Autoantibodies Against Dihydrolipoamide S-Acetyltransferase in Immune-Mediated Neuropathies.

BACKGROUND AND OBJECTIVES: This study aimed to identify disease-related autoantibodies in the serum of patients with immune-mediated neuropathies including chronic inflammatory demyelinating polyneuropathy (CIDP) and to investigate the clinical characteristics of patients with these antibodies. METHODS: Proteins extracted from mouse brain tissue were used to react with sera from patients with CIDP by western blotting (WB) to determine the presence of common bands. Positive bands were then identified by mass spectrometry and confirmed for reactivity with patient sera using enzyme-linked immunosorbent assay (ELISA) and WB. Reactivity was further confirmed by cell-based and tissue-based indirect immunofluorescence assays. The clinical characteristics of patients with candidate autoantibody-positive CIDP were analyzed, and their association with other neurologic diseases was also investigated. RESULTS: Screening of 78 CIDP patient sera by WB revealed a positive band around 60-70 kDa identified as dihydrolipoamide S-acetyltransferase (DLAT) by immunoprecipitation and mass spectrometry. Serum immunoglobulin G (IgG) and IgM antibodies' reactivity to recombinant DLAT was confirmed using ELISA and WB. A relatively high reactivity was observed in 29 of 160 (18%) patients with CIDP, followed by patients with sensory neuropathy (6/58, 10%) and patients with MS (2/47, 4%), but not in patients with Guillain-Barré syndrome (0/27), patients with hereditary neuropathy (0/40), and healthy controls (0/26). Both the cell-based and tissue-based assays confirmed reactivity in 26 of 33 patients with CIDP. Comparing the clinical characteristics of patients with CIDP with anti-DLAT antibodies (n = 29) with those of negative cases (n = 131), a higher percentage of patients had comorbid sensory ataxia (69% vs 37%), cranial nerve disorders (24% vs 9%), and malignancy (20% vs 5%). A high DLAT expression was observed in human autopsy dorsal root ganglia, confirming the reactivity of patient serum with mouse dorsal root ganglion cells. DISCUSSION: Reactivity to DLAT was confirmed in patient sera, mainly in patients with CIDP. DLAT is highly expressed in the dorsal root ganglion cells, and anti-DLAT antibody may serve as a biomarker for sensory-dominant neuropathies.

Granuloma, vasculitis, and demyelination in sarcoid neuropathy.

BACKGROUND: Despite the suggestion that direct compression by granuloma and ischemia resulting from vasculitis can cause nerve fiber damage, the mechanisms underlying sarcoid neuropathy have not yet been fully clarified. METHODS: We examined the clinicopathological features of sarcoid neuropathy by focusing on electrophysiological and histopathological findings of sural nerve biopsy specimens. We included 18 patients with sarcoid neuropathy who had non-caseating epithelioid cell granuloma in their sural nerve biopsy specimens. RESULTS: Although electrophysiological findings suggestive of axonal neuropathy were observed, particularly in the lower limbs, all but three patients showed ≥1 abnormalities in nerve conduction velocity or distal motor latency. Additionally, a conduction block was observed in 11 of the 16 patients for whom waveforms were assessed; five of them fulfilled motor nerve conduction criteria strongly supportive of demyelination as defined in the European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) guideline for chronic inflammatory demyelinating polyneuropathy (CIDP). In most patients, sural nerve biopsy specimens revealed a mild to moderate degree of myelinated fiber loss. Fibrinoid necrosis was observed in one patient, and electron microscopy analysis revealed demyelinated axons close to granulomas in six patients. CONCLUSIONS: Patients with sarcoid neuropathy may meet the EAN/PNS electrophysiological criteria for CIDP due to the frequent presence of conduction blocks. Based on our results, in addition to the ischemic damage resulting from granulomatous inflammation, demyelination may play an important role in the mechanism underlying sarcoid neuropathy.

Early ultrastructural lesions of anti-neutrophil cytoplasmic antibody- versus complement-associated vasculitis.

