Plasma Cell Targeting for Durable Remission in an Antibody Associated Subgroup of Long COVID

Passive transfer studies show that immunoglobulin G (IgG) from some people with Long COVID can induce neurological abnormalities in mice. These findings support pathogenic IgG activity in experimental systems, but do not establish the antibody source, its necessity for ongoing human illness, or the reversibility of established injury. I propose that, in a subgroup with neuropathic or autonomic manifestations and reproducible pathogenic IgG activity, long-lived plasma cells contribute to persistent disease and may represent a target for durable remission. This proposal contains three separable hypotheses: IgG contributes to disease; a persistent plasma-cell compartment maintains the relevant IgG; and reducing that compartment improves clinical outcomes. Negative trials of antibody-directed interventions constrain these hypotheses and cannot be dismissed solely as failures of patient selection or transient antibody removal. A staged program should first validate functional assays against experimental pathogenicity, then investigate antibody production and persistence, and only then undertake a biomarker-enriched randomized trial with adequate safety oversight. Clinical efficacy should be assessed by a prespecified between-group comparison, with longitudinal antibody activity and target engagement providing supporting mechanistic evidence. Durable clinical improvement would support further development but would not, by itself, prove a long-lived plasma-cell mechanism. This manuscript proposes research; it reports no new patient data and does not establish a treatment for Long COVID.