{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T13:14:20Z","timestamp":1790082860739,"version":"4.0.1"},"reference-count":154,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Contemporary immunology models are based primarily on reductionist concepts. However, they face limitations in reconciling clinical discordances such as the \u2018viral load paradox\u2019 in severe infections and the teleological enigma of the \u2018autoimmune paradox\u2019. To bridge these systemic conceptual gaps, this paper proposes the protein-homeostasis-system (PHS) hypothesis, a novel paradigm based on organicism that views the living organism as a unified, self-regulating biosystem. It is asserted that all diseases, including autoimmune disorders and malignancy, are triggered by specific etiological substances\u2014ranging from toxic elements and monoamines to pathogenic peptides and proteins, many of which originate from self-cells injured by infection, traumas, and cytokine storm. Within this overarching framework, the immune system\u2019s role is fundamentally redefined from an adversarial defense mechanism into a metabolic and regulatory management utility for cell protection and systemic homeostasis. Governed by the PHS, T cells and B cells regulate the systemic load of pathogenic peptides and proteins, while the innate immune system, including prions and amyloid proteins, manages non-protein materials. Acute clinical phenomena like cytokine storms are reinterpreted not as immune system autotoxicity, but as the desperate hyper-activation of non-specific immune clones responding to an overwhelming endogenous etiological load. This holistic perspective provides a robust translational rationale for the early, preemptive clinical use of systemic immunomodulators, including corticosteroids, intravenous immunoglobulins and biologics, to disrupt pathological feedback loops and restore rapid immunological stabilization, and views cancer as an independent biosystem\u2019s survival strategy.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1944127","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T12:45:21Z","timestamp":1790081121000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A new immunological paradigm for diseases: the protein-homeostasis-system hypothesis"],"prefix":"10.3389","volume":"17","author":[{"given":"Kyung-Yil","family":"Lee","sequence":"first","affiliation":[{"name":"The Catholic University of Korea College of Medicine","place":["Seoul, Republic of Korea"]},{"name":"Junglock Biomedical 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