proteins might cause severe toxicity has not been observed with first‐generation inhibitors. Among SE proteins regulating genes associated with activation, stress and differentiation, the bromodomain and extra‐terminal (BET) family has emerged as a prime target for inhibition. BET inhibition decreased macrophage expression of inflammatory genes induced by lipopolysaccharide by preferentially inhibiting de novo expression of SE genes. BET inhibitors also blocked de novo SE gene expression in endothelial cells, markedly reduced CD4 Th cells differentiation to polarized subsets, and prevented effector cytokine production by already polarized Th cells. BET inhibitors also impacted B cells by inhibiting proliferation and ability to switch the isotype of their antibodies. More importantly, BET inhibitors have reduced inflammation and protected from disease in animal models of T1DM, MS, RA, and psoriasis. These data indicate that BET‐specific, and more generally SE‐related, mechanisms are promising therapeutic targets.

Table 2.3 Current and future therapeutic approaches to control autoimmune diseases.

	Approaches	Goal	Status
Increase regulatory control of autoimmune responses	Infuse low‐dose IL‐2	Expand existing autoantigen‐specific iTregs in vivo	POC established. Clinical trials ongoing
Infuse iTregs generated ex vivo to control Th cell and cytokine responses	Ex vivo generation of disease and autoantigen‐specific iTregs	POC of iTreg generation established. No infusion trials to date. Viability, function and distribution after infusion unknown
Bromodomain and extra‐terminal (BET) family of proteins	Inhibit disease‐specific epigenetic enhancers, super enhancers and eRNA production	POC established. Clinical trials ongoing
Mesenchymal stem cells	Inhibit innate immune cells, effector T cells. Induction of iTregs. Reduction of proinflammatory TNF‐α	POC established. Clinical trials ongoing
Decrease numbers and/or functions of autoimmune effector cells and pathogenic autoantibodies	Immunosuppressive drugs: CNI, mTOR, antiproliferative agents	Reduce functional mass of activated T cells using immunosuppressive drugs	SOC in multiple autoimmune diseases. Active research to refine target specificity and reduce toxicities. Combinations of drugs working at different sites of action using subtoxic doses preferred
Anti‐CD20	B‐cell depletion	SOC and off‐label uses
Anti‐BAFF	Initial B‐cell depletion followed by mobilization of memory B cells. Concurrent inhibition of BAFF signaling in T cells	SOC in SLE. Broad future potential, especially in combination regimens
Anti‐BAFF, followed by anti‐CD20	Depletion of memory B cells mobilized by anti‐BAFF	Sequential use to eliminate mobilized memory B cells to increase efficacy
Anti‐CD40	Block CD40–CD40L (CD154) costimulation of T cells and B cells	POC. Clinical trial initiated in transplantation
Block IgG recycling and increase IgG clearance	First in class antibody fragment to block FcRn (efgartigimod)	POC to reduce pathogenic autoantibodies and formation of immunoglobulin–autoantigen complexes
Prevent egress of activated T cells from lymph nodes	Block sphingosine‐1‐phosphate receptors	SOC in MS, new agents in development
MDSCs	Inhibit activation and proliferation of autoreactive T cells	POC in preclinical models. Plans for clinical trials in RA
Decrease proinflammatory cytokines	Anti‐TNF‐α or TNF‐α receptor	Decrease TNF‐α mediated tissue injury and proinflammatory signaling	SOC in multiple autoimmune diseases
Anti‐IL‐6 or anti‐IL‐6R	Decrease pathological consequences of proinflammatory IL‐6 signaling in innate and adaptive immune response	SOC in RA, clinical trials ongoing
Anti‐IL‐12	Decrease pathological consequences of proinflammatory IL‐12 signaling in innate and adaptive immune response	Monoclonal antibody against p40 subunit. SOC in psoriasis and Crohn's disease. Also blocks IL‐23 signaling
Anti‐IL‐23	Decrease pathological consequences of proinflammatory IL‐23	Monoclonal antibody against p40 subunit. SOC in psoriasis and Crohn's disease. Blocks IL‐23 stimulation of Th17 cells
Anti‐IL‐17	Decrease pathological consequences of Th17 production of IL‐17	SOC for psoriasis and psoriatic arthritis. Clinical trials designed
Anti‐IL‐21	Decrease multiple pathological consequences of IL‐21 in innate and adaptive immune responses	Clinical trials in RA, T1DM, Crohn's disease
Inhibition of proinflammatory cytokine signaling	IL‐2	Decrease proliferation of activated CD4 and CD8 T cells	SOC CNI and mTOR inhibitors. POC JAK3 inhibition
IL‐6	Decrease proinflammatory IL‐6R‐mediated signaling	POC and SOC indications for JAK1/2 inhibition
IL‐12/IL‐23	Decrease proinflammatory IL‐12 and IL‐23 signaling that polarize to a Th1 response, increase secretion of IFN‐γ and TNF‐α, increase cytotoxicity of NK cells and CD8 CTLs and drive differentiation of pathogenic Th17 cells	POC and SOC indications for JAK2 inhibition
IFN‐α/IFN‐β	Decrease gene expression induced by type 1 IFNs	POC and SOC indications for JAK1 inhibition
IFN‐γ	Decrease proinflammatory actions of IFN‐γ produced by NK, NKT, CD4 and CD8 T cells	POC and SOC indications for JAK1/JAK2 inhibition
Immunosuppressant cytokines	rHuIL‐10	Antagonize Th1‐mediated pathology	SOC to prevent pancreatitis post‐ERCP. Trial in ulcerative colitis terminated for concern over Guillain–Barré syndrome
Inhibition of transendothelial migration of effector cells	Anti‐chemokine receptors or integrins	Prevent injury by blocking egress of effector cells from blood into target tissues	Block of α4β7 integrin ineffective in PSC. Potential for studies of other FDA‐approved chemokine/integrin inhibitors
Physiologic immunoregulation	PIF	Administration to recreate immunosuppressive and immunomodulatory environment of the fetus and mother during pregnancy	Phase 1b trial of synthetic PIF in AIH completed

AIH, autoimmune hepatitis; BAFF, B‐cell‐activating factor; CNI, calcineurin inhibitor; ERCP, endoscopic retrograde cholangiopancreatography; IL, interleukin; iTregs, inducible T regulatory cells; JAK, Janus kinase; MDSCs, myeloid‐derived suppressor cells; MS, multiple sclerosis; mTOR, mechanistic target of rapamycin; PIF, pre‐implantation factor; POC, proof of concept; PSC, primary sclerosing cholangitis; RA, rheumatoid arthritis; rHuIL‐10, recombinant human IL‐10; SLE, systemic lupus erythematosus; SOC, standard of care; T1DM, type 1 diabetes mellitus; Th, T helper cell; TNF, tumor necrosis factor.