M. leprae components induce nerve damage by complement activation: identification of lipoarabinomannan as the dominant complement activator

Abstract

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 = 0.01 and p = 0.001, respectively), with a highly significant association between LAM and MAC in the diseased samples (r = 0.9601, p = 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-015-1404-5) contains supplementary material, which is available to authorized users.

In Situ complement activation and T-cell immunity in leprosy spectrum: An immunohistological study on leprosy lesional skin

“…We also found that LAM deposition was also significantly higher in skin lesions of ENL and RR patients compared to BL patients with no reaction. We previously showed that there is a correlation between the BI or LAM and MAC deposition in nerves of leprosy patients [17]. Here, we show that both the BI and LAM also correlate with C3d and MAC deposition in skin of leprosy patients indicating a strong link between the presence of M .…”

“…leprae induced nerve damage [17]. MAC was also found deposited on axons in nerve biopsies of leprosy patients.…”

Complement activation in leprosy: a retrospective study shows elevated circulating terminal complement complex in reactional leprosy

“…Particularly in the context of leprosy, we showed recently that the membrane attack complex (MAC) of complement is generated upon cognate interaction of the axon of the peripheral nerve with the M. lepraespecific PAMP LAM [19]. In addition, we showed that MAC formation results in nerve damage, and its inhibition is neuroprotective in a mouse model for M. leprae-induced nerve damage.…”

“…Deposits of MAC or the soluble terminal complement complex (TCC) were demonstrated in association with damaged nerve in leprosy patients [19]. In this context, we recently showed the association between persistence of the M. leprae antigen LAM and complement activation in the damaged nerve.…”

The immunology of other mycobacteria: M. ulcerans, M. leprae

“…The LAM of M. tuberculosis is a major modulator in the immune response to tuberculosis [98]. However, little of the corresponding research has been conducted in the case of leprosy, and only two studies are reported in the literature [99,100].…”