Gila Moalem

Autoimmune T cells protect neurons from secondary degeneration after central nervous system axotomy

Autoimmunity to antigens of the central nervous system is usually considered detrimental. T cells specific to a central nervous system self antigen, such as myelin basic protein, can indeed induce experimental autoimmune encephalomyelitis, but such T cells may nevertheless appear in the blood of healthy individuals. We show here that autoimmune T cells specific to myelin basic protein can protect injured central nervous system neurons from secondary degeneration. After a partial crush injury of the optic nerve, rats injected with activated anti–myelin basic protein T cells retained approximately 300% more retinal ganglion cells with functionally intact axons than did rats injected with activated T cells specific for other antigens. Electrophysiological analysis confirmed this finding and suggested that the neuroprotection could result from a transient reduction in energy requirements owing to a transient reduction in nerve activity. These findings indicate that T–cell autoimmunity in the central nervous system, under certain circumstances, can exert a beneficial effect by protecting injured neurons from the spread of damage.

Innate and adaptive immune responses can be beneficial for CNS repair

The limitation of immune responsiveness in the mammalian CNS has been attributed to the intricate nature of neuronal networks, which would appear to be more susceptible than other tissues to the threat of permanent disorganization when exposed to massive inflammation. This line of logic led to the conclusion that all forms of CNS inflammation would do more harm than good and, hence, the less immune intervention the better. However, mounting evidence indicates that some forms of immune-system intervention can help to protect or restore CNS integrity. We have shown that the innate immune system, represented by activated macrophages, can facilitate the processes of regeneration in the severed spinal cord. More recently, we found that autoimmune T cells that are specific for a component of myelin can protect CNS neurons from the catastrophic secondary degeneration, which extends traumatic lesions to adjacent CNS areas that did not suffer direct damage. The challenge, therefore, is to learn how to modify immune interactions in the traumatized CNS in order to promote its post-injury maintenance and repair.

Autoimmune T cells as potential neuroprotective therapy for spinal cord injury

Autoimmune T cells against central nervous system myelin associated peptide reduce the spread of damage and promote recovery in injured rat spinal cord, findings that might lead to neuroprotective cell therapy without risk of autoimmune disease.

Differential T cell response in central and peripheral nerve injury: connection with immune privilege

The central nervous system (CNS), unlike the peripheral nervous system (PNS), is an immune‐privileged site in which local immune responses are restricted. Whereas immune privilege in the intact CNS has been studied intensively, little is known about its effects after trauma. In this study, we examined the influence of CNS immune privilege on T cell response to central nerve injury. Immunocytochemistry revealed a significantly greater accumulation of endogenous T cells in the injured rat sciatic nerve than in the injured rat optic nerve (representing PNS and CNS white matter trauma, respectively). Use of the in situ terminal deoxytransferase‐catalyzed DNA nick end labeling (TUNEL) procedure revealed extensive death of accumulating T cells in injured CNS nerves as well as in CNS nerves of rats with acute experimental autoimmune encephalomyelitis, but not in injured PNS nerves. Although Fas ligand (FasL) protein was expressed in white matter tissue of both systems, it was more pronounced in the CNS. Expression of major histocompatibility complex (MHC) class II antigens was found to be constitutive in the PNS, but in the CNS was induced only after injury. Our findings suggest that the T cell response to central nerve injury is restricted by the reduced expression of MHC class II antigens, the pronounced FasL expression, and the elimination of infiltrating lymphocytes through cell death.—Moalem, G., Monsonego, A., Shani, Y., Cohen, I. R., Schwartz, M. Differential T cell response in central and peripheral nerve injury: connection with immune privilege. FASEB J. 13, 1207–1217 (1999)

Accumulation of passively transferred primed T cells independently of their antigen specificity following central nervous system trauma.

