02362nas a2200205   4500000000100000008004100001100002300042700001000065700001400075700001200089700001600101700001300117700001300130700001100143700001500154245014500169856008600314520174200400022001402142       2015                            d1 aBahia El Idrissi N1 aDas P1 aFluiter K1 aRosa PS1 aVreijling J1 aTroost D1 aMorgan P1 aBaas F1 aRamaglia V00aM. leprae components induce nerve damage by complement activation: identification of lipoarabinomannan as the dominant complement activator.  uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405335/pdf/401_2015_Article_1404.pdf3 a<p>Peripheral nerve damage is the hallmark of leprosy pathology but its etiology is unclear. We previously identified the membrane attack complex (MAC) of the complement system as a key determinant of post-traumatic nerve damage and demonstrated that its inhibition is neuroprotective. Here, we determined the contribution of the MAC to nerve damage caused by Mycobacterium leprae and its components in mouse. Furthermore, we studied the association between MAC and the key M. leprae component lipoarabinomannan (LAM) in nerve biopsies of leprosy patients. Intraneural injections of M. leprae sonicate induced MAC deposition and pathological changes in the mouse nerve, whereas MAC inhibition preserved myelin and axons. Complement activation occurred mainly via the lectin pathway and the principal activator was LAM. In leprosy nerves, the extent of LAM and MAC immunoreactivity was robust and significantly higher in multibacillary compared to paucibacillary donors (p&nbsp;=&nbsp;0.01 and p&nbsp;=&nbsp;0.001, respectively), with a highly significant association between LAM and MAC in the diseased samples (r&nbsp;=&nbsp;0.9601, p&nbsp;=&nbsp;0.0001). Further, MAC co-localized with LAM on axons, pointing to a role for this M. leprae antigen in complement activation and nerve damage in leprosy. Our findings demonstrate that MAC contributes to nerve damage in a model of M. leprae-induced nerve injury and its inhibition is neuroprotective. In addition, our data identified LAM as the key pathogen associated molecule that activates complement and causes nerve damage. Taken together our data imply an important role of complement in nerve damage in leprosy and may inform the development of novel therapeutics for patients.</p>
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