Autoimmune Polyglandular Syndrome Type 1 is known to be a monogenic, recessive autoimmune disease that primarily affects organs of the endocrine axis. Due to the complications of studying disease in humans, little is known about the pathogenicity of B and T cells in APS1. While many previous reports have focused on the presence of autoantibodies in both aire-deficient animals and APS1 patients, no reports have demonstrated a pathogenic role for either B or T cells. Here, we show that T cells are absolutely critical to autoimmunity by generating mice deficient for both aire and TCRα. These mice, which lack αβ T cells, are completely healthy and free of immune infiltrates. To further delineate the effective contribution of CD4+ and CD8+ T cells to this process, we performed adoptive transfer of lymphocyte populations depleted of CD4+ or CD8+ T cells and analyzed CIITA deficient mice. In both cases, CD4+ T cells appeared to play a major role in disease pathogenesis. Upon further dissection, many of the CD4+ T cells resident in the infiltrated tissues produced the Th1 cytokine IFN-γ while few produced IL-17 or IL-10. The importance of Th1-like cells being effectors in aire-deficient mice was confirmed by genetic studies using STAT4 and STAT6 deficient animals. Due to these findings, we reasoned that depletion of CD4+ T cells in vivo would be an effective means of modulating disease. Indeed, administration of neutralizing antibodies significantly altered the degree of infiltration in tissues targeted by the immune system.
While the number of case reports described in the primary literature is limited, published studies of immunosuppressive regimens in APS1 patients suggest synergy with our data. In a patient of French-Canadian descent, several aspects of the disease responded to cyclosporine A treatment, including a remission of exocrine pancreatitis, keratoconjunctivitis, and alopecia (27
). A 5 year old patient of Iranian descent who underwent two liver transplants responded poorly to the immunosuppressive regimen initiated during the first transplant, but well to the regimen initiated during the second transplant. In the former, prednisone, azathioprine, and cyclosporine A was administered, however, autoantibodies were detected to multiple known organ targets and disease progression was unchecked. In the latter case, the patient was given tacrolimus, prednisone, and mycophenolate mofetil and all APS1-related symptoms (including candidiasis and autoantibodies) decreased (28
). Finally, in a study on children with autoimmune hepatitis and APS1, two of three patients responded well to steroids and azathioprine (29
). Our own results in the mouse model would suggest that T-cell targeted therapies may hold the best promise, as specific depletion of CD4+ T cells significantly ameliorates disease.
One question unanswered by the human data is the relative role of B cells in disease pathogenesis, as the immunosuppressive regimens administered equally affect B and T lymphocytes. Despite the identification of many autoantibody specificities in both the aire-deficient mouse and APS1 patients, our data suggests that B cells play a limited role in disease pathogenesis in the mouse model. Sera transfers of autoantibodies were unable to elicit any observable autoimmunity and a genetic deficiency in the B cell compartment had a limited effect on the autoimmune infiltrates. Why then is the generation of multiple autoantigen specificities observed so clearly? The loss of central tolerance in the absence of Aire permits the escape of high-affinity autoreactive T cells (20
). It is likely that these T cells, upon their escape into the periphery, provide B cell help and result in the generation of high affinity autoantibodies. It remains possible, however, that B cells influence additional aspects of the disease not analyzed in this work. For example, APS1 patients have been reported whose clinical history include autoimmune diseases such as Graves and idiopathic thrombocytopenic purpura (1
), in which a clear role for a pathogenic autoantibody has been established. To date, no one has established such a disease mechanism in the mouse model.
Recently, there has been a vigorous discussion in the literature about the potential parallels between this animal model and human patients (30
). Our findings in the animal model, when compared with the extensive clinical experience of clinicians (1
), indicate that a majority of the organs targeted in the absence of Aire expression are shared between the two species (1
). Thus, aire-deficient mice and APS1 patients have been reported to develop adrenal failure, hypoparathyroidism, premature ovarian failure, thyroiditis, autoimmune hepatitis, exocrine pancreatitis, gastritis, pneumonitis, dacryoadenitis and sialitis. Further strengthening the connection between the mouse model and APS1 is preliminary data in our lab where we have found an APS1 patient with photoreceptor-specific autoantibodies and retinitis that is highly similar to our published work (7
) detailing the uveitis in aire-deficient mice (unpublished data).
The larger view of what drives autoimmunity in the absence of Aire is becoming increasingly clear. Previous results from our lab identified IRBP as the primary target of the immune response in the retina. Confirming an important role of aire in autoantigen expression within mTECs, transplantation of a thymus derived from an IRBP-deficient mouse into nude
recipients was sufficient to result in autoimmunity (7
). Thus, absence of a single antigen within the thymic compartment, despite the presence of functional aire protein, allowed for the generation of an aberrant immune response. This immune response likely results from a failure in negative selection, rather than a deficit in positive selection of regulatory T cells. In the murine model, no defect in the number of or selection of FoxP3+ regulatory T cells has been reported (20
), although data in humans remains controversial (35
). Recent data also suggests that the innate immune response, in particular signals generated through Toll like receptors, plays a limited role in driving the autoimmunity in the mouse model (36
In what direction, then, does the future of APS1 treatment lie? Our results suggest that specific targeting of T cells may be an effective way to modulate disease. While depletion of CD4+ T cells in APS1 patients may not be a practical clinical approach given the severe immunosuppression associated with it, other antibody-based therapies may prove useful. For example, immunomodulation using monoclonal antibodies against CD3 has been proven to delay onset of the T-cell driven disease, type 1 diabetes and also is associated with more acceptable levels of immunosuppression (37
). Likewise, targeting of Th1-related cytokines such as IFN-γ or TNF-α may prove to be efficacious given our data supporting a role for Th1 T these cells as key effectors in the mouse model. Finally, identifying the autoantigens that are targeted in APS1 patients could result in antigen-specific therapies involving the suppression of activated autoreactive cells, via regulatory T cells, or other forms of antigen specific tolerance such as coupled cell tolerance (38
). In support of this notion is recent data from our group that demonstrated that the uveitis in the mouse model is driven by a single self-antigen (7
). The studies presented here should help provide the framework for targeted immunotherapy that can be used in the treatment of this rare, but severe clinical syndrome.