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Tissue fluid is filtered by non-encapsulated (or partially encapsulated) aggregations of lymphoid tissue

(sometimes called Mucosa Associated Lymphoid Tissue (MALT)). This makes up 85% of lymphoid tissue,

in the non-sterile mucosa. They are usually small, around 1mm in diameter, with the exceptions beting the

tonsils, peyers patches and the appendix.

These lymphoid aggregations are frequently found close to moist epithelial surfaces e.g mucous

membranes of the digestive, respiratory and reproductive systems. Although the epithelia of these tissues

has mechanisms to keep bacteria etc out of the body, this is not foolproof. Thus the lymphoid cells in theseareas are able to respond to any bacteria or micro-organisms that do get through the epithelia. Activated B-

cells in these areas can develop into plasma cells, and produce antibodies, in situ. Lymphocytes from the

larger permanent organs (such as the tonsils) are able to patrol the surrounding tissue, and quickly respond

to foreign antigens.

Tonsils are large partially-encapsulated masses of lymphoid tissue, found in the walls of the pharynx and

nasopharynx, and at the base of the tongue. They form an incomplete ring around the gastrointestinal and

respiratory tracts, where they cross over.

More information about tonsils.

Peyer's patches are large masses of confluent lymphoid follicles, found in the walls of the ileum, part of 

the small intestine.

More information about MALT and Peyer's patches.

The appendix is covered in the topic Digestive System, Appendix 

MALT (Mucosal Associated Lymphoid Tissues) A variety of lymphoid tissues are found at various mucosal sites [within digestive system,respiratory system, and urogenital system]. In humans, these lymphoid tissues function assecondary lymphoid tissues. Most antigens enter the body via the mucosal route, so the mucosalimmune system is incredibly important and was previously under-emphasized by immunologists. The MALT exists both as loosely organized clusters of lymphoid tissue and as well organizeddiscrete lymphoid structures. In general, dispersed lymphoid tissue of the digestive mucosa is termed GALT (gut-associatedlymphoid tissue). Dispersed lymphoid tissue of the respiratory tract is termed BALT (bronchus-associated lymphoid

tissue). Organized structures include the 3 tonsil groups: lingual at the base of the tongue, palatine atthe sides of the throat, nasopharyngeal in the roof of the nasopharynx (adenoids). The appendix and the Peyer's patches are both organized clusters of MALT associated with thedigestive tract. Within the digestive tract, antigens (including microorganisms) are delivered from the lumen of the digestive tract across the epithelial cell boundary of the mucosa by specialized cells known asM cells. The specialized epithelial cells have broad membrane processes on the lumen side anda deep pocket (termed the basolateral pocket) on the basolateral side of the cell. Antigens are endocytosed (or enter via transcytosis) into membrane-bound vesicles that movethe internalized materials to cells contained within the basolateral pocket of the M cell. The cellspresent within the pocket include macrophages, B lymphocytes, and T lymphocytes. B cells areknown to be activated by antigen within the pocket, T cells are presented with antigen by dendritic

cells in the underlying lamina propria. Within the primary follicles of theMALT, B cells begin to enlarge into lymphoblasts and secondary folliclesthen develop which contain active germinal centers (sites of intense Bcell proliferation and differenitation). The resulting plasma cells thensecrete large quantities of antigen-specific IgA. IgA IgA is the major isotype of Ig present in mucosal secretions. Two IgAmonomers are held together in a dimer conformation by a polypeptideknown as the J chain. The IgA must pass through the mucosal epithelial

cells in order to enter the lumen of the digestive, respiratory, or urogenital tract. The IgA dimers

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first bind to a protein projecting from the surface of the mucosal epithelial cells known as the polyIg receptor . The poly Ig receptor - IgA complex is then internalized, and IgA with part of thepoly Ig receptor still attached is secreted into the mucus on the lumen side. The portion of thepolyIg receptor which remains attached is termed the secretory component. The secretorycomponent protects the IgA dimer from proteolysis within the mucus. Interesting Note-- Several pathogens have exploited the M cell as a portal of entry to mucosal tissues. Normally,tight junctions between mucosal epithelial cells prevent the entry of microoganisms. The M cell isused by Vibrio cholerae, Salmonella sp., and the polio virus to establish infection within thedigestive tract

