Immune mechanisms in acute and chronic inflammatory polyneuropathies

Journal of Neuroimmunology, 20 (1988) 277-281

277

Elsevier JNI 00664

Immune mechanisms in acute and chronic inflammatory polyneuropathies K.V. Toyka, H.-P. Hartung, B. Schafer, K. H e i n i n g e r a n d W. Fierz 1 Department of Neurology, Universityof Dusseldorf, Dusseldorf, F.R.G., and ~Division of Immunology, Department of Medicine, University of Zurich, Zurich, Switzerland (Received 13 April 1988) (Revised, received 15 June 1988) (Accepted 20 June 1988)

Key words: Inflammatory polyneuropathy; Immune mechanism; Guillain-Barr6 syndrome

Introduction This short review summarizes some recent advances in our understanding of immune mechanisms in inflammatory polyneuropathies including therapeutic aspects.

Disease subgroups 1. A c u t e polyneuritis - - Guillain-Barr~ s y n d r o m e

In this acute inflammatory demyelinating disorder, some patients show a fulminant clinical course with electrophysiologic studies pointing to acute conduction failure in addition to conduction slowing and block (LSffel et al., 1977; Feasby et al., 1986). It is now clear that the prognosis of this subgroup with axonal degeneration is less favorable with supportive treatment or even plasma exchange than other forms of the disease (French Cooperative Group, 1987; McKhann et al., 1988). The etiology of the acute Guillain-Barr6 syndrome (GBS) is still not clear. A new variant

Address for .correspondence: Prof. K.V. Toyka, Neurologisehe Klinik der Universit~it Diisseldorf, Moorenstr. 5, 4000 Diisseldorf 1, F.R.G.

associated with early human immunodeficiency virus (HIV) infection has recently been described which is distinguished only by its pleocytosis in the cerebrospinal fluid (CSF) (Piette et al., 1986; Cornblath et al., 1987). In general, viral infections may function as a trigger to set off the autoimmune response to peripheral nerve. It has long been proposed that both cellmediated and humoral immune factors contribute to the clinical disease. Until recently no definite antigen in human disease has been defined. In the humoral arm of the immune response both antibodies to peripheral nervous system (PNS) antigens and unspecific proinflammatory factors have been looked for but could only rarely be demonstrated (Toyka and Heininger, 1987). Recently, a complement-fixing IgM antibody to a neutral glycolipid of myelin has been described (Koski et al., 1986) and soon thereafter IgM antibodies to acidic glycolipids such as gangliosides (Ilyas et al., 1988). A role for antibodies is further supported by the demonstration of activated complement in CSF (Sanders et al., 1986; Hartung et al., 1987). Indeed, intraneural injection of serum from patients into normal recipient animals leads to acute conduction block and demyelination (Sumner et al., 1982; Harrison et al., 1984). The nature of this serum factor has not been defined.

0165-5728/88/$03.50 © 1988 Elsevier Science Publishers B.V. (Biomedical Division)

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Convincing evidence for a specific cell-mediated immune reaction against peripheral nerve antigens has not been forthcoming in the human disease to date. It is possible to isolate and propagate human CD4-positive T-cell lines specific for the P2-protein but this seems not disease specific (Burns et al., 1986). There is now indirect evidence that a local immunostimulation may take place at the myelin sheath because Schwann cells are capable of expressing M H C class II antigens (Pollard et al., 1987). In the animal model, experimental autoimmune neuritis (EAN), different forms of the disease can be induced by varying the antigenic challenge. With a low immunizing dose of myelin, EAN in Lewis rats will be mild and essentially display electrophysiological and morphological signs of demyelination while immunization with a higher dose (e.g. 5 mg per animal) will result in a more profound disorder with 20-30% of the inflammatory foci showing profound edema and axonal damage. Additional support comes from adoptivetransfer of EAN by P2-specific T-cell lines (Heininger et al., 1986) where injection of a higher dose of line cells leads to profound inflammation, edema and admixed axonal damage, but injection of a lower dose results in mild disease with predominant demyelination. From experiments with adoptive-transfer EAN, it is evident that CD4-positive P2-specific T-cells can mediate the disease without need for circulating autoantibodies. Invading activated T-line cells may both induce the host's own immune system in the PNS and exert direct cytotoxic effects (Linington et al., 1986). The Schwann ceils may serve a dual role. For one, they can function as antigenpresenting cells that express M H C class II surface markers and process antigen. On the other hand, the Schwann cell may be the target of a cytotoxic T-cell-mediated lysis by means of the expression of MHC class I antigens (Wekerle et al., 1986). The observation of infiltrating macrophages early and late in the course of acute polyneuritis has prompted a series of experiments in EAN investigating the possible pathogeneic contribution of macrophage-derived inflammatory factors such as eicosanoids and oxygen radicals. In myelin-induced EAN in the Lewis rat signs of the disease can be reduced or prevented by selective

