Multiple sclerosis: In situ evidence for antibody‐ and complement‐mediated demyelination

Abstract

We describe a case of multiple sclerosis characterized by deposition of immunoglobulin and complement in the areas of active demyelination. This was particularly evident for the C9neo antigen, which is a marker for the activated lytic complement complex and was exclusively deposited in the areas of active myelin destruction. In addition, macrophages in the lesions contained degradation products that were immunoreactive for myelin antigens, immunoglobulins, and C9neo antigen. Destruction of myelin sheaths was associated with incomplete loss of oligodendrocytes in the active areas and reappearance of oligodendrocytes with remyelination in the inactive plaque center. Patient and Methods PatientThe patient was a 47-year-old woman with unremarkable family history. At 15 years of age she had an episode of diplopia and strabismus and bilateral extensor plantar reflexes were observed. A similar transient episode occurred in the subsequent year, and a diagnosis of MS was entertained. At age 28, her vision deteriorated and her gait was described as spastic and atactic. During pregnancy, at age 29, she developed spastic paraparesis and generalized sensory deficiency below T6-7, as well as urinary incontinency. Her optic discs were pale, and her cerebrospinal fluid (CSF) protein concentration was moderately elevated. After treatment with adrenocorticotropic hormone (ACTH) her condition improved and she had a stable remission of the disease for 18 years.At age 47, after an upper respiratory tract infection, her condition suddenly worsened, with abrupt onset of severe paralysis of the left upper extremity. In addition, the patient From the

Clonally expanded plasma cells in the cerebrospinal fluid of MS patients produce myelin‐specific antibodies

“…This hypothesis has been supported by the presence of oligoclonal IgG bands (OCB) [2] in the cerebrospinal fluid (CSF) of MS patients and antibody and complement depositions in MS lesions [3]. Additionally, clonally restricted Ig genes suggesting the presence of an antigendriven immune response have been found in MS lesion tissue [4].…”

B cells in multiple sclerosis

“…More recently, the activated terminal lytic complex of complement as identified by antibody to the cryptic C9 neo antigen was found exclusively co-deposited with IgG in areas of ongoing myelin breakdown (23,24). Additionally, C9 neo and IgG are found in macrophages containing myelin debris in active MS lesions, providing evidence of a direct role for complement in myelin breakdown (23). This notion is further supported by the presence of membrane attack complex-enriched membrane vesicles in MS CSF (25).…”

“…Applying multifactorial cluster analysis to very early MS lesions, Gay et al (22) suggested that the primary lesion in MS is mediated by activated microglia and macrophages containing membrane-bound fixed complexes of both IgG and complement C3d. More recently, the activated terminal lytic complex of complement as identified by antibody to the cryptic C9 neo antigen was found exclusively co-deposited with IgG in areas of ongoing myelin breakdown (23,24). Additionally, C9 neo and IgG are found in macrophages containing myelin debris in active MS lesions, providing evidence of a direct role for complement in myelin breakdown (23).…”

Cancer and the Complement Cascade

“…This latter property is a recognized pathogenic factor in a wide spectrum of chronic inflammatory diseases, including rheumatoid arthritis (13), glomerulonephritis (14), atherosclerosis (15), asthma (16,17), and multiple sclerosis (18). Thus, it is not surprising that evidence for complement-mediated disease pathogenesis has centered primarily on dysfunctional immunity caused by the absence, alteration, or overactivity of complement proteins (19)(20)(21).…”