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I would like to share with you my latest review article. The Epstein-Barr virus (EBV) has long been known to be behind the development of autoimmune diseases, cancer and is even suspected to be behind the development of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Long COVID. But it is still unclear what pathways it uses.
In this review I describe how the possession of certain ancestral HLA-II alleles (a system used by our immune system to recognize which proteins are foreign, such as pathogens, and which are not) makes the individual genetically weak to control EBV latent cells, thus developing different diseases. EBV infects B cells through a protein on its surface called gp42, which allows it to bind to HLA-II molecules on the B cell surface. If the individual possesses ancestral HLA-II alleles susceptible to EBV, it will cause that after the infection of B cells and the establishment of the latent form, the antigen presentation of these cells will be altered, since gp42 would remain bound to HLA-II molecules interfering in the presentation of antigens to T lymphocytes (necessary to eliminate infected cells), and in the activation of these. This protects the cell from being recognized by CD4+ T lymphocytes and thus surviving, since B cells are one of the main cells that regulate our immune system. But the consequence of possessing these weak alleles against EBV is the development of a type of immunodeficiency, by preventing the activation of CD4 T cells by the interaction of gp42.
Another advantage of infecting B cells is that they have the ability to form ectopic lymphoid aggregates in any tissue. This, under normal conditions, is useful to fight infections in the affected tissue better and faster, since these cells are responsible (among others) for presenting antigens to CD4 T cells and generating antibodies. But EBV takes advantage of this pathway to survive, since any inflammatory process (due to infection or for any other reason) occurring in any tissue recruits both healthy B cells and B cells with latency to the inflamed tissue. In this inflamed tissue they form ectopic lymphoid aggregates similar to germinal centers (central factories for the generation of high affinity immunoglobulins against pathogens). Finally, these ectopic lymphoid aggregates become reservoirs of EBV latent cells generating a chronic infection with viral reactivations in these tissues. Moreover, being B cells, they have the capacity to present antigens. Therefore, those B cells and epithelial cells modified by EBV could present antigens from that tissue as foreign proteins and thus cause the development of autoimmune diseases. This occurs by presenting self-antigens on HLA-II molecules altered by gp42. Thus, depending on the tissue infiltrated by these cells with EBV latency, one type of autoimmune disease or another will be generated. For example, if they infiltrate the thyroid they could generate autoimmune thyroiditis, in the intestinal mucosa they could generate celiac disease, if they infiltrate the pancreatic islets they would generate type 1 diabetes, if they do so in the central nervous system they would generate multiple sclerosis, in the exocrine glands they would generate Sjögren's syndrome, in the thymus they would generate myasthenia gravis, in the synovial joints they would generate rheumatoid arthritis and so on with the rest of the tissues. In addition, if these latent cells are not controlled, cancer may develop after a few years. For this reason, patients with autoimmune diseases have a higher risk of developing them.
This model not only explains the development of the diseases described here, but also others, such as EBV-associated gastric carcinoma, in which the formation of these ectopic lymphoid structures in the gastric mucosa in response to Helicobacter pylori infection or another inflammatory process causes the infiltration of B cells with EBV latency in the lymphoid aggregates, and the subsequent infection of epithelial cells when expressing MHC-II, due to an increase in IFN-γ. Finally, the immune evasion microenvironment generated by these EBV-transformed cells and the clonal growth of EBV-latent epithelial cells would lead to the development of the disease. This model could even explain the involvement of EBV in the development of chronic fatigue syndrome or myalgic encephalomyelitis and Long COVID. Both diseases present similar EBV reactivations and chronic symptoms, which could suggest a common EBV immunopathology. In the case of Long COVID, inflammation caused by SARS-CoV2 infection of tissues would recruit B cells with EBV latency, where ectopic lymphoid aggregates could form and lead to viral reactivations. Likewise, it could also help us understand why EBV-associated autoimmune diseases, Long COVID and chronic fatigue syndrome/myalgic encephalomyelitis are more common in women. Estrogens, by increasing B-cell survival, would allow a greater permanence of these ectopic lymphoid aggregates with EBV latency in the inflamed tissues of patients with "ancestral" HLA-II alleles and, therefore, a chronification of symptoms.
Attached is the link to the manuscript with some treatment proposals:
https://www.mdpi.com/2076-0817/11/8/831
You can also read this other article to understand how EBV can develop Chronic Fatigue Syndrome or Myalgic Encephalomyelitis:
https://www.frontiersin.org/articles/10.3389/fimmu.2021.656797/full
You can enter in this twitter thread where I am answering your questions:
Best regards,
Manuel.