pharmacologic inhibition at this level (Hartung et al., 1988b, c). In fully developed adoptive transfer EAN, numerous infiltrating macrophages can also be seen in the inflammatory lesions. Experimental blockade of macrophages by silica or dexamethasone effectively prevents or treats this condition while, surprisingly, the application of the more selective inhibitors of eicosanoid formation and scavengers of oxygen radicals is not very effective (Heininger et al., 1988). These findings, therefore, extend earlier suggestive experiments in which macrophages were depleted by silica quartz (Tansey and Brosnan, 1983). In addition to macrophages, mast cells may also play a role by release of vasoactive amines and proteases (Brosnan and Tansey, 1984; Johnson et al., 1988). There may also be a role for another macrophage-derived cytotoxic factor, tumor necrosis factor (TNF) (Brosnan et al., 1988), but this has not been formally tested in EAN. The cooperation between antibodies to myelin and macrophages by means of antibody-mediated macrophage activation or antibody-dependent cellular cytotoxicity reaction may also be an important effector mechanism in inflammatory nerve damage (Sobue et al., 1982; Trotter et al., 1986). Another group of circulating immune factors consists of lymphokines and monokines which may augment the immune attack to the PNS. Interleukin 1 and 2 and T N F (see above) and interferon-,{ (IFN-'~) are candidate compounds. Because their mechanisms of action are complex and the net result of their systemic activity cannot be predicted, animal experiments are needed to elucidate their possible role. Recently, in EAN, recombinant IFN-y has shown different effects depending on the stage of EAN in relation to treatment. Application before manifestation of clinical signs augmented severity of nerve inflammation while later treatment produced some attenuation (Hartung et al., 1988a). On the basis of the available immunological and experimental data, we propose the following hypothesis for the sequence of events that may be important in acute PNS inflammation (Fig. 1). A viral infection preceding the onset of the disease may initiate an immune reaction, cross-reactive immunization to peripheral nervous system antigens may then occur due to some sequence ho-

279 local ischemia and hypoxia. At this stage axons may be affected as much as Schwann cells.

Treatment of acute Guillain-Barr~ syndrome.

ti o, ////////,

Fig. 1. Simplifiedscheme depicting major putative mechanisms in immuno-inflammatory polyneuropathies (see text). APC, antigen-presenting cell; IFN-~,, interferon-~,; TH, T-helper lymphocyte; B, B-lymphocyteproducing antibodies to peripheral nerve antigens; OH, hydroxyl radical; PGE, prostaglandin E; C, complement; TNF, tumor necrosis factor; LTC4, leukotriene C4; P2, P2 protein of myelin. Granules in the macropliage cytoplasm represent lysosomal enzymes that can attack the myelin sheath. Mast cells are not included here but may also play a role (see text). mology between viral proteins and peptide sequences of myelin proteins (Jahnke et al., 1985). Alternatively, systemic production of IFN-y associated with a viral infection may cause M H C class II expression on vascular endothelium and, later, on macrophages and Schwann cells. Activated and possibly pre-existing autoreactive T-cells traverse the blood-nerve barrier and recognize M H C class II antigens in conjunction with peripheral nerve antigens on antigen-presenting cells such as resident macrophages and Schwann cells. In turn, a local inflammatory reaction will attract further hematogenous cells to invade and will induce mast cells to release vasoactive amines and proteases (not shown in Fig. 1). Demyelination may be caused by activated macrophages as a consequence of direct phagocytic attack, or through secreted inflammatory mediators. Eventually these reactions may further be enhanced by systemic and local antibody formation, complement, and cytokines (possibly TNF). The neuroelectric functional deficits may result from direct damage to the myelin sheath or by direct Schwann cell damage effected by either one of these processes. If the formation of intraneural edema progresses, further damage may be mediated by pressure and

