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| Biologic Therapy : The Immunobiology of Psoriasis |
The Immunobiology of Psoriasis
Since the mid-1980s, it has been known that psoriasis is an immune disorder, and a growing body of evidence indicates that abnormal T-cell activity is a critical component of disease pathogenesis. T cells, one of the three major classes of cells responsible for mediating immune system processes, coordinate the overall immune response to an antigen. Three lines of evidence implicate T cells in the pathophysiology of psoriasis (Figure 1). First, T lymphocytes have been identified in psoriatic plaques. Second, it has been demonstrated that the initiation and maintenance of lesions requires activated T cells. Finally, clinical studies have shown that drugs that suppress T-cell activity contribute to the improvement of psoriatic plaques.1-6
Antigen-presenting cells (APCs) are also relevant to psoriasis because they are required for T-cell activation.7 In psoriasis, it is believed that an unknown antigen causes APCs to be activated in the epidermis. The APCs internalize and process the antigen, which is then presented on the APC surface. Activated APCs then travel to the lymph nodes and activate naive T cells. During this activation, a T cell and an APC bind to each other at many points on their surfaces by means of receptor-ligand pairs (Figure 2).7,8 These binding events are critical to any subsequent immune response. The first such event is the recognition of intracellular adhesion molecule-1 (ICAM-1) on the surface of the APC by lymphocyte function-associated antigen-1 (LFA-1) on the surface of the T cell. This interaction sends a necessary but insufficient activation signal to the T cell. Also necessary for activation are signals produced by other ligand-receptor pairs. For example, the APC displays antigen on its surface in a format that the T-cell receptor can recognize.
Additional costimulatory signals are sent to the T cell as a result of several other interactions.7,8 These include the binding of leukocyte function antigen-3 (LFA-3) on the APC to the CD2 antigen on the T cell. The net effect of all of these signals is an activated T cell with enhanced affinity for endothelial cells.
The activated T cell rolls along the microvasculature toward peripheral tissues, a process mediated in part by the binding between T-cell LFA-1 and endothelial ICAM-1 (Figure 3).8,9 Persons with psoriasis have activated T cells that traffic into the dermis and then into the epidermis.
Once in the skin, activated T cells undergo a second activation (reactivation) similar to the previous encounter with APCs in the lymph node. Reactivated T cells are then able to produce cytokines (soluble proteins that can exert both direct and indirect effects on other cells). These cytokines include interleukin-2 (IL-2) and interferon-gamma (IFN-g). Such factors may induce other cells to produce the postsecretory cytokines tumor necrosis factor-alpha (TNF-a), interleukin-8 (IL-8), and granulocyte-macrophage colony-stimulating factor (GM-CSF).
While not all events in the etiology of psoriasis have been fully explained, it appears that cytokines such as TNF-a induce pathologic changes in keratinocytes. One of these changes, the induction of ICAM-1 on the keratinocyte surface, could provide a means for T cells to directly bind via their LFA-1 molecules (Figure 3).9,10 Regardless of the mechanism, activated T cells and the cytokines they produce cause aborted maturation and excessive proliferation of the keratinocytes. The turnover in the epidermal cells is reduced from 2 weeks to 1 day. These histopathological alterations are clinically evident as plaques.
Such advances in our understanding of the pathophysiology of psoriasis suggest several new targets for therapeutic intervention. An agent that disables the psoriatic cascade of immunological events (Figure 4) at any point from T-cell activation to cytokine binding would have the potential for clinical benefit. The biologic agents currently available or in development for the treatment of moderate to severe psoriasis have been specifically designed to interfere at one or more points in this disease pathway.
Some of the specific strategies that have been employed in the development of biologic agents include:
- Blockade of interactions leading to T-cell activation or migration to tissue
- Elimination of the pathologic T cells by therapies targeted against activated T cells
- Alteration of the balance of T-cell types, for example, by redirecting T-cell differentiation away from the TH1 type implicated in psoriasis toward the TH2 type
- Binding of cytokines following their secretion by T cells before they can act on keratinocytes to drive the formation of psoriatic plaques
- Interfering with, or activating binding proteins for, pathways responsible for the expression of cytokines (eg, blockade of interferon receptors or IL-18)
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