Lymphoid organs

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  • Transforming growth factor
  • FOXP3 (forkhead box P3) also known as scurfin is a protein involved in immune system responses. A member of the FOX protein family, FOXP3 appears to function as a master regulator (transcription factor) in the development and function of regulatory T cells.

Transcript

  • 1. Dr.Bharti Bais Professor Organs and cells of immune system
  • 2. There are over 400 known pathogens of man and each of us is likely to come into contact with at least 150 of them within our life span HOST IMMUNE SYSTEM Viruses (10-20 nm) Bacteria (1-2 um) Protozoa (50-100um) Fungi (10um-10cm) Parasites (Worms & Flukes) (>10cm) Include:
  • 3. Replication rate of extracellular bacteria with an average doubling time of 20 minutes Why Do We Need An Innate Immune System? Dead within 24hrs !!! = 2 x 1021
  • 4. Immune system  Latin term immunis, meaning “exempt”- free from burden  It is part of lymphoreticular system  In vertebrates immune system have integration of complex cellular interaction  Leads to differentiation of cells and antigen handling  Immune system consist of lymphoid organs and tissues present through out body and interconnected by blood and lymph  It comprised of lymphocytes, macrophages, epithelial cells and stromal cells
  • 5. Immune system • Functions-Defends against invading pathogens • Protects against disease as inactivates/destroys foreign substances - viruses, bacteria, parasites and other cells (virus--infected cells, cancer cells, cells of transplanted organs) • Provide immunocompetant cells and trap antigen, recognize them and generate immune response • Has the ability to distinguish self from non self • Removes “worn-out” cells, & identifies and destroys abnormal or mutant cell • Inappropriate immune responses lead to allergies or autoimmune responses.
  • 6. Lymphoid organs  Central (primary)  Foetal liver & Post-natal bone marrow( equivalent to Bursa of fabricius)  Thymus  Peripheral (secondary)  Organized & Unorganized  Organized or encapsulated  Spleen  Lymph nodes  Unorganized  Mucosa associated and cutaneous associated lymphoid tissue
  • 7. Cells of immune system  Lymphocytes • T-lymphocytes • B-lymphocytes • Natural killer (NK ) cells  Non lymphocytes • Monocytes/macrophages • Neutrophils • Eosinophil • Basophils • Mast cells • Platelets
  • 8. ORGANS OF IMMUNE SYSTEM Thymus Bone marrow
  • 9.  Pluripotent or multipotent Hematopoietic stem cell (HSC) originate in yolk sac in first week  In 3rd month of gestation HSC migrate to fetal liver  Just before or after birth remains in bone marrow and gives rise to progenitor cell that can grow to many lineage  Develops in microenvironment of sessile stromal cells -fat cells, endothelial cells, fibroblasts, and macrophages  Under influence of many soluble substances as SCF,TGFβ into granulocyte, monocyte, erythrocyte, lymphocyte and platelets Lymphoid organs
  • 10. Primary lymphoid organs  They are the major site of lymphopoisis  They provide microenvironment under which uncommitted lymphoid progenitor cell proliferate and mature into a functional cell  There they can acquire or leave specific receptors for antigen to cope antigenic challenge and to learn between self and non self
  • 11. Primary lymphoid organs Bursa of fabricius Lymphoepithelial organ arising from dorsal part of cloaca in birds  Site of lymphocytic proliferation & differentiation  Lymphocytes maturing here called ‘Bursal’ or ‘B’ Lymphocytes  In humans, Fetal Liver and post natally- Bone Marrow act as bursa equivalents
  • 12. Primary lymphoid organs Bone marrow  Multipotent hematopoietic stem cells generate all the cells of immune system after birth (Lymphocytes and Non- Lymphocytes)  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
  • 13. Bone marrow  The production of blood cells in bone marrow begins roughly 4-5 months after conception.  Stem cells immigrate from the liver into the bone marrow.  Bone marrow stroma consists of a fibre framework and reticular cells, endothelial cells, fat cells, osteoblasts and fibrocytes.  The stroma have the role of supporting the hematopoietic part of the marrow, as well as the production of different growth and development factors for the activation of the stem cells produced in the hematopoietic part
  • 14. Bone marrow  This creates an "microenvironment" that, according to need, stimulates the proliferation and differentiation of the precursor cells  The hematopoietic area, in the parenchyma of the bone marrow, is formed by cell colonies or nests located in the reticular fiber net.  The stem cells are called "Colony Forming Units".  These cells will give rise to different cellular lines, forming the main hematopoietic organ.  Here, among others, mature the B lymphocytes.  As soon as these cells are mature they proceed through the openings in the sinusoids from the bone marrow into the blood stream