The mucosal lymphatic tissues are nonencapsulated submucosal lymphoid nodules and diffuselymphocytic infiltrates in the submucosa of intestinal and respiratory tracts. These organs workcollectively with regional lymph nodes and spleen to produce B- and T-effector cells which lodgein lamina propria and in intraepithelial locations wherever there is mucosa. Nasopharyngeallymphatic tissues (ie tonsils and adenoids in man), bronchus associated lymphatic tissues, Peyer's patches, appendix and isolated follicles in intestitinal mucosae vary with regard to type of surface epithelium (statified squamous, ciliated columnar, or absorptive columnar) and relative

proportions of T- and B-cells

(Tonsils have 60% T-cells compared to 25%-40% T-cells in respiratory or intestinal patches) butthe similarity of these tissues to Peyer's patches is greater than the difference, especially since allhave "M" cells in their follicle associate epithelium.

The prototypical Mucosal Lymphatic Tissue is the Peyer's patch which has a unique domeepithelium that is specialized to sample environmental antigens. Peyer's patches containlymphoid compartments that are analogous to the deep cortex and follicles of lymph nodes, butthere are no afferent lymphatics and no medullary cords for local accumulation of plasma cells(Parrott 1976). Each Peyer's patch contains multiple individual B-cell follicles separated by diffuselymphoid tissue in interfollicular areas.

FUNCTIONS OF MUCOSAL LYMPHATIC TISSUES . The mucosal immune system appears tohave two paradoxically opposite immune purposes while also participating in continueddiversification of the immunoglobulin repertoire. Mucosal lymphatic tissues amplify developmentof committed B-cells for secretory IgA responses to enviromental antigens IgA responses toenvironmental antigens and programs certain environmental antigens for systemic toleranceinduction. The tolerance that results from mucosal immunization does not effect production of B-cells committed to IgA secretion. "Mucosal" tolerance is manifested by antigen-specificsuppression of delayed cutaneous hypersensitivity and reduced IgG expression. The mucosalimmune system therefore exerts a Yin Yang effect on local versus systemic immunity initiated inunique mucosal and peripheral lymphoid microenvironments.

The mucosa-associated lymphoid tissue (def) or MALT refers to the diffuse system of small

concentrations of lymphoid tissue found in various sites of the body such as the gastrointestinaltract, thyroid, breast, lung, salivary glands, eye, and skin. MALT is populated by loose clustersof T-lymphocytes, B-lymphocytes, plasma cells (def), activated Th cells (def), andmacrophages (def). MALT can be subdivided into:

• GALT (gut-associated lymphoid tissue, such as the Peyer's patches inthe lining of the small intestines)

• BALT (bronchial-associated lymphoid tissue in the bronchi)

• SALT (skin-associated lymphoid tissue beneath the epidermis)

• NALT (nose-associated lymphoid tissue)

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• LALT (larynx-associated lymphoid tissue)

• CALT (conjunctiva-associated lymphoid tissue in the eye)Lymph nodes contain many reticular fibers that support fixed macrophages and dendritic cells aswell as everchanging populations of circulating B-lymphocytes and T-lymphocytes. Whenmicroorganisms and other antigens enter tissues, they are transported by tissue fluid into thelymph vessels. Lymph vessels, in turn, carry these antigens, now in the lymph, to regional lymph

nodes. Here the microbes and other antigens in the lymph encounter changing populations of B-lymphocytes, are filtered out and phagocytosed by the fixed macrophages and dendriticcells, and are presented to changing populations of T-lymphocytes. Approximately 25 billiondifferent lymphocytes migrate through each lymph node every day.Like the lymph nodes, the spleen contains many reticular fibers that support fixed macrophagesand dendritic cells as well as everchanging populations of circulating B-lymphocytes and T-lymphocytes. When microorganisms and other antigens enter the blood, they are transported bythe blood vessels to the spleen. Here they encounter changing populations of B-lymphocytes, are filtered out and phagocytosed by the fixed macrophages and dendriticcells, and are presented to changing populations of T-lymphocytes.Microorganisms and other antigens entering the respiratory tract, gastrointestinal tract, eye,and skin encounter macrophages, dendritic cells, and the changing populations of B-lymphocytes and T-lymphocytes in MALT.As cen be seen, no matter how microbes and other antigens enter the body, they will eventuallyencounter the lymphoid system to initiate adaptive immune responses. 

