The role of macrophages in immune-mediated damage to the peripheral nervous system

Progress in Neurobiology 64 (2001) 109– 127 www.elsevier.com/locate/pneurobio

The role of macrophages in immune-mediated damage to the peripheral nervous system Reinhard Kiefer a,*, Bernd C. Kieseier b, Guido Stoll c, Hans-Peter Hartung b a

Department of Neurology, Westfa¨lische Wilhelms-Uni6ersita¨t, Albert-Schweitzer-Strasse 33, D-48129 Mu¨nster, Germany b Department of Neurology, Karl-Franzens-Uni6ersita¨t, Graz, Austria c Department of Neurology, Heinrich-Heine-Uni6ersita¨t, Du¨sseldorf, Germany Received 13 July 2000

Abstract Macrophage-mediated segmental demyelination is the pathological hallmark of autoimmune demyelinating polyneuropathies, including the demyelinating form of Guillain-Barre´ syndrome and chronic inflammatory demyelinating polyneuropathy. Macrophages serve a multitude of functions throughout the entire pathogenetic process of autoimmune neuropathy. Resident endoneurial macrophages are likely to act as local antigen-presenting cells by their capability to express major histocompatibility complex antigens and costimulatory B7-molecules, and may thus be critical in triggering the autoimmune process. Hematogenous infiltrating macrophages then find their way into the peripheral nerve together with T-cells by the concerted action of adhesion molecules, matrix metalloproteases and chemotactic signals. Within the nerve, macrophages regulate inflammation by secreting several pro-inflammatory cytokines including IL-1, IL-6, IL-12 and TNF-a. Autoantibodies are likely to guide macrophages towards their myelin or primarily axonal targets, which then attack in a complement-dependent and receptor-mediated manner. In addition, non-specific tissue damage occurs through the secretion of toxic mediators and cytokines. Later, macrophages contribute to the temination of inflammation by promoting T-cell apoptosis and expressing anti-inflammatory cytokines including TGF-b1 and IL-10. During recovery, they are tightly involved in allowing Schwann cell proliferation, remyelination and axonal regeneration to proceed. Macrophages, thus, play dual roles in autoimmune neuropathy, being detrimental in attacking nervous tissue but also salutary, when aiding in the termination of the inflammatory process and the promotion of recovery. © 2001 Elsevier Science Ltd. All rights reserved. Keywords: Inflammatory; Demyelination; T-cell

Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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2. Sequence of events in autoimmune neuropathy. . . . . . . . . . . . . . . . . . . . . . . .

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3. Resident and hematogenous macrophages in the normal and inflamed 3.1. Resident macrophages . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Hematogenous macrophages . . . . . . . . . . . . . . . . . . . . . 3.3. Differentiation of resident and hematogenous macrophages . . .

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Abbre6iations: CNS, central nervous system; CIDP, chronic inflammatory demyelinating polyneuropathy; CR3, complement receptor3; EAN, experimental autoimmune neuritis; GBS, Guillain-Barre´ syndrome; ICAM-1, intercellular adhesion molecule-1; IL, interleukin; MHC, major histocompatibility complex; NO, nitric oxide; PNS, peripheral nervous system; TGF, transforming growth factor; TNF, tumor necrosis factor. * Corresponding author. Tel.: +49-251-83-48323; fax: + 49-251-83-48181. E-mail address: [email protected] (R. Kiefer). 0301-0082/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S0301-0082(00)00060-5

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4. Role of macrophages in antigen presentation . . . . . . . . . . . . . . . . . . . . . . . . .

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5. Macrophage recruitment into the inflamed peripheral nerve . . . . . . . . . . . . . . . .

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6. Macrophages as sources of pro-inflammatory cytokines . . . . . . . . . . . . . . . . . . .

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7. Effector functions of macrophages in autoimmune neuropathy . . . . . . . . . . . . . . 7.1. Immune-mediated demyelination and axonal loss 7.2. Tissue damage by toxic mediators: radicals, cytokines, nitric oxide, and others . . 7.3. Macrophages in secondary Wallerian degeneration . . . . . . . . . . . . . . . . . .

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8. Role 8.1. 8.2. 8.3.

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9. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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of macrophages during recovery . . . . . . . . . . . Interaction of macrophages with T-cell apoptosis . Macrophage-derived anti-inflammatory mediators . Role of macrophages in remyelination and axonal

1. Introduction Several human peripheral neuropathies are thought to be caused by attacks of the immune system on targets within the peripheral nervous system (PNS). While in the early years of neuroimmunology, the PNS was considered to be ‘immune-privileged’, this concept no longer holds true. ‘Immune privilege’ was suspected in organs such as brain, eye and testes (Streilein, 1995), as tissues transplanted into these organs did not undergo rejection to the extent as observed in other areas of the body. However, in 1980s, it was recognized that Schwann cells of the PNS may present antigen in vitro (Wekerle et al., 1986a) and that peripheral nerves, much like the brain (Wekerle et al., 1986b), are under constant surveillance by patrolling activated T-cells. Even earlier, a population of putative immune cells, the resident endoneurial macrophages, were found to reside within the PNS (Arvidson, 1977). Thus, the PNS is more and more recognized as a site of active immunological processes and a target for autoimmune injury. Prototypic neuropathies of presumably autoimmune origin are the Guillain-Barre´ syndrome (GBS), which is an acute neuropathy with spontaneaous recovery (Hartung et al., 1995a; Ho and Griffin, 1999; Hughes et al., 1999), and chronic inflammatory demyelinating polyneuropathy (CIDP) which may take a chronic progressive or a relapsing remitting course (Toyka and Hartung, 1996; Dalakas, 1999). Rarer conditions of putative autoimmune origin are multifocal motor neuropathy (Biessels et al., 1997) and neuropathies associated with monoclonal gammopathies, particularly of the IgM type (Ropper and Gorson, 1998; Simmons, 1999; Steck et al., 1999). In the vasculitides of the PNS,

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the autoimmune attack is directed at vessel walls and their components, and the PNS suffers secondarily as a consequence of ischemia and vascular inflammation (Davies et al., 1996; Said, 1997; Moore, 1999). The pathological hallmark of the demyelinating autoimmune neuropathies, mainly GBS and CIDP, is a process termed macrophage-mediated demyelination, where macrophages virtually strip off the myelin sheath from the axon leaving behind a nude, demyelinated axon (Prineas, 1972; Prineas and McLeod, 1976) which is no longer able to safely conduct nerve impulses. More recently, primary axonal forms of GBS have been described, where macrophages contribute to the axonal loss which occurs prior to subsequent secondary myelin breakdown (Feasby et al., 1986; Griffin et al., 1995, 1996a; Sobue et al., 1997; Hadden et al., 1998). Knowledge of the etiology and the pathogenetic steps in autoimmune neuropathies that lead to macrophage-mediated demyelination and axonal damage is rapidly growing but still incomplete. Information in humans is mainly based on diligent clinicopathological studies of biopsies and autopsy material, and on analyses of blood and serum samples for the presence and function of autoreactive cells, autoantibodies, and inflammatory serum components. Much additional knowledge has been gained from studies in several variants of an animal model of peripheral nerve inflammation, termed experimental autoimmune neuritis (EAN), where both antibody- and T-cell mediated autoimmune inflammation of the PNS can be induced in disease-susceptible laboratory animals (Gold et al., 2000). Depending on the experimental paradigm, conditions resembling GBS and CIDP can be evoked and the various pathogenetic

