Role of Palatine Tonsil and Epipharyngeal Lymphoid Tissue in the Development of Glomerular Active Lesions (Glomerular vasculitis) in Immunoglobulin A Nephropathy

Abstract

Hematuria is an essential symptom of immunoglobulin A nephropathy (IgAN). Although the etiology of hematuria in IgAN has not been fully elucidated, it is thought that the rupture of the glomerular basement membranes caused by intra-capillary leukocyte influx, so-called glomerular vasculitis, is the pathological condition responsible for severe hematuria. Glomerular vasculitis are active lesions that exist in the glomeruli of acute phase IgAN and it is important because it is suspected to make the transition to segmental glomerular sclerosis (SGS) as a repair scar lesion in the chronic phase, and the progression of SGS would eventually lead to glomerular obsolescence. Worsening of hematuria concomitant with acute pharyngitis is common in patients with IgAN; therefore, elucidating the relationship between the immune system of Waldeyer’s ring, including the palatine tonsil and epipharyngeal lymphoid tissue, and the glomerular vasculitis may lead to understanding the nature of IgAN. The epipharynx is an immunologically activated site even under normal conditions, and enhanced activation of innate immunity is likely to occur in response to airborne infection. Hyperactivation of innate immunity via upregulation of Toll-like receptors in the interfollicular area of the palatine tonsil and epipharyngeal lymphoid tissue, followed by enhanced fractalkine/CX3CR1 interactions, appears to play an important role in the development of glomerular vasculitis in IgAN. As latent but significant epipharyngitis is present in most patients with IgAN, it is plausible that acute upper respiratory infection may contribute as a trigger for the innate epipharyngeal immune system, which is already upregulated in a chronically inflamed environment. Given that epipharyngitis and its effects on IgAN are not fully understood, we propose that the so-called “epipharynx–kidney axis” may provide an important focus for future research.

Epipharyngeal Abrasive Therapy (EAT) Has Potential as a Novel Method for Long COVID Treatment

“…Similar to COVID 19, upper respiratory tract infections (URTIs) of viral etiology begin in the epipharynx [ 32 , 33 ]. Chronic epipharyngitis, which may be secondary to URTI, is considered a residual immune response and causes not only various upper respiratory tract symptoms, such as postnasal drip, throat pain, and cough, but also systemic symptoms, such as chronic fatigue, headache, systemic pain, and dizziness [ 12 , 13 , 31 , 32 ]. Some of these systemic symptoms resemble those of MS/CFS, and chronic epipharyngitis is reported to activate epipharyngeal inner immunity and produce neuroexcitatory molecules, such as TNF-α, IFN-γ, and IL-1, which activate the immune system of the brain, resulting in low-grade inflammation in the brain associated with MF/CFS [ 12 , 13 , 34 , 35 , 36 , 37 ].…”

“…Chronic epipharyngitis, which may be secondary to URTI, is considered a residual immune response and causes not only various upper respiratory tract symptoms, such as postnasal drip, throat pain, and cough, but also systemic symptoms, such as chronic fatigue, headache, systemic pain, and dizziness [ 12 , 13 , 31 , 32 ]. Some of these systemic symptoms resemble those of MS/CFS, and chronic epipharyngitis is reported to activate epipharyngeal inner immunity and produce neuroexcitatory molecules, such as TNF-α, IFN-γ, and IL-1, which activate the immune system of the brain, resulting in low-grade inflammation in the brain associated with MF/CFS [ 12 , 13 , 34 , 35 , 36 , 37 ]. In this study, we found that 90% of long COVID patients had moderate or severe chronic epipharyngitis and that all patients complained of either fatigue, headache, attention disorder, or a combination of the three, confirming the findings of other reports on long COVID ( Figure 3 and Figure 4 ).…”

“…Epipharyngeal abrasive therapy (EAT) was originally developed in Japan and is the only treatment known to be effective for chronic epipharyngitis [ 9 , 13 ]. The mechanisms of EAT are reported to be the anti-inflammatory effect of ZnCl 2 , the blood-letting effect, and vagus nerve stimulation [ 38 ].…”

“…To increase the effectiveness of EAT, it is important to thoroughly scrub the epipharyngeal wall with cotton swabs. ZnCl 2 solution is commonly used as a chemical solution for EAT [ 9 , 13 , 15 , 17 ].…”

“…The activated lymphoid tissue of the epipharynx produces various inflammatory cytokines for the clearance of pathogens and this immune activation is considered to be one of the pathologies of ME/CFS [ 10 , 11 , 12 ]. A relationship has already been established between chronic epipharyngitis and ME/CFS, and epipharyngeal abrasive therapy (EAT), a treatment for chronic epipharyngitis in Japan, is reported to be effective against ME/CFS [ 9 , 13 , 14 , 15 ]. In this study, we endoscopically confirmed that all patients with long COVID had residual inflammation of the epipharynx.…”