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Prolidase deficiency causes spontaneous T cell activation and lupus-like autoimmunity

ABSTRACT: Prolidase Deficiency (PD) is a multi-system disorder caused by mutations in the PEPD gene, which encodes a ubiquitously-expressed metallopeptidase essential for the hydrolysis of dipeptides containing C-terminal proline or hydroxyproline. PD typically presents in childhood with developmental delay, skin ulcers, recurrent infections and in some patients, autoimmune features which can mimic systemic lupus erythematosus (SLE). The basis for the autoimmune association is uncertain, but might be due to self-antigen exposure with tissue damage, or indirectly driven by chronic infection and microbial burden. Here we address the question of causation and show that Pepd null mice have increased anti-nuclear autoantibodies and raised serum IgA, accompanied by kidney immune complex deposition, consistent with an SLE-like disease. These features are associated with an accumulation of CD4 and CD8 effector T cells in the spleen and liver. Pepd deficiency leads to spontaneous T cell activation and proliferation into the effector subset, which is cell intrinsic and independent of antigen receptor specificity or antigenic stimulation. However, an increase in KLRG1+ effector CD8 cells is not observed in mixed chimeras, in which the autoimmune phenotype is also absent. Our findings link autoimmune susceptibility in PD to spontaneous T cell dysfunction, likely to be acting in combination with immune activators that lie outside the haemopoietic system but result from the abnormal metabolism or loss of non-enzymatic prolidase function. This knowledge provides insight into the role of prolidase in the maintenance of self-tolerance and highlights the importance of treatment to control T cell activation.

ORGANISM(S): Mus musculus

PROVIDER: GSE221410 | GEO | 2022/12/20

REPOSITORIES: GEO

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Project description:This is system 1, the model with linear antigen uptake by pAPCs, described in the article: Self-tolerance and Autoimmunity in a Regulatory T Cell Model. Alexander HK, Wahl LM. Bull Math Biol. 2010 Mar 2. PMID:20195912, doi:10.1007/s11538-010-9519-2; Abstract: The class of immunosuppressive lymphocytes known as regulatory T cells (Tregs) has been identified as a key component in preventing autoimmune diseases. Although Tregs have been incorporated previously in mathematical models of autoimmunity, we take a novel approach which emphasizes the importance of professional antigen presenting cells (pAPCs). We examine three possible mechanisms of Treg action (each in isolation) through ordinary differential equation (ODE) models. The immune response against a particular autoantigen is suppressed both by Tregs specific for that antigen and by Tregs of arbitrary specificities, through their action on either maturing or already mature pAPCs or on autoreactive effector T cells. In this deterministic approach, we find that qualitative long-term behaviour is predicted by the basic reproductive ratio R (0) for each system. When R (0) 1, this equilibrium loses its stability and a stable non-trivial equilibrium appears. We interpret the absence of self-damaging populations at the trivial equilibrium to imply a state of self-tolerance, and their presence at the non-trivial equilibrium to imply a state of chronic autoimmunity. Irrespective of mechanism, our model predicts that Tregs specific for the autoantigen in question play no role in the system's qualitative long-term behaviour, but have quantitative effects that could potentially reduce an autoimmune response to sub-clinical levels. Our results also suggest an important role for Tregs of arbitrary specificities in modulating the qualitative outcome. A stochastic treatment of the same model demonstrates that the probability of developing a chronic autoimmune response increases with the initial exposure to self antigen or autoreactive effector T cells. The three different mechanisms we consider, while leading to a number of similar predictions, also exhibit key differences in both transient dynamics (ODE approach) and the probability of chronic autoimmunity (stochastic approach). Originally created by libAntimony v1.4 (using libSBML 3.4.1)

Project description:This is system 2, the model with Michelis Menten type antigen uptake by pAPCs, described in the article: Self-tolerance and Autoimmunity in a Regulatory T Cell Model. Alexander HK, Wahl LM. Bull Math Biol. 2010 Mar 2. PMID: 20195912 , doi: 10.1007/s11538-010-9519-2 ; Abstract: The class of immunosuppressive lymphocytes known as regulatory T cells (Tregs) has been identified as a key component in preventing autoimmune diseases. Although Tregs have been incorporated previously in mathematical models of autoimmunity, we take a novel approach which emphasizes the importance of professional antigen presenting cells (pAPCs). We examine three possible mechanisms of Treg action (each in isolation) through ordinary differential equation (ODE) models. The immune response against a particular autoantigen is suppressed both by Tregs specific for that antigen and by Tregs of arbitrary specificities, through their action on either maturing or already mature pAPCs or on autoreactive effector T cells. In this deterministic approach, we find that qualitative long-term behaviour is predicted by the basic reproductive ratio R (0) for each system. When R (0) 1, this equilibrium loses its stability and a stable non-trivial equilibrium appears. We interpret the absence of self-damaging populations at the trivial equilibrium to imply a state of self-tolerance, and their presence at the non-trivial equilibrium to imply a state of chronic autoimmunity. Irrespective of mechanism, our model predicts that Tregs specific for the autoantigen in question play no role in the system's qualitative long-term behaviour, but have quantitative effects that could potentially reduce an autoimmune response to sub-clinical levels. Our results also suggest an important role for Tregs of arbitrary specificities in modulating the qualitative outcome. A stochastic treatment of the same model demonstrates that the probability of developing a chronic autoimmune response increases with the initial exposure to self antigen or autoreactive effector T cells. The three different mechanisms we consider, while leading to a number of similar predictions, also exhibit key differences in both transient dynamics (ODE approach) and the probability of chronic autoimmunity (stochastic approach). Originally created by libAntimony v1.4 (using libSBML 3.4.1)

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Prolidase deficiency causes spontaneous T cell activation and lupus-like autoimmunity

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