Pathogens can enter the body by many routes and set up an infection anywhere, but antigen and

lymphocytes will eventually encounter each other in the peripheral lymphoid organs—the lymph nodes, the

spleen, and the mucosal lymphoid tissues (see Fig. 1.7

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). Lymphocytes are continually recirculating through these tissues, to which antigen is also carried from

sites of infection, primarily within macrophages and dendritic cells. Within the lymphoid organs,

specialized cells such as mature dendritic cells display the antigen to lymphocytes. 

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Figure 1.8

Organization of a lymph node

Figure 1.8

.

Organization of a lymph node 

As shown in the diagram on the left, a lymph node consists of an outermost cortex and an inner medulla. The cortex is composed of an outer cortex of B cells organized into lymphoid follicles, and deep, or

paracortical, areas made up mainly of T cells and dendritic cells. When an immune response is underway,

some of the follicles contain central areas of intense B-cell proliferation called germinal centers and are

known as secondary lymphoid follicles. These reactions are very dramatic, but eventually die out as

senescent germinal centers. Lymph draining from the extracellular spaces of the body carries antigens in

phagocytic dendritic cells and macrophages from the tissues to the lymph node via the afferent lymphatics.

Lymph leaves by the efferent lymphatic in the medulla. The medulla consists of strings of macro-phages

and antibody-secreting plasma cells known as the medullary cords. Naive lymphocytes enter the node from

the bloodstream through specialized postcapillary venules (not shown) and leave with the lymph through

the efferent lymphatic. The light micrograph shows a section through a lymph node, with prominent

follicles containing germinal centers. Magnification × 7. Photograph courtesy of N. Rooney.

The lymph nodes are highly organized lymphoid structures located at the points of convergence of vessels

of the lymphatic system, an extensive system of vessels that collects extracellular fluid from the tissues andreturns it to the blood. This extracellular fluid is produced continuously by filtration from the blood, and is

called lymph. The vessels are lymphatic vessels or lymphatics (see Fig. 1.7

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). Afferent lymphatic vessels drain fluid from the tissues and also carry antigen-bearing cells and antigens

from infected tissues to the lymph nodes, where they are trapped. In the lymph nodes, B lymphocytes are

localized in follicles, with T cells more diffusely distributed in surrounding paracortical areas, also referred

to as T-cell zones. Some of the B-cell follicles include germinal centers, where B cells are undergoing

intense proliferation after encountering their specific antigen and their cooperating T cells (Fig. 1.8

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). B and T lymphocytes are segregated in a similar fashion in the other peripheral lymphoid tissues, and we

shall see that this organization promotes the crucial interactions that occur between B and T cells upon

encountering antigen. 

Figure 1.9

Organization of the lymphoid tissues of the spleen

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Figure 1.9

.

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  Organization of the lymphoid tissues of the spleen 

The schematic at top right shows that the spleen consists of red pulp (pink areas in the top panel), which is

a site of red blood cell destruction, interspersed with lymphoid white pulp. An enlargement of a small

section of the spleen (center) shows the arrangement of discrete areas of white pulp (yellow and blue)

around central arterioles. Lymphocytes and antigen- loaded dendritic cells come together in the

periarteriolar lymphoid sheath. Most of the white pulp is shown in transverse section, with two portions in

longitudinal section. The bottom two schematics show enlargements of a transverse section (lower left) andlongitudinal section (lower right) of white pulp. In each area of white pulp, blood carrying lymphocytes and

antigen flows from a trabecular artery into a central arteriole. Cells and antigen then pass into a marginal

sinus and drain into a trabecular vein. The marginal sinus is surrounded by a marginal zone of 

lymphocytes. Within the marginal sinus and surrounding the central arteriole is the periarteriolar lymphoid

sheath (PALS), made up of T cells. The follicles consist mainly of B cells; in secondary follicles a germinal

center is surrounded by a B-cell corona. The light micrograph at bottom left shows a transverse section of 

white pulp stained with hematoxylin and eosin. The T cells of the PALS stain darkly, while the B-cell

corona is lightly stained. The unstained cells lying between the B- and T-cell areas represent a germinal

center. Although the organization of the spleen is similar to that of a lymph node, antigen enters the spleen 

from the blood rather than from the lymph. Photograph courtesy of J.C. Howard.

