Palmoplantar pustulosis (PPP) is an autoimmune disease characterized by psoriasis-like erythematous lesions on palms and/or soles due to an abnormal humoral immune response. Tonsillectomy is effectively employed for the treatment of PPP; however, how tonsils are involved in the aetiology of PPP remains unclear. Here we analysed surgically resected palatine tonsils from 36 cases of PPP as well as usual recurrent tonsillitis (RT) as a control. Histological examination revealed that a unique lesion, with lymphoid follicles surrounded by reticular crypt epithelial cells, was more frequently observed in tonsils of patients with PPP than in those with RT (p < 0.0001; PPP vs RT). Interestingly, crypt epithelial cells in primary cultures derived from PPP tonsils showed marked production of interleukin-6 (IL-6). Moreover, these epithelial cells from PPP tonsils expressed p53-related transcription factors in their nuclei that were found to contribute to the up-regulation of IL-6 gene expression. These findings suggest that, at least in part, the specialized lymphoepithelial symbiosis of PPP tonsils, under the control of p53-related factors, may be relevant to the generation of the impaired micro-environment underlying the aberrant production of autoantibodies.