  • 15. Bone marrow
  • 16. Hematopoiesis  HSC (Hematopoietic Stem Cell)  HSC -Differentiates to lymphoid progenitor cell or myeloid stem cell  Growth factors and cytokines determine path  Once LPC or MSC, Committed  Hematopoietic Growth Factors  Colony Stimulating Factors  4 types  Multi-CSF (IL-3)  M-CSF (Macrophage CSF)  G-CSF (Granulocyte CSF)  GM-CSF (Granulocyte Monocyte CSF)  EPO (erythropoietin)  Induces production of RBCs
  • 17. Primary lymphoid organs Bone marrow Stromal cells within the bone marrow interact directly with the B cells and secrete various cytokines that are required for development  It act as a secondary lymphoid organ also
  • 18. Bone marrow
  • 19. Bone marrow
  • 20. Bone marrow
  • 21. Thymus  Develops from 3rd and 4th pharyngeal pouches in 6th week of gestation as two endodermal buds  First organ to become predominantly lymphoid  8th week of gestation precursors of lymphocytes start reaching thymus for further development  Lymphocytes maturing here called ‘Thymic’ or ‘T’ Lymphocytes
  • 22. Thymus…  In mammals bilobed organ  Behind upper part of sternum  Overlies heart and major blood vessels  Size just before birth 12-15gms  Reaches maximum at puberty 30-40 gms  Involute after puberty  At 60 years of age 10-15 gms  Involution in response to the production of sex hormones at the onset of puberty.  Sensitive to corticosteroid level atrophy begins in cortex
  • 23. Thymus
  • 24. Structure of thymus
  • 25. Structure of thymus  Each lobe is surrounded by a capsule and divided into lobules which are seperated from each other via connective tissue called trabeculae  Each lobe is organized into 2 compartments  The outer component is the cortex (packed with immature T cells)  The inner component is the medulla (sparsely populated with more mature thymocytes)  Criss-crossing the entire organ is a stromal network of epithelial cells, dendritic cells and macrophages
  • 26. Thymus… STRUCTURE: With in each lobule:  Outer cortex  Highly packed with dividing immature thymocytes very little space in between developing cells  Many epithelial cells are there provide microenvironment for T cell differentiation  Specialized large epithelial cells in outer cortex known as nurse cells  Have long epithelial strands forming pockets holding many developing lymphocytes
  • 27. Thymus…
  • 28.  Other cells are cortical epithelial cells have branched dendritic processes rich in class II MHC present in deep cortex  Forming a network through which every cortical lymphocyte must pass in their way to medulla  The only blood vessels in the cortex are capillaries  At the periphery of the cortex, subjacent to the capsule, and around all blood vessels, the processes of cells form a continuous cellular layer constituting the blood-thymus barrier Thymus…
  • 29. Thymus…  Blood vessels are impermeable to plasma protein to come in contact with developing thymocytes  The barrier prevents exposure of the immature lymphocytes to blood borne antigens  At junction macrophages present through which the lymphocytes are to be passed to medulla
  • 30. Thymus…  Medulla  Contains mature cells are small and loosely arranged  Blood vessels are highly permeable  Medullary epithelial cells present have broader epithelial processes and rich in MHC class I and II  Interdigitating cells also present which are bone marrow derived antigen presenting cells  Thymocytes with appropriately rearranged T-cell receptor genes escape to the capillaries at the boundary with the medulla and contribute to the circulating pool of T-cells.
  • 31. Thymus…  At corticomedullary junction, post capillary venules are found, which represent specialized sites of transit of matured lymphocytes into the blood  The post capillary venules are devoid of a muscular tunic, and have specialized cuboidal endothelial lining cells  High endothelial venules T- Cell progenitors enter thymus and mature T- Cells leave thymus  Hassall’s Corpuscles- They are named for Arthur Hill Hassall, who discovered them in 1849. (1817-1894, an English physician) seen in medulla are rounded eosinophilic structures, which consist of concentrically arranged, flattened cells.
  • 32. Thymus…  Thymic corpuscles are likely to be formed by eosinophilic type VI epithelial reticular cells arranged concentrically  Hassall's corpuscles vary in size with diameters from 20 to more than 100μm, and tend to grow larger with age  Human Hassall's corpuscles express thymic stromal lymphopoietin (TSLP) which activates thymic CD11c+ dendritic cells to express high levels of CD80 and CD86.  These dendritic cells are then able to induce the proliferation and differentiation of CD4+ CD8- CD25- thymic T cells into CD4(+)CD25(+)FOXP3(+) regulatory T cells.