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steps studied. In fact, many of the concepts of human autoimmunity in the PNS are based on presumed analogies between experimental results obtained in animal studies and the pathobiology of human disease, rather than actual observations in patients. Macrophages, in addition to T- and B-cells, play a crucial role in autoimmune neuropathies before and beyond the final act of macrophage-mediated demyelination. They are found early on in large numbers in nerve biopsies from affected patients (Hughes et al., 1992; Schmidt et al., 1996; Kiefer et al., 1998) and EAN nerve samples (Hartung et al., 1988; Griffin et al., 1992). In addition, there is microglia activation in the spinal cord, both in human GBS and EAN (Gehrmann et al., 1992; Maier et al., 1997). Macrophages are putatively involved in virtually all steps of the pathogenetic process, from early immune surveillance, antigen presentation and activation of the cellular immune cascade throughout the disease to antigen-specific demyelination and axonal damage, non-specific secondary tissue destruction, removal of debris and regeneration. During disease, numerous inflammation-associated antigens are enhanced or expressed de novo by endoneurial macrophages (Kiefer et al., 1998). Depletion of macrophages in experimental models results in greatly reduced severity of the disease (Jung et al., 1993). Activation of macrophages by pro-inflammatory cytokines like interferon-g (IFNg) causes greatly enhanced disease severity (Hartung et al., 1990). This review will critically analyze the role of macrophages during immune-mediated neuropathies, trying to dissect relevant pathobiological features and attribute them to the different stages of the autoimmune process. Other recent reviews have focussed on clinical aspects of autoimmune polyneuropathies (Hahn, 1998; Hartung et al., 1998; Ho and Griffin, 1999), infections preceding Guillain-Barre´ syndrome (Allos, 1997; Yuki, 1997), antibody reactions and the immunology of T-cells as it relates to the peripheral nervous system (Hartung et al., 1996; Ho et al., 1998; Gold et al., 1999a; Hughes et al., 1999; Quarles and Weiss, 1999) and the role of macrophages in Wallerian degeneration (Bru¨ck, 1997). As axonal loss and Wallerian degeneration, either primary in the axonal forms of GBS or secondary as a consequence of inflammation, occur frequently in autoimmune polyneuropathies (Berciano et al., 1997; Massaro et al., 1998; Nagamatsu et al., 1999) and EAN (Rostami et al., 1990; Powell et al., 1991), lessons from studies in Wallerian degeneration are included where relevant to PNS autoimmunity.

2. Sequence of events in autoimmune neuropathy Although the presumed autoantigenic targets and

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the consecutive clinical presentations are different between the various forms of autoimmune neuropathies, a sequence of events may be recognized that occurs similarly in all conditions of this category (Fig. 1). The presumably first step in the pathogenetic cascade is the recognition of an autoimmune epitope presented by an antigen-presenting cell. This does not necessarily occur within the PNS. In postinfectious GBS, epitopes of the infective agent are recognized by T- and B-cells during the infectious disease as part of the normal immune defense. If such epitopes occur in other structures of the body such as the PNS, the consecutive immune response against the infectious agent may be directed against this structure, and immune defense converts into autoimmunity. This mechanism of malrecognition of self epitopes that are similar or identical to foreign epitopes is termed molecular mimicry (Barnett and Fujinami, 1992; Yuki, 1997). As an example, postinfectious GBS may be caused by crossreactivity of antibodies generated against ganglioside moieties present on certain strains of Campylobacter jejuni with the same ganglioside epitopes present within the PNS (Yuki, 1997). Other ways to generate autoreactive T- and B-cells are epitope spreading, the action of bacterial or viral superantigens, and bystander activation by cytokines, all reviewed elsewhere. In the next step, activated T-cells then, circulate and enter the PNS as part of normal immunosurveillance. There, recognition of the autoantigen occurs with the help of local antigen-presenting cells, leading to clonal expansion and cytokine excretion. Macrophages are then activated and monocytes recruited into the nerve in response to cytokines and chemokines. During the effector phase of the disease, destruction of the autoimmune target occurs

Fig. 1. Schematic drawing of the pathogenetic steps during autoimmune inflammation of the peripheral nerve. Macrophages are crucially involved as antigen-presenting cells during the initiation of the immune response, as sources of numerous immunoregulatory molecules, as cytotoxic effector cells and finally as contributors to disease termination and recovery.

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Fig. 2. Resident macrophages and macrophage activation during inflammatory neuropathy. Resident macrophages are easily detected in normal rat nerve by antibody ED2 (A) and express major histocompatibility complex class II antigens (B). On longitudinal sections, they are elongated cells with occasional small ramifications at their ends. During acute Guillain-Barre´ syndrome, macrophages as detected by antibody against CD68 (C, D), massively infiltrate the nerve roots (* in C, higher magnification in D) and dorsal root entry zone (arrows in C) of the spinal cord and newly express inflammation-associated antigens such as the calcium-binding protein MRP14 (E) and B-1 costimulatory molecules (arrows) which are required for antigen presentation (F). While (C) and (D) are from autopsy material, (E) and (F) are stains performed on sural nerve biopsies.

through cytotoxic T-cells and complement-fixing antibodies, and non-specific tissue destruction is implemented through cytotoxic cytokines, toxic radicals and macrophage-mediated cytotoxicity. Depending on the autoantigen, the primary site of the autoimmune attack may be the myelin sheath resulting in segmental demyelination and conduction block (Hafer-Macko et al., 1996a), or the axon leading to primary axonal loss (Hafer-Macko et al., 1996b). The former, macrophage-mediated segmental demyelination, is considered the pathological hallmark of autoimmune demyelinating neuropathies, and is pathognomonic for these conditions (Prineas, 1972; Prineas and McLeod, 1976). In GBS and the remitting forms of CIDP, the autoimmune attack is terminated presumably due to loss of antigenic stimulation, apoptosis of autoreactive T-cells (Gold et al., 1997), and the action of immunosuppressive cytokines (Kiefer et al., 1996). Once inflammation is subsiding, regeneration of destroyed axons and myelin sheaths may commence, leading to remyelination and axonal sprouting.

