Nerve damage no doubt is the most feared complication in leprosy since it causes most of leprosy’s characteristic and stigmatizing disabilities. Paradoxically and sadly, however, its etiology and pathogenesis remain poorly understood, its clinical management difficult and its prevention far out of sight. Leprosy nerve damage particularly occurs during leprosy reversal reactions, which represent idiopathic episodes of increased host inflammatory responses and cell-mediated immune reactivity, often accompanied by acute inflammation and destruction of peripheral nerves and other forms of immunopathology. Well documented characteristics of leprosy reactions include: increased T cell reactivity to antigens of M. leprae, lesional infiltration by activated T cells, enhanced local expression of inflammatory cytokines such as TNF-a and cellular adhesion molecules, increased local macrophage activation and increases in levels of pro-inflammatory circulating cytokines in the blood. In the early phase of infection,M. leprae can attach to myelinated Schwann cells (SC) and induce rapid nerve demyelination. This process of early nerve damage is mediated directly, at least in part, by the M. leprae specific cell wall constituent phenolic glycolipid, in the absence of any immune cells, and is dependent on intracellular signaling through the ErbB2 receptor tyrosine kinase. Despite the importance of early nerve damage, innate-immunity associated with this early process does not explain fully a series of clinical observations in leprosy. First, it is well known that episodes of acute nerve damage mostly occur during type1 leprosy reactions, and often can cause severe and even irreversible nerve damage. Although immunosuppressive drugs can be helpful in mitigating those events, not all patients respond adequately to such regimens, unfortunately. In addition, the process of demyelination and nerve damage seen in patients with multibacillary leprosy which have high bacterial loads in their lesions is mostly chronic and relatively slow. These patients are immunologically distinct as they present with low or non existing T cell mediated immunity to antigens of M. leprae while displaying highM. leprae specific antibody titers. Thus, in the absence of strong