Nature: There is something in plasma that produces neuronal apoptosis

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Multiple sclerosis plasma IgG aggregates induce complement-dependent neuronal apoptosis

https://www.nature.com/articles/s41419-023-05783-3

Abstract

Grey matter pathology is central to the progression of multiple sclerosis (MS). We discovered that MS plasma immunoglobulin G (IgG) antibodies, mainly IgG1, form large aggregates (>100 nm) which are retained in the flow-through after binding to Protein A.

Utilizing an annexin V live-cell apoptosis detection assay, we demonstrated six times higher levels of neuronal apoptosis induced by MS plasma IgG aggregates (n = 190, from two cohorts) compared to other neurological disorders (n = 116) and healthy donors (n = 44).

MS IgG aggregate-mediated, complement-dependent neuronal apoptosis was evaluated in multiple model systems including primary human neurons, primary human astrocytes, neuroblastoma SH-SY5Y cells, and newborn mouse brain slices. Immunocytochemistry revealed the co-deposition of IgG, early and late complement activation products (C1q, C3b, and membrane attack complex C5b9), as well as active caspase 3 in treated neuronal cells. Furthermore, we found that MS plasma cytotoxic antibodies are not present in Protein G flow-through, nor in the paired plasma.

The neuronal apoptosis can be inhibited by IgG depletion, disruption of IgG aggregates, pan-caspase inhibitor, and is completely abolished by digestion with IgG-cleaving enzyme IdeS. Transmission electron microscopy and nanoparticle tracking analysis revealed the sizes of MS IgG aggregates are greater than 100 nm.

Our data support the pathological role of MS IgG antibodies and corroborate their connection to complement activation and axonal damage, suggesting that apoptosis may be a mechanism of neurodegeneration in MS.

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Chat GPT says this.

Can plasma IgG antibodies form large aggregates?

Yes, under certain conditions, plasma IgG antibodies can form large aggregates or immune complexes.

Immune complexes are formed when antibodies bind to antigens, such as those found on the surface of pathogens, and then come together to form larger structures. These complexes can be cleared from the body by various mechanisms, including phagocytosis by immune cells and filtration by the kidneys. However, if the immune complexes are too large or if there is an excess of them, they can accumulate in tissues and cause inflammation and tissue damage.

The formation of immune complexes can occur naturally in response to infection or immunization, but it can also occur in certain autoimmune diseases, where the immune system mistakenly attacks the body's own tissues. In these cases, immune complexes can form when antibodies bind to self-antigens, leading to inflammation and tissue damage.

Overall, the formation of immune complexes is a normal part of the immune response, but when it becomes dysregulated, it can contribute to a variety of diseases and disorders.