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Lymphatic System (Constituents and function of immune system: Lymphocytes,…

- - - - Helper T cells (Th) that initiate antigen responses by activating B lymphocytes, secretes interleukins that mediate activation, clonal expansion and maturation of B or cytotoxic T cell response
        
        CD2,3 and 4
        
        T helper 2: B cells, use interleukin
        
        T helper 1: Macrophages, use interferon gamma
      - Killer (Cytotoxic) T cells (Tc) that directly contact infected cells causing cell death
        
        CD2, 3 and 8
      - Regulatory T cells (T reg) regulate magnitude and duration of immune response
        
        CD4 and FOXP3
      - Memory T cells
    - - Removal of Neoplastic Cells
      - Rejection of transplanted organs
      - Mediation of certain autoimmune diseases
      - Recovery from intracellular microbial and viral infections
  - - - IgG: 75% of serum immunoglobin, most common, can pass placenta, secondary response, neutralize toxins, opsonization
      - IgA: in colostrum (milk), saliva, tears and in secretions from nasal, bronchial, vaginal and prostatic tissue (dimer)
      - IgM: early immune response, first AB produced (pentamer, better at bringing antigen and cells together)
      - IgE: by Plasma cells but attach to mast cells and basophils where it serves as receptors for allergens
      - IgD: receptor for antigens on surface of B cells
      - Class switch recombination: plasma cells produced by GC secrete IgG or IgA AB rather than IgM (early immune response)
      - Heavy chain (middle) + light chain
        Variable and constant region
    - - Antibody binding (block binding sites)
      - Opsonisation (mark for phagocytosis)
      - Complement activation through antigen-antibody complex (MAC -punctures outer membrane of foreign organism and Phagocytosis)
      - Antibody-dependent cell toxicity
      - Antibody bound to toxins inactivates and facilitates removal of foreign cells by phagocytotic bodies
  - - - destruction by apoptosis of abnormal cells by Tc, NK cells or antibody dependent cytotoxic cells
  - - - Genes have different V regions (V1, V2) and J regions (J1 and J2) and even D regions
      - These genes have different arrangement s(V1J2, V1J1 etc)
      - Diversity arises from imprecise enzymatic machinery to cut and paste the DNA during gene rearrangement
      - All connected to C (constant)
      - Same concept applies to alpha and beta gene chains
- - - - Enables antigens to cross the epithelium and enter intra-epithelial pocket beneath basal surface in which lymphocytes and dendritic cells reside
      - Enables efficient transfer of luminal antigens to adjacent lymphatic nodule (Transcytosis)
      - Seen as a stop in microvilli structure in lumen side
  - - - Immediate underneath subcapsular sinus
        
        antigen enter either as soluble or particulate antigen or as antigen carried by dendritic cells
        
        Soluble antigens (small) able to pass to stromal compartment via pores in subcapsular sinus, transported in conduits and interact with APC and lymphocytes
        
        Larger: phagocytosed by sinus macrophages and process before presentation
        
        This is why intact bacteria and virus cannot pass rapidly through lymph node to enter the blood
      - Contains nodules (follicles) of B cells and diffuse lymphatic tissue called paracortical region (consist of Th and Tc cells)
    - - Central region of node
      - No nodules in medulla, contains lymphocytes, macrophages, and plasma cells organized into strands called medullary cords
      - Cords Separated by sinuses
      - Lymph exits node via efferent lymphatic vessel at hilus
    - - artery enters through hilus, branches into arterioles which pass through medullary cords to enter cortex as small capillaries
      - Capillaries perfuse nodules, and drain into venules in paracortical region
      - Post capillary venules are called high endothelial venules (HEV) which allow small lymphocytes to cross from blood into the lymph
      - Blood then exits node at hilus in a single efferent vein
    - - Sites where pathogens are trapped and acquired immunity develops in confined space as lymphocytes and immunoglobins are added to lymph, and circulating small lymphocytes are recruited (HEV)
      - When fighting infection, nodes become tender and swollen
      - Slowly return to normal 2-4 weeks after infection is resolved
      - Timeline
        
        Antigen presentation occurs 24-48 hr after infection
        
        Antigens enter lymph node via afferent lymphatic vessels taken up by macrophages and APC in subcapsular sinus, cortex and/or medulla
        
        foreign antigen becomed degraded, and displayed on cell surfaces (MHC II)
        
        Some intact antigen may be retained by follicular reticular cells in nodule region of cortex for presentation to B cells
        
        T and B cell activation 2-3 days after infection
        
        Small T cells enter node through HEV, encounter processed antigen and differentiate within diffuse cortex, giving rise to memory T cells and Th cells
        
        Th cells migrate into nodule, where small B cells with appropriate receptor react with processed antigen of Th cells, giving rise to memory and effector B cells
        
        Focus of dividing Th and B cells, as well as active macrophages builds up germinal center that compresses rest of the nodule (resting lymphocytes) into a crescent around it called a mantle
        
        Paracortical reaction: T cell dominated immune response
        
        Germinal centers appear 3-5 days
        
        May remain for several days
        
        Plasma cells (mature effector B cells) begin to settle between sinusoids of medulla to form medullary cords
        
        Other activated B cell progeny and activated T cell progeny percolate through lymph node and exit via efferent lymph vessels to spread to other lymphatic tissues and eventually the blood circulation
        