The central nervous system (CNS) enjoys a unique relationship with the immune system. Under non-pathological conditions, T cells move through the CNS but do not accumulate there. CNS trauma has been shown to trigger a response to CNS self-antigens such as myelin basic protein (MBP). Here, we examined whether the injured CNS tissue undergoes changes that permit T cell accumulation. We found that injury to CNS white matter, such as the optic nerve, led to a transiently increased accumulation of T cells (between days 3 and 21). In Lewis rats with unilaterally injured optic nerves, systemic administration of passively transferred T cells recognizing either self-antigen (MBP) or non-self-antigen (ovalbumin) resulted in accumulation of the T cells in injured optic nerve, irrespective of their antigenic specificity. The effect of the T cells on the damaged nerve, the lack of selectivity in T cell accumulation and the mechanism underlying non-selective accumulation are discussed.

Autoimmune T cells retard the loss of function in injured rat optic nerves.

We recently demonstrated that autoimmune T cells protect neurons from secondary degeneration after central nervous system (CNS) axotomy in rats. Here we show, using both morphological and electrophysiological analyses, that the neuroprotection is long-lasting and is manifested functionally. After partial crush injury of the rat optic nerve, systemic injection of autoimmune T cells specific to myelin basic protein significantly diminished the loss of retinal ganglion cells and conducting axons, and significantly retarded the loss of the visual response evoked by light stimulation. These results support our challenge to the traditional concept of autoimmunity as always harmful, and suggest that in certain situations T cell autoimmunity may actually be beneficial. It might be possible to employ T cell intervention to slow down functional loss in the injured CNS.

Beneficial immune activity after CNS injury: prospects for vaccination

A recent study in our laboratory showed, against all expectations, that macrophages and a particular type of T cell, by promoting regrowth and reducing the post-traumatic spread of damage in the injured rat optic nerve or spinal cord, have a beneficial effect on the injured CNS. Macrophages in the CNS have long been thought to have predominantly destructive effects. Autoimmunity in general, and in the CNS in particular, has never been documented as a purposeful physiological response of benign character. Our results suggest that after traumatic injury to the central nervous system (CNS), both of these immune cell types potentially have beneficial effects: macrophages can promote repair and T cells of a particular specificity can reduce the spread of damage. However, possibly because of the immune-privileged character of the CNS, the spontaneously evoked physiological activities of both macrophages and T cells in the CNS are restricted, and appear to need well-controlled boosting in order to be effective. It thus appears that (i) a stress signal transmitted from the traumatized tissue (in this case the CNS) for recruitment of the adaptive immune system does not have to be pathogen-related in order to evoke a response, (ii) a response to self is not necessarily a quirk of nature, and (iii) an autoimmune response, provided that it is well-regulated, helps the individual to cope with stress signals from the traumatized CNS, and thus plays a role in maintenance of the injured tissue without posing a threat to the organism.

Factor XIIIa as a nerve-associated transglutaminase

Recent findings have led to changes in the traditional concept of nerve recovery, including the realization that injured nerves, like any other injured tissue, need the assistance of blood‐derived cells and factors in order to heal. We show that factor XIIIa (FXIIIa, the potentially active a2‐subunit of factor XIII), an enzyme that participates in blood coagulation by stabilizing the fibrin clot, is also active in the nervous system where it may play a key role in the healing of injured tissue. We demonstrate that the plasma, macrophages and nerves of fish contain a 55 kDa form of transglutaminase that cross‐reacts immunologically with the a‐subunit of FXIII in mammals (80 kDa). The fish enzyme in the plasma, unlike its mammalian counterpart, is active, pointing to a difference in control of the coagulation pathway in the two species. Analysis of FXIIIa expression in mammalian neural tissues and their response to injury revealed high levels of the enzyme in media conditioned by peripheral nerves as compared with medium conditioned by nerves of the central nervous system. Furthermore, similarity was observed in the postinjury behavior of FXIIIa in regenerating nerve tissues (peripheral nervous system of mammals and the central nervous system of fish). We suggest that the postinjury level of factor XIIIa in the nervous system may be related to the tissues regenerative capacity, and that FXIIIa may therefore be a link underlying a possible association between the processes of blood coagulation and nerve healing.—Monsonego, A., Mizrahi, T., Eitan, S., Moalem, G., Bárdos, H., Ádány, Róza, Schwartz, M. Factor XIIIa as a nerve‐associated transglutaminase. FASEB J. 12, 1163–1171 (1998)