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Tamas Fulop,1 Shreyansh Tripathi,2,3 Serafim Rodrigues,3,4 Mathieu Desroches,5,6 Ton Bunt,7 Arnold Eiser,8 Francois Bernier,9 Pascale B Beauregard,10 Annelise E Barron,11 Abdelouahed Khalil,1 Adam Plotka,12 Katsuiku Hirokawa,13 Anis Larbi,14 Christian Bocti,15 Benoit Laurent,16 Eric H Frost,17 Jacek M Witkowski12 1Research Center on Aging, Geriatric Division, Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada; 2Cluster Innovation Centre, North Campus, University of Delhi, Delhi, 110007, India; 3Ikerbasque, The Basque Foundation for Science, Bilbao, Spain; 4Mathematical Computational and Experimental Neuroscience (MCEN), BCAM - The Basque Center for Applied Mathematics, Bilbao, Spain; 5MathNeuro Team, Inria Sophia Antipolis Méditerranée, Sophia Antipolis, France; 6Department of Mathematics, Université Côte d’Azur, Nice, France; 7Izumi Biosciences, Inc., Lexington, MA, USA; 8Leonard Davis Institute, University of Pennsylvania, Drexel University College of Medicine, Philadelphia, PA, USA; 9Morinaga Milk Industry Co., Ltd, Next Generation Science Institute, Kanagawa, Japan; 10Department of Biology, Faculty of Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada; 11Department of Bioengineering, Stanford School of Medicine, Stanford, CA, USA; 12Department of Pathophysiology, Medical University of Gdansk, Gdansk, Poland; 13Institute of Health and Life Science, Tokyo Med. Dent. University, Tokyo and Nito-Memory Nakanosogo Hospital, Department of Pathology, Tokyo, Japan; 14Singapore Immunology Network (SIgN), Agency for Science Technology and Research (A*STAR), Immunos Building, Biopolis, Singapore, Singapore; 15Research Center on Aging, Department of Medicine, Division of Neurology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada; 16Research Center on Aging, Department of Biochemistry and Functional Genomics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada; 17Department of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, CanadaCorrespondence: Tamas FulopResearch Center on Aging, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001, 12th Avenue North, Sherbrooke, Quebec, J1H 5N4, CanadaTel +1 819 780 2220Fax +1 819 829 7141Email tamas.fulop@usherbrooke.caSerafim RodriguesIkerbasque Prof. Dr., Ikerbasque, The Basque Foundation for Science Bilbao, Spain and BCAM - The Basque Center for Applied Mathematics, Mathematical, Computational and Experimental (MCEN) Research Group, Alameda de Mazarredo 14, Bilbao, Bizkaia, Basque-Country, 48009, SpainTel +34 946 567 842Email srodrigues@bcamath.orgAbstract: Alzheimer’s disease (AD) is the most common form of dementia and aging is the most common risk factor for developing the disease. The etiology of AD is not known but AD may be considered as a clinical syndrome with multiple causal pathways contributing to it. The amyloid cascade hypothesis, claiming that excess production or reduced clearance of amyloid-beta (Aβ) and its aggregation into amyloid plaques, was accepted for a long time as the main cause of AD. However, many studies showed that Aβ is a frequent consequence of many challenges/pathologic processes occurring in the brain for decades. A key factor, sustained by experimental data, is that low-grade infection leading to production and deposition of Aβ, which has antimicrobial activity, precedes the development of clinically apparent AD. This infection is chronic, low grade, largely clinically silent for decades because of a nearly efficient antimicrobial immune response in the brain. A chronic inflammatory state is induced that results in neurodegeneration. Interventions that appear to prevent, retard or mitigate the development of AD also appear to modify the disease. In this review, we conceptualize further that the changes in the brain antimicrobial immune response during aging and especially in AD sufferers serve as a foundation that could lead to improved treatment strategies for preventing or decreasing the progression of AD in a disease-modifying treatment.Keywords: Alzheimer’s disease, mild cognitive impairment, neuroinflammation, antimicrobial immunity, brain, treatment

