1. Development of immunity_MWM.pdf
- 1. Presenter: Md. Waseque Mia Assistant Professor Department of Biochemistry & Molecular Biology Shahjalal University of Science and Technology Sylhet-3114, Bangladesh. Development of Immune System
- 2. Immune defense Innate (nonspecific defense) Surface barriers • Skin • Mucosal membrane Internal barriers • Phagocytes • Fever • NK cells • Inflammation Adaptive (specific defense) Humoral Immunity • B cells Cellular Immunity • T cells
- 4. Development of the Immune System @The body’s capability to react to antigens depends on a person’s age, type of antigen, maternal factors, and the area of the body affected. @The body’s ability to defend against antigens varies throughout the lifespan.
- 5. Neonates are physiologically immunodeficient, meaning both their innate and adaptive immunological responses are greatly suppressed. Early in life, the immune system is not mature enough to fight off pathogens and must depend on antibodies from the mother. Infants respond well to protein antigens but not as well to glycoproteins and polysaccharides. In neonates, opsonic activity and the ability to activate the complement cascade is very limited. Due to which phagocytic activity is also greatly impaired in newborns. Immunology in Newborns
- 6. After 24 months of age, a child can defend well against glycoproteins and polysaccharides. Although the number of total lymphocytes in newborns is significantly higher than in adults, the cellular and humoral immunity is impaired. Antigen-presenting cells in newborns have a reduced capability to activate T cells, proliferate poorly, and produce very small amounts of cytokines like IL-2, IL-4, IL-5, IL-12, and IFN-Ƴ. This limits the capacity of these cells to activate the humoral response and the phagocytic activity of macrophages. B cells develop early in gestation but are not fully active. Immunology in Newborns
- 7. The lymphoid vs. myeloid model describes the process of lymphopoiesis from pluripotent hematopoietic stem cells. These give rise to prolymphocytes and finally common lymphoid progenitors, which can become NK cells, B cells, dendritic cells, and other immune system cells. Hematopoiesis is the process by which all mature blood cells are produced. Immunology in Newborns
- 9. Immunity During Adolescence During adolescence, the human body undergoes physical, physiological, and immunological changes, triggered and mediated by various hormones. Depending on the sex, testosterone or 17-β-oestradiol act on males and females respectively, starting at around age 12 for boys and 10 for girls. There is evidence that these steroids act directly not only on the primary and secondary sexual characteristics, but also affect the development and regulation of the immune system. Pubescent and post-pubescent females and males are at increased risk for autoimmune disorders. There is some evidence that cell surface receptors on B cells and macrophages may detect sex hormones in the system.
- 10. Aging and the Immune System Immunosenescence refers to the gradual deterioration of the immune system brought on by aging. Hematopoietic stem cells diminish in their self-renewal capacity, due to the accumulation of oxidative damage to DNA by cellular metabolic activity and shortening of telomeric terminals of chromosomes. Reducing the supply of leukocyte progenitors. The number and function of phagocytes, natural killer (NK) cells, and dendritic cells decline with age. The functional capacity of T-cells declines with age.
- 11. T cell maturation, activation and differentiation
- 13. T cell maturation, activation and differentiation T cell is a type of lymphocyte which develops in the thymus gland and plays a central role in the immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor on the cell surface. These immune cells originate as precursor cells, derived from bone marrow and develop into several distinct types of T cells once they have migrated to the thymus gland.
- 14. The pathway of T cell development T cells...precursors are born in the bone marrow and “educated” in the thymus.
- 15. T cell maturation Maturation of thymocytes into mature T cells occur in distinct stages: Changes in the status of the T-cell receptor genes Expression of the T- cell receptor protein Production of other T-cell surface glycoproteins (essential for receptor’s full function, such as CD4, CD8 and CD3 complex). What allows T cell maturation? Direct contact with thymic epithelial cells Influence of thymic hormones (thymosin) Growth factors (cytokines, CSF)
- 16. Two-step Selection Process of Thymocytes Positive Selection: permits the survival of only those T-cells whose TCRs recognize self-MHC molecules generation of a self-MHC-restricted repertoire of T cells. Negative Selection: eliminates T cells that react too strongly with self-MHC or with self-MHC plus self- peptides generation of a T-cell repertoire that is self-tolerant. How adaptive immune cells distinguish between self and non-self? Answer lies in the processes of positive and negative selection.
- 17. Phenotypic Variations of T-cell during maturation After T cells enter the thymus they begin to proliferate and differentiate into what will be the T cells. Stage 1 ( early thymocytes): These are the cells which enter the subcapsular region of the thymus, arriving as pre-T cells from the bone marrow. (progenitor cells). In this region, progenitor cells interact with thymic stromal cells, they get signaled to proliferate, within a week they express certain T-cell specific glycoproteins, such as: CD44 (adhesion molecule), CD25 (receptor for IL-2). At this stage, they do not express TCR complex or the co-receptors CD4 & CD8. These cells develop into large, actively proliferating, self-renewing lymphoblasts which generate the thymocyte population. They are 3% of the cells in the thymus.
