The immune system

Function
Protect organism against biomacromolecules that enters body and disturbs the inner environment o Maintain homeostasis There is a specific and non-specific function:

Non-specific function
Called the natural immunity Established from genetic information not in contact with antigen o Rapid protection against new foreign substances Encounter defense in first meeting with specific antigen Components o Soluble factors (humoral immunity) Lysozym Complement Interferon o Cellular immunity Phagocytes Natural killers (NK-cells) o Non-immunological mechanisms Barriers (skin, mucosa) Acidic environment Enzymes Activity of ciliary epithelium

Specific immunity
Acquired immunity Established after encountering antigen Takes several days for specific immune response o Protects only against antigen that has evoked this reaction Primary immune response After elimination of antigen, immunocompetent cells carrying reseptors capable of binding same antigen can survive for many years in organism. o Enables rapid development of immune response during a repeated invasion of antigen. Components o Specific humoral immunity (soluble) Antibodies o Specific cellular immunity Lymphocytes

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Cells of the immune system

Cells of the non-specific immunity
Professional phagocytes o Macrophages cells of mononuclear phagocyte sustem o Microphages Neutrophils see lymphocytes

Function
Migration o Migrate toward highest consentration of chemotaxins a specific chemical just like the egg attract a sperm o Abilities required: Adhesion Diapedisis (passage through intact capillary walls) Transfer across extracellular structures (BL, etc) Chemotaxis (migration toward high consentration of chemotaxins) Phagocytosis o Adhesion to surface or particle Enhanced via opsonins (target for anti-immune response). Bound to a microorganism mediated through Fc-reseptors and reseptors on phagocytose plasmalemma o Ingestion Pseudopodia grasps a particle membrane of pseudopodia fuse and particle occurs inside a cytoplasmic vacuole (phagosome) o Fusion of phagosome with lysosomes forms the heterophagolysosome o Killing of phagocytosed microorganisms (pH, enzymes, etc.) Production of humoral factors o Components of complement, interferons and cytokines Presentation of antigen to immunocompetent cells o Macrophages process an antigen partially digest foreign particles and incorporate their antigen into plasmalemma Antigen is then presented to T-lymphocytes Class II MHC antigen; must be present in order to present antigen o Antigen presenting cells (APCs) Some APCs are non-phagocytosing and bind foreign particles directly to its surface Langerhans cells of skin B-lymphocytes Can do this because surface is highly irregular dendritic cells (elongated dendrites) Also express reseptors for lymphokines o Lymphokines proliferation of macrophages and co-ordinate lymphocytes with other immune cells during immune reaction o Defect in phagocytosis: Decreased protection => more frequent infection diseases

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Mononuclear phagocyte system Cells Monocytes Wandering macrophages Histocytes Alveolar Macrophages Pleural & perifoneal Macr. Fixed macrophages Kupfer cells Chondro/osteoclasts Microglia Synovial macrophages Fixed tissue macrophages

Location Bone marrow Connective tissue (CT) Lung Sereous cavities Liver Cartilage / bone CNS Joints Spleen, lymph nodes, bone marrow etc.

NK-cells natural killers

Set of different lymphoid cells with granular cytoplasm Bind target all via reseptor Released cytolysin lyzes target cell membrane o Antibody is responsible for recognition of a target ADCC and their Fcreseptor can be bound to cell Typical ADCC-cells: NK-cells, macrophages, neutrophils and mastcells (eosinophils)

Cells of the specific immunity

Mature lymphocytes o Carry membrane reseptor for specific antigen = Immunocompetent cells o Its ability to bind antigen corresponds to shape of reseptor and if it fits the spatial shape of antigen One lymphocyte carry only one type of antigen reseptor o Specific resetors are produces without previous contact with antigen Antigen o Macromolecular biological compound (usually protein, polysaccharide, nucleic acid etc.) Gets recognized by the immune system as a foreign particle Immune reaction is evoked o Can contain more than one epiptope Epiptope: The characteristic arrangments of atoms on antigen surface where immune response is directed o And immune response is only to antigen that evoked response!! Blastic transformation o Activation of an immunocompotent cell after binding of an antigen Blastic transformation of lymphocytes Proliferation and increased number of lymphocytes of the same specifity = Clonal expansion Lymphocytes o Agranular leukocytes It is possible to distinguish two types of lymphocytes according to the surface CD molecules (clusters of differentiation)

