The gut is still the biggest lymphoid organ in the body
It is an article of faith among mucosal immunologists that the gut is the largest immune organ in the body. However, Ganusov and De Boer have challenged this view.1 Pabst and colleagues, in responding to Ganusov and De Boer concerning antibody-secreting cells, make a persuasive case that indeed 70% of these cells in the body reside in the gut lamina propria.2 However, they are reluctant to make a similar case for T cells and non-antibody-secreting B cells, mainly because good data are not available. In adult humans the thymus is small and contains few lymphocytes; the systemic (non-gut) sites where lymphocytes are present in largest numbers are the spleen, bone marrow, and lymph nodes, so the critical question is whether the number of lyphocytes in these organs is greater than the number in the gut.
The lymphoid tissue of the human gut comprises Waldeyer's tonsillar ring (adenoids, palatine tonsils), Peyer's patches (PPs), the appendix, isolated mucosal lymphoid follicles, and the mesenteric lymph nodes, which in humans are close to the serosa on the mesenteric side of the gut. Langman and Rowland counted the mucosal follicles in the human large intestine and in five specimens found between 12,761 and 18,432 (average: 15,807) (ref. 3). Interestingly, they also measured the colon and found it to be between 1.1 and 1.7 m long (average: 1.38 m). Cornes measured the small bowel in adults and obtained values ranging from 4.9 m in a 95-year-old woman to 9.1 m in a 32-year-old man, with an average of 6.63 m (ref. 4). According to these data, the small bowel is 4.8 times longer than the colon, and, if the follicle density is the same, there are about 76,000 isolated follicles in the small bowel and thus about 92,000 in the small and large bowels together. Cornes's data were generated in the 1960s; over the past 40–50 years there has been an increase in median population height in the United Kingdom, even over the past 10 years (http://www.ic.nhs.uk/pubs/hse06trends). Since gut length is related to height,5 it seems reasonable to conclude that people have longer intestines than in the 1960s; accordingly, they have more follicles. It is difficult to determine the extent of the increase, but a reasonable case could be made that it is now around 100,000.
Cornes also counted the PPs and divided them into categories: those with more than five follicles, those with more than 25 follicles, and those that were more than 4 cm long.4 He did not count aggregates with five or fewer follicles. In adults between 20 and 40 years of age, there were an average of 159 PPs with more than five follicles, 81 PPs with more than 25 follicles, and 5.3 PPs more than 4 cm long. The PPs in this last group contained at least 500 follicles—in fact, the largest had almost 1,000 follicles. The total was about 250 PPs containing 5,470 follicles (probably many more, because Cornes did not mention, for example, whether PPs with more than 25 follicles had, say, 50, and how many there were with two to four follicles). Figure 1 shows an isolated lymphoid follicle in the duodenum and a serpiginous PP in the ileum.
It is difficult to estimate cell numbers in tissues of Waldeyer's ring, but specimens removed for therapeutic tonsillectomy are approximately 2–3 cm in diameter. It is similarly difficult to obtain estimates of cell yields from the appendix, although the organ is about 1 cm in diameter and 10 cm long. Finally, there is no reported estimate of the number of mesenteric lymph nodes along the gut in humans, nor of the contribution of the acquired gut-associated lymphoid tissue (GALT) in the stomach of patients with Helicobacter pylori infection.
In a comparison of GALT with systemic tissues, the critical question is how many peripheral lymph nodes are present in humans. Good data are difficult to find, but it may vary between 600 and 1,200 (ref. 6; see also http://en.wikipedia.org/wiki/lymph_node). It also must be emphasized that in healthy people, peripheral nodes are inactive whereas GALT is highly reactive. So, although the gut wall contains fewer PP (counting those having more than five follicles) than lymph nodes (250 vs. 600–1,200), the fact that they are constantly stimulated by gut antigens suggests that they are more cellular than peripheral nodes. The vast numbers of single lymphoid follicles in the gut, however, more than compensate for the smaller numbers of PPs than of lymph nodes.
Finally, we come to the bone marrow and spleen. It would be difficult to make a case that there are more lymphocytes in the marrow than in the lamina propria and epithelium on the size of the tissues alone; in fact, the mature lymphocytes in the gut mucosa vastly outnumber those in the marrow. Likewise, the spleen weighs about 500 g (and has abundant red pulp), which is probably the same weight as that of the mesenteric nodes, tonsils, adenoids, and appendix combined.
Overall, then, the case that Ganusov and De Boer have put forward is flawed because they vastly underestimate the numbers of lymphoid follicles in the gut. I will continue to tell my students that 70% of the immune system is present in the gut, and also continue to suggest that the gut is an immune organ we have to feed, rather than a digestive organ we have to protect.
Thomas T MacDonald, President-Elect, SMI
©2008 Society for Mucosal Immunology
Ganusov, V.V. & De Boer, R.J. Do most lymphocytes in humans really reside in the gut? Trends Immunol. 28, 514–518 (2007).
Pabst, R., Russell, M.W. & Brandtzaeg, P. Tissue distribution of lymphocytes and plasma cells and the role of the gut. Trends Immunol. 29, 206–208 (2008).
Langman, J.M. & Rowland, R. The number and distribution of lymphoid follicles in the human large intestine. J. Anat. 149, 189–194 (1986).
Cornes, J.S. Number, size, and distribution of Peyer's patches in the human small intestine. Part I. The development of Peyer's patches. Part II. The effect of age on Peyer's patches. Gut 6, 225–233 (1965).
Weaver, L.T., Austin, S. & Cole, T.J. Small intestinal length: a factor essential for gut adaptation. Gut 32, 1321–1323 (1991).
Qatarneh, S.M., Kiricuta, I.C., Brahme, A., Tiede, U. & Lind, B.K. Three-dimensional atlas of lymph node topography based on the visible human data set. Anat. Rec. B New Anat. 289, 98–111 (2006).
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FEMS Microbiology Reviews (2013)
Digestive Diseases (2012)
Biochemical Society Transactions (2011)
Expert Review of Clinical Immunology (2010)
Annual Review of Medicine (2009)