  • 33. STRUCTURE OF THYMUS LOBULE Thymus…
  • 34. THYMUS…
  • 35. Lymphostromal interactions in thymic development and function
  • 36. Organs of immune system  Peripheral (Secondary):  Lymphocytes accumulate after acquiring immunocompetence  Exert their effector functions  Organs included:  Bone marrow  Spleen  Lymph Nodes  Mucosa and Cutaneous Associated Lymphoid Tissue ( CALT & MALT)
  • 37. Spleen  Upper left quadrant of abdomen  Size-13×8 cm  180- 250 gm  Largest of the lymphoid organs  Primarily an organ to respond to blood borne pathogens  Fibrous capsule, giving off short trabeculae  Main types of tissues:  White pulp  Red pulp
  • 38. Spleen Red pulp:Red pulp contains RBCs, splenic cords and splenic sinuses lined by endothelial cells Containing large numbers of macrophages, and is actively involved in the removal of dying and dead erythrocytes, as well as in the removal of infectious agents. Splenic cords (cords of Billroth) are a network of reticular fibres.. Cellular cords contains macrophages, erythrocytes, platelets, granulocytes, lymphocytes and plasma Cells
  • 39.  The white pulp contains the lymphoid tissue, arranged around a central arteriole as a periarteriolar lymphoid sheath (PALS).  PALS composed of a Germinal Centre surrounded by a Mantle (B cells) and Marginal Zones(B and T cells). follicles containing germinal centres.  The germinal centres are where B cells are stimulated to become plasma cells which produce and secrete antibodies. Spleen
  • 40. Spleen…  Marginal zone: Surrounds the white pulp  Two major features:  Vascular organization:  Blood vessels form a system of communicating sinuses  Receive blood from central arteriole  Most of the blood goes to red pulp cords and then to venous sinuses  Small portion passes directly into venous sinuses (forms a closed system)  Resident cells:  APC: Macrophages, Dendritic Cells  B Cells and B-1 Cells, respond strongly to thymus independent antigens (Capsular polysaccharides of bacteria)
  • 41. Structure of spleen
  • 42. Spleen…  Functions:  Responsive to blood borne antigens:  Central arterioles surrounded by PALS end with arterial capillaries which open in red pulp cords- traps the circulating cells  Phagocytosed by macrophages  Serves as a graveyard for effete blood cells:  Aged platelets and erythrocytes are destroyed  Serves as a reservoir for blood cells  Undestroyed blood cells reach circulation by squeezing through endothelial walls
  • 43. Spleen
  • 44. Germinative Center Central artery Lymphoid Nodule
  • 45. Lymph nodes  Placed along the course of lymphatic vessels  Usually at branching sites  Superficial/Subcutaneous  Visceral/Deep  Placed in areas that drain various superficial and deep regions of the body:  Neck  Axillae  Groin  Mediastinum  Form a network that drains and filters interstitial fluid from tissue spaces- reaches Thoracic Duct- eventually into left Sub Clavian Vein
  • 46. THE LYMPHATIC SYSTEM
  • 47. Lymph nodes…  2-10 mm in diameter  Round/Kidney shaped  Hilus: Indentation for blood vessels  Collagenous capsule gives off trabeculae  Cellular components:  Cortex  Para cortex  Medulla
  • 48. Lymph nodes…  Subcapsular sinus located beneath the capsule..  Outer cortex comprised of diffuse lymphoid tissue have macrophages, T-lymphocytes, plasma cells, and reticular cells  Lymphoid nodules (primary follicles) composed of B- lymphocytes  Germinal centers composed of activated B, T, and macrophages  The inner (or deep) cortex (paracortex) is a continuation of the outer cortex. contains diffusely arranged T-lymphocytes lymphoid nodules are not normally present.
