Immunology | Immune system| Immunity

The mucous membranes lining the digestive,respiratory,and urogenital systems have a combined surface area of about 400 metre per square(nearly the size of a basket ball court)and are the major sites of entry for most pathogens.These vulnerable membrane surfaces are defended by a group of organized lymphoid tissues mentioned earlier and known collectively as mucosa-associated lymphoid tissue (MALT). Structurally,these range from loose,barely organized clusters of lymphoid cells in the lamina propria of intestinal villi to well-organized structures such as the familiar tonsils and appendix,as well as Peyer's patches,which are found within the submucosal layer of the intestinal lining.The functional importance of MALT in the body's defense is attested to by its large population of antibody-producing plasma cells,whose number far exceeds that of plasma cells in the spleen,lymph nodes,and bone marrow combined.

The tonsils are found in three locations:lingual at the base of the tongue;palatine at the sides of the back of the mouth;and pharyngeal(adenoids) in the the roof of the nasopharynx.All three tonsil groups are nodular structures consisting of a meshwork of reticular cells and fibers interspersed with lymphocytes,macrophages,granulocytes and mast cells.The B cells are organized into follicles and germinal centers; the latter are surrounded by regions showing T-cell activity.The tonsils defend against antigens entering through the nasal and oral epithelial routes.
 The best studied of the mucous membranes is the one that lines the gastrointestinal tract.This tissue,like that respiratory and urogenital tracts,has the capacity to endocytose antigen from the lumen.Immune reactions are initiated against pathogens and antibody can be generated and exported to the lumen to combat the invading organisms.The lymphoid cells are found in various regions within this tissue.The outer mucoal epithelial layer contains so-called intraepithelial lymphocytes(IELs).Many of these lymphocytes ate T cells that express unusual receptors,which exhibit limited diversity for antigen.Although this population of T cells is well situated to encounter antigens that encounter through the intestinal mucous epithelium.their actual function remains largely unknown.The lamina propria,which lies under the epithelial layer,contains large numbers of B cells,plasma cells,activated T-Helper cells,and macrophages in loose clusters.Histologic sections have revealed more than 15000 lymphoid follicles within the intestinal lamina propria of a healthy child.The submucosal layer beneath the lamina propria contains Peyer's patches,nodules of 30-40 lymphoid follicles in other sites,those that compose Peyer's patches can develop into secondary follicles with germinal centers.
The epithelial cells of mucous membranes play an important role in promoting the immune response by delivering small samples of foriegn antigen from the lumina of the respiratory,digestive,and urogenital tracts to the underlaying mucosal-associated lymphoid tissue.This antigen transport is carried out by specialized M cells.

Structure of M cells :

Structure of M cells and production of IgA at inductive sites.

         The structure of M cells is striking: These are flattened epithelial cells lacking the microvilli that characterize the rest of the mucous epithelium.In addition,M cells have deep invagination,or pocket,in the basolateral plasma membrane;this pocket is filled with cluster of B cells,T cells,and macrophages.Luminal antigens are endocytosed into vesicles that are transported from the luminal membrane to the underlying pocket membrane .The vesicle then fuse with the pocket membrane,delivering the potentially response-activating antigens to the clusters of lymphocytes contained within the pocket.
         M cells are located in so-called inductive sites-small regions of a mucous membrane that lie over organized lymphoid follicles.Antigens transported across the mucous membrane by M cells can activate B cells within these lymphoid follicles.The activated B cells differentiate into plasma cells,which leave the follicles and secrete the IgA into the lumen,where they can interact with antigens.            
        Mucous membranes are an effective barrier to the entrance of most pathogens,which thereby contributes to nonspecific immunity.One reason for this is that the mucosal epithelial cells are cemented to one another by tight junctions that make it difficult for pathogens,including both bacteria and viruses,have exploited the M cell as an entry route through the mucous-membrane barrier.In some cases,the pathogen is internalized by the M cell and transported into the pocket.In other cases,thus allowing entry of the pathogen.Among the pathogens that use M cells in these ways are several invasive Salmonella species,Vibrio cholerae,and the polio virus.