This study aims to describe electron microscopic findings of vasculitis associated with anti-neutrophil cytoplasmic antibody (ANCA) and complement. Sural nerve biopsy specimens were obtained from 10 patients with microscopic polyangiitis (MPA), a representative ANCA-associated vasculitis, and six patients with nonsystemic vasculitic neuropathy (NSVN), who were negative for ANCA but positive for complement deposition. In patients with MPA, attachment of neutrophils to epineurial vascular endothelial cells, migration of neutrophils to the extravascular space via the penetration of the endothelial layer, and release of neutrophil components to the extracellular space were observed. Such neutrophil-associated lesions were not observed in patients with NSVN. Nonetheless, morphological changes in epineurial vascular endothelial cells, such as increases in cytoplasmic organelles and cytoplasmic protrusions into the vascular lumen, were observed in patients with NSVN. Since these findings were observed where light microscopy-based findings suggestive of vasculitis (e.g., the disruption of vascular structures and fibrinoid necrosis) were absent, they were considered early lesions that preceded the formation of the so-called necrotizing vasculitis. In conclusion, this study enabled the visualization of distinctive early ultrastructural lesions associated with ANCA and complement. Further studies are needed to elucidate the molecular basis of the induction of these fine structural changes, which will contribute to the development of targeted therapies based on specific mechanisms of vasculitis.

Dosage effects of PMP22 on nonmyelinating Schwann cells in hereditary neuropathy with liability to pressure palsies.

Focal thickening of the myelin sheath, also known as tomacula, is a characteristic pathological feature of patients with hereditary neuropathy with liability to pressure palsies (HNPP). However, a deeper understanding of the pathology underlying unmyelinated fibers and nonmyelinating Schwann cells is required. Electron microscopic examination of sural nerve biopsy specimens was performed for 14 HNPP patients with peripheral myelin protein 22 (PMP22) deletion, and their results were compared to 12 normal controls and 14 Charcot-Marie-Tooth disease type 1A (CMT1A) patients with PMP22 duplication. The number of unmyelinated axons in a single axon-containing nonmyelinating Schwann cell subunit in the HNPP group significantly increased compared with that in normal controls (1.99 ±â€¯0.66 vs. 1.57 ±â€¯0.52, p < 0.05). Conversely, these numbers significantly decreased in the CMT1A group compared with those in normal controls (1.16 ±â€¯0.16, p < 0.05). Some unmyelinated axons in patients with HNPP were incompletely surrounded by the cytoplasm of Schwann cells, almost as if the Schwann cells failed to form mesaxons; such failure in mesaxon formation was not observed in normal controls or in patients with CMT1A. These findings suggest that PMP22 dosage affects nonmyelinating as well as myelinating Schwann cells.

Role of complement components in vasculitic neuropathy associated with systemic lupus erythematosus and rheumatoid arthritis.

INTRODUCTION/AIMS: The mechanism of complement-mediated neurological injury in vasculitic neuropathy associated with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) is unknown. The current study aimed to investigate the local activation of the complement system in vasculitic neuropathy associated with SLE and RA. METHODS: We analyzed sural nerve biopsy specimens collected from patients with SLE (n = 12) and RA (n = 12). The deposition of complement components comprising the classical and lectin pathways was assessed via immunohistochemistry. RESULTS: The disease duration was longer in the RA group than in the SLE group (median [interquartile range]: 11.5 [5.5-31.0] and 4 [2-10] y, respectively). Complement components were found in the epineurial blood vessel walls in patients with SLE and RA, but not in controls. Deposition of the classical pathway component C1q in the blood vessel wall was more commonly observed in the SLE group (71.3% [25.6-85.8]) than in the RA group (20.1% [10.5-35.6]). As for the lectin pathway component, the incidence of ficolin-3 deposition in the blood vessel wall was higher in the SLE group (42.3% [25.7-51.3]) than in the RA group (17.2% [10.3-26.8]). On the contrary, the mannose-binding lectin level was higher in the RA group (37.5% [21.7-51.4]) than in the SLE group (17.8% [11.4-31.0]). DISCUSSION: The classical and lectin pathways of the complement system may be involved in vasculitic neuropathy associated with SLE and RA.

In vivo visualization of eosinophil secretion in eosinophilic granulomatosis with polyangiitis: An ultrastructural study.

