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Interleukin-2 (IL-2) has been implicated in the pathogenesis of neurodevelopmental and neurodegenerative disorders. Studies from our lab have shown that adult IL-2 knockout (KO) mice exhibit septohippocampal pathology and related behavioral deficits. Compared to IL-2 wild-type (WT) mice, IL-2 KO mice have a marked and selective loss of septal cholinergic neurons that occurs between the third postnatal week and adulthood. Given that the development of septal neurons is completed by embryonic day 17 and that IL-2 KO mice exhibit peripheral autoimmunity that develops progressively post-weaning, our data and others led us to postulate that the loss of septal neurons in adult IL-2 KO mice is due to selective autoimmune neurodegeneration that coincides with increasing levels of peripheral autoimmunity. Thus, the present study tested the hypotheses: 1) that T cells selectively target the septum, and; 2) that T lymphocyte infiltration to the septum would correlate with peripheral autoimmune disease. We quantified CD3+ T cells in the septum, hippocampus, and cerebellum of IL-2 KO and IL-2 WT mice at ages ranging from 2–14 weeks. T cells infiltrated the brains of IL-2 deficient mice, but were not selective for the septum. Brain T lymphocyte levels in IL-2 KO mice positively correlated with the degree of peripheral autoimmunity. We did not detect CD19+ B lymphocytes, IgG-positive lymphocytes or IgG deposition indicative of autoantibodies in the brains of IL-2 KO mice. Further study is needed to understand how IL-2 deficiency-induced autoimmune T lymphocytes interact with endogenous brain cells to alter function and promote disease.

Following peripheral axotomy of the facial nerve in mice, T lymphocytes cross the blood-brain-barrier (BBB) into the central nervous system (CNS), where they home to neuronal cell bodies of origin in the facial motor nucleus (FMN) and act in concert with microglial cells to support the injured motor neurons. Several lines of evidence suggested normal aging may alter the injury-related responses of T cells, microglia, and motor neurons in this model. In this study, we therefore sought to test the hypothesis that compared to 8 week old mice (young adult), 52 week old mice (advanced middle age) would exhibit more neuronal damage and increased T cell trafficking into the injured FMN following facial nerve resection. Comparison of 8 and 52 week old mice at 7, 14, 21 and 28 days post-resection of the facial nerve, confirmed our hypothesis that age influences the kinetics of CD3+ T lymphocyte trafficking in the axotomized FMN. The peak T cell response was significantly higher, occurred later, and remained elevated longer in the injured FMN of mice in the 52 week age group. Although the kinetics of motor neuron death (identified by quantifying CD11b+ perineuronal microglial phagocytic clusters engulfing the dead neurons at 7, 14, 21 and 28 days post-rection) differed between the age groups, motor neuron profile counts at day 28 showed that levels of cummulative motor loss did not differ between the age groups. Compared to 8 week old mice, however, there was small reduction in the mean cell size of the surviving motor neurons in the 52 week age group. Since T lymphocyte function decreases with normal aging, it will be important to determine if increased T cell trafficking into the injured CNS is a compensatory response to the decreased function of older T cells, and if these and related neuroimmunological changes are more pronounced in mice in the late stages of the life cycle.

The effects of IL-2 on brain development, function, and disease are the result of IL-2's actions in the peripheral immune system and its intrinsic actions in the central nervous system (CNS). Determining whether, and under what circumstances (e.g., development, acute injury), these different actions of IL-2 are operative in the brain is essential to make significant advances in understanding the multifaceted affects of IL-2 on CNS function and disease, including psychiatric disorders. For several decades, there has been a great deal of speculation about the role of autoimmunity in brain disease. More recently, we have learned a great deal about the role of cytokines on neurobiological processes, and there have been many studies that have found peripheral immune alterations in patients with neurological and neuropsychiatric diseases. Despite a plethora of published literature, almost all of this data in humans is correlative and much of the basic research has understandably relied on simpler models (e.g., in vitro models). Good animal models such as our IL-2 knockout mouse model could provide valuable new insight into understanding how the complex biology of a cytokine such as IL-2 can have simultaneous, dynamic effects on multiple systems (e.g., regulating homeostasis in the brain and immune system, autoimmunity that can affect both systems). Animal models can also provide much needed new data elucidating neuroimmunological and autoimmune processes involved in brain development and disease. Such information may ultimately provide critical new insight into the role of brain cytokines and autoimmunity in prominent neurological and neuropsychiatric diseases (e.g., Alzheimer's disease, autism, multiple sclerosis, schizophrenia).

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Coronary artery calcification (CAC) is a well-known marker of subclinical coronary atherosclerosis, which is always detectable in non ECG-gated routine chest CT examinations, and its visual estimation is correlated to clinical outcomes. Agatston scoring is not routinely performed on these examinations. We sought to validate a visual scoring scheme we derived against ECG-gated CT's and compare our system with another previously published visual scoring scheme in a different cohort of lung cancer screening participants. 50 COPDGene participants received, regular dose full inspiration (non-gated high mA), and low dose expiration CT (non-gated low mA) and ECG-gated CT's at the same time. CAC was visually scored by 3 readers using our total visual scoring (TVS) method and compared to the Agatston score. The second portion of the study involved visual and Agatston scoring of a larger sample of 198 lung cancer screening patients, comparing visual scoring described by Shemesh et. al. and our TVS method. For the COPDGene participants, scores were highly correlated among readers (all ICC≥0.92), between the ECG-gated CT, non-gated high mA CT, and the non-gated low dose CT (all p<0.001), and with the Agatston score (all ICC≥0.90). For the cancer screening cohort there was very good agreement of our system and Shemesh scores. Correlations between reader scores, our system, Shemesh scores, and Agatston scores were also very good, ranging from 0.81-0.96. We derived cutoff values corresponding to Agatston risk quartiles for our system and Shemesh. There was excellent correlation of visual scoring with Agatston scoring on ECG-gated and non-gated CT. In lung cancer screening CT's both ours and Shemesh visual scoring correlated well with Agatston scores and with each other. Visual scoring may predict clinically significant CAC in major Agatston categories.

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