3. Resident and hematogenous macrophages in the normal and inflamed PNS

3.1. Resident macrophages Whereas axons and Schwann cells form the main cellular constituents of the PNS, a considerable number of local macrophages reside within the endoneurium of peripheral nerve (Griffin et al., 1993). First recognized by Arvidsson (Arvidson, 1977) due to their phagocytozing capacity, resident macrophages are known to comprise 2–4% (Arnason and Soliven, 1993) or even up to 9% of the cellular components of normal peripheral nerve according to some reports (De Waal Malefyt et al., 1991; Griffin et al., 1993). Resident endoneurial macrophages of normal nerve (Fig. 2A and B) are elongated cells stretching along the longitudinal axis of peripheral nerves and show small ramifications with two or three terminal branches at their ends (Stevens et al., 1989; Monaco et al., 1992; Griffin et al., 1993). They are found close to endoneurial blood vessels but also scattered throughout the endoneurium. In rats,

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they are easily recognized by the ED2 antibody (Dijkstra and Damoiseaux, 1993), placing them in relationship with perivascular ED2-positive cells of the CNS which form a macrophage population of the brain, distinct from microglia (Graeber et al., 1989). Further, immunohistochemical studies have shown that resident endoneurial macrophages in normal nerve carry typical macrophage markers like the CD68 antigen in humans (Bonetti et al., 1993) and the F4/80 antigen in mice (Perry et al., 1987), and express MHC I and II antigens, CD4 antigen and complement receptors in humans, rat and mice (Stevens et al., 1989; Griffin et al., 1992; Monaco et al., 1992; Bonetti et al., 1993). They are thus antigenically similar, yet distinct from resident microglia of the brain (Kreutzberg, 1996; Raivich et al., 1999). However, whereas microglial cells are mostly a truly resident population with very little turnover and replacement by hematogenous macrophages (Hickey et al., 1992), resident macrophages of the PNS undergo a relatively rapid turnover with blood derived macrophages (Vass et al., 1993). Studies in radiation bone marrow chimeric rats have demonstrated that around 60% of resident endoneurial macrophages are replaced by bonemarrow derived macrophages after 3 months (Vass et al., 1993). It is, however, presently unknown whether resident macrophages constitute a uniform population or are heterogenous (Monaco et al., 1992) like macrophages in other organs (Dijkstra and Damoiseaux, 1993), and the presence of a truly resident macrophage population has neither been excluded nor definitely proven.

3.2. Hematogenous macrophages Whenever the peripheral nervous system becomes inflamed or injured, large amounts of hematogenous macrophages are attracted and invade the nerve. This is particularly evident, when a peripheral nerve is cut or crushed (Perry et al., 1987; Stoll et al., 1989; Griffin et al., 1992; Taskinen and Roytta, 1997). The degenerating nerve segment, distal to the lesion, is then virtually flooded with macrophages. Similarly, in severe inflammatory lesions, innumerable macrophages enter the nerve (Fig. 3A and B) (Hartung et al., 1988). Evidence that these macrophages are blood-derived, stems from the studies where macrophages were eliminated by silica particles, irradiation or toxic liposomes. In such studies, depletion of blood-derived macrophages greatly reduced macrophage densities in sciatic nerve in EAN (Jung et al., 1993) and diminished Wallerian degeneration (Beuche and Friede, 1986; Perry et al., 1995). Elimination of hematogenous macrophages also resulted in markedly attenuated disease severity of EAN (Jung et al., 1993), indicating that hematogenous macrophages are required for full-blown inflammatory disease. On the other hand, resident macrophages ap-

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pear unable to compensate for the lack of hematogenous macrophages under these conditions, either due to insufficient activation or to insufficient number. Thus, hematogenous macrophages are critical components in peripheral nerve inflammation.

3.3. Differentiation of resident and hematogenous macrophages The individual contribution of resident and blood derived macrophages and their differential function, if any, in inflammatory neuropathies and other pathologies of the PNS is presently largely unknown. Resident and hematogenous macrophages share in common many macrophage markers, and their expression may vary according to their state of activation, rather than their origin and primary location. Antibodies recognizing specifically either cell type are presently not available. Although this is similar to the situation in brain, where resident microglia and infiltrating macrophages need to be differentiated, the blood-nerve barrier is less tight than the blood-brain barrier, allowing for the rapid influx of hematogeneous cells following PNS lesions. Attempts to circumvent this problem have led to investigations in short term organ cultures, where cultured nerve segments can be studied in the absence of blood-derived cells (Hann Bonnekoh et al., 1989). Others have implanted peripheral nerve segments encapsulated in millipore chambers into the peritoneum (Beuche and Friede, 1984). However, such systems, although providing interesting information, are artificial and may not reflect the situation in normal and diseased nerves in situ. Irradiation bone marrow chimeric rats and mice serve as a more suitable alternative for the conduct of such investigations in vivo. Following lethal irradiation with complete destruction of bone marrow, animals are transplanted with donor bone marrow that may be differentiated from local cells by certain polymorphisms such as MHC haplotypes (Vass et al., 1993) or the presence of a transgene (Mu¨ller et al., 1999). However, although such systems have successfully been applied in brain research, studies in PNS inflammation and degeneration are still awaited. In human nerve biopsy, differentiation between resident and infiltrating endoneurial macrophages is essentially impossible at present. Thus, when reviewing studies where macrophages are considered in situ, no distinction can be made as to their origin.

4. Role of macrophages in antigen presentation Antigen presentation to T-cells describes the interaction between an antigen-presenting cell and a T-cell recognizing its specific antigen in a processed form. It

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requires the exhibition of a processed antigenic peptide in the context of an MHC molecule on the surface of the antigen-presenting cell, the recognition by the T-cell receptor, and the action of numerous co-stimulatory molecules to provide adhesion and appropriate activation. These costimulatory signals are delivered through the interaction of CD3, adhesion molecules, CD40, and B7 molecules with their respective counter-receptors, and also involve the action of cytokines such as IL-1 and IL-12. In autoimmune neuropathy, antigen presentation of PNS-specific antigens may occur within the peripheral nerve and outside within the lymphatic tissue. As the latter is not specific to PNS autoimmune disease, the following discussion will be restricted to antigen presentation within the PNS. Resident endoneurial macrophages constitutively ex-

press MHC class I and II molecules and are thus potential candidates for antigen presentation in the PNS (Stevens et al., 1989; Scarpini et al., 1990; Vass and Lassmann, 1990; Griffin et al., 1992; Monaco et al., 1992; Bonetti et al., 1993). In EAN, MHC class II antigens are strongly upregulated on macrophages underlining their potential role in antigen presentation during autoimmune inflammation. The T-cell derived pro-inflammatory cytokine IFN-g is probably one of the most potent inducers of MHC II in this situation, as it is strongly upregulated during EAN (Schmidt et al., 1992) and, when systemically applied in vivo, markedly augments MHC class II antigen expression on macrophages (Vass and Lassmann, 1990). In GBS and CIDP, MHC class I and II molecules are also strongly upregulated on macrophages in sural nerve

Fig. 3. Cytokine expression by endoneurial macrophages during experimental autoimmune neuritis. While TNF-a is detected early during disease (A, immunocytochemistry), IL-10 mRNA expression (B, non-radioactive in situ hybridization histochemistry) remains elevated during recovery pointing towards a role in terminating the disease. Similarly, TGF-b1 mRNA expression peaks just prior to the onset of recovery (C; dark field micrograph of radioactive in situ hybridization histochemistry) and remains upregulated in peripheral nerves from animals that have already made a complete recovery (D). TGF-b1 mRNA (black silver grains in E) co-localizes with endoneurial macrophages (brown, arrows in E) and is translated into protein as shown by immunocytochemistry for TGF-b1 (F).