In this review I describe how the possession of certain ancestral HLA-II alleles (a system used by our immune system to recognize which proteins are foreign, such as pathogens, and which are not) makes the individual genetically weak to control EBV latent cells, thus developing different diseases. EBV infects B cells through a protein on its surface called gp42, which allows it to bind to HLA-II molecules on the B cell surface. If the individual possesses ancestral HLA-II alleles susceptible to EBV, it will cause that after the infection of B cells and the establishment of the latent form, the antigen presentation of these cells will be altered, since gp42 would remain bound to HLA-II molecules interfering in the presentation of antigens to T lymphocytes (necessary to eliminate infected cells), and in the activation of these. This protects the cell from being recognized by CD4+ T lymphocytes and thus surviving, since B cells are one of the main cells that regulate our immune system. But the consequence of possessing these weak alleles against EBV is the development of a type of immunodeficiency, by preventing the activation of CD4 T cells by the interaction of gp42.
Another advantage of infecting B cells is that they have the ability to form ectopic lymphoid aggregates in any tissue. This, under normal conditions, is useful to fight infections in the affected tissue better and faster, since these cells are responsible (among others) for presenting antigens to CD4 T cells and generating antibodies. But EBV takes advantage of this pathway to survive, since any inflammatory process (due to infection or for any other reason) occurring in any tissue recruits both healthy B cells and B cells with latency to the inflamed tissue. In this inflamed tissue they form ectopic lymphoid aggregates similar to germinal centers (central factories for the generation of high affinity immunoglobulins against pathogens). Finally, these ectopic lymphoid aggregates become reservoirs of EBV latent cells generating a chronic infection with viral reactivations in these tissues. Moreover, being B cells, they have the capacity to present antigens. Therefore, those B cells and epithelial cells modified by EBV could present antigens from that tissue as foreign proteins and thus cause the development of autoimmune diseases. This occurs by presenting self-antigens on HLA-II molecules altered by gp42. Thus, depending on the tissue infiltrated by these cells with EBV latency, one type of autoimmune disease or another will be generated. For example, if they infiltrate the thyroid they could generate autoimmune thyroiditis, in the intestinal mucosa they could generate celiac disease, if they infiltrate the pancreatic islets they would generate type 1 diabetes, if they do so in the central nervous system they would generate multiple sclerosis, in the exocrine glands they would generate Sjögren's syndrome, in the thymus they would generate myasthenia gravis, in the synovial joints they would generate rheumatoid arthritis and so on with the rest of the tissues. In addition, if these latent cells are not controlled, cancer may develop after a few years. For this reason, patients with autoimmune diseases have a higher risk of developing them.
This model not only explains the development of the diseases described here, but also others, such as EBV-associated gastric carcinoma, in which the formation of these ectopic lymphoid structures in the gastric mucosa in response to Helicobacter pylori infection or another inflammatory process causes the infiltration of B cells with EBV latency in the lymphoid aggregates, and the subsequent infection of epithelial cells when expressing MHC-II, due to an increase in IFN-γ. Finally, the immune evasion microenvironment generated by these EBV-transformed cells and the clonal growth of EBV-latent epithelial cells would lead to the development of the disease. This model could even explain the involvement of EBV in the development of chronic fatigue syndrome or myalgic encephalomyelitis and Long COVID. Both diseases present similar EBV reactivations and chronic symptoms, which could suggest a common EBV immunopathology. In the case of Long COVID, inflammation caused by SARS-CoV2 infection of tissues would recruit B cells with EBV latency, where ectopic lymphoid aggregates could form and lead to viral reactivations. Likewise, it could also help us understand why EBV-associated autoimmune diseases, Long COVID and chronic fatigue syndrome/myalgic encephalomyelitis are more common in women. Estrogens, by increasing B-cell survival, would allow a greater permanence of these ectopic lymphoid aggregates with EBV latency in the inflamed tissues of patients with "ancestral" HLA-II alleles and, therefore, a chronification of symptoms.
Attached is the link to the manuscript with some treatment proposals:
https://www.mdpi.com/2076-0817/11/8/831
You can also read this other article to understand how EBV can develop Chronic Fatigue Syndrome or Myalgic Encephalomyelitis:
https://www.frontiersin.org/articles/10.3389/fimmu.2021.656797/full
You can enter in this twitter thread where I am answering your questions:
Best regards,
Manuel.
