Immunity Across Generations PDF

Immunity Across Generations Dr Lotti Tajouri  Tissues of the immune system: Lymphoid Organs At any one time, only a small fraction of lymphocytes are in ci...

Immunity Across Generations Dr Lotti Tajouri  Tissues of the immune system: Lymphoid Organs At any one time, only a small fraction of lymphocytes are in circulation Primary lymphoid tissue is where lymphocytes develop and/or mature Secondary lymphoid tissue is where mature lymphocytes are stimulated to respond RED = primary lymphoid tissue YELLOW = secondary lymphoid tissue  (also known as hemocytoblast or pluripotent stem cell) Also known as granulocytes  Blood Leukocytes Leukocyte type % total blood Function leukocytes Neutrophils* 40-75 Engulf and digest bacteria Lymphocytes 20-50 Targeted immune response (include NK cells) Monocytes 2-10 Engulf and digest bacteria; develop into tissue macrophages Eosinophils* 1-6 Kill parasitic worms Basophils* mature of Neutrophils in blood  Natural Killer (NK) Cells FcγR: Adhesion is low CD56 BRIGHT Minority of NK cell type Poorly cytotoxic High cytokine production FcγR: Adhesion is High CD56 DIM Majority of NK cell type ADCC of infected cells (with perforin and granzymes) Low cytokine production Monocytes/macrophages Monocytes circulate in blood; progenitors of: Tissue macrophages: – Act as phagocytes. Clean up dead cells and debris as well as microorganisms – Produce cytokines (cellular messengers) that promote inflammation Macrophages: - in liver :Kupffer - in bones: ostepoclasts - in brain: Microglia - In skin: Langerhans - In tissues: histiocytes - In kidney Mesangial cells - In placenta: Hofbauer - In lungs: Alveolar macrophages  Dendritic cells Related to macrophages Unique star shaped morphology Carry degraded and intact pathogens from site of infection to lymphoid organs: Stimulate adaptive immune response PAMP=pathogen-associated molecular pattern  Lymphocytes (adaptive)  Lymphocytes and NK cells are derived from the same progenitor cell  Types:  B cells (with BCR)  T cells (with TCR)  T8 (αβ) (MHCI binding)  T4 (αβ) (MHCII binding)  Th1: TNFα /IL2/Infɣ  Th2: IL 4,5,10,13  Ts (or Treg)  Ɣδ T (no MHC binding) Histologically: Lymphocyte recognised by nuclear large volume compared to overall cell. Maturation of T cells Maturation of thymocytes + -  Clonal selection theory T and B-cells of many specificities exist BEFORE there is any contact with foreign antigen Lymphocytes have antigen specific receptors on their surfaces (1 in 10,000 to up to 1 in a million chance of being specific for an antigen) Each lymphocyte carries on its surface, receptor molecules of a single specificity Antigen binding to this receptor will activate cells and cause them to proliferate (produce clones of the same specificity) Immature, self-reactive cells are prevented from maturing The lymphatic system Network of vessels originating in connective tissues; collect plasma & Prot that leak out of blood vessels Returned to blood via thoracic duct (empties into left subclavian vein)  Lymph nodes lie at junctions of lymphatic vessels Anatomy of a lymph node Weigh 1g or less Anatomy of a lymph node Pathogens & dendritic cells carrying pathogens arrive via afferent lymphatic vessel Pathogens picked up by resident macrophages Macrophages and dendritic cells both stimulate lymphocytes  Circulation of a naïve B cell through lymph node Enters via blood vessels and enter cortex of lymph node through the: High Endothelial Venules Capsule (HEV) If no antigen encountered, Marginal sinus leaves via efferent lymph vessel (Migration loop between Bone marrow and Interfollicular sinus lymphoid organs)  B cells encountering antigen (germinal proliferation & plasma cells) Re-enter the node, encounter Ag  co-activation with T cells Germinal centre = site of B cell division & differentiation Memory B cells Other B cells migrate to medulla and become Ab- secreting plasma cells  Exit to efferent lymphatic vessel [As immune response subsides, some germinal centre B cells develop into memory B cells: long life]  lymphoid areas of note  GALT (gut-associated lymphoid tissue): Tonsils (Palatine/ Lingual/ Pharyngeal/ Tubal), adenoids, appendix, Peyer’s patches  BALT (bronchial-associated lymphoid tissue): aggregates of tissue on the lining of respiratory tract  MALT (mucosa-associated lymphoid tissue Cells of the immune system In adults, haematopoiesis takes place in bone marrow of skull, ribs, sternum, vertebral column, pelvis and femurs.  Immunity foetus -Axenic conditions of foetus: No antigenic challenge within amniotic sac, placenta. -Tolerance induced: mother and foetus active on this tolerance set up. T4 Tregs ~15% in fetus (enhanced proliferation following exposure to alloantigens from mother; mediated by TGFβ) rather than 5% in infants  Placenta Tregs are numerous: FoxP3+, CD127 neg (Il7R), CD25+  Mother Th2 (IL10) trend but low Th1 (Interferon Gamma) response. -Foetal Hematopoiesis: - Foetal Thymus: - wk 6; 3rd branchial arch  Thymus; -~wk 9: ectodermic cells reach cortex; endodermic cells reach medulla. - wk 12, clear cortex & medulla; first pro-thymocytes called triple negative.  Baby & Immunity - Born with Intact immunity but suboptimal immunity: Phagocytes slow migration Cytokines low (Th1) NK function incomplete (antiviral response Low) Complement system develops 1yo (phagocytosis function Low) T an B cells appear early but Naïve Low Ig (M/A/E) -Born with Intact immunity but NAÏVE Immune cells: Need exposure to antigens to mount proper immunity BABY Needs time and receives HELP from Mother after birth  Immune Protection from Mother to baby continues even after Baby is born: “NAPI” Placental nFCR allowed the passage of mother IgGs to fetus wk 17:Transfer of antibodies begins & increases as gestation advances.  Maximal transfer occurs from the 3rd trimester onwards.  wk 33: Maternal IgG = Fetal IgG  wk 40: Fetal IgG concentration is higher than maternal IgG  Circulatory till 6 months after birth _Breast Milk Bioactive compounds in breast milk:  Macrophages, stem cells;  IgA/IgG/IgM  Cytokines [IL6,IL7,IL8,IL10, inFγ, TGFβ, Growth factors]  Antimicrobials [lactoferrin, lactoadherin; MUC1/4 (mucins)]  Prebiotics  Immune risk Phenotype and Immuno-senescence the Elderly Immunity CD8 T cells: -CD8 high CD28 null + short telomeres (end differentiation; along with killer-cell lectin like receptor G1 (KLRG-1) age related increase expression: inhibitor of T cells and NK cells)  CD4T cells: -Low proliferative response e.g. upon IL-2 so Low CD4 cells Overall Diminished CD4:CD8 ratios [