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biopsies (Pollard et al., 1986, 1987). However, MHC expression is not specific for inflammatory disease but also occurs during non-inflammatory activation of macrophages in genetically determined degenerative polyneuropathies (Stoll et al., 1998). MHC II expression may thus, represent a more general state of activation of endoneurial macrophages following lesions preparing them for antigen presentation, if, warranted. In contrast, the costimulatory B7 molecules (Greenfield et al., 1998) required for effective antigen presentation appear to be more specifically expressed in inflammatory neuropathy. They are undetectable by immunocytochemistry in normal nerves and nerves with degenerative neuropathies but may be induced on endoneurial as well as epineurial macrophages during infectious or autoimmune inflammatory neuropathies (Kiefer et al., 2000). The strongest expression was found in cases with neuroborreliosis where, there was strong upregulation of B7-1 on both epi- and endoneurial macrophages. Conspicuous expression of B7-1 immunoreactivity was also observed on putative macrophages in several biopsies from patients with GBS and CIDP, particularly within the endoneurium (Fig. 3). In contrast, only little B7-2 was detected, pointing towards a preferential bias of T-cells towards the Th1 phenotype (Greenfield et al., 1998). These immunocytochemical data are supported by upregulation of B7-1 mRNA but only rarely of B7-2 mRNA in subsets of biopsies from patients with inflammatory but not hereditary neuropathies. PNS endo- and epineurial macrophages thus fulfill another molecular requirement for effective antigen presentation by expressing costimulatory B7 molecules, particularly B7-1. As a further requirement for antigen presentation, PNS macrophages express the adhesion molecule — intercellular adhesion molecule-1 (ICAM-1) allowing cell adhesion with its counter-receptor lymphocyte function associated antigen-1 (LFA-1) on T-cells (Stoll et al., 1993a,b). ICAM-1 is also critically involved in the transendothelial migration of monocytes during recruitment into the PNS as discussed below. The expression of CD40 and its ligand, another pair of costimulatory ligands, has to date not been studied in PNS. Finally, several pro-inflammatory cytokines including IL-1 and IL-12 necessary for costimulatory activation of T-cells and antigen presenting cells are expressed in diseased nerves, both in humans and in experimental models, and will be discussed further below (Scarpini et al., 1990; Zhu et al., 1997; Gillen et al., 1998). Macrophages within the PNS, presumably both resident endoneurial macrophages as well as those of hematogenous origin, are thus equiped with several tools enabling them to present antigen. However, although it appears reasonable to assume that antigen presentation occurs within the PNS in vivo, direct evidence is still lacking. Schwann cells, in contrast, do

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not express MHC II molecules in EAN (Schmidt et al., 1990) although in some studies, MHC II positive Schwann cells were described in sural nerve biopsies from patients with inflammatory neuropathies (Pollard et al., 1987; Scarpini et al., 1990; Rizzuto et al., 1998). In vitro, Schwann cells can readily be induced to express MHC antigens (Kingston et al., 1989; Armati et al., 1990; Gold et al., 1995) and present antigen to T-cells (Wekerle et al., 1986a; Gold et al., 1995). It is thus conceivable that Schwann cells may contribute to antigen presentation in autoimmune neuropathies upon very strong stimulation and under selected conditions, but resident and infiltrating endoneurial macrophages are clearly the professional antigen-presenting cells within the PNS. 5. Macrophage recruitment into the inflamed peripheral nerve Hematogenous macrophages enter the PNS in large numbers both during Wallerian degeneration and during autoimmune neuropathy (Perry et al., 1987; Stoll et al., 1989; Griffin et al., 1992; Avellino et al., 1995; Taskinen and Roytta, 1997). As primary and secondary axonal degeneration may occur during autoimmune neuropathy (Berciano et al., 1997; Massaro et al., 1998; Nagamatsu et al., 1999), some mechanisms discovered in studies of Wallerian degeneration may also be applicable to autoimmune neuropathy. Recruitment of monocytes into the PNS requires several consecutive and coactive steps — (i) rolling and loose contact between circulating monocytes and vascular endothelium; (ii) establishing a firm adhesion between monocytes and endothelial cells; (iii) perception of chemoattractive signals; (iv) penetration of endothelium and the underlying basal lamina; and (v) differentiation into tissue macrophages. As a first step, blood monocytes roll along the vascular endothelium and form loose reversible connections mediated by selectins (Tedder et al., 1995; Luscinskas et al., 1996). A functional role for L-selectin during the induction and effector phase of EAN was demonstrated by the application of blocking antibodies, which resulted in attenuation of the disease (Archelos et al., 1997). This view is supported by the observation of elevated levels of another selectin, E-selectin/endothelial leukocyte adhesion molecule-1 (ELAM-1) during GBS and CIDP (Hartung et al., 1994; Oka et al., 1994). A possible mediator of selectin upregulation in EAN may be endothelial monocyte activating polypeptide II (EMAP II), which is constitutively expressed in resident macrophages of the peripheral nerve and rapidly upregulated during nerve inflammation (Schluesener et al., 1997). This peptide has been shown to be able to upregulate E- and P-selectin on endothelial cells (Kao et al., 1994).

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In the next step, firm irreversible connections between monocytes and endothelial cells mediated by integrins and their ligands are established (Hartung et al., 1995b; Archelos et al., 1999). ICAM-1, a ligand for the complement receptor type 3 (CR3; Mb2 integrin), was upregulated on endothelial cells in EAN (Stoll et al., 1993a), and raised serum levels of soluble ICAM-1 were found in GBS patients (Trojano et al., 1998). Functional studies in EAN using antibodies against ICAM-1 (Archelos et al., 1993a) demonstrated strongly attenuated disease and reduced macrophage recruitment, although this effect may be mediated at least in part by blocking the interaction between ICAM-1 and another counter-receptor present on lymphocytes, lymphocyte function associated antigen-1 (Archelos et al., 1994). However, complement receptor 3 is expressed by macrophages, and the interaction between ICAM-1 and macrophage complement receptor is presumably required for adhesion of macrophages to endothelial cells and macrophage recruitment to the peripheral nerve. This view is further supported by studies in Wallerian degeneration (Bru¨ck, 1997). In vitro and in vivo experiments using neutralizing antibodies against complement receptor 3 and mice genetically deficient of ICAM-1, strongly support a role for these adhesion molecules in macrophage recruitment during Wallerian degeneration (Bru¨ck and Friede, 1990a,b; Vougioukas et al., 1998). Inhibition of macrophage invasion of in vitro degenerating nerve segments by pentoxifylline may also be due to ICAM-1 inhibition (Liefner et al., 1998). By contrast, another study of Wallerian degeneration using blocking antibodies against ICAM-1 and CR3 showed no effect on macrophage recruitment (Brown et al., 1997), and in vitro cell adhesion of macrophages to sections of peripheral nerve was unaffected by antibodies against CR3. Another adhesion molecule that is upregulated in capillaries during EAN and may thus be involved in inflammatory cell recruitment is b3 integrin (Previtali et al., 1998). On the other hand, a1, av and b4 integrin chains are downregulated on capillaries during EAN (Previtali et al., 1998). Other adhesion molecules relevant in EAN are the CD2 antigen (Jung et al., 1996) and vascular cell adhesion molecule with its counter-ligand, very late antigen 4 (VLA-4) (Enders et al., 1998) which is present on T-cells only and not involved in macrophage immigration (Brown et al., 1997). Once adhesion has been established, chemotactic signals are perceived that guide the adhering monocytes towards the interior of the nerve. Whereas many cytokines have chemotactic properties, a subgroup termed chemokines, are of particular relevance (Luster, 1998). In EAN, the chemokine macrophage inflammatory protein 1a(MIP1a) is upregulated in peripheral nerve macrophages with a peak prior to the height of the disease, suggesting a role in macrophage recruitment