The spleen is a fist-sized organ just behind the stomach (see Fig. 1.7

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) that collects antigen from the blood. It also collects and disposes of senescent red blood cells. Its

organization is shown schematically in Fig. 1.9

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. The bulk of the spleen is composed of red pulp, which is the site of red blood cell disposal. The

lymphocytes surround the arterioles entering the organ, forming areas of  white pulp, the inner region of 

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which is divided into a periarteriolar lymphoid sheath (PALS), containing mainly T cells, and a flanking B-

cell corona.

Figure 1.10

Organization of typical gut-associated lymphoid tissue (more...)

Figure 1.10

.

Organization of typical gut-associated lymphoid tissue 

As the diagram on the left shows, the bulk of the tissue is B cells, organized in a large and highly active

domed follicle. T cells occupy the areas between follicles. The antigen enters across a specializedepithelium made up of so-called M cells. Although this tissue looks very different from other lymphoid

organs, the basic divisions are maintained. The light micrograph shows a section through the gut wall. The

dome of gut-associated lymphoid tissue can be seen lying beneath the epithelial tissues. Magnification ×

16. Photograph courtesy of N. Rooney.

The gut-associated lymphoid tissues (GALT), which include the tonsils, adenoids, and appendix, and

specialized structures called Peyer's patches in the small intestine, collect antigen from the epithelial

surfaces of the gastrointestinal tract. In Peyer's patches, which are the most important and highly organized

of these tissues, the antigen is collected by specialized epithelial cells called multi-fenestrated or M cells.

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The lymphocytes form a follicle consisting of a large central dome of B lymphocytes surrounded by

smaller numbers of T lymphocytes (Fig. 1.10

). Similar but more diffuse aggregates of lymphocytes protect the respiratory epithelium, where they are

known as bronchial-associated lymphoid tissue (BALT), and other mucosa, where they are known

simply as mucosal-associated lymphoid tissue (MALT). Collectively, the mucosal immune system is

estimated to contain as many lymphocytes as all the rest of the body, and they form a specialized set of 

cells obeying somewhat different rules.

Although very different in appearance, the lymph nodes, spleen, and mucosal-associated lymphoid tissues

all share the same basic architecture. Each of these tissues operates on the same principle, trapping antigen 

from sites of infection and presenting it to migratory small lymphocytes, thus inducing adaptive immune

responses. The peripheral lymphoid tissues also provide sustaining signals to the lymphocytes that do not

encounter their specific antigen, so that they continue to survive and recirculate until they encounter their

specific antigen. This is important in maintaining the correct numbers of circulating T and B lymphocytes, 

and ensures that only those lymphocytes with the potential to respond to foreign antigen are sustained.

In addition to the organized lymphoid tissue in which induction of immune responses occurs within the

mucosal immune system, small foci of lymphocytes and plasma cells are scattered widely throughout the

lamina propria of the gut wall. These represent the effector cells of the gut mucosal immune system. The

life history of these cells is as follows. As naive lymphocytes, they emerge from the primary lymphoid

organs of bone marrow and thymus to enter the inductive lymphoid tissue of the mucosal immune system

via the bloodstream. They may encounter foreign antigens presented within the organized lymphoid tissueof the mucosal immune system and become activated to effector status. From these sites, the activated

lymphocytes traffic via the lymphatics draining the intestines, pass through mesenteric lymph nodes, and

eventually wind up in the thoracic duct, from where they circulate in the blood throughout the entire body

(Fig. 10.18

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). They reenter the mucosal tissues from the small blood vessels lining the gut wall and other sites of MALT, such as the respiratory or reproductive mucosa, and the lactating breast; these vessels express the

mucosal adressin MAdCAM-1. In this way, an immune response that may be started by foreign antigens 

presented in a limited number of Peyer's patches is disseminated throughout the mucosa of the body. This

pathway of lymphocyte trafficking is distinct from and parallel to that of lymphocytes in the rest of the

peripheral lymphoid system (see Fig. 1.11).