Normal human thymuses at various ages were immunohistologically examined in order to determine whether adult or aged thymus maintained the microenvironment for the T cell development and thymopoiesis was really ongoing. To analyze the thymic microenvironment, two monoclonal antibodies (MoAb) were employed. One is MoAb to IL-1 receptor (IL-1R) recognizing medullary and subcapsular cortical epithelial cells of normal infant human thymus. The other is UH-1 MoAb recognizing thymic epithelial cells within the cortex, which are negative with IL-1R-MoAb. Thymus of subjects over 20 years of age was split into many fragments and dispersed in the fatty tissue. However, the microenvironment of each fragment was composed of both IL-1R positive and UH-1 positive epithelial cells, and the UH-1 positive portion was populated with lymphocytes showing a follicle-like appearance. Lymphocytes in these follicle-like portions were mostly CD4 + CD8 + double positive cells and contained many proliferating cells as well as apoptotic cells. Thus these follicle-like portions in adult and aged thymus were considered to be functioning as cortex as in infant thymus. Proliferative activity of thymocytes in the thymic cortex and the follicle-like portions definitely declined with advance of age, while incidence of apoptotic thymocytes increased with aging. [ABSTRACT FROM AUTHOR]

We have shown that autoallergic sialadenitis develops in C3H/He (H-2k) mice thymectomized 3 days after birth and then immunized at 4 or 6 weeks of age with a homogenate of the submandibular salivary gland emulsified in Freund's complete adjuvant. Significant inflammatory changes did not develop in other inbred strains, such as BALB/c (H-2d), and C57BL/6 (H-2b) mice, examined by the same experimental protocol, or in the control groups, i.e. animals thymectomized at day 3 but not immunized, and animals not thymectomized but immunized. The cellular infiltrates observed in C3H/He mice with sialadenitis consisted of small and medium-sized lymophocytes stained with anti-Thy-1.2 antibody (the major proportion positive with anti-L3T4 and the lesser, with anti-Lyt 2). Anti-salivary duct antibodies were detected frequently in the seraof the C3H/He mice with sialadenitis. [ABSTRACT FROM AUTHOR]

Autoimmune MRL-lpr/lpr (lpr) mice were previously demonstrated to have an abnormal proliferation of intermediate T-cell receptor (TCR) cells of extrathymic origin in the liver. Despite this situation, thymectomy in lpr mice resulted in amelioration of autoimmune disease. To understand the underlying mechanism, we investigated associated T-cell differentiation in the thymus and other organs of these mice. When the disease was evoked, T cells with extrathymic properties, i.e. intermediate TCR-αβ cells expressing double-negative (DN) CD4-8- phenotype and interleukin-2 (IL-2) receptor β-chain, became prominent not only in the liver, but also in the thymus. Such thymic T cells mainly resided in the medulla. A small-scale localization of such T cells was seen in the thymic medulla even in normal control mice. There was a heterogeneity among intermediate TCR cells in terms of the composition of DN cells and the expression of CD2 and B220 antigens, depending on the organs and the sites in the same organ. Intermediate TCR cells in the liver, thymus and autoimmune target organs (e.g. kidney) contained a high proportion of the active form (CD2+B220-), while intermediate TCR cells accumulating in peripheral organs, the spleen and lymph nodes, were mainly of the inactive form (CD2-B220+). The active form had an ability to proliferate in response to IL-2 and SEB, whereas the inactive form did not. The present results suggest that the proliferation of intermediate TCR cells occur at multiple sites; this may explain the effect of thymectomy, namely, the retarded onset of disease, in lpr mice. [ABSTRACT FROM AUTHOR]