(Zou et al., 1999). Another chemokine, monocyte chemoattractive protein 1 (MCP-1), increases in macrophages with a time course similar to that of disease progression. The neutralizing antibodies against MIP-1a resulted in delayed onset of EAN and greatly diminished severity and macrophage recruitment, whereas, inhibition of MCP-1 only slightly delayed disease onset. The chemokine MIP-2, mainly involved in the attraction of neutrophils, was expressed only late during disease, and blocking did not result in an altered disease course (Zou et al., 1999). Chemokines are also involved in the pathophysiology of Wallerian degeneration. Here, MCP-1 mRNA was found to be upregulated very early following a traumatic lesion and remained elevated for a long time (Carroll and Frohnert, 1998; Toews et al., 1998). While Schwann cells were thought to express MCP-1 in one study (Toews et al., 1998), another study (Carroll and Frohnert, 1998) would suggest that macrophages may also participate. Another cytokine that may be involved in macrophage recruitment is, transforming growth factor-b1 (TGF-b1). Although mainly an immunosuppressive cytokine, it has been shown to be chemoattractive for macrophages and is expressed already early in EAN, although peak expression is not reached until just prior to recovery (Kiefer et al., 1996). Finally, complement components, specifically C5a, are chemotactic for monocytes and may aid in macrophage recruitment as discussed below (Springer, 1994). To penetrate endothelial cells and the underlying basal lamina, the action of proteases is required. There is good experimental evidence that matrix metalloproteases (MMP) are involved in this process (BirkedalHansen, 1995; Woessner, 1994). Several MMPs including the 72 kD gelatinase are constitutively expressed in peripheral nerve (Hughes et al., 1999; Kieseier et al., 1998). During EAN, mRNA for the MMPs 92 kD gelatinase, stromelysin and macrophage metalloelastase are rapidly and heavily upregulated, and there is increased zymographic activity at different molecular weights in EAN (Hughes et al., 1998; Kieseier et al., 1998). Immunocytochemical studies revealed rapid upregulation of stromelysin and 92 kD gelatinase around blood vessels prior to cellular infiltration. Matrilysin and macrophage metalloelastase followed slightly later and were localized to macrophages and T-cells, whereas 92 kD gelatinase was localized to Tcells and endothelial cells. Schwann cells constitutively expressed all MMPs mentioned. Furthermore, matrilysin and 92 kD gelatinase were also found in sural nerve biopsies from patients with GBS around blood vessels by immunocytochemistry and functionally by zymography (Kieseier et al., 1998). In CIDP, however, no increase of matrilysin was found, whereas MMP-2 and 92 kD gelatinase were upregulated in T-cells (Leppert et al., 1999). Finally, a functional inhibitor of

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MMPs was able to reduce disease activity and macrophage infiltration in EAN, either directly or through inhibition of TNF-a (Redford et al., 1997). Taken together, the time course of MMP expression, the localization to blood vessels and infiltrating inflammatory cells and functional studies strongly suggest that MMPs play a key role in macrophage recruitment and penetration through the blood nerve barrier in PNS autoimmunitiy. Once monocytes have entered the PNS, they differentiate into macrophages, a process discussed below, and migrate to their site of action.

6. Macrophages as sources of pro-inflammatory cytokines Macrophages within inflammatory nerve lesions express and elaborate a multitude of regulatory molecules that may modulate the course of the inflammatory neuropathy. They, thus, not only act as chief effector cells in demyelination and tissue destruction as discussed below but are also intimately involved in the control of the pathogenetic process. Pro-inflammatory mediators derived from macrophages that propagate inflammation include interleukin 12 (IL-12), TNF-a and possibly IL-6 whereas, TGF-b and IL-10 have predominantly anti-inflammatory effects. During early stages of the disease, IL-12, which is active as a p35/p4O heterodimer, may regulate the expression of the costimulatory B7 molecules on antigen-presenting cells with a preference for B7-1, thus, driving the ensueing T-cell response towards a proinflammatory Th-1 phenotype (Greenfield et al., 1998). In addition to Th-1 T-cells, macrophages are capable of expressing IL-12 p40 (Trinchieri, 1995). In EAN, IL-12 mRNA is expressed in cells within the inflamed nerve with a time course parallel to disease activity (Zhu et al., 1997). However, IL12 p35 and IL12 p40 were not investigated separately in this study, and the exact cellular source was not identified. In another study using PCR, IL-12 p40 was found relatively late during disease, not supporting a role in early lesion development (Gillen et al., 1998). The late expression of IL12 p40 may possibly point towards an immunosuppressive function during EAN as IL12 p40 homodimers may antagonize the biological effects of the functional IL12 p35/p40 heterodimer (Yasuda et al., 1998). In the sister model of EAE, however, intervention studies using neutralizing antibodies against functional IL-12 prevented disease pointing towards a disease-promoting effect as in other experimental models of autoimmunity (Leonard et al., 1995). A pro-inflammatory effect within the PNS is further supported by results from an experiment where IL-12 injected into healthy peripheral nerve provoked inflammation and caused marked de-

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myelination (Pelidou et al., 1999). Collectively, these observations provide circumstantial evidence that macrophages might promote inflammation and demyelination by expressing IL-12, although IL12 p40 homodimers possibly formed late during disease may have immunosuppressive effects. Elevated serum and/or cerebrospinal fluid levels of TNF-a were detected in patients with GBS during active disease in most studies and were correlated with disease activity (Creange et al., 1996; Exley et al., 1994; Sharief et al., 1993). The extent of TNF-a elevation is correlated with electrophysiological abnormalities (Sharief et al., 1997). In EAN, TNF-a mRNA expression parallels the evolution of clinical disease (Zhu et al., 1997). Immunocytochemical studies on teased fiber preparations revealed TNF-a expression in macrophages adhering to the fibers, and a pathogenetic role of macrophage-derived TNF-a was suggested by amelioration of EAN by neutralizing antibodies given intraperitoneally (Stoll et al., 1993c). Macrophages are the main source of TNF-a also in human biopsies from patients with CIDP (Armati et al., 1990; Oka et al., 1998), and particularly pronounced expression was found in macrophages around myelinated nerve fibers (Oka et al., 1998). Others have suggested that TNF-a is also expressed in Schwann cells during CIDP (Mathey et al., 1999). When injected into peripheral nerve, TNFa much like IL-12 causes inflammation, demyelination and damage to endothelial cells possibly promoting blood-nerve barrier breakdown (Redford et al., 1995), although this was debated by others (Uncini et al., 1999). Administration of a matrix metalloprotease inhibitor causing decreased processing of TNF-a precursor lead to ameliorated disease (Redford et al., 1997). However, animals genetically deficient of TNF-a develop more severe disease in an EAE model, and this effect is reversible by the application of TNF-a (Liu et al., 1998). These results suggest a protective role of TNF-a which might be due to the induction of T-cell apoptosis (Weishaupt et al., 2000). Although macrophage derived TNF-a may have a potent pro-inflammatory role, this is still disputed and most likely, much like other cytokine actions, depends on the molecular and cellular context in which TNF-a expression occurs (Nathan and Sporn, 1991). Several studies point towards a rather complex role of another cytokine, IL-6. IL-6 mRNA is expressed in EAN peripheral nerve early in yet unidentified cells even before the onset of clinical disease, but IL-6 immunoreactivity did not peak until the height of the disease was reached (Zhu et al., 1997). Macrophages are known sources of IL-6 in other systems and are candidate cells to express IL-6 also in human neuropathy and EAN. In human studies, IL-6 was found in cerebrospinal fluid samples of 13/23 GBS cases and 3/7 CIDP cases (Maimone et al., 1993), whereas only little

