At the Root of 3 "Long" Diseases: Persistent Antigens Inflicting Chronic Damage on the Brain and Other Organs in Gulf War Illness, Long-COVID-19, and Chronic Fatigue Syndrome

Abstract

Several foreign antigens such as those derived from viruses and bacteria have been linked to long-term deleterious effects on the brain and other organs; yet, health outcomes subsequent to foreign antigen exposure vary depending in large part on the host's immune system, in general, and on human leukocyte antigen (HLA) composition, in particular. Here we first provide a brief description of 3 conditions characterized by persistent long-term symptoms, namely long-COVID-19, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and Gulf War Illness (GWI), followed by a brief overview of the role of HLA in the immune response to foreign antigens. We then discuss our Persistent Antigen (PA) hypothesis and highlight associations between antigen persistence due to HLA-antigen incongruence and chronic health conditions in general and the 3 "long" diseases above in particular. This review is not intended to cover the breadth and depth of symptomatology of those diseases but is specifically focused on the hypothesis that the presence of persistent antigens underlies their pathogenesis.

Keywords: Gulf War illness; Human leukocyte antigen; long-COVID; myalgic encephalomyelitis/chronic fatigue syndrome; persistent antigen.

Figure 1.

Evidence for the presence of anthrax protective antigen (PA63) in the serum of veterans with GWI. Data are from 15 GWI patients (P1-P15) compared to a healthy GW veteran control. Ordinate is percent apoptosis (cell death) in neuroblastoma N2A cultures following incubation with the stated treatment. (A) much higher percent apoptosis in incubation with each GWI patient serum vs. control. (B) systematic beneficial effect (reduction in apoptosis) in each patient when antibody against anthrax PA63 was added to the patient’s serum. (C) apoptosis in GWI + anti anthrax antibody vs. apoptosis in control; the apoptosis in GWI + anti anthrax antibody is still higher than in the control presumably due to the presence of other persistent antigens in GWI. The figure is a composite of figures 12, 13 and 14 in Bai et al.

Figure 2.

Schematic diagram to illustrate the normal HLA mechanism of antigen processing. See text for details.

Figure 3.

Schematic diagram to illustrate the altered antigen processing in the absence of HLA match. See text for details.

Figure 4.

Beneficial but limited effect of added pooled human IgG to GWI serum in reducing apoptosis. The limited effect is presumably due to the expected lack of antibodies in IgG of rare diseases (anthrax, botulism, plague, rabies, etc.) to which the general population is not typically exposed and for which no vaccines are given routinely. Bars are SEM. From Rouse and Kaistha.