💬That is only partly true. If this were simply a baseline antigen-presenting cell defect, many of these patients would likely have been chronically ill long before SARS-CoV-2. The real issue is not that APCs are globally “broken” from the start. The issue is that in susceptible individuals those APCs carry hyperreactive HLA-II backgrounds, meaning they can present more epitopes from the same antigen and drive a stronger pro-inflammatory response. But the key trigger is still the infection. Without the infection, the disease would not have developed. What you need is susceptible ancestral HLA-II haplotypes plus a pathogen with enough immune-evasion capacity to generate chronic infection or persistent antigenic stimulation. That is what creates the perfect scenario for autoimmunity. With chronic stimulation, IFN-γ rises, MHC-II expression increases in cells and tissues that were not presenting antigens so actively before, and those tissues begin presenting not only pathogen-derived peptides, but also self-peptides and sometimes neoepitopes generated in the inflammatory environment. That is exactly how autoreactive B and T cells that escaped negative selection can become activated and expanded. And from there, you get both sides of the problem: chronic infection or persistent antigen on one side, and autoimmunity on the other. Both then contribute to PD-1-high exhausted T cells, not only because of the chronic infection itself, but also because the immune system is now chronically responding to self-antigens as well. That leads to a form of functional immunodeficiency, which in turn favors reactivation of latent pathogens. So the final consequence in many Long COVID and ME/CFS patients is not just chronic infection, and not just immune dysfunction in the abstract. It is often a combination of persistent infection or antigenic stimulation, reactivation of latent pathogens, autoimmune disease or autoimmune subgroups, and functional immune exhaustion. That is why a large part of the symptom burden is likely coming from both chronic infection and autoimmunity. And that is also why, therapeutically, you cannot just treat one side and ignore the other. If both layers are present, you need to treat both.