Aqeel Shamran Tashi Al Masoudi1✉ and Raheem Tuama Obayes Al Mammori2✉
Clinical Immunology, Marjan Teaching Hospital, Iraq
Clinical Immunology, Babylon GIT and Liver Center, Iraq
(✉) Corresponding Author: greetoop@gmail.com & rheemalmammori@gmail.com
Received: Aug 9, 2026/ Revised: Sept 16, 2026/Accepted: Sept 20, 2026
Highlights
- The ASAR hypothesis proposes that tissue-specific molecular alterations may precede immune-mediated disease.
- Cellular stress, oxidative injury, metabolic imbalance, and defective protein processing may generate altered self-antigens.
- Post-translational modifications and abnormal antigen processing may change self-molecular identity.
- HLA-dependent antigen presentation may facilitate immune recognition of altered self-antigens.
- Persistent antigen generation and presentation may contribute to chronic inflammation and disease progression.
- Epitope spreading and inflammatory amplification may sustain immune-mediated pathology.
- The hypothesis is explored across diseases including Type 1 diabetes, celiac disease, multiple sclerosis, rheumatoid arthritis, and lupus.
- Experimental validation is needed to determine whether altered self-antigens act as initiating events in specific immune-mediated diseases.
Abstract
Immune-mediated diseases are traditionally interpreted through the hypothesis of impaired immune tolerance, autoreactive lymphocyte activation, and dysregulated inflammatory responses. While these mechanisms explain important aspects of disease progression, they do not fully clarify why immune responses demonstrate remarkable tissue specificity, selective antigen targeting, and distinct temporal patterns across different diseases. The hypothesis will introduce the Altered Self-Antigen Recognition (ASAR) hypothesis, a conceptual hypothesis proposing that, in a subset of immune-mediated diseases, the earliest initiating events may involve molecular alterations occurring within susceptible tissues before the establishment of chronic immune pathology. The ASAR hypothesis proposes that cellular stress, metabolic imbalance, oxidative injury, defective protein processing, or other disturbances of tissue homeostasis may generate Altered Self-Antigens through mechanisms including posttranslational modifications, abnormal peptide processing, structural changes, and impaired molecular clearance. These altered molecular structures may subsequently become recognized by adaptive immune mechanisms through genetically determined antigen presentation pathways, particularly HLA-dependent peptide presentation. Within this hypothesis, immune activation is not viewed solely as an initial failure of self-tolerance, but as a highly specific biological response to a modified molecular state generated within stressed tissues. Chronic disease progression may then result from sustained antigen generation, epitope spreading, persistent antigen presentation, inflammatory amplification, and failure of tissue restoration. The ASAR hypothesis is examined across representative immune-mediated diseases, including Type 1 Diabetes Mellitus, Celiac Disease, Multiple Sclerosis, Rheumatoid Arthritis, Hashimoto’s Thyroiditis, Crohn’s Disease, Systemic Lupus Erythematosus, and Myasthenia Gravis. Across these conditions, recurring biological patterns suggest potential interactions between tissue stress, altered molecular identity, immune recognition, and chronic inflammation. In conclusion This document introduces the theory in which that the Altered Self-Antigen Recognition (ASAR) hypothesis, proposing that tissue-specific molecular alterations precede and initiate immune-mediated diseases.
Keywords: Altered self-antigens; Autoimmunity; Antigen recognition; Immune tolerance; Tissue-specific inflammation
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How to cite this article
Al Masoudi, A. S. T., & Al Mammori, R. T. O. (2026). The altered self-antigen recognition (ASAR) hypothesis: A novel reading of autoimmunity and immune-mediated diseases initiation and persistence. Science Archives, 7(3), 337–346. https://doi.org/10.47587/SA.2026.7305
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