🔴I agree with the general idea that elevated IgG titers to latent or persistent pathogens should not simply be dismissed as meaningless.
But I would add a few mechanistic clarifications.
First, not all herpesviruses establish latency in B lymphocytes as their main reservoir.
EBV is the classic herpesvirus with a major B-cell reservoir. But CMV, HHV-6, VZV and other herpesviruses have different latency biology and different cellular or tissue reservoirs. So it is important not to generalize EBV biology to all herpesviruses.
Second, latency is not simply a state in which infected cells become completely invisible or biologically inactive.
This is especially clear with EBV.
EBV has different latency programs. Latency 0 is the most immunologically silent state, but latency I, II and III still express viral antigens to different degrees, and these infected cells can be controlled by EBV-specific CD4 and CD8 T cells.
For example, latency I, classically seen in Burkitt lymphoma, expresses EBNA1, and EBNA1-specific CD4 T-cell responses are part of the immune control of EBV-infected cells.
But the same general principle applies more broadly: many latent or persistent pathogens are not simply “doing nothing.”
Latently infected or persistently infected cells can express viral non-coding RNAs, microRNAs, latency-associated transcripts or other regulatory RNA species that can modulate immune sensing, inflammation, cell survival, antiviral responses and immune evasion.
In herpesviruses, viral microRNAs and non-coding RNAs can help maintain latency, suppress lytic genes, reduce immune recognition, alter host-cell survival and shape the local inflammatory environment.
Even latently infected EBV cells can express non-coding viral RNAs such as EBERs and EBV microRNAs. These can modulate inflammation, interfere with antiviral sensing, shape B-cell survival and contribute to immune evasion.
EBV also has immunomodulatory strategies, including viral IL-10-like activity mainly associated with lytic or reactivation contexts, which can help dampen antiviral immune responses and reduce immune recognition.
So “latent” does not necessarily mean silent, harmless or irrelevant.
It often means that the virus is being actively contained by immune surveillance.
In healthy people, the key point is not that latent viruses become totally invisible. The key point is that CD4 and CD8 T-cell surveillance, NK-cell function and other antiviral mechanisms keep these reservoirs highly contained.
This is why most healthy carriers do not have constant clinically relevant reactivation. The pathogen is usually controlled, restricted to limited reservoirs, and only reactivates more meaningfully during periods of immune stress, acute infection, immunosuppression or loss of immune control.
Where things become more interesting is in genetically susceptible individuals.
Immunogenetic and evolutionary studies suggest that some ancestral HLA-II haplotypes, especially DR2-DQ6, DR3-DQ2 and DR4-DQ8, have broader or more promiscuous peptide-binding repertoires than many other HLA-II backgrounds.
This broader antigen-presentation capacity may have been advantageous during acute infections, because it allowed stronger and more diverse CD4 T-cell responses against pathogens.
But if the pathogen persists, reactivates, or uses latency/evasion mechanisms, the immune system can remain chronically stimulated.
That chronic stimulation can induce sustained IFN-γ, tissue inflammation, ectopic HLA-II expression in tissues that do not normally present antigen at high levels, and continuous presentation of both pathogen-derived and self-derived peptides.
In that environment, the probability of activating autoreactive T and B cells increases.
This is where HLA background matters.
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Continued in the next post.👇🏻
B cells, go dormant and become undetectable to the immune system. The virus isn't eliminated, just silenced. Then, when we receive a challenge to our immune health (physiological/emotional/physical stress, malnutrition, aging) or we are infected by a pathogen that is known to
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