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was found in GBS patients in another study (Sivieri et al., 1997). When injected into healthy nerve, IL-6 caused inflammation and demyelination (Deretzi et al., 1999a) similar to TNF-a and IL-12 as discussed above. On the other hand, IL-6 given as interventive therapy was able to prevent EAN (Deretzi et al., 1999b), once again pointing towards a complex action of IL-6. Other potentially pro-inflammatory cytokines noted in EAN and human autoimmune neuropathy that are likely to be macrophage-derived are IL-1 and the colony-stimulating factors. IL-1b mRNA and protein expressing cells were detected in EAN peripheral nerve even before clinical signs in one study (Zhu et al., 1997) and at the time of disease onset in another (Gillen et al., 1998). Elevated levels were measured in cerebrospinal fluid from patients with GBS (Sivieri et al., 1997), and IL-1 immunoreactivity was localized to endoneurial macrophages in CIDP (Rizzuto et al., 1998). There is also evidence for the expression of macrophage-colony stimulating factor in CIDP (Sivieri et al., 1997). TGF-b1, although mainly an anti-inflammatory cytokine discussed below, may have some proinflammatory properties, and some TGF-b1 is expressed already early in the disease by macrophages (Kiefer et al., 1996). However, it should be noted that many of the cytokines mentioned above, including IL1, IL-6, TNF-a and TGF-b1, are also generated during Wallerian degeneration by macrophages and other cells (Lindholm et al., 1987; Scherer et al., 1993; Stoll et al., 1993c; Rufer et al., 1994; Bolin et al., 1995; Kiefer et al., 1995; Bourde et al., 1996; Hirota et al., 1996; Reichert et al., 1996), and their elaboration by macrophages is not specific to autoimmune neuropathies.

7. Effector functions of macrophages in autoimmune neuropathy

7.1. Immune-mediated demyelination and axonal loss Macrophage-mediated segmental demyelination is the pathological hallmark of autoimmune demyelinating neuropathies including CIDP and the demyelinating forms of GBS (Prineas, 1972; Prineas and McLeod, 1976; Prineas, 1981). It is considered an active immunological process, where macrophages attack intact myelin sheaths wrapped around healthy axons. Another form of myelin phagocytosis by macrophages occurs in Wallerian degeneration. Here, axons degenerate and leave their myelin sheaths behind which are then degraded and removed (Bru¨ck, 1997). As Wallerian degeneration occurs in CIDP and GBS, both types of myelin phagocytosis by macrophages occur in autoimmune neuropathies.

The immunological mechanisms leading to macrophage-mediated segmental demyelination have only partially been explored. Macrophages, in contrast to T-cells, do not act in a cognizant antigen-specific manner and need to be targeted by additional mechanisms. There is good evidence that antibodies may direct macrophages towards their myelin or axonal targets in autoimmune neuropathies and that, macrophages attack sites of antigen binding, in a complement dependent manner. In EAE, myelin lamellae are attached to macrophage coated pits prior to phagocytosis, pointing towards a receptor-mediated type of interaction (Epstein et al., 1983), and a similar mechanism may operate in autoimmune neuropathy. Receptor-ligand pairs involved are Fc-receptors/immunoglobulins and complement receptor/complement. In vitro, myelin can be opsonized by antibody causing enhanced phagocytosis by macrophages which is mediated by Fc receptors (Trotter et al., 1986; Goldenberg et al., 1989; Mosley and Cuzner, 1996a). Antibody deposition in peripheral nerve biopsies was demonstrated in GBS and CIDP (Luijten and Baart, 1972; Nyland et al., 1981), and increased levels of complement fixing autoantibodies circulate in the blood of GBS patients (Latov et al., 1981; Koski et al., 1985 Vriesendorp et al., 1991). Similarly, autoantibodies against various myelin compounds are produced during the course of EAN (Archelos et al., 1993b; Zhu et al., 1994; Koehler et al., 1996). The role of complement is further supported by the demonstration of its deposition on Schwann cells in GBS (Koski et al., 1987; Hays et al., 1988; Koski, 1997) and other autoimmune neuropathies (Monaco et al., 1990; Ferrari et al., 1998) as well as EAN (Stoll et al., 1991), elevated circulating complement levels in serum and cerebrospinal fluid (Hartung et al., 1987; Koski et al., 1987) during GBS, demyelination induced by intraneural or intraperitoneal transfer of EAN serum, and successful treatment of EAN by complement inhibition (Jung et al., 1995; Vriesendorp et al., 1995, 1998). Autoantibodies against various ganglioside chains are crucially involved in the pathogenesis of GBS (Hartung et al., 1996; Quarles and Weiss, 1999), and their specificity and the distribution of their targets may determine the primary site of the autoimmune attack, i.e. myelin or axonal (Ho and Griffin, 1999; Ho et al., 1999). In a recent series of excellent pathological studies, the deposition of antibody and complement components was investigated in axonal and demyelinating forms of GBS. In acute motor axonal neuropathy, a variant observed in epidemics in China, India and South America, immunoglobulin and complement were localized at the axolemma mainly at the nodes of Ranvier, and macrophages accumulated, extending their processes into the periaxonal space. Subsequently, it appeared that the axons degenerated while the outer Schwann

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cell surface and the myelin remained intact for some more time (Griffin et al., 1996a,b; Hafer-Macko et al., 1996b), possibly due to CD59 expression (Vedeler et al., 1999). In demyelinating GBS, complement was localized to the outer surface of Schwann cells, leading to early vesicular changes of myelin which were later followed by macrophage accumulation and myelin stripping, although this was not always the case (Hafer-Macko et al., 1996a). These observations strongly support the role of antibody in immune mediated neuropathy, and also in targeting macrophages towards their site of action, suggesting that tissue destruction may be both mediated directly by complement as well as indirectly through the action of macrophages.

