Unraveling the immune response during AIHA

Tregs in individuals with AIHA were shown to recognize a peptide epitope derived from the Rh proteins, correlating with the known anti-Rh specificity of red cell autoantibodies in this disease. Their work has, for the first time, enabled the cloning (based on the propensity of Tregs to secrete IL-10) and subsequent characterization of Tregs that are primarily responsible for this autoimmune condition, which is of significant clinical importance in hematology. It is generally accepted that Tregs (which represent roughly 5% of the CD4⁺ T cell population) play a fundamental role in the development of tolerance to self antigens and also in the pathology of autoimmune disease.¹ 

The management of autoimmune diseases represents a major challenge to medicine in the 21st century. These diseases constitute a major cause of long-term dehabilitation, and the only effective treatment is often global immunosuppression, which has considerable, sometimes disastrous, side effects. AIHA is a classical example of such conditions, and front-line treatment almost invariably requires immunosuppression involving administration of corticosteroids and sometimes even splenectomy.^2,3  In extreme cases, AIHA can cause significant problems during transfusion, as panagglutinating or red cell–bound autoantibodies interfere with crossmatching and may reduce the effectiveness of transfusion due to the production of alloantibodies.⁴  A better understanding of the pathogenesis of the aberrant immune response to autoantigens is a long-term goal in the treatment of AIHA and other autoimmune diseases.

AIHA is the first disease in which Tregs have been identified to respond to autoantigen—a peptide epitope derived from the human red cell Rh proteins. Ward et al confirm that one hallmark of Tregs involved in the pathology of AIHA is that they express IL-10 and the transcription factor FoxP3. However, more importantly, the authors confirm that autoreactive Tregs show discrete phenotypic differences that indicate they derive from a Th1 effector T-cell population specific for the Rh proteins, a result that warrants further investigation. Ward et al also demonstrate that CTLA-4 ligation costimulates (along with interaction with the TCR) the isolated Tregs to express cytokines (IL-10 and IFN-γ) involved in their further proliferation. Now that the individual cells and their surface markers involved in the pathogenesis of AIHA have been defined, further studies may reveal precisely how effector cells that promote inflammation switch to tolerance-inducing Tregs during the course of disease. This will ultimately lead to better regimes for the clinical management of autoimmunity, which currently lacks specific therapies.