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First administered to a human subject as a tuberculosis (TB) vaccine on July 18, 1921, Bacillus Calmette-Guérin (BCG) has a long history of use for the prevention of TB and later the immunotherapy of bladder cancer. For TB prevention, BCG is given to infants born globally across over 180 countries and has been in use since the late 1920s. With about 352 million BCG doses procured annually and tens of billions of doses having been administered over the past century, it is estimated to be the most widely used vaccine in human history. While its roles for TB prevention and bladder cancer immunotherapy are widely appreciated, over the past century, BCG has been also studied for nontraditional purposes, which include (a) prevention of viral infections and nontuberculous mycobacterial infections, (b) cancer immunotherapy aside from bladder cancer, and (c) immunologic diseases, including multiple sclerosis, type 1 diabetes, and atopic diseases. The basis for these heterologous effects lies in the ability of BCG to alter immunologic set points via heterologous T cell immunity, as well as epigenetic and metabolomic changes in innate immune cells, a process called "trained immunity." In this Review, we provide an overview of what is known regarding the trained immunity mechanism of heterologous protection, and we describe the current knowledge base for these nontraditional uses of BCG.

The incidence of type 1 diabetes is increasing worldwide. In Poland, the number of cases tripled during the last two decades. The aim of this study was to test the hypothesis that the increase may be at least partly explained by a shift in predisposing alleles' frequencies - resulting from treating the otherwise lethal disease, generally better health care as well as selective pressure imposed by pathogens affecting humankind throughout history. The source of DNA was skeletal remains of 232 individuals excavated in four burial sites, dating back to 11th-14th centuries. With all necessary precautions required in ancient DNA analysis, frequencies of HLA DQB(57), CTLA4+49A/G and INS -23A/T alleles were assessed and compared with available data, characterising contemporary Polish population. Frequency of HLA DQB(57-Asp) protective allele is much higher in present-day population of Poland (50.6%) than in the group of 155 medieval specimens successfully typed for this polymorphism (28.4%, P < 0.001). Out of 86 medieval individuals typed for CTLA4+49A/G, 29.1% were homozygous for the predisposing G allele, which is significantly more than contemporarily - 7.6% (P < 0.001). No statistically significant difference was found in alleles and genotypes frequencies of INS-23A/T polymorphic site. Contrary to the initial assumptions, genetic predisposition towards type 1 diabetes, conferred by HLA DQB(57), CTLA4+49A/G and INS -23A/T alleles is much lower contemporarily than it was approximately 700 years before present. This suggests involvement of other than genetic factors in the fast growing incidence of the disease.

The etiological heterogeneity of idiopathic diabetes has been recognized for 25 years, and subdivision into type 1 and type 2 diabetes is fundamental to the way we think about the disease. Review of the literature suggests that the concept of type 1 diabetes as an immunemediated disease emerged rapidly over the period from 1974 to 1976 and showed many of the features of a classic paradigm shift. A few key observations triggered recognition and acceptance of the new paradigm, but the necessary context was provided by scientific developments in areas mainly unrelated to diabetes. The disease paradigm established by 1976 is still widely accepted, and its essential features have been modified only in detail by the revolution in molecular biology that has occurred over the intervening period. Notwithstanding, some of the underlying assumptions remain imprecise, unchallenged, or unconfirmed. Appreciation of the historical origin and subsequent evolution of these fundamental concepts could stimulate critical analysis and help prepare the way for a new paradigm.

Studies conducted over the last 60 years in animals and in vitro have provided considerable evidence that the mammalian kidney can make glucose and release it under various conditions. Until quite recently however, it was generally believed that the human kidney was not an important source of glucose except during acidosis and after prolonged fasting. This review will summarize early work in animals and humans, discuss methodological problems in assessing renal glucose release in vivo, and present results of recent human studies that provide evidence that the kidney may play a significant role in carbohydrate metabolism under both physiological and pathological conditions.