SPLEEN:
     The spleen plays a major role in mounting immune response to antigens in the blood stream.It is a large,ovoid secondary organ sitauted high in the left abdominal cavity.While lymph nodes are specialized for trapping antigen from local tissues,the spleen specializes in filtering blood and trapping blood-borne antigens;thus ,it can reepond to systemic infections.Unlike the lymph nodes,the spleen is not supplied by lymphatic vessels.Instead,blood-borne antigens and lymphocytes are carried into spleen through the splenic artery.

       The spleen is surrounded by a capsule that extends a number of projections(trabaculae)into the interior to form a compartmentalized structure.The compartments are of two types,the red pulp and white pulp,which are separated by a diffuse marginal zone.The splenic red pulp consists of a network of sinusoids populated by macrophages and numerous red blood cells(erythrocytes)and few lymphocytes;it is the site where old and defective red blood cells are destroyed and removed.Many of the macrophages within the red pulp contain engulfed red blood cells or iron pigments from degraded hemoglobin.The splenic white pulp surrounds the branches of the splenic artery,forming a periarteriolar lymphoid sheath(PALS)populated mainly by T lymphocytes.Primary lymphoid follicles are attached to thePALS.These follicles are rich in B cells and some of them contain germinal centers.The marginal zone,located peripheral to the PALS,is populated by lymphocytes and macrophages.

         Lymph nodes are the sites where immune responses are mounted to antigens in lymph.They are encapsulated bean-shaped structures containing a reticular packed with lymphocytes,macrophages,and dendritic cells.Clustered at junctions of the lymphatic vessels,lymph nodes are the first organized lymphoid structure to encounter antigens that enter the tissue spaces.

Morphologically, node can be divided into three roughly concentric regions:the cortex,the paracortex and the medulla,each of which supports a distinct microenvironment. The outermost layer,the cortex,contains lymphocytes(mostly B cells),macropahges,and follicular dendritic cells arranged in primary follicles.After antigenic challenge,the primary follicles enlarge into secondary follicles ,each containing a germinal center.In children with B-cell deficiencies,the cortex lacks primary follicles and germinal centers.Beneath the cortex is the paracortex,which is populated largely by T lymphocytes and also contains interdigitating dendritic cells thought to have migrated from tissues to the node.These interdigitating dendritic cells express high levels of class II MHC molecules,which are necessary for presenting antigen. Lymph nodes taken from neonatally thymectomized mice have unusually few cells in the paracortical region; the paracortex is therefore sometimes referred to as thymus-independent area in contrast to the cortex,which is a thymus-independent area.The innermost layer of a lymph node,the medulla,is more sparsely populated with lymphoid-lineage cells;of those present,many are plasma cells actively secreting antibody molecules.

FUNCTIONS OF LYMPH NODES :
         This work suggests an explanation for the curious fact that patients receiving a liver transplant sometimes inherit the donor’s allergies and immune repertoire, so in keeping with the idea that donor immune information is being transplanted. It also suggests that the liver as an immune organ is an evolutionary remnant from the time before lymph nodes developed in higher birds and mammals. Cold-blooded vertebrates have functioning T and B cells but no lymph nodes. The main achievement of the development of lymph nodes in mammals is a drastic improvement for the production of better antibodies. T cells on the other hand have not changed their function much during evolution and the work by the Zurich group finally provides solid evidence for the versatility and promiscuity of this cell type.

              In humans and mice,bone marrow is the site of B-cell origin and development.Arising from lymphoid progenitors,immature B cells proliferate and differentiate within the bone marrow, and stromal cells within interact directly with B cells and secrete various cytokines that are required for development.


Bone marrow is not  the site of B-cell development in all species..In birds,a lymphoid organ called the bursa of fabricus,a lymphoid tissue associated with the gut,is the primary site of B-cell maturation,proliferation.In mammals such as primates and rodents,there is no bursa and no single counterpart to it as a primary lymphoid organ.In cattle and sheep,the primary lymphoid tissue hosting the maturation the maturation,proliferation,and diversification of B cells early in gestation is the fetal spleen.


Later in gestation,this function is assumed by a patch of tissue embedded in the wall of the intestine called the ileal Peyer's patch,which contains a large number of B cells.The  rabbit,too,uses gut-associated tissue suchas the appendix as primary lymphoid tissue for important steps in the proliferation and diversification of B cells.