        Thus, most memory and effector T cells and some memory B cells eventually re-enter general blood circulation but effector B cells retained within lymph node
        
        Centroblast found at dark zone (closer to medulla), centrocytes found at light zone (closer to cortex), follicular dendritic cells and tingible body Macrophages also found in GC
        
        Sinus macrophages in medullary sinus, with fine reticular strands providing support, Dendritic cells wrap the Reticular cells, macrophage have plentiful lysosomes and endocytoic vacuoles, with plentiful cell processes to increase surface area
        
        Lymph node swells 6-8 days
        
        Activated T and B cells also release soluble factors that cause local blood vessels to dilate, allowing leakage of plasma into the lymph node
        
        Some factors attract macrophages while others retain lymphocytes within the lymph node
        
        Resulting accumulation of cells and fluid may plug medullary sinusoids leading to efferent lymphatic vessel
        
        As a result, lymph node enlarges rapidly
    - - All lymphatic tissues except thymus are part of a surveillance system which lymphocytes migrate from blood to interstital space to lymph and back to blood via right lymphatic duct and thoracic duct
      - Made possible with HEV where lymphocytes can move quickly from blood to lymph
      - Allows for quick sampling and surveillance
      - T lymphocytes are circulating while B tend to reside in the spleen, lymph nodes and peyer's patches
      - Lymphatic drainage also provides route for distributing pathogens and cancer cells
        
        If these cells evade detection adn removal in lymph node, they are then delivered to the blood circulation for distribution throughout the body
        
        Metastasis to the regional lymph node from lymphatic vessels draining an organ is a common step in the progression of many cancers and is an important prognostic indicator (take a sample of lymph node to test)
        
        E.g. Breast cancer
    - - Wrapped in basement membrane which in turn cover fibroblastic reticular cells, which produce collagen framework of node and bring together dendritic cells and t cells to facilitate antigen presentation
- - - - This is an APC rich zone and is the entry site for lymphocytes which then migrate to white pulp
      - here, macrophages and lymphocytes examine soluble antigens, and antigen laden APC and/or antigen activated lymphocytes then migrate into the white pulp (either PALS or follicles)
    - - Central artery is called pulp artery
      - Branches into parallel arterioles which are wrapped often by macrophages (sheathed arterioles)
      - Arterioles end abruptly, releasing blood cells into a meshwork of cells called Cords of Billroth
        
        Open circulation (vessel free)
      - Move through space to enter venous sinusoids, lined by endothelium called littoral cells (stave cells) that have intercellular pores of fixed diameter (2-5 microns)
      - To go through these pores, RBC have to be deformable, cells that are rigid remain in the cords of Billroth and are removed quickly by macrophages lurking there
      - Despite open nature, such blood flow is very efficient (98-99% of RBC entering spleen flow through it in 30s
    - - Lymphatic vessels of spleen are not of major functional importance
      - Blind lymphatic capillaries start at the marginal zone where lymphocyte and plasma enriched blood is dumped
      - Here, lymphocytes can exit the blood circulation and directly enter lymphatic circulation
- - - - oxidizing agents and phagocytosis
      - Signal the presence of foreign substances to lymphocytes
  - - - Protection from pathogens or invaders
      - Removal of dead or damaged tissues and cells
      - Recognition and removal of abnormal cells
  - - - Migratory
      - Transiently lurk and often accomplish jobs within tissues and organs distributed diffusely throughout body
- - - - attach to ea other by desmosomes and have an intracellular system of tonofilaments (intermediate filaments)
      - No extracellular CT fibers
      - Endodermal in origin, secrete hormones (e.g. thymosin) critical for maturation and proliferation of immunocompetent T cells
    - - primarily of small T lymphocytes actively dividing and differentiating
    - - Lighter appearance
      - Fewer lymphocytes, more reticular cells
      - Concentric layered structures: Hassal's corpuscles
        
        Endocrine function: secrete lymphopoietin, critical for differentiation of T cell subclasses
      - Dendritic cells, macrophages and mast cells are present in the medulla as well
    - - At cortex-medulla boundary, arterioles give off capillaries which enter either cortex or medulla.
      - Within cortex and medulla, capillaries anastomos extensively and then return to cortex-medulla boundary where they drain into venules
      - Capillaries are continuous, sealed with tight junctions, surrounded by phagocytic epithelial reticular cells to ensure no leakage of antigen
        
        BLOOD-THYMUS BARRIER
        
        Ensures exclusion of non-self antigens for proper selection of T cells
        
        epithelial framework of cortex more delicate and finely branched than medulla and cells cannot be distinguished in H&E stain, but immunostaining can
    - - Immature T cell enter parenchyma from blood at post capillary venules located at cortex medulla boundary, immunocompetent T cells exit organ by the same venules
    - - Severe Combined Immune Deficiency (SCID)
        
        Absence of either bone marrow stem cells or immuno-incompetent T cells
        
        At risk of fungal and viral infection (cell mediated immunity) and for bacterial infections (humoral immunity)
        
        Bone marrow replacement, enzyme replacement (PEG-ADA) and gene therapy
      - Aquired Immune Deficiency (AIDS)
        
        HVTL III virus destroy mature T helper cells
        
        Immune deficiency, at risk of fungal, viral and bacterial infections
      - Autoimmune disease
        
        Failure of self-tolerance
        
        e.g. Grave's disease, rheumatoid arthritis