Recent neurophysiological and pathological studies have led to a reclassification of the diseases that underlie Guillain‐Barre syndrome (GBS) into acute inflammatory demyelinating polyradiculoneuropathy (AIDP), acute motor and sensory axonal neuropathy (AMSAN) and acute motor axonal neuropathy (AMAN). The Fisher syndrome of ophthalmoplegia, ataxia and areflexia is the most striking of several related conditions. Significant antecedent events include Campylobacter jejuni (4–66%), cytomegalovirus (5–15%), Epstein‐Barr virus (2–10%), and Mycoplasma pneumoniae (1–5%) infections. These infections are not uniquely associated with any clinical subtype but severe axonal degeneration is more common following C.jejuni and severe sensory impairment following cytomegalovirus. Strong evidence supports an important role for antibodies to gangliosides in pathogenesis. In particular antibodies to ganglioside GM1 are present in 14–50% of patients with GBS, and are more common in cases with severe axonal degeneration associated with any subtype. Antibodies to ganglioside GQ1b are very closely associated with Fisher syndrome, its formes frustes and related syndromes. Ganglioside‐like epitopes exist in the bacterial wall of C.jejuni. Infection by this and other organisms triggers an antibody response in patients with GBS but not in those with uncomplicated enteritis. The development of GBS is likely to be a consequence of special properties of the infecting organism, since some strains such as Penner O:19 and O:41 are particularly associated with GBS but not with enteritis. It is also likely to be a consequence of the immunogenetic background of the patient since few patients develop GBS after infection even with one of these strains. Attempts to match the subtypes of CBS to the fine specificity of anti‐ganglioside antibodies and to functional effects in experimental models continue but have not yet fully explained the pathogenesis. T cells are also involved in the pathogenesis of most or perhaps all forms of GBS. T cell responses to any of three myelin proteins, PZ, PO and PMP22, are sufficient to induce experimental autoimmune neuritis. Activated T cells are present in the circulation in the acute stage, up‐regulate matrix metalloproteinases, cross the blood‐nerve barrier and encounter their cognate antigens. Identification of the specificity of these T cell responses is still at a preliminary stage. The invasion of intact myelin sheaths by activated macrophages is difficult to explain according to a purely T cell mediated mechanism. The different patterns of GBS are probably due to the diverse interplay between antibodies and T cells of differing specificities.
To clarify the association between Campylobucter jejuizi (Cj) infection and antibodies to ganglioside GM, (anti-GM,) in Guillain-Barre syndrome (GBS), we have carried out a prospective case-control study of 96 patients with GRS. Cj infection occurred in 25 (26%) patients. IgG and/or IgM anti-GM, were identified in 24 (25%) patients and in 1 of 71 (1.4%) household controls ( p < 0.001). Thirteen of the 25 (52%) Cj-positive patients had anti-GM, compared with 11 of the 71 (15%) Cj-negative patients ( p < 0.001). Neither the peak overall disability nor the 1-year disability differed between the anti-GM,-positive and anti-GM,-negative patients. However, patients with the combination of Cj infection and anti-GM, positivity recovered more slowly than Cj/anti-GM,-negative patients ( p = 0.05), were more likely to have axonal degeneration, and were significantly more disabled at the end of 1 year ( p = 0.02). The presence of Cj infection is more important than anti-GM, positivity in determining the extent of axonal involvement and, hence, prognosis. Since the presence of anti-GM, is not a significant poor-prognostic factor, a search should be made for other properties of Cj infection that would account for its relationship to axonal degeneration.
An experimental model of inflammatory radiculoneuropathy is induced by immunising rats with peripheral myelin protein 22 (PMP22). We have investigated whether PMP22 may be important in inducing human inflammatory neuropathy. We examined sera of patients with Guillain‐Barre syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), other neuropathies (ONP) and normal controls for IgM and IgG antibodies against PMP22 by ELISA (against synthetic PMP22 extracellular peptide fragments) and Western blot (against cauda equina). Antibodies were detected by both methods in 52% of patients with GBS, 35% with CIDP, 3% with ONP and no normal controls. We conclude that an immune response against PMP22 may play a role in the pathogenesis of the inflammatory neuropathies.
METHODSAdult and new-born Wistar rats were used throughout. New-born refers to animals 0-24 hr old and adult to animals at least 18 months old.Preparation of mitochondrial fraction. Brain suspensions in 0.32 M-SUCrOSe containing 1 m~-EDTA, were fractionated according to ADAMS, . After the density gradient separation, myelin, if present, was removed from the 0.32-0.8 M-SUCrOSe interface and discarded with some of the 0-8 M-sucrose. The tube was gently agitated and the loosely-packed portion of the pellet poured off. The remaining tightly-packed portion of the pellet constituted the mitochondrial fraction. This material was resuspended in 0-15 M-KCI to a known volume. Liver mitochondria were prepared by the same procedure, to allow for direct comparison. Enzyme assays. Succinafe dehydrogenase (succinate: tetrazolium oxidoreductase EC 1.3.99.1) was estimated colorimetrically using p-iodo-p-nitrophenyltetrazolium (INT) as the final acceptor (ADAMS et al., 1963). This method, assuming 100% trapping efficiency, gave rates of succinate oxidation of 0.171 and 0493 pmoles succinate/min/mg of protein in the neonatal and adult brain mitochondria respectively. ATPase (ATP phosphohydrolase, Mg stimulated EC 3.6.1.4) activity was estimated at 30" in tris buffer ( BRUNI and LUCIANI, 1962) in the absence and presence of 10 mM-dinitrophenol (DNP). Activity was measured on the day that the mitochondria were prepared.Cytochrome c oxidase (cytochrome c: oxygen oxidoreductase EC 1.9.3.1) was estimated colorimetrically (COOPERSTEIN and LAZAROW, 1951). The change in absorbancy at 550 mp was followed using the Perkin-Elmer (137 U.V.) spectrophotometer, with the output fed into a Kent 2 mv recorder, type 2 M. Maximum activity was obtained with Lubrol W., approximately 10 mg/100 mg of protein.Chemical estimations. Protein was estimated by an ultraviolet difference method (MURPHY and KIES, 1960), using Armour bovine serum albumin of known nitrogen content as the standard.Cytochromes Q, b and c + c1 were estimated from the reduced-oxidized difference spectrum obtained by the method of ROODYN, FREEMAN and TATA (1965). The spectrum was obtained with the Perkin-Elmer (137, U.V.) spectrophotometer using a Kent Mk 2 recorder as external amplifier and recorder. The cytochrome concentrations were estimated from the difference in extinction of the wavelength pairs, 605-625 m,u for cytochrome a, 562-575 mp for cytochrome 6, and 551-540 mp for cytochrome c + c l .Deoxyribonucleic acid was estimated in total, washed, trichloracetic acid-insoluble material from the homogenate. DNA was hydrolysed in 1 ~-perchloric acid at 90" for 20 min after hydrolysis of RNA by N-NaOH at 37" for 1 hr. The DNA in the hydrolysate was estimated from the extinction at 266 mp using EM(P) = 9930 (ALDRIDGE and JOHNSON, 1959).
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