- 18. Stage II (Intermediate) thymocytes: Expressing CD1+, CD44-, CD25- At this stage, the cells develop the CD3:TCR complex, CD4 and CD8. Therefore the cells are CD3+, CD4+, CD8+. Genes encoding the TCR α-chain are rearranged in this stage. They are about 80% of cells in the thymus. Stage III (mature) thymocytes. Show major phenotypic changes; Loss of CD1 cell surface CD3 is associated with high density by TCR mature T cells express either CD4 or CD8
- 21. The central event in the generation of both humoral and cell-mediated immune responses is the activation and clonal expansion of TH cells. Interaction of a TH cell with Ag initiates a cascade of biochemical events that induces the resting TH cell to enter the cell cycle, proliferating and differentiating into effector cells or memory cells. TH -Cell Activation
- 22. TCR Engagement Initiates Multiple Signaling Pathways Overview of Common Themes in Signal Transduction (hydrophobic)
- 25. Multiple Signaling Pathways Are Initiated by TCR Engagement ITAM: immunoreceptor tyrosine-based activation motif
- 28. Activation of the small G protein, Ras
- 29. Naïve T cells require 2 distinct signals for activation and proliferation into effector cells. o Signal 1: the initial signal, is generated by interaction of an antigenic peptide with the TCR-CD3 complex. o Signal 2: a subsequent Ag-nonspecific co-stimulatory signal, is provided by interactions between CD28 on the T-cell and members of the B7 family on the APC. Co-stimulatory Signals Are Required for Full T-cell Activation
- 31. TH-cell Activation Requires a Co-stimulatory Signal Provided by APCs CD28 is expressed by both resting and activated T cells. B7 (B7-1 and B7-2) are constitutively expressed on dendritic cells, and induced on activated macrophages and activated B cells. CTLA-4 is expressed on activated T cells. B7-1 (CD80) B7-2 (CD86) (CD152) CD28 & CTLA-4 act antagonistically. + -
- 32. Clonal Anergy (Unresponsiveness): inability of cells to proliferate in response to a peptide- MHC complex. If a resting TH cell receives the TCR-mediated signal (signal 1) in the absence of a suitable co-stimulatory signal (signal 2), the TH cell become anergic. In the presence of both signal 1 and signal 2, clonal expansion results. Clonal Anergy Ensues if a Co-stimulatory Signal Is Absent
- 33. Clonal Anergy Ensues if a Co-stimulatory Signal Is Absent Signal 1 without signal 2 produces ANERGY
- 34. • Superantigens, a class of antigens, result in excessive activation of the immune system. • Not processed by antigen presenting cells. • Specifically it causes non-specific activation of T-cells resulting in polyclonal T cell activation and massive cytokine release. • SAgs are produced by some pathogenic viruses and bacteria most likely as a defense mechanism against the immune system. • Compared to a normal antigen-induced T-cell response where 0.0001- 0.001% of the body’s T-cells are activated, these SAgs are capable of activating up to 20% of the body’s T-cells. • The large number of activated T-cells generates a massive immune response which is not specific to any particular epitope on the SAg. • Thus undermining one of the fundamental strengths of the adaptive immune system, that is, its ability to target antigens with high specificity. What is Super-Antigens???
- 35. Superantigen-mediated Crosslinkage of TCR and Class II MHC Molecules Exogenous superantigens : exotoxins secreted by G(+) bacteria, e.g., staphylococcal enterotoxin A & B (SEA, SEB). Endogenous superantigens: cell-membrane proteins encoded by certain viruses that infect mammalian cells, e.g., mouse mammary tumor viral (MMTV) protein. Viral or bacterial proteins that bind simultaneously to particular Vβ sequences of TCR and to the α chain of a class II MHC molecule – induce polyclonal T-cell activation & proliferation
- 36. GOAL: 1. Regulation of T cell numbers, 2. Removal of “turned off” T cells, 3. Deletion of cells with high avidity for MHC Cell death (apoptosis) Programmed cell death is an essential homeostatic mechanism
- 37. Two Pathways to T-cell Apoptosis Fas-associated protein with death domain AICD : activation- induced cell death TCR- mediated negative selection: apoptosis- inducing factor apoptotic protease- activating factor 1
- 38. T cell differentiation: • Remember: Naïve T cells continually re-circulate between the blood and lymph system search for appropriate antigen. • Once activated (Remember signal 1 and 2) Primary response where T cells proliferate and differentiate into effector and memory T cells. • CD4 effector T cells can form two subpopulations based on cytokine production: TH1 subset (IL-2, IFN-γ) and TH2 subset (IL-4, IL-5, IL-10). • TH1: associated with cell-mediated functions inflammation (delayed-type hypersensitivity, activation of Macrophages and CD8 T cells); • TH2: associated with B-cell activation.
