Costimulatory molecules and their ligands as therapeutic targets in autoimmune disease

The initiation and progression of autoimmune diseases are complex processes that depend on a selective breakdown of tolerance and additional factors like genetic susceptibility and environmental factors, e.g. drugs, infections, toxins and UV light. The causative failure of the immune system to tolerate self can be initiated by molecular mimicry or polyclonal activation with the consequence of a breakdown of anergy or a failure of activation induced cell death. It presents itself in multiple forms including a disturbed balance between TH1 and TH2, alterations in the cytokine milieu and undue modulation of the expression of costimulatory molecules. Although all these features may vary between patients and within the individual patient depending on the state of disease, recent years have provided convincing evidence that, in particular, disease progression is markedly influenced by the expression profile of costimulatory molecules. Since in many forms of autoimmune diseases the causative self-antigen(s) are unknown, therapy largely depends on anti-inflammatory agents or in severe cases on a general immunosuppression. Increasing knowledge of the functional activities of costimulatory molecules in autoimmune disease now provides a new and promising therapeutic modality, which in a more selective way interferes with the pathological activities of immune cells. Here I discuss evidence for the involvement of costimulatory molecules, particularly of CD44 variant isoforms, in autoimmune diseases and their possible use as a therapeutic target. Due to the regulated and restricted expression of these molecules, treatment should not be burdened by severe side effects.