The bone marrow is found within the central cavities of axial and long bones. It consists of hematopoietic tissue islands and adipose cells surrounded by vascular sinuses interspersed within a meshwork of trabecular bone. It accounts for approximately 3% of the body weight in adult rats , ~2% in dogs and ~5% in humans . The bone marrow is the major hematopoietic organ, and a primary lymphoid tissue, responsible for the production of erythrocytes, granulocytes, monocytes, lymphocytes and platelets.

           A number of morphologically and functionally diverse organs and tissues have various functions in the develpoment of immune responses.These can be distinguished by functions as the primary and secondary lymphoid organs.The thymus and bone marrow are the primary(or central) lymphoid organs,where maturation of lymphocytes takes place.The lymph nodes,spleen,and various mucosal-associated lymphoid tissue(MALT) such as gut-associated lymphoid tissue(GALT) are the secondary (or peripheral)lymphoid organs,which trap antigen and provide sites for mature lymphocytes to interact with that antigen.In addition,tertiary lymphoid tissues,which normally contain fewer lymphoid cells than secondary lymphoid organs,can import lymphoid cells during inflammatory response.Most prominent of these are cutaneous-associated lymphoid tissues.Once mature lymphocytes have been generated in the primary lymphoid organs,they circulate in the blood and lymphatic system,a network of vessels that collect fluid that has escaped into the tissues from capillaries of the circulatory system and ultimately return it to blood.

1. c.f I- Fibrinogen
2. c.f  II- Prothrombin
3. c.f III - Tissue factor /Thromboplastin
4. c.f - IV - Calcium ions 
5. c.f V - Proaccelerin (labile factor)
6. c.f VII - Serum Prothrombinconversion accelarator.
7. c.f VIII - Anti haemophilic factor (AHF)
8. c.f  IX- Christmas factor,plasma thromboplastin component (PTC) stuart factor, Thrombokinase
9. c.f XI - Plasma Thromboplastin antecedent (PTA)
10. c.f  XII -Hageman factor,contact factor
11. c.f  XII - Fibrin stabilizing factor,Fibrinase.

NOTE: There is no factor VI. Prothrobinase is a combination of activated factors V and X .

         The intrinsic pathway of blood clotting is more complex than extrinsic and it occurs more slowly. It is so named because its activators are in direct contact with blood.In other words,the activators are in direct contact with blood.In other words the activators are within or intrinsic to blood.If the endothelial cells become damaged,blood can come in contact with the exposed collagen.In addition the trauma to the endothelial cells causes damage to the blood platelets resulting in the release of phospholipids by the platelets contact with collagen activates c.f  XII.Activated c.f XII further activates c.f.XII Activation of c.f XI in presence of co-factor Calcium ions activates c.f IX.activation of c.f IX under the influence of co-factor Calcium ions,c.f VIII and phospholipids of platelets will activate c.f X. Activation of c.f X in combination with c.f V again under the influence of co-factor Calcium results in formation of Prothombinase.This takes several minutes.As a result completion of stage I in intrinsic pathway is of longer duration as compared to that in Extrinsic pathway.
Stage 2 and stage 3 are similar as described for Extrinsic pathway.
The last step involved which is common to both the pathways is conversion of loose fibrin threads into more stabilizing and strengthened fibrin threads is done by activated c.f XIII. C.f. XIII is activated by thrombin,then at the end the clot becomes sturdy whereby blood corpuscles have been trapped in the meshwork of stabilized fibrin in threads and what oozes out is watery straw coloured fluid serum which is plasma protein and other coagulation factor.

CLOT RETRACTION:
Once a clot is formed it plugs the ruptured area of blood vessel and prevents bleeding hemorrhage. Clot retraction or syneresis is consolidation or tightening of the fibrin clot. The fibrin threads attached to the damaged surface of blood vessel gradually contract.As the clot retracts it pulls the edges of damaged blood vessels closer and thus the risk of hemorrhage is further decreased and during this retraction some serum escapes betweeen the fibrin threads.
At times clotting mechanism starts at site which may spread beyond the area of damaged blood vessels.This is because thrombin has 2 positive feedback effects,whereby it may directly activate c.f V or result in release of phospholipids from the activated platelets from activated platelets.The combined effect of these resulting in synthesis of prothrombinase which in turn accelarates more and more synthesis of thrombin.If this remains unchecked a clot would continue to get larger and larger.Normally,however fibrin has the ability to inactivate much of the thrombin formed and this helps to stop the spread of thrombin into blood :Thus limiting the spread of the blood clot beyond the site of damage.