- 40. B cell maturation, activation and differentiation
- 41. Overview of B-cell Development Sites of B-cell maturation – • before birth: yolk sac fetal liver fetal bone marrow • after birth: bone marrow
- 42. The discovery of B cell immunity Studies on the function of the bursa of Fabricius, a lymphoid organ in the cloacal region of the chicken (1954 - Bruce Glick, Ohio State University) Bursectomy – no apparent effect Bursectomised chickens were later used in experiments to raise antibodies to Salmonella antigens None of the bursectomised chickens made anti-Salmonella antibodies Bursa was later found to be the organ in which antibody producing cells developed –antibody producing cells were thereafter called B cells. Mammals do not have a bursa of Fabricius
- 43. Origin of B cells and organ of B cell maturation Transfer marked foetal liver cells No Mature B cells Normal bone marrow Defective bone marrow Mature marked B cells in periphery B cell development starts in the foetal liver. After birth, development continues in the bone marrow.
- 44. B cell development in the bone marrow Bone Marrow provides a Maturation & Differentiation Microenvironment for B cell development. B Regulates construction of an antigen receptor Ensures each cell has only one specificity B Checks and disposes of self-reactive B cells B Exports useful cells to the periphery B Provides a site for antibody production B
- 45. B-cell Activation, Proliferation and Differentiation Occur in a Peripheral Lymph Node
- 46. Bone marrow stromal cells nurture developing B cells Types of cytokines and cell-cell contacts needed at each stage of differentiation are different. Secreted Factors -CYTOKINES 2. Secretion of cytokines by stromal cells. B Stromal cell 1. Specific cell-cell contacts between stromal cells and developing B cells Cell-cell contact
- 47. Cytokines and cell-cell contacts at each stage of differentiation are different Early pro-B Receptor Tyrosine kinase Stem cell factor Cell-bound growth factor VLA-4 (Integrin) Stem Stromal cell Cell adhesion molecules VCAM-1 (Ig superfamily)
- 48. Early pro-B Interleukin-7 receptor Stromal cell Late pro-B Pre-B Interleukin-7 Growth factor Cytokines and cell-cell contacts at each stage of differentiation are different
- 49. Peripheral Stages of B cell development Stem Cell Early pro-B cell Late pro-B cell Large pre-B cell Small pre-B cell Immature B cell Mature B cell Each stage of development is defined by rearrangements of IgH chain genes, IgL chain genes, expression of surface Ig, expression of adhesion molecules and cytokine receptors.
- 50. pattern recognition receptors (PRRs) Two Distinct Signals for B-Cell Activation
- 51. Signal Transduction Pathways and the Activation of B Cells Compartmentalization of function within receptor subunits. Activation by membrane-associated Src family protein tyrosine kinases (Lyn, Blk, and Fyn). Assembly of a large signaling complex with protein-tyrosine- kinase activity (Syk). Recruitment of other signal-transduction pathways. Changes in gene expression.
- 52. Signal Transduction Pathways Activated by the BCR
- 54. Sequence of Events in B-Cell Activation by a Thymus-Dependent Ag
- 56. The B-Cell-Co-receptor Complex Can Enhance B- Cell Responses: TAPA-1 (CD81), CR2 (CD21), and CD19 ITIM: immunoreceptor tyrosine inhibitory motif
- 57. 1. Affinity maturation 2. Class switch 3. Formation of plasma cells and memory cells Three Important B-cell Differentiation Events Take Place in Germinal Centers
- 58. Cytokines Affect Proliferation and Class Switching of B Cells During the Differentiation of B Cells into Plasma Cells
- 59. B cells play an important role in multiple aspects of immunity……..how? • B cell-derived cytokines, including lymphotoxin, are essential for the ontogenesis, homeostasis and activation of secondary lymphoid organs, as well as for the development of tertiary lymphoid tissues. • Other B cell-derived cytokines, such as interleukin-6 (IL-6), interferon-γ and tumor necrosis factor, influence the development of effector and memory CD4+ T-cell responses. Lymphotoxin (previously known as tumor necrosis factor-beta) is a lymphokine cytokine. It is a protein that is produced by Th1 type T- cells and induces vascular endothelial cells to change their surface adhesion molecules to allow phagocytic cells to bind to them. ……by producing various Cytokines
- 60. THANK YOU