We previously demonstrated that the liver may be a major site of extrathymic T-cell differentiation in mice. In the present study, the ontogeny and subsequent development of such T cells in the liver and other organs were investigated. This study was possible because these T cells have T-cell receptors (TcR) of intermediate intensity (i.e. intermediate TcR cells) and constitutively express a high level of interleukin-2 receptor β chain (IL-2Rβl). Therefore the two-color staining for CD3 (or αβ TcR) and IL-2Rβ identifies even a small proportion of intermediate TcR cells. The total numbers of mononuclear cells obtained from the liver, thymus and spleen varied from foetal to adult life. Especially in the liver, many haematopoietic cells were present in the parenchymal space at the foetal stage. There were no lymphocytes in the sinusoidal lumen at this period. In contrast, lymphocytes appeared in the hepatic sinusoids after birth and increased with ageing. Phenotypic analysis revealed that intermediate TcR cells appeared in the liver and spleen on Day 4 after birth. Bright TcR cells of thymic origin were also present in the peripheral organs on Day 4. Thereafter, intermediate TcR cells increased in the liver, whereas bright TcR cells increased in the periphery as a function of age. Similarly, thymectomized and congenitally athymic mice had mainly intermediate TcR cells in the liver and, to some extent, periphery. It is concluded that intermediate TcR cells, possibly of extrathymic origin, are generated only after birth and expand with ageing. [ABSTRACT FROM AUTHOR]

Necropsy findings of an acute fatal case of idiopathic interstitial myocarditis were reported. The patient was a 33 year old housewife who had acute cardiac failure on the sixteenth day after the onset of the disease. Necropsy showed important pathological changes confined to the heart. Both ventricles were affected by confluent granulomas with an ill defined patchy appearance. Histologically these lesions consisted of round cells, histiocytes, eosinophils and myogenic giant cells. The findings were compatible with those of interstitial myocarditis associated with a proliferation of giant cells. Both atriums were also affected to a minor extent, detectable only by histological examination. Electron microscopy and cytochemistry showed that most giant cells noted in the lesion showed myofibrils and primary lysosomes in the cytoplasm. Giant cells were positive for myoglobin. Though the macrophage origin of the giant cell in this disorder has been emphasised in a recent report, these cytological results suggest that giant cells observed in the cardiac granulomatous lesions of this case were mainly myogenic in origin. [ABSTRACT FROM PUBLISHER]

We have shown that spontaneously occurring, organ-specific autoimmune lesions develop in aged C57BL/6 mice of both sexes, especially in 24-month-old senescent mice. The inflammatory lesions were found in the multiple organs such as salivary gland, kidney, pancreas, lung, and liver, associated with ageing process. Organ-specific autoimmune lesions first appeared in 6-month-oid C57BL/6 mice, and were aggravated with advancing age. In contrast, significant inflammatory changes did not develop in the thyroid, stomach, testis, ovary, and prostate in aged C57BL/6 mice. The incidence and severity of organ-specific autoimmune lesions in this strain of non-autoimmune mice increase with advance of age. The most severely affected lesion was sialadenitis developed in the submandibular salivary gland of aged mice, and a significant difference between male and female mice was noted only in the salivary gland. The infiltrating cells within the lesions of multiple organs consisted mainly of Thy 1.2+ and L3T4+ cells. Autoantibodies were detected in the sera of the mice with each corresponding organ-specific autoimmune lesions. [ABSTRACT FROM AUTHOR]

The incidence of mononuclear cell infiltration in the adrenal cortex was examined in autopsy cases of young and old subjects, and the infiltrating mononuclear cells were immunohistologically characterized by monoclonal antibodies, Histologically, 110 of 174 autopsy cases of persons > 60 years (63.2%) were shown to have mononuclear cell infiltration of varying degree within the adrenal cortex, whereas such a lesion was observed in lesser incidence (7.4%) in the 54 younger, control subjects aged < 49 years. In addition, severely infiltrating lesions in the adrenal cortex were found frequently in the elderly > 70 years, Immunohistochemical study revealed that the infiltrating mononuclear cells were mainly composed of CD3+ T cells. The major proportion of CD3+ T cells expressed CD4. whereas CD8+ T cells were less in number. Moreover, a considerable proportion of CD4+ T cells was activated as judged by interleukin 2 receptor expression. These findings indicate that T lymphocytes infiltration in aged human adrenal cortex may represent a pre-clinical manifestation of organ-specific autoimmune adrenalitis which is based on autoimmunity associated with ageing process. [ABSTRACT FROM AUTHOR]