7.2. Tissue damage by toxic mediators: radicals, cytokines, nitric oxide, and others However, antibody-dependent macrophage cytotoxicity is not the only mechanism by which segmental demyelination may occur. Harvey and colleagues demonstrated focal demyelination in rat nerves at sites of intraneural ovalbumin injection in animals pre-immunized with ovalbumin (Harvey et al., 1995). They thus conclusively showed that demyelination may occur by antigen-nonspecific mechanisms as the immune attack in their system is not directed against a structural component of axons or Schwann cells. There are also numerous reports that massive inflammation may lead to secondary axonal loss and tissue destruction beyond the actual immunological targets (Berciano et al., 1997; Massaro et al., 1998; Nagamatsu et al., 1999). Such changes are mediated by toxic mediators released from macrophages that may be intended to destroy the target of the macrophage attack but may leak into the surrounding tissues, particularly if there is a vigorous inflammatory response. Toxic attacks upon myelin and other structures in vitro are mediated at least in part by reactive oxygen species (van der Goes et al., 1998) and are associated with the secretion of nitric oxide (NO) (Mosley and Cuzner, 1996b) and TNF-a into culture supernatants (van der Laan et al., 1996). Nitric oxide synthase may be expressed by macrophages upon stimulation by encephalitogenic T-cells through the action of IFN-g (Misko et al., 1995). Reactive oxygen species may damage myelin (Chia et al., 1983; Konat and Wiggins, 1985) and Schwann cells, rendering them susceptible to attacks by macrophages (Bru¨ck et al., 1994), as does TNF-a (Selmaj and Raine, 1988). More recent studies have shown that peroxynitrite, generated as a consequence of molecular interactions between reactive oxygen species and NO, may act as the ultimate effector molecule rather than NO itself (van der Veen and Roberts, 1999). In vivo, some inhibitors of

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NO formation attenuated adoptive transfer EAN but investigations with different inhibitors in different models of EAE and EAN gave conflicting results, pointing towards a complex regulation and role of NO (Zielasek et al., 1995; Willenborg et al., 1999). Eicosanoids and prostaglandins are other mediators involved in macrophage cytotoxicity (Hartung et al., 1988). TNF-a is expressed in macrophages both during EAN (Stoll et al., 1993c) and CIDP (Oka et al., 1998), when it was found to be associated with phagocytosing macrophages. A role for TNF-a in myelin damage is supported by the application of pentoxifylline, a phosphodiesterase inhibitor that also inhibits TNF-a. Pentoxifylline reduces myelin phagocytosis by macrophages in vitro, suggesting an enhancing effect of TNF-a (Liefner et al., 1998). In contrast, TNF-a suppressed macrophage phagocytosis in peripheral nerve explant cultures but not their invasion (Bru¨ck et al., 1992), whereas direct injection of TNF-a into peripheral nerve in vivo produced demyelination and tissue destruction in most studies (Said and Hontebeyrie-Joskowicz, 1992; Redford et al., 1995; Spies et al., 1995), but not in another (Uncini et al., 1999). The differing results may depend on regulatory effects of TNF-a rather than direct toxic effects, and the net effect of TNF-a upon demyelination and tissue destruction remains unresolved (Lisak et al., 1997). Other cytokines including IL-6 and IL-12 also precipitate demyelination, when injected into peripheral nerve (Deretzi et al., 1999a; Pelidou et al., 1999). However, it is not clear whether these are direct effects or the consequence of severe inflammation. Finally, various proteases are involved in non-specific tissue breakdown by macrophages during inflammation (Said and Hontebeyrie-Joskowicz, 1992). More recently, the expression of MMPs has been investigated in detail in EAN, GBS and CIDP (Hughes et al., 1998; Kieseier et al., 1998; Leppert et al., 1999). Their role in blood-nerve barrier breakdown was discussed above. It is, however, interesting to note that MMPs are not only upregulated around blood vessels but also within the endoneurium. In particular, matrilysin and macrophage metalloprotease was upregulated in macrophages during EAN later in the disease and was related to myelin breakdown (Hughes et al., 1998), suggesting a role for MMPs also in tissue destruction. In summary, a multitude of toxic mediators are released by macrophages that could contribute to tissue destruction in inflammatory neuropathy. However, neither of these mediators is specific for any target, and the full-blown destructive effect of macrophages can only be effected by the concerted action of the entire armamentarium of these cells.

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7.3. Macrophages in secondary Wallerian degeneration As autoimmune inflammation may cause axonal degeneration either due to a primary attack upon the axon or as a consequence of non-specific ‘bystander’ damage, mechanisms of myelin breakdown and debris removal that occur in Wallerian degeneration are also relevant to autoimmune neuropathies. The role of macrophages in Wallerian degeneration was recently carefully reviewed (Bru¨ck, 1997) and will, therefore, not be discussed in detail. However, it should be noted that macrophages, and, as it appears, hematogenous macrophages rather than their resident endoneurial counterparts, are critically involved in myelin phagocytosis and thus pave the way for subsequent successful regeneration (Dailey et al., 1998).

8. Role of macrophages during recovery One of the cardinal clinical features in the great majority of GBS patients is recovery, although not necessarily complete. The mechanisms are incompletely understood, but loss of antigenic drive, elimination of autoreactive T-cells by apoptosis, and the expression of anti-inflammatory cytokines all are involved. Once the inflammatory process subsides repair processes are initiated that include remyelination of denuded axons and axonal regeneration where Wallerian degeneration occured as a consequence of inflammation. Macrophages within the peripheral nerve not only participate in the propagation of inflammation and tissue destruction but may also promote recovery.

8.1. Interaction of macrophages with T-cell apoptosis One crucial mechanism to terminate nervous system inflammation is apoptosis of autoreactive T-cells (Gold et al., 1997). In EAN, T-cells undergo apoptosis within the peripheral nerve early with peak apoptotic activity at the time of maximal T-cell infiltration (Zettl et al., 1994; Creange et al., 1998), although the extent of apoptosis is certainly much less than in EAE spinal cord (Gold et al., 1997). Macrophages might participate in the induction of apoptosis by secreting pro-apoptotic mediators including nitric oxide and TNF-a and possibly direct cell contact (Wu et al., 1995; Aliprantis et al., 1996; Weishaupt et al., 2000). Studies with neuritogenic autoreactive T-cell lines transferring EAN revealed that NO and reactive oxygen intermediates induced apoptosis also in this model (Zettl et al., 1997). In a coculture system between macrophages and neuritogenic T-cells, it was further demonstrated that macrophage-derived reactive oxygen intermediates may exert their action only when close contact between macrophages and T-cells was allowed (Mix et al., 1999). Macrophages,

thus, may contribute to the induction of T-cell apoptosis by secreting toxic radicals if they reach immediate contact with their targets.

