The American College of Rheumatology presented a consensus document in 1999 proposing the classification of 19 different syndromes defined by neurological and psychiatric manifestations of systemic lupus erythematosus (SLE). The detection of autoantibodies in patient's serum or cerebrospinal fluid has not been used as diagnostic markers for the proposed neuropsychiatric lupus classifications as their disease associations remain highly contentious. Autoantibodies detected in the serum and/or cerebrospinal fluid, that have been reported to segregate with patients presenting with neuropsychiatric lupus include: (1) anti-neuronal antibodies, (2) brain-lymphocyte cross-reactive antibodies, (3) anti-ribosomal P antibodies, (4) anti-phospholipid antibodies and (5) anti-ganglioside antibodies. Tests for anti-neuronal, anti-brain-lymphocyte cross-reactive and anti-ganglioside antibodies remain highly specialized whereas tests for ribosomal P antibodies and for antiphospholipid antibodies are currently routinely available in most diagnostic laboratories. Anti-ribosomal antibodies segregate with SLE. Antiphospholipid P antibodies are markers for the antiphospholipid syndrome. This syndrome may be associated with another disease, commonly SLE. In this setting, neuropsychiatric manifestations in SLE may arise as a consequence of thrombotic episodes involving the cerebral vasculature. There is a pressing need for antibodies to ribosomal P and to phospholipids to be standardized for routine diagnostic application. We conclude that the search for specific antibody marker(s) that can be applied for the routine laboratory diagnosis for neuropsychiatric lupus remains elusive.
Serum autoantibodies to the glycolytic enzyme enolase have been reported in a diverse range of inflammatory, degenerative, and psychiatric disorders. Diseases in which these antibodies have been reported in high incidence include autoimmune polyglandular syndrome type 1 (80%, 35 of 44), primary (69%, 60 of 87), and secondary (58%, 14 of 24) membranous nephropathy, cancer-associated retinopathy (68.8%, 11 of 16), autoimmune hepatitis type 1 (60%, 12 of 20), mixed cryoglobulinemia with renal involvement (63.6%, seven of 11), cystoid macular edema (60%, six of 10), and endometriosis (50%, 21 of 41). In autoimmune polyglandular syndrome type 1 patients, all had chronic mucocutaneous candidiasis with demonstrated antibody reactivity to candida enolase, which is suggestive of cross reactivity or epitope mimicry. Formation of autoantibodies to enolase may be a normal process, with reported incidence in apparently healthy subjects ranging from 0% (zero of 91) to 11.7% (seven of 60). Nonetheless, we suggest that excessive production of these autoantibodies, which are generated as a consequence of uptake of enolase by antigen-presenting cells and subsequent B cell activation, can potentially initiate tissue injury as a result of immune complex deposition.
Although the pathology of discoid lupus erythematosus is well documented the causative agents are not known. Here, we report the identity of the target antigen of an autoantibody present in high titre in the serum of a patient with discoid lupus erythematosus. We have demonstrated that the antigen is enolase; first, because it has properties consistent with this glycolytic enzyme (47 000 MW, cytosolic localization and ubiquitous tissue distribution). Secondly, limited amino acid sequence determination after trypsin digestion shows identity with α‐enolase. Finally, the autoimmune serum immunoblots rabbit and yeast enolase and predominantly one isoelectric form of enolase (pI∼6·1). These results indicate that the reactive autoepitopes are highly conserved from man to yeast. The results also suggest that the autoantibodies are most reactive to the α‐isoform of enolase, although it is possible that they may also be reactive with γ‐enolase, and have least reactivity to β‐enolase. The anti‐enolase autoantibodies belong to the immunoglobulin G1 (IgG1) isotype. This is the first report of IgG1 autoantibodies to evolutionarily conserved autoepitopes of enolase in the serum of a patient with discoid lupus erythematosus. Previous reports of autoantibodies to enolase have suggested associations with autoimmune polyglandular syndrome type I and cancer‐associated retinopathy. This report and an earlier report of what is likely to be enolase autoantibodies in two patients without systemic disease suggest that enolase autoantibodies have a broad association and are not restricted to any particular disease.
This is the first report of autoantibodies that are reactive to synapsin Ia. Autoantibodies that are reactive to synapsin Ia are not restricted to discoid lupus erythematosus patients, because we found identical reactivity in two of 18 sera from dsDNA-positive systemic lupus erythematosus patients and in two of 14 rheumatoid factor-positive sera. Whether autoantibodies to synapsin I are associated with neuropsychiatric manifestations is currently unknown.
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