Until recently, the human appendix is considered as rudimentary part of intestine. The appendix has been considering as a safe house for commensal gut flora, in this blog we will see how commensal bacteria can be reintroduced from appendix to intestine in case of disease, therefore appendix can be considered as an important part of intestinal health.

Evolutionary perspective 

Appendix consider as a believable function in searching for homology with other mammalians. The fact that appendix is much larger in certain lower mammalian such as rabbits, resulted in human appendix being considered a vestigial organ. In evolution terms human appendix is consider as remnant of the mammalian caecum. Originally, this part of intestine had a digestive function, primarily facilitating the digestion of cellulose with help of resident microorganisms, this cellulose digestive trait is lost in human caecum, although in human appendix a relative abundance of micro-organisms presents in biofilm still exist with presence of lymphoid tissue. Moreover, in other non-primates like amphibians and reptiles show lack of both the present of caecum and appendix and the need of cellulose digestion. This give idea that appendix for sheltering the commensal gut flora may have evolved prior to the caecum, rather than having derived from it. The digestive trait has developed in bulging proximal large intestine that eventually became the caecum, which would imply that the immunological function existed before the digestive one. 

Histology of appendix 

Similar like intestinal wall of colon, the appendiceal wall consist of mucosa, submucosa, muscularis externa and serosa. However, the function and quantity of cells differ in between appendix and colon.

Screenshot 2020 07 27 at 7.51.30 PM 2
Table: characteristics of cells and molecules found in human appendix. 

Mucosa

Mucosa consist of enterocytes and goblet cells, a lamina propria and muscularis mucosae. Intraepithelial lymphocytes (IELs) in appendix consist of CD8+ regulatory T cells, M cells, human leucocyte antigen D-related (HLA-DR) bearing T and B cells found in appendix. As this show the sign of antigen presentation and transportation, so can be an area of immune stimulation. Crypts of Lieberkühn present in appendix as in colon, which produce anti-microbial peptide as the main functions.

Submucosa

It mainly consists of connective tissue. The lymphoid tissue presents here densely packed B lymphocytes and T lymphocytes. The germinal center is localized far from the lumen and contains macrophages and centroblasts, proliferating B cells that give rise to follicle by monoclonal expansion (many copies of daughter cells with same affinity and specificity). Some part around germinal center consists of light zone which consist of follicle dendritic cells (FDCs). FDCs activate some cells by antigen presentation which stimulates production of immunoglobulins prolongs their lifespan. Interaction of CD40-CD40L with T cells, differentiate some cells into plasma blasts or memory B cells, this zone has eight-fold times more CD4+ and CD8+ T cells. 

Lymphocytes in appendiceal tissue

The appendix has abundance of natural killer CD3+ T cells that can produced cytokines and chemokines after activation. A contribution factor to abundance of lymphocytes may be presence of CCL21 this promotes the recruitment of B and T lymphocytes to the appendiceal lymphoid tissue and migration of activated dendritic cells (DCs) back to lymph nodes. T cells in appendiceal also express more integrin subunit β7 as compared to intestinal lymphocytes, and αEβ7 is responsible for adhesion of lymphocytes via E-cadherin.

Interaction with microbial flora

The intestinal biofilm 

The most luminal lining of large intestine wall contains biofilm ( a layer of commensal gut bacteria), this thick, firm mucin that lays directly upon the intestinal epithelial cells is insoluble, thus preventing pathogens bacteria from being in contact with epithelium and therefore bacteria inside biofilm are less likely to cross the epithelial barrier compared to single, planktonic bacteria. Apart from barrier it also shed bacteria actively form their surface. Conversely the shedding of parts of biofilm itself is rather believed to recolonization of beneficial bacteria. In disease like diarrhea turnover enterocytes and thus shedding of biofilm is accelerated, thus leaving the intestinal wall derived of its protective barrier.

Special role of appendiceal biofilm

In the case of diarrhoeal clearance the biofilm in appendix is safe and acts as safe house for commensal bacteria and to facilitate their reinoculation of gut after a gastrointestinal infection. Scientist found secretory IgA stimulate agglutination of bacteria and mucin bind these bacteria to mucus layer. Interaction of commensal flora helps the GALT in developing an adequate immune response to pathogens. This also suggest that appendiceal biofilm has a crucial role in aiding the development of a normal immune system.  The intestine of germ-free animals shows a decrease IELs, IgA and lamina propria lymphocytes, an impaired maturation of lymphocyte aggregates into isolated lymphoid follicles or Peyer’s patches and caused possibly by the absence of proliferating B cells.

Characteristic appendicular changes in inflammatory bowel disease

Acute appendicitis 

Typical histological characteristics of acute appendiceal inflammation are mucosal ulceration, and serositis. Studies on mice show that high amount of CD4+ and CD8+ T cells and higher amount of FoxP3+CD25+ T cells in acutely inflamed appendices, regulation of FoxP3+CD25+ T cells have a regulatory function, increase in absence of anti-microbial substance such as antibiotics. 

Immunological link between acute appendicitis and ulcerative colitis

The pathway by which appendectomy seems to protect patients from ulcerative colitis is not yet clear. The protection against the development of UC by the combination of appendicitis and appendectomy suggest that characteristic immunological processes make appendix a ready for action for ulcerative colitis. 

image 12

In UC, the number of CD5+ B lymphocytes decreased, CD5+ has a protective role against UC. Although dysbiosis (an imbalance between the type of organism present in a person natural microflora) microflora is often seen during UC, studies examining the effect of antibiotics or probiotics in IBD patients have inconsistent and disappointing result, can be explain by the variation in gut flora of UC patients.

Conclusion

The vermiform appendix is a rudimentary organ but rather an important part of immune system with distinct function within GALT different from lymphoid tissue in other parts of intestine. Appendix influence GALT by stimulating its development and aids recovery of colon commensal flora after diarrheal illness. The interaction with gut flora and appendix plays an essential role in manner of causation of disease, and also in onset of UC. It remains uncertain whether the dysbiosis seen in appendices of many UC patients is the cause or result of inflammation, based on this observation we concluded that appendix has an important immune function both in health and disease.

Reference

Kooij, I.A., Sahami, S., Meijer, S.L., Buskens, C.J. and Te Velde, A.A., 2016. The immunology of the vermiform appendix: a review of the literature. Clinical & Experimental Immunology186(1), pp.1-9.

This Post Has One Comment

  1. Lys Marie

    I loved this post!! Specially the Histology part… I was reading and remember my Histology lab classes. You’re wonderful, thanks for share this great content!! ❤️❤️

Leave a Reply