BACKGROUND: Although eosinophilic granulomatosis with polyangiitis (EGPA) has been considered as a single disease entity belonging to anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, several studies have suggested that in addition to the mechanisms associated with ANCA, those associated with eosinophils play a vital role in tissue damage. Nevertheless, the morphological bases underlying eosinophil-associated lesions have not been completely elucidated. METHODS: We investigated the electron microscopic findings of sural nerve biopsy specimens obtained from 18 patients with EGPA by focusing on the behavior of eosinophils, particularly the mode of secretion. RESULTS: Eosinophils tended to be located at sites close to endothelial cells within the lumina of epineurial small vessels. Attachment of eosinophils to endothelial cells was observed, particularly at the junction between neighboring endothelial cells, and some of these eosinophils appeared to escape from the vascular lumen to migrate into the extravascular interstitium. Furthermore, we observed eosinophil degranulation via piecemeal degranulation and cytolysis. Degranulating eosinophils were identified in both intravascular and extravascular compartments. Some of the small vessels appeared to be occluded by numerous eosinophils, and eosinophils attached by platelets were also observed, suggesting that coagulopathy occurs in EGPA. CONCLUSIONS: Both extravascular and intravascular eosinophils can induce tissue damage unrelated to classical necrotizing vasculitis associated with ANCA in patients with EGPA. Further research is necessary to elucidate the molecular basis of the induction of these fine structural changes, which will contribute to the development of targeted therapies based on specific mechanisms of eosinophil-related diseases.

ANCA-Associated Vasculitic Neuropathies: A Review.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a systemic disorder that frequently affects the peripheral nervous system and consists of three distinct conditions: microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA, previously Wegener's granulomatosis), and eosinophilic granulomatosis with polyangiitis (EGPA, previously Churg-Strauss syndrome). The neuropathic features associated with this condition usually include mononeuritis multiplex, which reflects the locality of lesions. Findings suggestive of vasculitis are usually found in the epineurium and occur diffusely throughout the nerve trunk. Nerve fiber degeneration resulting from ischemia is sometimes focal or asymmetric and tends to become conspicuous at the middle portion of the nerve trunk. The attachment of neutrophils to endothelial cells in the epineurial vessels is frequently observed in patients with ANCA-associated vasculitis; neutrophils play an important role in vascular inflammation by binding of ANCA. The positivity rate of ANCA in EGPA is lower than that in MPA and GPA, and intravascular and tissue eosinophils appear to participate in neuropathy. Immunotherapy for ANCA-associated vasculitis involves the induction and maintenance of remission to prevent the relapse of the disease. A combination of glucocorticoids along with cyclophosphamide, rituximab, methotrexate, or mycophenolate mofetil is considered depending on the severity of the condition of the organ to induce remission. A combination of low-dose glucocorticoids and azathioprine, rituximab, methotrexate, or mycophenolate mofetil is recommended to maintain remission. The efficacy of anti-interleukin-5 therapy (i.e., mepolizumab) was demonstrated in the case of refractory or relapsing EGPA. Several other new agents, including avacopan, vilobelimab, and abatacept, are under development for the treatment of ANCA-associated vasculitis. Multidisciplinary approaches are required for the diagnosis and management of the disorder because of its systemic nature. Furthermore, active participation of neurologists is required because the associated neuropathic symptoms can significantly disrupt the day-to-day functioning and quality of life of patients with ANCA-associated vasculitis.

Two distinct mechanisms of neuropathy in immunoglobulin light chain (AL) amyloidosis.

INTRODUCTION: Although polyneuropathy in patients with immunoglobulin light chain (AL) amyloidosis has been considered to be attributable to axonal degeneration resulting from amyloid deposition, patients with nerve conduction parameters indicating demyelination that mimics chronic inflammatory demyelinating polyneuropathy (CIDP) have also been reported anecdotally. METHODS: We evaluated the electrophysiological and pathological features of 8 consecutive patients with AL amyloidosis who were referred for sural nerve biopsy. RESULTS: Although findings of axonal neuropathy predominantly in the lower limbs were the cardinal feature, all patients showed one or more abnormalities of nerve conduction velocities or distal motor latencies. In particular, 2 of these patients fulfilled the definite electrophysiological for CIDP defined by the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS). On electron microscopic examination of sural nerve biopsy specimens, Schwann cells apposed to amyloid fibrils became atrophic in all patients, suggesting that amyloid deposits directly affect neighboring tissues. Additionally, detachment of the neurilemma from the outermost compacted myelin lamella was seen where amyloid fibrils were absent in 4 patients. Electrophysiological findings suggestive of demyelination were more conspicuous in these patients compared with the other patients. The detachment of the neurilemma from the outermost compacted myelin lamella was particularly conspicuous in patients who fulfilled the definite EFNS/PNS electrophysiological criteria for CIDP. CONCLUSION: Abnormalities of myelinated fibers unrelated to amyloid deposition may frequently occur in AL amyloidosis. Disjunction between myelin and the neurilemma may induce nerve conduction abnormalities suggestive of demyelination.