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T-lymphocytes
Undergo development in thymus and nest in secondary lymphatic organs Mediate specific cellular immunity specifity of a reaction is mediated by membrane reseptor According to surface marker they are divided into 4 subsets: o T helper cells (TH-cells) o Supressor lymphocytes (Ts-cells) o Cytotoxic lymphocytes (Tc-cells) o Memory T-lymphocytes Initiate most immunological reactions o After activation with an antigen presenting cells (present antigen with calss II MHC molecules) Th- lymphocytes secrete mediators called interleukins which activate other cells of immune system Blymphocytes, cytotoxic T-cells and macrophages) Essential for differentiation of B-lymphocytes to plasma cells (which is cells that remembers diseases) o Interleukins (IL) helps in this process Repetetive division of T-helper cells are also stimulated leads to rapid divition of lymphocytes of same specifity

Helper T-cells (Th)

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Cytotoxic T-cells (Tc)

Able to find specifically a target and kill virus-infected and some cancer cells. Requires interaction with helper-T-cells to be activated Can use at least two different ways to kill unwanted cells: o Perforin + granzyme B Perforine perforates membranes of target cells Granzymes enter cytoplasm via holes made by perforins Activate intercellular reactions leading to degradiation of DNA and apoptosis (programmed cell death) o FasL (Fas ligand on membrane of Tc-lymphocytes) Initiates apoptosis of target cell after binding its Fas reseptor Requires close interaction Ask Dr. Mraz: Do we need to know differences in intracellular and extracellular defence /immune response and which cells is in which defence? -

Suppressor lymphocytes (Ts)

Switch off response when antigen is removed May suppress immune responsiveness to self-antigens Developed from activated T-cells to provide a rapid reaction force for a potentially later attack with same antigen Long living, carrying TcR Leads to a rapid clonal expansion of lymphocytes of same specifity after activation

T-memory cells

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B-lymphocytes
Derive from precursors (forerunners) in the bone marrow and also mature there. o Can also mature in lymphoid tissue as of ileum, appendix and tonsils. Specificity of B-lymphocytes is mediated by membrane reseptor BcR They can mature into: o Plasma cells o B-memory cells Mitotic divided B-lymphocyte Mediate specific humoral immunity Secrete antibodies into body fluids o Same specificity for reaction because the antigen-binding sites for antibody have same specifity for antigen as BcR reseptor expressed on plasmalema of B-lymphocyte. Produce immunoglobulin the humoral immunity Mitotic divided lymphocyte, small percentage of total B-lymphocytes. Nest usually in mucousal surfaces, where they wait for invading antigens (exogenousantigen) o After binding antigen it presents it for a T-lymphocyte This interaction induces a secondary immune response leading to rapid expansion of a clone of the required specifity.

Plasma cells
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B memory cells

Antibodies
High molecular glycoproteins (immunoglobulins) Circulate in the blood Divided into 5 classes: o IgG: 75%, in serum (two reseptors: Y) o IgA: Protection of mucosa (in tears, saliva) o IgM: 10%, (has 5 reseptors like a star highly reactive) But when it first has hit something it becomes IgG (two reseptors) which remembers. o IgE: Allergic reactions, parasite infections Bound to receptors in plasmalemma of mastocytes and basophils o IgD: Not important, please forget this as soon as possible

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Graft rejection
When cells of an organ is dissimilar of the cells that is yours (say you have triangles on your cells and the organ has pentagons) and the organ will be rejected because it is not histocompatible = histoincompatible o The triangles / pentagons are just for the image, in real world they are called either: HLA = Human leukocyte antigen MHC = Major Histocompatibily complex Which is basically two words for the same thing So what happens? o Tcell with surface CD molecules interact with HLA o All T-cells must before released into blood stream be checked by thymus that they can recognize what is foreign cells and what is body-cells. This is done by learning them to recognize host MHC! If they react to self-antigens => Apoptosis happens. If not (and they still attack sef-antigens): o You get a autoimmune disease where your own Tcells attack your body. This is basically what happens in transplantation too Lymphatic vessels o Bring graftderived cells and cellular debris to regional lymph nodes where they initiate immune response When activated lymphocytes enter blood and bring them to graft endothelial cells get damaged, blood vessels destroyed and when graft loose nourishment it undergo necrosis (cell death) GVH reaction (graft versus host) o Can happen if transplanted tissue contains immunocompetend lymphocytes from donor and recognize recipients tissue as foregin. Attack on recipients tissue is the result.

How to escape graft rejection?

