Leukocyte Migration and Inflammation Lecture Notes PDF

Leukocyte Migration Learning goals: • To know the molecular and cellular elements involved in leukocyte trafficking • To integrate the function of adhesion molecules and chemokines in migration processes • To integrate processes of leukocyte trafficking in homeostatic conditions and upon antigen...

Leukocyte Migration Learning goals: • To know the molecular and cellular elements involved in leukocyte trafficking • To integrate the function of adhesion molecules and chemokines in migration processes • To integrate processes of leukocyte trafficking in homeostatic conditions and upon antigen entry in lymphoid organs and in the periphery Lymphocyte re-circulation • Immunity depends upon the continual circulation of leukocytes through the body to provide systemic protection • Lymphocytes constantly re-circulate from blood to spleen, lymph nodes, and tertiary lymphoid tissues • Continual circulation: A complete circuit can be performed 1-2 times per day: – Increases chance of lymphocytes contacting Ag (~1 in 105) – Proper lymphocyte localization Secondary lymphoid organs Lymph nodes • • • They filter antigens coming from peripheral tissues Adaptive immunity against tissue-derived antigens Lymphocytes enter through efferent lymphatic and blood vessels Spleen • • Filtering of blood-born antigens Adaptive immunity against these antigens How do leukocytes transit the bloodstream? They must first bind to endothelial cells lining the walls of blood vessels. • Endothelial cells express ‘cell adhesion molecules’ (CAM’s) • Lymphocytes, granulocytes, and monocytes have receptors which bind to CAM’s hemhine-molecule with high affinity for their receptor • Leukocytes follow chemokine gradients according to the chemokine receptor expression patterns The four types of cell adhesion molecules MUCINS Glycosylated proteins which bind: -Endoth. Selectins - Other mucins on LN endothelium SELECTINS Initial contacts between leukocytes and endothelial cells. Bind specific carbohydrates (i.e. mucins) INTEGRINS Heterodimers which bind: -ICAMs along vascular endothelium Inflammation ICAM’s CAM’s with Ig domains on vasc. endoth binding: -Integrins - MadCAMs (mucosal endoth) Chemokines • Small peptides (90-130 Aa), that selectively control the chemotaxis, activation and adhesion of many types of leukocytes. Major regulators of leukocyte traffic. • They possess four conserved cysteine residues: Grouped based on position of two cysteines: C-C and C-X-C. • Action mediated by receptors: 7 transmembrane family • Chemokine signal increases adhesiveness and initiates signal transduction generating 2nd messengers and activating small G proteins. Chemokine receptor expression Leukocyte subsets Leukocyte activation Immune cell behavior before antigen is introduced COLUMNAR • Naïve lymphocytes circulate between secondary/tertiary lymphoid tissues • High-endothelial venules (HEVs): regions of vascular endothelium in postcapillary venules of various baid anymore) /not They lymphoid organs > - art Columnar And High RECEPTOR CONCENTRATION • Lymphocytes exit blood by extravasating at highendothelial venules (HEVs) • Adhesion molecules controlling extravasation: – HEVs express ligands for L-selectin – L-selectin is expressed on naïve lymphocytes 1,4 x 104 lymphocytes extravasate every second through HEVs into a single lymph node. Immune cell behavior before antigen is introduced: Extravasation of naïve T cells • They do not exhibit a preference for a particular type of secondary lymphoid tissue • Circulate indiscriminately through the body by recognizing adhesion molecules in the HEV. • Trafficking helps to maximize the probability for antigen encounter (only 1 in 105 lymphocytes is specific for a particular antigen) Selectins Chemokines Integrins Immune cell behavior before antigen is introduced: lymphocyte distribution • B and T cells are guided by different chemokine interactions to distinct microenvironments ü B cells enter the follicles: CXCL13 attracts naïve CXCR5+ B cells ü T cells enter the paracortex: CCL21 and CCL19 (T-cell zone) attract naïve CCR7+ T cells • Here they will scan for antigens using their Ag receptors Immune cell behavior before antigen is introduced: lymphocyte egress 1 S1P ↑ ↑ in lymph Recently arrived naive T cells: low S1PR1 Exit of Tn cells to the lymph 2 Naive T cells, minutes to hours later: S1PR1 re-expressed Inmunología celular y molecular. 9ª Ed. Abbas AK. 3 Immune cell behavior during the innate immune responses • Innate immunity depends on recognition of PAMPs by PRRs – This induces intracellular signals that: • Coordinate direct killing of pathogens • Alert adaptive immunity to the infection – Granulocytes/APCs secrete cytokines/chemokines that attract more innate cells (neutrophils, NK cells) – Peripheral DC migrate to secondary lymphoid organs for Ag presentation to T cells Interaction between innate and adaptive immune responses • APCs alerted by pathogens travel to lymph nodes and enter via afferent lymphatics • There, DC present processed antigen to T cells • Unprocessed Ag from blood gains access to lymph node B cells (opsonized by complement and/or delivered by macrophages in the subcapsular sinus) Immune cell behavior during the adaptive T cell immune response Immune cell behavior during the adaptive T and B cell immune response ANTIGEN Immune cell behavior during the adaptive cell response: Egress of effector lymphocytes Effector T cells Days after activation: S1PR1 re-expressed * Proliferation 1 3 S1P ↑ ↑ in lymph Recently arrived naive T cells: low S1PR1 Antigen recognition 2 Exit of Teff cells to the lymph Fingolimod: ↓ S1PR1 Prevents lymphocyte egress MS therapy 4 TEN ACTIVATED Tze) g to inflamed regions depending on aherion molecules Inmunología celular y molecular. 9ª Ed. Abbas AK. expressed Immune cell behavior in peripheral tissues: effector lymphocytes • Teff cells exit via lymphatics and reach inflammed tissues through blood. • They downregulate L-selectin to avoid homing back to lymph nodes • They express adhesion molecules (e.g. LFA-1) and chemokine receptors to home to sites of infection • Chemokine receptors and adhesion molecules (e.g. ICAM-1) expression patterns regulate homing of effector lymphocytes to peripheral tissues (imprinting tissue localization). Immune cell behavior in peripheral tissues: Neutrophil extravasation in inflammation Blood flow Rolling Activation Adhesion Summary • Leukocytes traffic throughout the organism to find pathogens and ensure systemic protection • This process takes places during homeostatic conditions and upon antigen entry • Leukocyte trafficking is governed by specific expression of adhesion molecules and chemokines that guide arrival to lymphoid organs and the periphery