8.2. Macrophage-deri6ed anti-inflammatory mediators In addition to mainly pro-inflammatory cytokines discussed above, macrophages also elaborate anti-inflammatory mediators. One example is the immunosuppressive cytokine IL10, which was shown to inhibit EAN, when given before or after onset of the disease (Bai et al., 1997). In EAN, IL-10 mRNA was found to be expressed in unidentified cells during recovery and much later than the pro-inflammatory cytokines IL-12, TNF-a and IL-1 (Zhu et al., 1997). In another study of EAN using PCR, IL-10 mRNA was found early but expression was maintained well into the recovery phase (Gillen et al., 1998). Using in situ hybridization and co-localization with cellular markers, the same authors were able to identify endoneurial macrophages as the primary source of IL-10 during later stages of EAN (Jander et al., 1996). Another cytokine known to suppress a number of experimental autoimmune diseases is TGF-b. In EAN, both TGF-b1 and TGF-b2 inhibited the disease, reducing clinical severity and curtailing the extent of mononuclear infiltration of peripheral nerve (Gregorian et al., 1994; Jung et al., 1994). Studies in adoptive transfer and actively induced EAN revealed strong upregulation of TGF-b1 mRNA in peripheral nerve and spinal roots as well as spinal cord with maximum expression just prior to the onset of clinical recovery. In search of the cellular source, macrophages were identified to express both TGF-b1 mRNA and protein using in situ hybridization and immunocytochemistry, while Schwann cells did not participate in TGF-b1 expression (Kiefer et al., 1996). In addition, activated microglial cells in the spinal cord express TGF-b1 during EAN (Kiefer et al., 1993). Similar findings may be expected in human autoimmune neuropathies as TGF-b1 mRNA is also expressed in sural nerve biopsy specimens from patients with GBS (R. Kiefer, unpublished). TGF-b1 expression, however, is not specific for inflammatory neuropathies but may also occur in experimental Wallerian degeneration (Kiefer et al., 1995) and human degenerative neuropathies. As in other neuroimmunological diseases, senial determinations of TGF-b1 in GBS patients revealed an association between TGF-b1 and recovery. In one study, TGF-b1 was decreased during disease progression and rose back to normal during recovery (Creange et al., 1998). In another study, particularly marked expression of TGF-b1 mRNA was found in cerebrospinal fluid mononuclear cells during recovery from GBS (Sindern et al., 1996). Taken together, TGF-b1 is expressed in patients with GBS and in EAN with a time course, suggesting an association with recovery, and

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macrophages are the primary source of this immunosuppressive cytokine. In addition, macrophages synthesize other mediators that may exert anti-inflammatory effects. The possible role of IL12 p40 homodimers was already discussed above. Lipocortin-1 has potent inhibitory effects on T-cells and is expressed in macrophages during EAN (Gold et al., 1999b). IL-6 and TNF-a may in a certain context act as inhibitory molecules (Liu et al., 1998; Deretzi et al., 1999b). On the other hand, TGF-b1 may have pro-inflammatory effects under certain circumstances (Wyss Coray et al., 1997). The actual effect of any given cytokine may thus be difficult to predict and depends on a multitude of local co-regulatory factors involved in a complex network (Nathan and Sporn, 1991).

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addition, it supports Schwann cell differentiation towards myelinating cells (Haggiag et al., 1999). IL-6 is thus involved in an extremely complex manner in virtually all processes from inflammatory regulation to myelin and axon repair, and it is expressed not only by macrophages but also by Schwann cells and neurons. It is easily conceivable that the biological effect of IL-6 at any given site and time during the pathogenetic process may greatly differ and depend on the local microenvironment, the availability of cofactors and the susceptibility of receptor-bearing cells.

8.3. Role of macrophages in remyelination and axonal regeneration Macrophages are tightly involved in the repair of peripheral nerve, once inflammation has stopped. The contributions of macrophages to Schwann cell proliferation and survival, to remyelination and to axonal outgrowth are certainly not specific for autoimmune neuropathies but occur similarly following other insults. In a series of recent reviews, the molecular basis of Schwann cell repair and nerve regeneration was discussed in detail (Lisak et al., 1997; Apfel, 1999; Mirsky and Jessen, 1999; Stoll and Mu¨ller, 1999). As a brief outline, Schwann cells proliferate following a lesion, a process thought to be triggered by macrophages although Schwann cell proliferation is not entirely dependent on macrophage infiltration. Macrophages secrete numerous growth and differentiation factors for Schwann cells and promote remyelination. In addition, they facilitate axonal regeneration by secreting growth factors or cytokines that in turn stimulate growth factor secretion by Schwann cells. They also contribute to the modulation of extracellular matrix components allowing axonal regeneration. Discussion of the cytokine IL-6 may illustrate the complexity of effects of individual macrophage products. As mentioned before, IL-6 is expressed during EAN and in GBS patients, in a time course, suggesting a disease-promoting effect, although intervention with IL-6 treatment resulted in reduced disease severity (Maimone et al., 1993; Sivieri et al., 1997; Zhu et al., 1997; Deretzi et al., 1999b). IL-6 is also expressed at high levels during Wallerian degeneration, presumably by macrophages and Schwann cells (Bolin et al., 1995; Bourde et al., 1996; Reichert et al., 1996). IL-6 acts as a neurotrophic agent on certain neurons (Gadient and Otten, 1997) and supports nerve regeneration (Hirota et al., 1996; Zhong et al., 1999), and it is expressed by axotomized sensory and motoneurons themselves (Murphy et al., 1995, 1999). In

Fig. 4. Schematic drawing summarizing the role of macrophages during autoimmune neuropathy. (A) Endoneurial macrophages act as antigen-presenting cells by expressing MHC antigens and co-stimulatory B7-molecules. (B) Hematogenous macrophages cross the blood nerve barrier (BNB) with the help of cellular adhesion molecules (CAMs) and matrix metalloproteases (MMPs) and enter the nerve attracted by chemokines. (C) Once within the nerve, macrophages promote inflammation by releasing pro-inflammatory cytokines like IL-1 and TNF-a. They are guided towards their targets presumably by antibodies and attack them in a complement-dependent, receptormediated manner. In addition, non-specific tissue destruction occurs through cytotoxic radicals and other toxic secretory products including cytokines. Macrophages contribute to recovery by promoting T-cell apoptosis and secreting anti-inflammatory cytokines like IL-10 and TGF-b.

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9. Conclusions The main pathobiological functions of macrophages are summarized in Fig. 4: 1. Endoneurial macrophages act as antigen-presenting cells by expressing MHC antigens and costimulatory B7-molecules. 2. Hematogenous macrophages enter the nerve attracted by chemotactic signals and with the help of adhesion molecules and matrix metalloproteases. 3. Once within the nerve, macrophages promote inflammation by releasing pro-inflammatory cytokines. 4. Macrophages are guided towards their targets presumably by antibodies and attack them in a complement-dependent, receptor-mediated manner. In addition, non-specific tissue destruction occurs through cytotoxic radicals and other toxic secretory products including cytokines. 5. Macrophages contribute to recovery by promoting T-cell apoptosis and secreting anti-inflammatory cytokines like IL-10 and TGF-b. 6. Once inflammation has subsided they promote myelin repair and axonal regeneration. Macrophages thus take over critical functions in promoting inflammation, as effector cells, in terminating the immune reaction and in peripheral nerve recovery following the autoimmune insult. They have a Janus face, making the patients sick but also helping them to recover. One might speculate that macrophages support the normal intact microenvironment of the PNS, but when disturbed by autoimmunity, they loose their normal control and develop their destructive potential. The fault, however, is not with the macrophages but with the distorted specific immune response following, for example, a preceding infection as in GBS.

Acknowledgements Work cited from the authors’ laboratories were supported by grants from the Deutsche Forschungsgemeinsschaft and Gemeinniitzige Hertie-Stiftung and funds from the Universities of Mu¨nster, Graz and Wu¨rzburg.

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