Cerebrospinal fluid immunoglobulins in primary progressive multiple sclerosis are pathogenic

Area of Science:

• Neuroimmunology
• Neuropathology
• Demyelinating diseases

Background:

• Multiple sclerosis presents with diverse clinical courses: relapsing-remitting (RRMS), secondary progressive (SPMS), and primary progressive (PPMS).
• The distinct pathological underpinnings of these MS subtypes remain incompletely understood.
• Investigating the unique pathological drivers of PPMS is crucial for targeted therapeutic development.

Purpose of the Study:

• To determine if cerebrospinal fluid (CSF) from PPMS patients possesses unique pathogenic properties.
• To elucidate the role of antibodies in PPMS-associated pathology.
• To differentiate the pathological mechanisms of PPMS from RRMS and SPMS.

Main Methods:

• Utilized a novel mouse model to assess the effects of PPMS patient CSF on motor function and spinal cord pathology.
• Investigated the impact of immunoglobulin G (IgG) removal from PPMS CSF.
• Administered recombinant antibodies derived from PPMS CSF to recapitulate pathology.

Main Results:

• PPMS CSF induced motor disability and spinal cord pathology, including demyelination, impaired remyelination, astrogliosis, and axonal damage in mice.
• Attenuated pathogenicity was observed after removing IgG from PPMS CSF.
• Recombinant antibodies from PPMS CSF replicated the observed pathology.

Conclusions:

• The clinical and pathological features of PPMS are driven by specific antibodies.
• PPMS appears pathogenically distinct from RRMS and SPMS.
• Findings suggest antibody-mediated mechanisms in PPMS, opening avenues for targeted therapies.