  • 49. Lymph nodes Cortex: B- Cell area  Aggregates present in the form of lymphoid follicles:  Primary:- Virgin B- Cells  Secondary:  Stimulated follicles  Germinal centre  Mantle  Activated B- Cells  Also contain Follicular Dendritic Cells (FDC), Macrophages and few T- Cells  B- Cells also found in sub capsular region: Similar to those seen in marginal zone of spleen (B Cells and B-1 Cells, respond strongly to thymus independent antigens )
  • 50. Lymphoid follicle
  • 51. Lymph nodes Paracortex:  T- Cell area  Contains many APC: Inter digitating cells migrating from skin/mucosa to transport processed antigens to the lymph node  HEVs: allow trafficking of lymph in the node
  • 52. High High endothelial venules Constitutively present in secondary lymphoid tissue Need to allow egress of naive cells from the circulation to lymphoid tissue
  • 53. Lymph nodes
  • 54. Lymph nodes…  Medulla:  Organized into cords separated by medullary sinuses  Sinuses drain in terminal sinus- to the efferent lymphatic vessel  Phagocytic cells : Capture antigens present in the lymph and transport to lymphoid tissue of the node  Lymph empties into the medullary sinuses via the cortical or Para trabecular sinuses
  • 55. Lymph nodes…  Functions:  Act as filter for lymph, each group draining specific body part  Phagocytosis of foreign antigens occurs  Sites of proliferation and circulation of lymphocytes
  • 56. Structure of lymph node
  • 57. Structure of lymph node
  • 58. MALT  Unencapsulated lymphoid aggregates  Sites of first encounter of immune cells with antigens entering via mucosal surfaces  More than 50% of body’s lymphoid tissue  Occur either as aggregates or as scattered follicles  The mucosal surfaces of the gastrointestinal and respiratory tracts
  • 59. MALT… Present in:  Intestinal tract (GALT)  Respiratory tract (BALT)  Genito-urinary tract • Tonsils (Waldeyer’s Ring) • Protects against exposure to foreign antigens that enter the respiratory or GI tract  Lymphoid cells stimulated in MALT reach blood via regional lymph nodes and then to the effector mucosal site  Response is predominantly of Activated T-Cells and Plasma Cells secreting IgA antibodies  Antigen exposure at one site may cause response at other MALT sites also
  • 60. MALT…  Follicle associated epithelium is specialized to transport pathogens  Lymphoid cells stimulated in MALT reach blood via regional lymph nodes and then to the effector mucosal site  Response is predominantly of Activated T-Cells and Plasma Cells secreting IgA antibodies  Function: Protection of mucosal surfaces  Antigen exposure at one site may cause response at other MALT sites also
  • 61. MALT
  • 62. Tonsils / Adenoids  They in effect act as lymph nodes capturing microbes and processing them.  Lymphoid follicles largely B cells  Larger in childhood & diminish with age
  • 63. Tonsils / Adenoids  Palantine Tonsils • Stratified squamous non keratinized epithelium • Tonsilar crypts, germinal centers • Dense irregular capsule, septa present  Lingual Tonsils • Stratified squamous non keratinized epithelium • Lymphatic nodules with germinal centers • Thin, ill-defined capsule Seromucous glands open into crypt base  Pharyngeal Tonsils (adenoids) • Pseudostratified ciliated columnar epithelium • Thin capsule, germinal centers, lack true crypts • Seromucous glands, ducts present
  • 64. Other Lymphoid organs  Peyers patches (B&T cells) • Located in ileum • Each “patch has up to 200 nodules • Contains Microfold(“M”) cells to transfer antigen across gut  GALT: Mucosa asociated lymphoid tissue of the Gut
  • 65. Appendix Appendix, Lamina propria  T cells &Plasma cells
  • 66. CALT or SALT The skin contains a specialized cutaneous immune system consisting of lymphocytes and APCs (such as Langerhan’s cell)
  • 67. Thymus…  Thymic corpuscles are likely to be formed by eosinophilic type VI epithelial reticular cells arranged concentrically  Hassall's corpuscles vary in size with diameters from 20 to more than 100μm, and tend to grow larger with age  Human Hassall's corpuscles express thymic stromal lymphopoietin (TSLP) which activates thymic CD11c- positive dendritic cells to express high levels of CD80 and CD86.  These TSLP-conditioned dendritic cells are then able to induce the proliferation and differentiation of CD4(+)CD8(-)CD25(-) thymic T cells into CD4(+)CD25(+)FOXP3(+) (forkhead box P3) regulatory T cells.
  • 68. High-Endothelial Venules and post-capillary venules High-Endothelial Venules and post-capillary venules are the sites of Lymphocyte Extravasation High endothelial venules(HEV) •Constitutively present in secondary lymphoid tissue •Need to allow egress of naive cells from the circulation Post-capillary venules(PCV) •Present in non-lymphoid tissues? •Injury and inflammation alters morphology to resemble HEV •Need to allow egress of effector/memory cells to sites of infection