Transplant autografts or isografts (genetically identical) that are histocompatible o In some cases they just have to look very much alike Suppress immune response directed against the graft (e.g. immunosuppression)

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Lymphatic system
Divides into o Lymphatic vessels Capillaries Small/medium lymph veins Large lymph veins o Lymphoepithelial tissue With accumulated Ly in close association with epithelial cells Thymus Peyers patches Appendix Tonsils o Lymphoreticular tissue Type of reticular CT with a lot of Ly Lymph nodes Spleen Diffuese infiltration with Ly: o Peyers patches o Appendix o Tonsils Located around the body to make a defence Also remember this according to location: o MALT: Mucosa-associated lymphatic tissue o GALT: GIT-ass. Ly. T BALT: Bronchus-ass. Ly. T

Lymphatic vessels
Formed by endothelial cells Short nexus and maculae occludens (membrane-to-membrane) o Creates interendothelial openings with great permeability Consist of three layers: o Tunica intima: Endothelial cells over BL. Cushions of smooth muscle bulge into lumen => Endothelium forms valves that prevent lymph fluid from flowing back o Tunica media: Smooth muscle cells o Tunica externa: LCT. Collection vessels contract rhythmically toward lymphatic ducts.

Parenchymal organs
All glands, liver, lymphatic organs, kidney, spleen, ovary, testis, brain etc.

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Parenchyma
Consist of all elements in body that makes up a specific morphological and functional part of an organ o Epithelial tissue o Lymphatic (blood) tissue Secretory units and ducts, blood cells, wandering cells of CT, epithelial reticular cells of thymus

Stroma
Supporting tissue of organ Formed by: o DCT Capsule and septa or trabeculae o LCT Interstitial, e.g. areolar CT

Thymus
Primary lymphoid organ o Immature T-lymphocytes mature in thymus and become immunocompetent cells. Undergo immunological surveillance. Parenchyma o Lymphoepithelial tissue Reticular epithelium Lymphatic cells (thymocytes) Morphology o Cortex Darker part o Medulla central zone lighter (with germinal center) Contain o Reticular cells (epithelium) Large, stellate-shaped and light nuclei (1 or 2) Cover vessels (outside) Create a microenviroment to help T-cells stay and develop in cortex Connected by desmosomes o Macrophages In cortex and medulla Responsible for capture and eat unwelcomed guests (dont mix this up with Gavinizing) o Lymphocytes Also in cortex and medulla Stains denser in cortex Development of T-lymphocytes o Precursor cells are produced by bone marrow released in blood stream and carried to thymus cortex where they nest. o Immature T-lymphocytes proliferate (increase in numbers) and mature. Also get reseptors that differ in specifity without presence of exogenous antigen

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o Some of T-lymphocytes made can by random fashion exhibit reactivity against self antigens therefore they have to go through two selection procedures before they can leave thymus: Positive selection: Enables further development of thymocytes. Give them receptors that bind self MHC molecules (tolerance of self antigen) Lymphocytes that does not meet these requirement which means they can not receive MHC molecules will be executed, eliminated by apoptosis, gavinized etc Negative selection Here will the thymocytes specifity be tested. This means basically that if they cant distinguish between a self antigen and a exogenous antigen they will undergo apoptosis and their remains will be eaten by macrophages. o Fun fact: More than 95% of T-lymphocytes is eliminated by apoptosis! So what happens with to ones making it? They get to enter the blood stream via the corticomedullary zone. There is not formed any lymph nodes in thymus because the emigration of T-lymphocytes are continuous. Settle in thymus-dependent areas, like lymph nodes, Peyers patches, etc. How does it look?

Cortex = Dark (Dense accumulation of small T-lymphocytes) Medulla = Pale (Contain less lymphocytes, but medium and large size) Assi Benassi

Hassals corpsules = Eosinophilic structures (only in thymic medulla) made by keratinized epithelial cells => Concentrically arranged flattened cells of reticular epithelium connected by desmosomes.

White area: Corticomedullary zone

Thymic parenchyma consist of lobules o = Cortex + medulla Septa enter cortex but not the medulla. o Portions of parenchyma divided by such septa are not true lobules but pseudolobules.

Thymus in childhood
Same size as heart Biggest size in puberty (30-40g) and then undergo involution Morphology o Well apparent pseudolobules o Easily recognize cortex from medulla Boundary = corticomedullary zone o Sporadic Hassals corpsules.

Thymus in involution
After puberty Parenchyma is gradually replaced by adipose tissue o Creates isolated islands of functional parenchyma (still functioning) No boundary between medulla and cortex Septa thicken Large and numerous Hassals corpsules spread over whole parenchyma and central cells undergo hyaline degeneration

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Lymph nodes
Cells: o B and T lymphocytes o Macrophages o Reticular cells Recicular cells o With reticular fibers form a delicate network of capsule and trabeculae house macrophages and lymphocytes Lymphocytes o Outer cortex: B-lymphocytes o Germinal center: Mature B-lymphocytes = Plasma cell o Paracortex: Between nodules = deep part of cortex: T-lymphocytes Macrophages o Scattered around everywhere.

