Getting Under the Skin: Targeting Cutaneous Autoimmune Disease

Abstract

Autoimmune diseases of the skin occur when the immune system attacks normal skin. The immune system can be broadly divided into an effector arm responsible for fighting infections and cancer and a regulatory arm that reduces autoreactivity and maintains immune homeostasis. Cutaneous autoimmunity develops when the equilibrium between the effector arm and regulatory arm of the immune system is disrupted. Recent insights into the inflammatory pathways that are overactive in some cutaneous autoimmune diseases have led to therapies targeting the effector arm of the immune system with greater treatment efficacy than previously used broad immunosuppressants. The current paradigm of inhibiting excessive immune activation for treating cutaneous autoimmunity will be discussed including cytokine blockade, cellular depletion, intracellular signaling blockade and costimulatory blockade. Despite the success of this approach many cutaneous autoimmune diseases lack a clearly delineated pathway to target and therefore new strategies are needed. An emerging therapeutic strategy targeting the regulatory arm of the immune system to induce tolerance and disease remission provides new hope for treating cutaneous autoimmunity. Such an approach includes cellular therapy with regulatory T cells and chimeric autoantibody receptor T cells, cytokine therapy with low-dose interleukin-2, immune checkpoint stimulation, tolerogenic vaccines and microbiome biotherapy. This mini-review will discuss the current and emerging therapeutic strategies for cutaneous autoimmune diseases and provide an organizational framework for understanding distinct mechanisms of action.

Keywords: CAAR T cells; CAR T cells; Janus kinase inhibitors; cutaneous autoimmunity; inhibitory receptor stimulation; monoclonal antibodies; novel therapeutics; regulatory T cells; tolerance.

Figure 1

The effector arm and the regulatory arm of the immune system. In this simplified schematic, the effector arm of the immune system is represented by antigen presenting cells stimulating naïve T cells to differentiate into distinct effector T cell subsets. Each effector T cell subset plays a role in distinct cutaneous autoimmune disease. The regulatory arm of the immune system feedbacks and reduces T cell activation, thereby limiting autoimmune pathogenesis. Breg, regulatory B cell, CD, cluster of differentiation; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; DC, dendritic cell; IFN, interferons; IL, interleukin; Mϕ, macrophage; NK, natural killer cell, NK2GD/A, natural killer group 2D/A; tDC, tolerogenic DC; TGFβ, transforming growth factor beta; Treg, regulatory T cell.

Figure 2

Current therapeutic approaches for treating cutaneous autoimmunity. These approaches predominately focus on targeting the excessive immune activation of the effector arm of immunity. For cytokine blockade, monoclonal antibodies bind pathogenic cytokines such as IL-17A and IL-23 for psoriasis and prevent engagement with cytokine receptors. For cellular depletion, monoclonal antibodies directed against CD20 result in cellular destruction of CD20-expressing B cells, including autoreactive B cells specific for DSG3 that drive pathogenesis in pemphigus vulgaris. For signaling blockade, small molecule JAK inhibitors prevent JAK activation of STATs that are downstream of cytokine receptor signaling. For costimulatory blockade, a soluble CTLA-4-Ig fusion protein (abatacept) binds to CD80 on DCs and prevents T cell activation through CD28. CD, cluster of differentiation; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; DC, dendritic cell; DSG3, desmoglein-3; IL, interleukin; JAK, Janus kinase; mAb, monoclonal antibody; MHC, major histocompatibility complex; STAT, signal transducer and activator of transcription; TCR, T cell receptor.

Figure 3

New emerging therapeutic approaches for treating cutaneous autoimmunity. These approaches predominately focus on targeting the regulatory arm of the immune system. For cytokine therapy, low-dose IL-2 preferentially expands Tregs which subsequently inhibit effector T cells. For cellular therapy, three distinct approaches may be used, including polyclonal Tregs that inhibit effector responses, CAR-Tregs that recognize autoantigens displayed on antigen presenting cells or other tissues to induce tolerance, and CAAR T cells that recognize autoreactive B cells and target them for destruction. One example is DSG3 CAAR T cells that recognize B cells expressing anti-DSG3 autoantibodies. For coinhibitory stimulation, agonist monoclonal antibodies bind to PD-1 on activated T cells and inhibit downstream TCR signaling. CAAR, chimeric autoantibody receptor; CAR, chimeric antigen receptor; CD, cluster of differentiation; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; DC, dendritic cell; DSG3, desmoglein-3; IL, interleukin; MHC, major histocompatibility complex; PD-1, programmed death-1; TCR, T cell receptor; Treg, regulatory T cell.