The only treatment of proven efficacy to date is plasma exchange by which plasma is nonspecifically replaced by albumin/electrolyte solutions (Guillain-Barr6 Study Group, 1985). Many o f the inflammatory mechanisms described above are open to being properly studied in prospective clinical trials by investigating the effects of more or less specific anti-inflammatory or immunosuppressive agents. One good candidate to be studied in conjunction with plasma exchange is high-dose corticosteroids.

2. Chronic inflammatory demyelinating polyneuropathy (CIDP) CIDP has been separated from acute polyneuritis on the basis of clinical and immunologic differences. In particular, an antecedent viral infection is less common (McCombe et al., 1987). The putative pathogenetic role of circulating antibodies has been formally tested by passive transfer experiments to marmoset monkeys where they induce a transient functional deficit in the recipient animals but no full-blown polyneuropathy (Heininger et al., 1984). Recently, complement-fixing antibodies have been discovered as in acute polyneuritis (Koski et al., 1985; Ilyas et al., 1988). In sural nerve biopsies depositions of immunoglobulins were also demonstrated (Dalakas and Engel, 1981; Liebert et al., 1985). A newly recognized variant of CIDP is associated with early HIV infection and can only be distinguished from the idiopathic cases by CSF pleocytosis (Cornblath et al., 1987). There are various animal models of CIDP. The one most closely mimicking the human disease is EAN in rabbits induced by galactocerebroside (Saida et al., 1979; Stoll et al., 1986a). Intraneural passive transfer of hyperimmune serum from these animals leads to an acute conduction block and to demyelination in recipient healthy animals. This reaction is complement dependent (Saida et al., 1980). Both the hyperacute effects of this serum from a slowly progressive disease and recent experimental findings in a degeneration-remyelination model of galactocerebroside EAN argue against the hypothesis that antibodies to galac-

280 tocerebroside are the p r e d o m i n a n t pathogeneic factor in this c h r o n i c p o l y n e u r o p a t h y (Stoll et al., 1986b). T o date, the c o n c l u s i o n s that can be d r a w n from the chronic E A N models are limited to a better u n d e r s t a n d i n g of the nerve pathology a n d the electrophysiologic effects rather t h a n to the u n d e r l y i n g i m m u n e mechanisms. D u e to the c h r o n i c course of the m o d e l disease, e x p e r i m e n t a l approaches to i m m u n o m o d u l a t i o n a n d p h a r m a c o t h e r a p y are m o r e difficult to test t h a n i n the acute m o d e l of E A N . Treatment of CIDP. Plasma exchange treatm e n t has b e e n s h o w n to be effective i n the majority of cases b y various studies. I n addition, some p a t i e n t s r e s p o n d e d d r a m a t i c a l l y to corticosteroids (Pollard, 1987). There m a y also be a Case for l o n g - t e r m i m m u n o s u p p r e s s i o n in severe cases ( M c C o m b e et al., 1987; Pollard, 1987) even though a small controlled trial did n o t yield favorable results with such a r e g i m e n (Dyck et al., 1985).

Acknowledgements W o r k from the a u t h o r s ' l a b o r a t o r y was supp o r t e d b y grants from D e u t s c h e Forschungsgem e i n s c h a f t SFB 2 0 0 / B 5 , G e m e i n n i i t z i g e HertieStiftung, a n d M i n i s t e r i u m fiir Wissenschaft u n d Forschung NRW.

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