The distinctiveness of the mucosal immune system from the rest of the peripheral lymphoid system is

further underlined by the different lymphocyte repertoires in the different compartments. The T cells of the

gut can be divided into two types. One type bears the conventional  : T-cell receptorsα β in conjunction with

either CD4 or CD8, and participates in conventional T-cell responses to foreign antigens as discussed in

earlier chapters. The second class is made up of T cells with unusual surface phenotypes such as TCR :γ δ 

and CD8 : TCR :α α α β. The receptors of these T cells do not bind to the normal MHC:peptide ligands but

instead bind to a number of different ligands, including MHC class IB molecules. These highly specialized

T cells are abundant in the epithelium of the gut and have a restricted repertoire of T-cell receptor 

specificities. Unlike conventional T cells, many of these cells do not undergo positive and negative

selection in the thymus (see Chapter 7), and express receptors with sequences that have undergone no or

minimal divergence from their germline-encoded sequences. These cells may be classified in phylogenetic

terms as being at the interface between innate and adaptive immunity.

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Figure 10.19

T cells of the mucosal immune system bearing : (more...)γ δ  

Figure 10.19.

T cells of the mucosal immune system bearing : T-cell receptors and an activating NK receptorγ δ  

recognize and kill injured enterocytes 

Infection or other injury to enterocytes, the epithelial cells lining the lumen of the gut, stimulates a stress

response, which causes expression on the cell surface of two atypical MHC class IB molecules, known as

MIC-A and MIC-B. Intraepithelial T cells carrying the NK receptor NKG2D bind MIC-A and MIC-B and

induce apoptosis in the injured enterocytes. The dying enterocyte is removed from the epithelium and the

local tissue injury is repaired.

T cells bearing a : receptor are especially abundant in the gut mucosa compared with other lymphoidγ δ  

tissues. One subset of these :γ δ T cells in humans, which expresses a T-cell receptor that uses the Vδ1 gene

segment, carries an activating C-type lectin NK receptor, NKG2D. This latter receptor binds to two MHC-

like molecules—MIC-A and MIC-B—that are expressed on intestinal epithelial cells in response to cellular

injury and stress. The injured cells may then be recognized and killed by this subset of :  γ δ T cells (Fig.

10.19 ). This illustrates one of the key roles of T cells, which is to patrol and survey the body,

destroying cells that express an abnormal phenotype as a result of stress or infection.

The Vδ1-containing receptor on these T cells may also play a part in allowing them to survey tissues for

injured cells. Some human T cells expressing this receptor bind to CD1c, one of the isotypes of the CD1

family of MHC class I-like molecules that we encountered in Section 10-5. This protein, which shows

increased expression on activated monocytes and dendritic cells, presents endogenous lipid and glycolipid

antigens to some types of T cell. In response to antigen presentation by CD1c, these T cells secrete IFN- ,γ  

which may have an important role in polarizing the response of conventional T cells bearing :α β receptors

toward a TH1 response. This is closely analogous, although opposite in effect, to the polarization toward

TH2 cells induced by secretion of IL-4 by NK 1.1+ T cells responding to CD1d discussed in Section 10-5.

A second group of specialized mucosal T cells, so far only characterized in mice, express : T-cellα β  receptors together with a CD8  : homodimer, instead of the normal α α CD8 :α β heterodimer that

characterizes MHC class I-restricted cytotoxic T cells. These cells can be found in the gut of mice lacking

conventional MHC class I molecules, which shows that their development is not dependent on positive

selection in the thymus by peptides bound to classical MHC class I molecules. They are, however, absent in

mice lacking expression of β2-microglobulin, which is necessary for the expression of MHC class IB

molecules. The ligand recognized by these T cells in mice has been identified as the nonpolymorphic MHC

class IB molecule known as Qa-2. These cells are likely to represent a further class of  T cells that have a

major role in maintaining the integrity of the gut mucosa by recognizing and destroying injured mucosal

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cells.