Immungenetische Marker im Wandel der Zeit

Abstract

The immunogenetic variability of mankind is in the focus of the medical fundamental research. A multitude of polymorphisms has been identified, which have an influence on susceptibility and mortality in numerous diseases as well as on the success of therapies. The enlightment of the evolutionary context is indispensable for a better understanding of the relevance of todays variability. Special importance is ascribed to the more recent history of mankind with its dramatic expansion in population size within the last centuries. This was preceded by an era of demographic decline caused by the medieval and early modern epidemics. The field of aDNA analysis allows the direct access to data on variability in historic populations by the investigation of genetic archives. Thus valuable information arises for modern sciences on the clarification of selective events, which shaped the immunogenetic background of European individuals.This study therefore analysed the allelic frequencies of single nucleotide polymorphisms (SNP) of the interleukins IL6, IL10 and IL4 as well as the receptors IL4Ra, TLR2 and TLR4. Their immunogenetic relevance in modern populations was shown by association studies. Main challenge of the study was the investigation of a historic epidemic skeletal collective from a mass grave of the plague called the Black Death in medieval Lübeck. This collective is compared to a contemporary collective from Lübeck, resembling a non-epidemic control. An older control and consequently pre-epidemic is the collective from the Lichtenstein cave in Dorste (Harz mountains), the modern population is used as post-epidemic control. The study thus spans a range of 3000 years of history of infectious diseases, from Bronze Age to Modern. We expected to detect a selection of pro-inflammatory alleles in eras of epidemic events, such as the Black Death. This should be accompanied by an increase of frequency of the pro-inflammatory alleles until modern times.The results show slight differences in allelic frequencies between the past and today. Though trends are observed, significant deviations exist only from single historic to the modern population. Remarkable is the high frequency of anti-inflammatory alleles of marker IL6, IL10 and IL4Ra in all eras. We take it as a clue to the importance of anti-inflammatory features in historic populations. Differences are found at the distribution of TLR4 D299G and IL10 G-1087A between the plague collective and modern population. A selection by the plague epidemic is discussed. The frequency of minor allele 753Q of TLR2 is elevated in both medieval collectives compared to the modern population. A selection by plague is therefore implausible, but it is assumed that a selection reducing the frequency of the minor allele taking place between Middle Ages and today. The SNP G-2849A of marker IL10 shows a significant difference from all historic samples to the modern population. Todays more seldom pro-inflammatory allele prevails in the historic collectives. Continual shifting of frequencies towards pro-inflammatory alleles through all collectives was not observed.The influence of 3000 years of epidemiology, especially plague itself, is therefore less than expected. This means the relevance of epidemic history on modern variability needs to be reconsidered. Another aspect to be reconsidered is the suitability of modern industrial populations as post-epidemic controls. The influence of modern medicine and nutrition has to be clarified. Here the investigation of an early modern population has to be considered as post-epidemic control.This study shows the potential of screening several markers in historic populations. The method of a single-base-extension reaction (SBE), also called minisequencing or SNaPshot, was used to permit the simultaneous analysis of all markers. It was combined with the analysis of the genetic fingerprint, which enabled the direct proof of the authenticity of results.