About the lymph nodes - Smallest secondary lymphatic organ specialized for filtration of lymph - Drain via afferent lymphatic vessels toward sinuses: o Subcapsular sinus Located between the capsule and cortex

Capsule (DCT) Reticular fibers (reticular CT cells) = Supporting framework of lymph node Litoral cells = flattened reticular cells. Devoid of Bl, discontinuous o Paratrabecular sinus Run alongside the trabeculi while passing through cortex o Medullary sinuses Found in medulla Walls lined by litoral cells (derived from reticular CT cells) Consist of: o Macrophages o Lymphocytes o Plasma cells During filtration trough these sinuses all the antigens are removed and lymph continues to flow in efferent lymphatic vessels

Parenchyma of a lymph node - Formed by lymphatic tissue - consist of 5 parts: o Outer cortex o Paracortex o Medulla Assi Benassi

o Stroma Outer cortex o Dark, contains many lymphatic nodules (Primary and secondary) ADD TO SLIDE TEST o B-dependent area Inner cortex (paracortex) o Densely spread lymphocytes o T-dependent area o High endothelial venules circular and cuboidal epithelium route for lymphocytes o T-lymphocytes stay B-lymphocytes migrate to outer cortex

Medulla o Located centrally pale because of numerous medullary sinuses separated by darker cords of lymphatic tissue o Medullary cords: Irregular branched strands of lymphatic tissue Reticular CT, lymphocytes and plasma cells and macrophages o B-cells mature into plasma cells here!! MS = Medullary sinus, MC = medullary cord Note: Major APCs of lymphatic follicles in medullary cord

Stroma o Consist of capsule and trabeculae (DCT) o Underlaying framework is of reticular connective tissue

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Germinal center (GC) Light region. Loosely arranged lymphoblasts, differentiating B-lymphocytes and plasma cells Mantle zone (MZ) Cap of half-moon shape- peripherally dense long-lived B-lymphocytes or memory Bcells (darkly stained)

Spleen
Function o Removal of aged blood elements (filtering) o Trapping exogenous antigens from blood (filtering) o Immune response to blood-borne antigens o Reservoir of the blood o Prenatal hemopoiesis (before birth) Stroma o Capsule DCT + smooth muscle o Trabecules (DCT) Extend into interior of spleen perpendicular to capsule branch and unite. Arteries and veins run through them. o Reticular CT framework o Outer aspect lined by peritoneum (mesothelium and submesothelial LCT) Splenic parenchyma (splenic pulp) o Consist of two parts:

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Red pulp because it contains blood Venous sinusoids o Special capillaries with rod-like fenestrated (with openings) endothelial cells. o Lack BM Billroths cords o Separates sunuses reticular CT, Macrophages, lymphocytes, plasma cells, blood elements White pulp because it contains lymphatic tissue B-dependent o Largest accumulation of lymphatic tissue give rise to lymphoid nodules = Malphighian corpsules T-dependent o Lymphoid tissue consentrated around central artery forms periarterial lymphatic sheats (PALS) Lymphoid artery usually placed inside

Tonsils
Local accumulations of lymphatic tissue near entry to respiratory and digestive passages Form tubular crypts

Palatine tonsils (mandlene)

Stratified squamous nonkeratinized epithelium o Enters inside deep branced crypts Lined with same type of epithelium but usually infiltrated by lymphocytes = reticulated epithelium o Bacteria tends to accumulate in crypts and this may be the reason why the palatine tonsils are more often subject to chronic infection Lymphoid tissue with nodules o Single layer under covering epithelium, primary and secondary (IgA, IgM) Skeletal muscle tissue o Found as underlying structure o Also rare sero-mucous glands

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Lingual tonsil
Single mass of lymphatic tissue Situated on dorsal median surface of posterior third of the tounge. Stratified squamous nonkeratinized epithelium Crypts: reticulated ep. Lymphoid tissue: In nodules mostly around crypts Not surrounded by a capsule (DCT) Underlying o Mucous glands of Weber empty in crypts o Skeletal muscle of the tounge

Nasopharyngeal tonsil
Single mass of lymphatic tissue Constitutes the adenoids Pseudostratified ciliated columnar epithelium !! (NO CRYPTS) Diffuse lymphoid tissue Thn capsule Sero-mucous glands Dence connective tissue

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