Gut-associated lymphoid tissue

Tissue

Gut associated lymphoid tissue (GALT) is a component of the mucosa associated lymphoid tissue (MALT) which works in the immune system to protect the body from invasion in the gut. Owing to its physiological function in food absorption, the mucosal surface is thin and acts as a permeable barrier to the interior of the body. Equally, its fragility and permeability creates vulnerability to infection and, in fact, the vast majority of the infectious agents invading the human body use this route. The functional importance of GALT in body's defense relies on its large population of plasma cells, which are antibody producers, whose number exceeds the number of plasma cells in spleen, lymph nodes and bone marrow combined. GALT makes up about 70% of the immune system by weight; compromised GALT may significantly affect the strength of the immune system as a whole.

The Peyer's patch is an aggregate of lymphoid cells projected to the lumen of the gut which acts as a very important site for the initiation of the immune response. It forms a subepithelial dome where large number of B cell follicles with its germinal centers, T cell areas between them in a smaller number and dendritic cells are found. In this area, the subepithelial dome is separated from the intestinal lumen by a layer of follicle associated epithelium. This contains conventional intestinal epithelial cells and a small number of specialized epithelial cells called microfold cells (M cells) in between. Unlike enterocytes, these M cells present a folded luminal surface instead of the microvilli, do not secrete digestive enzymes or mucus and lack a thick surface of glycocalix, so it can be in contact with microbiota and antigens presented in the content of gut.

Under normal circumstances, immune system of the whole organism needs intestinal source of antigens to train and regulate development of various immune cells. Without having such stimulation, many properties of immune systems do not develop, as it is shown on the case of germ free animals. Because immune cells are in constant touch with bacterial and food antigens, the primary response is set up as tolerogenic. Still there must be a robust defence in a case that pathogens cross either the border line of epithelium or produce harmful substances like bacterial toxins. Such a walking on the edge of a knife is ensured by diverse types of immune cells:

Plasma B cells residing at lamina propria produce high levels of specific secretory IgA (sIgA) antibodies. These IgA are secreted into the lumen of the gut through the epithelial layer by transcytosis. Firstly epithelial cell binds a dimer of IgA via polymeric Ig receptor at the basolateral side and transports it in a vesicle into the luminal space. Then the receptor is proteolytically cleaved and the dimer of IgA is released with a portion of the receptor called the secretory component. The secretory component protects secreted antibodies against the digestive milieu in the gut. A high level of secretory IgA results from the interaction of B cells and intestinal antigen presenting dendritic cell (DC) in cooperation with follicular T helper cell (Tfh) in the germinal centers (GCs) of Peyer's patches. There are two main ways of IgA production 1) T cell dependent resulting in sIgAs with high affinity and specificity and 2) T cell independent generation of sIgA, which utilizes dendritic cells and their production of BAFF and APRIL cytokines. T cell independently produced sIgAs have lower affinity and coat mainly commensals. General functions of secretory IgAs are to coat any of the intestinal bacteria (commensal or pathogenic ones) to impair their motility and to prevent them from getting in prolonged and direct contact with the intestinal epithelium and the host intestinal immune system. This is called immune exclusion. Secreted IgAs bind to bacterial toxins and neutralize them as well. Antigens received in this way ensure tolerance against them. Commensal microbiota activates immune response as well in a way that protects host intestinal tissue from damaging it by immune cell reactions. The outcome of T cell populations in healthy individuals differs from the spectrum of T cells resulting from acute infection or chronic inflammation. Inappropriate stimulation (typically by segmented filamentous bacteria SFB) of chronic Th1 or Th17 cell response plays a crucial role in pathological damage to the host. Several novel gut associated lymphoid cells have been described. They are of different origins and follow different maturation processes but share the same GALT role – to rapidly respond to pathogens and secrete effector cytokines. Such multi layered protection systems highlights the susceptibility of mucosal sites to invading agents. The mucosal route is the most frequent way for entering of pathogenic infections into the host. Robust engagement of a variety of lymphoid cells patrolling the epithelial layer also reflects evolutionary pressure and arms race between immune systems and pathogens escaping its control.

Long lived and residential intraepithelial lymphocytes (IELs) are one of the largest populations of T lymphocytes in the body. Such location in very special per itself – IELs patrol the condition within a single layer of cells and have dendritic look. They provide the first line of defense in case of pathogen crossing the epithelial barrier. IELs encompass surprising diversity of origins and divide into two main categories – conventional and nonconventional. It is based on molecular surface properties and the place where they acquire their final effector cytotoxic program.

Beside adaptive specific immunity, an innate immunity plays a significant role in GALT because it provides more rapid response. Recognition of microbial non self signature occurs by pattern recognition receptors (PRR) that can be found on dendritic cells, macrophages, monocytes, neutrophils and epithelial cells. PRRs bind to conserved microbial pattern like cell walls components (LPS, teichoic acid, flagellin, peptidoglycan) or viral or bacterial nucleic acid. PRRs are localized extracellularly as membrane bound receptors (Toll like receptors) or intracellularly (NOD like and RIG like receptors).

DCs present less than 10% of lamina propria APC and typically do not reside in lower layers. Inherent production of retinoic acid and TGF β (typical for gut associated DCs) induces expression of gut homing molecules and favor IgA switch during maturation of B cells in folicules. DCs also direct Treg and conventional IELs to receive their final phenotype of mature effector cells in intestine.

The adaptive immunity, mediated by antibodies and T cells, is only found in vertebrates. Whereas all of them have a gut associated lymphoid tissue and the vast majority have a version of spleen and thymus, not all vertebrates show bone marrow, lymph nodes or germinal centers, what means that not all vertebrates can generate lymphocytes in bone marrow. This different distribution of the adaptive organs in the different groups of vertebrates suggests GALT as the very first part of the adaptive immune system in vertebrates. It has been suggested that from this existing GALT, and due to the pressure put by commensal bacteria in gut that coevolved with vertebrates, later specializations as thymus, spleen or lymph nodes appeared as part of the adaptive immune system.