Tissue distribution of lymphocytes and plasma cells and the role of the gut.

Wewould like to thank Drs. Pabst, Russell and Brandtzaeg [1] for an extensive commentary of our recently published Opinion article on problems associated with the quantification of gut lymphocytes [2]. In their letter, the authors pointed out that the commonly used term ‘lymphocyte’ in a strict sense does not include plasma cells, even though lymphocytes and plasma cells are ‘lymphoid cells’. Because many of the studies we cited quantified lamina propria (LP) lymphocytes, Pabst et al. [1] argued that, in contrast to our claim, it remainsunknownwhether spleenand lymphnodes are the major lymphoid compartment in humans if one also accounts for the distribution of plasma cells in the body. Indeed, in many of the previous studies, lymphoid cells, isolated from lymph nodes, spleen, bone marrow, gut LP and gut epithelium were called lymphocytes. Unfortunately, most of these studies have not reported what cell types were included under the category of ‘lymphocytes’. In several papers on gut immunology, the term lymphocyte is used interchangeably with lymphoid cells, and it is unclear whether or not previous studies that we cited included gut plasma cells in their estimate of the LP lymphocytes. Nevertheless, using the strict definition of lymphocyte of Pabst et al. [1] for previously published studies, our analysis does suggest that approximately 10% of the total body lymphocytes (senso stricto) reside in the gut LP, and this estimate is reasonably consistent for several mammalian species analyzed [2]. Additional studies are needed to confirm this result for all lymphoid cells (meaning lymphocytes and plasma cells). Pabst et al. [1] argued that the distribution and the number of immunoglobulin (Ig)-secreting cells in humans is well understood. However, to the best of our knowledge, there is no single study that estimates both the number of Ig-secreting cells in the whole body and in the gut LP of humans, and only one such study exists in mice [3]. Moreover, there are some inconsistencies in estimating the number of lymphoid cells in the gut LP, both in humans and mice, casting doubt on whether the distribution of Igproducing cells in these species is in fact well understood. Estimation of the total number of Ig-secreting cells in the human gut has been done in a pioneering study by Brandtzaeg and Baklien [4]. Using histological samples, the authors defined a part of the gut LP as a ‘mucosal unit’ (Figure 1). The authors extensively examined the number of cells secreting IgA, IgG and IgM per mucosal unit in different parts of the human intestine [4]. A simple calculation suggests that the human small intestine contains at least 2 10 of Ig-secreting cells (see legend of Figure 1).