For decades, autoimmunity research has been organized around the question "what causes a break in self-tolerance?" In a 2022 position essay, Polly Matzinger argued that the scarcity of answers reflects that this is the wrong question, and that many autoimmune diseases may instead arise from defects in normal tissue physiology. The open problem is the one this challenge poses to the field: for major human autoimmune diseases, determine the actual disease-initiating defect — immune-intrinsic (a failure of tolerance mechanisms in the immune system itself) versus tissue-intrinsic (injury, defective handling of stressed or dying cells, or loss of local effector-class control in the target tissue) — together with what maintains the pathogenic response and what determines its effector class, without presupposing either side. Disease-specific literatures (e.g., the "inside-out" versus "outside-in" debate in multiple sclerosis, the beta-cell-stress/neoepitope thread in type 1 diabetes) show the attribution question is explicitly open; no later work resolves it.

Background

The immune system routinely contains lymphocytes (T and B cells) whose receptors can recognize the body's own proteins; healthy individuals do not normally develop disease from this "autoreactivity" because of self-tolerance, a set of deletion and suppression mechanisms operating in the thymus, bone marrow, and peripheral tissues. Classical autoimmunity research frames each disease — type 1 diabetes (T1D), multiple sclerosis (MS), lupus, rheumatoid arthritis, vitiligo, myasthenia gravis, and others — as the outcome of a mysterious "break" in these tolerance mechanisms, and asks what causes the break.

A competing framework, the danger model proposed by Polly Matzinger in 1994, holds that the ultimate control of immune responses lies with the body's tissue cells rather than with the immune system alone: tissues initiate responses when their cells are injured or stressed (by releasing damage-associated molecular patterns, DAMPs — also called alarm signals or alarmins — such as misplaced nucleic acids, heat shock proteins, ATP, and HMGB-1), tissues induce tolerance when healthy (resting tissue, without alarm signals, deletes or silences self-reactive T cells), and tissues help set the local default effector class — the type of immune response (e.g., Th1-type inflammatory responses with cytotoxic cells and complement-fixing antibodies, versus gentler classes) that a given organ can survive. On this view, most people's autoreactive lymphocytes are harmless not because tolerance is perfect but because their tissues are physiologically healthy.

In "Autoimmunity: Are we asking the right question?" (Frontiers in Immunology, 2022), Matzinger developed this into a direct attack on the organizing question of the field. She argued that many, if not most, autoimmune diseases arise from injury or non-physiological events in a tissue, or from defects in the detection and handling of dying, injured, or stressed cells — not from defects in the immune system — and sorted autoimmune diseases into four categories: (1) undetected infection in the target organ, (2) molecular mimicry (immune responses to pathogens that cross-react with self), (3) "bad death" and other glitches in normal cell physiology (e.g., defective clearance of dying cells in lupus), and (4) a wrongly set local effector class that a small, poorly regenerating organ cannot survive (her proposed reading of T1D). Her prescription is to replace "what broke tolerance?" with three questions: what initiates the response that causes the disease, what maintains it, and what determines its effector class.

The tissue side of this attribution problem has independent support in the disease-specific literature. In T1D, stressed pancreatic beta cells generate neoepitopes — new antigenic determinants created when proteins are modified after synthesis (e.g., by citrullination or deamidation) so that they are seen as foreign by T cells; work through 2026 implicates such responses in amplifying the autoimmune repertoire, while explicitly leaving open whether they initiate disease. In MS, the "inside-out" hypothesis (primary degeneration of the myelin-producing oligodendrocytes, with autoimmunity secondary) is debated against the classical "outside-in" autoimmunity hypothesis, with the initiating event still unclarified. On the immune side, genome-wide association studies (GWAS) of autoimmune diseases show that most causal risk variants lie in regulatory DNA of immune-cell subsets, suggesting a substantially immune-skewed genetic architecture — though susceptibility genetics does not by itself identify the initiating lesion. Thus both sides have evidence, the field's founding question may prejudge the answer, and a systematic, disease-by-disease attribution of the initiating defect does not exist.

Problem Statement

Determine, for the major human autoimmune diseases, where the pathogenic process is initiated — and replace the field's default question ('what breaks self-tolerance?') with the three questions proposed by Matzinger (2022):

  1. Initiation and attribution. For each disease (or well-defined disease subset), identify the initiating defect and adjudicate, without presupposing either side, whether it is immune-intrinsic (a failure of tolerance mechanisms within the immune system) or tissue-intrinsic (injury or non-physiological events in the target tissue, defective detection or handling of dying, injured, or stressed cells, or a mis-set local effector class that the tissue cannot survive), or pathogen-triggered (initiation by an immune response to an infecting pathogen — undetected infection of the target organ or molecular mimicry, the two Background categories that fit neither of the other routes). Every initiation category named in the Background must be assigned explicitly to one of these three routes rather than force-fit into a branch it does not match or left unassigned. The attribution must address initiation specifically, not merely later amplification such as epitope spreading (the expansion of the immune response to additional self-antigens as tissue damage exposes new targets).
  2. Maintenance. Identify what sustains the self-directed response once started (persistent tissue alarm signals, failure of tissue restitution, or genuine loss of immune regulation).
  3. Effector class. Identify what determines the effector class of the response in the target organ, and whether disease results from an inappropriate class rather than from autoreactivity per se.

The deliverable is a disease-resolved (or explicitly disease-subset-resolved) mechanistic attribution with the discriminating evidence for each of the three questions, together with an account of the mixed and heterogeneous cases Matzinger anticipates (diseases whose initiating causes differ across patients). The coverage boundary is explicit: a resolving answer adjudicates at least the diseases named in the Background — type 1 diabetes, multiple sclerosis, lupus, rheumatoid arthritis, vitiligo, and myasthenia gravis — each resolved at the disease level or at the level of well-defined disease subsets, and adds further major autoimmune diseases where the discriminating evidence permits; resolving a single disease or subset alone does not complete the task.

References

  1. Matzinger P. (2022). "Autoimmunity: Are we asking the right question?" Frontiers in Immunology 13:864633. DOI: 10.3389/fimmu.2022.864633. https://doi.org/10.3389/fimmu.2022.864633 (full text: PMC9671104, https://pmc.ncbi.nlm.nih.gov/articles/PMC9671104/)
  2. Matzinger P. (1994). "Tolerance, Danger, and the Extended Family." Annual Review of Immunology 12:991–1045. DOI: 10.1146/annurev.iy.12.040194.005015. https://doi.org/10.1146/annurev.iy.12.040194.005015
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