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Monday Article #42: Mechanisms of Autoimmunity

Autoimmune reactions reflect an imbalance between effector and regulatory immune responses, typically develop through stages of initiation and propagation, and often show phases of resolution and exacerbations (Figure 1). All stages of autoimmune disease are thought to be associated with a failure of regulatory mechanisms, with the resolution phase defined by a partial, and in most cases, short-term ability to restore the balance of effector and regulatory responses. The fundamental underlying mechanism of autoimmunity is defective elimination and/or control of self-reactive lymphocytes. (Michael D. Rosenblum, Kelly A. Remedious, and Adul K. Abbas , 2015)

Figure 1: Three major phases of autoimmune disease

The initiation of autoimmune reactions

Autoimmunity is initiated by a combination of genetic predisposition and environmental triggers. Patients in the initiation phase of disease are typically unaware of clinical symptoms (subclinical). Patients present with clinical disease during the propagation phase, which is characterized by self-perpetuating inflammation and tissue damage due to cytokine production, epitope spreading, and a disrupted effector T cell/Treg (Teff/Treg) balance. Autoimmune reactions resolve with the activation of cell-intrinsic (inhibitory pathways) and cell-extrinsic (Tregs) mechanisms to limit effector responses and restore the Teff/Treg balance. Patients in this phase often suffer from relapsing and remitting disease as a result of a persistent struggle between pathogenic effector responses and regulation. (Michael D. Rosenblum, Kelly A. Remedious, and Adul K. Abbas , 2015)

Autoimmune diseases, like many other complex disorders, are believed to arise from a combination of genetic and environmental factors. A simple hypothesis is that polymorphisms in various genes result in defective regulation or reduced threshold for lymphocytes activation, and environmental factors initiate or augment activation of self-reactive lymphocytes that have escaped control and are poised to react against self-constituents. (Figure 2) (Michael D. Rosenblum, Kelly A. Remedious, and Adul K. Abbas , 2015)

Figure 2: Genetic susceptibility, environmental stimuli, and defective regulation are responsible for initiating autoimmunity.

Genetic polymorphisms in immune-related genes (including HLA, cytokines/receptors, and those involved in central tolerance) may lower the threshold for the activation of autoreactive T cells. Environmental triggers such as infection, the microbiome, and tissue injury generate a proinflammatory environment that supports the activation of autoreactive lymphocytes. Tregs normally function to suppress autoreactive T cells, but defects in development, stability, or function may render these cells dysfunctional and unable to control autoreactive T cell responses. Alone or in combination, these factors can contribute to the escape, activation, and proliferation of autoreactive lymphocytes that result in tissue injury and clinical disease. (Michael D. Rosenblum, Kelly A. Remedious, and Adul K. Abbas , 2015)

The propagation of autoimmune reactions

Most patients present with clinical disease during the propagation phase, which is characterized by progressive inflammation and tissue damage. The self-perpetuating nature of autoimmune diseases may help to explain why these conditions reach the propagation phase. First, the self-antigens that drive the reaction can obviously not be eliminated. This problem is compounded by the emergence of new antigenic epitopes as a result of tissue damage and alterations in self-proteins, the phenomenon known as epitope spreading. Epitope spreading sets up a vicious cycle in which newly created antigenic epitopes activate more lymphocytes of different specificities and recruit these cells into the reaction, leading to more tissue damage and the emergence of even more novel epitopes targeted by autoreactive lymphocytes. Second, the autoimmune reaction creates an inflammatory environment in which multiple immune cells interact to produce cytokines and other mediators that amplify the reaction, creating a catastrophic inflammatory loop. Consistent with this notion is the finding that type I interferons, a product of plasmacytoid dendritic cells that is produced during inflammatory reactions, is a biomarker for the progression of SLE and may be involved in the propagation of this disease. (Banchereau J, Pascual V., 2006)

The resolution of autoimmunity

The control of autoimmune reactions likely involves the induction and activation of regulatory mechanisms that limit the effector response and restore the effector/regulatory balance. The most important of these control mechanisms appear to be Tregs. Tregs, which are best identified by expression of the transcription factor FOXP3, develop in the thymus and peripheral (secondary) lymphoid organs. Both populations of Tregs likely acquire their potent suppressive function only after encountering their target antigen, which in most cases is likely to be a self-antigen. Some of these activated Tregs may survive in tissues as long-lived populations that are capable of controlling autoimmune reactions in that tissue, termed “effector Tregs” or “effector memory Tregs” (Sanchez Rodriguez R, et al., 2014), (Rosenblum MD, Gratz IK, Paw JS, Lee K, Marshak-Rothstein A, Abbas AK., 2011), (Smigiel KS, et al., 2014 ), (Smigiel KS, Srivastava S, Stolley JM, Campbell DJ., 2014). In mouse models, there is convincing evidence that the induction of systemic or tissue-specific autoimmune inflammation is followed by the activation of Tregs and control of the inflammation, resulting in a cycle of disease and resolution. Mechanistically, it has been shown that IL-2 produced by effector T cells in the initial phases of the autoimmune response drives the activation and expansion of pre-existing Tregs and also plays a role in the development of new Tregs, explaining at least in part why effector responses may be followed closely by a wave of Treg-mediated suppression, as seen in many animal models of autoimmunity (Knoechel B, Lohr J, Kahn E, Bluestone JA, Abbas AK., 2005) If the generation or maintenance of these Tregs is defective, the inflammation fails to resolve, resulting in progressive, nonresolving disease.


  1. Michael D. Rosenblum, Kelly A. Remedious, and Adul K. Abbas . (2015, June 01). Mechanisms of human autoimmunity . Retrieved from PubMed :,factors%20that%20contribute%20to%20autoimmunity.

  2. Banchereau J, Pascual V. (2006, September). Type I interferon in systemic lupus erythematosus and other autoimmune diseases. Retrieved from ScienceDirect :

  3. Knoechel B, Lohr J, Kahn E, Bluestone JA, Abbas AK. (2005). Sequential development of interleukin 2-dependent effector and regulatory T cells in response to endogenous systemic antigen. . Retrieved from Journal of Experimental Medicine :

  4. Sanchez Rodriguez R, et al. (2014, February 10). Memory regulatory T cells reside in human skin. Retrieved from JCI :

  5. Rosenblum MD, Gratz IK, Paw JS, Lee K, Marshak-Rothstein A, Abbas AK. (2011, November 27). Response to self antigen imprints regulatory memory in tissues. Retrieved from nature:

  6. Smigiel KS, et al. (2014 , January 13). CCR7 provides localized access to IL-2 and defines homeostatically distinct regulatory T cell subsets. Retrieved from PubMed :

  7. Smigiel KS, Srivastava S, Stolley JM, Campbell DJ. (2014, April 09). Regulatory T-cell homeostasis: steady-state maintenance and modulation during inflammation. Retrieved from Wiley Online Library :


This article was prepared by Emeralda Erna Nordin


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