Oral Microbiology & Immunology (OMB 612) Lecture 2 PDF

ORAL MICROBIOLOGY & IMMUNOLOGY (OMB 612) Lecture No. (2) Dr. Walid Lotfy A. Professor of Microbiology Faculty of Dentistry - Pharos University ILOs Knowledge and Understanding:...

ORAL MICROBIOLOGY & IMMUNOLOGY (OMB 612) Lecture No. (2) Dr. Walid Lotfy A. Professor of Microbiology Faculty of Dentistry - Pharos University ILOs Knowledge and Understanding: By the end of this lecture, student will be able to: - Discuss in depth immune responses. Intellectual Skills: By the end of this lecture, student will be able to: - Explain in depth immune tolerance, immune hypoactivity, and immune hyperactivity. - Differentiate between innate and adaptive immunity.  Immunobiology - The immune system exists to maintain the integrity of the body by excluding or removing the myriad of threatening microorganisms.  Immunobiology - Antigen - Recognized by the immune system - Stimulates an immune response - Can be foreign or self - Foreign antigens (Heteroantigens) - Not part of human body - Self antigens (Autoantigens) - Own cells and molecules of human body  Immunobiology - First line of defense - Skin and mucous membranes - Second line of defense - Cells of the innate immunity, antimicrobial substances, inflammation, and fever - Third line of defense - T cells and B cells  Immunobiology - B and T cell receptors are encoded by random rearrangement of pre-existing gene segments. - This occurs in the early development of lymphocytes. - Antigen specific receptors are generated prior to the encounter of lymphocytes with the specific antigens. - The immune system generates  Immunobiology - Lymphocytes having receptors against self- antigens constantly being generated in our body. - Auto-reactive (self-reactive) lymphocytes have receptors against self-antigens. - How we still avoid attack on our own cells and tissues? - The immune system has the ability to react with enormous and diverse foreign  Immunobiology - Immune tolerance: the immune system avoid reacting against all normal components of the body. - Self-tolerance: the state of unresponsiveness of the immune system to self-antigens - Self tolerance  If fails  Autoimmunity  Autoimmune diseases  individual’s own molecules, cells, tissues and organs are  Immunobiology - How immune responses to self-antigens are prevented? - Self-tolerance: achieved by various mechanisms and processes operating on the cells of the immune system - Central tolerance - Peripheral tolerance  Immunobiology Immature Mature T cells T cells B cells B cells - Bone marrow is the origin of T and B cells. - Maturation of T cells takes place in the thymus. - Thymocytes: developing T cells in the thymus.  Immunobiology - Infinite number of lymphocytes each express unique antigen receptor. - Tolerance of T-cells and B-cells  Immunobiology - Precursor T cells from bone marrow enter the thymus. T cell development starts. Expression of TCRs. Central tolerance.  Immunobiology - T cells recognize only peptide antigens. - Peptide antigen : MHC molecule complex. - MHC molecules are self molecules.  Immunobiology - Thymic epithelial cells express MHC I molecules. - Bone marrow derived dendritic cells and macrophages in the thymus express MHC II molecules. - Fate of developing T cells depends on: The strength with which immature T cells interact with self peptide : self MHC molecules.  Immunobiology - Immature T cells undergo an elaborate screening process Non-selection Positive selection Negative selection  Immunobiology Non-selection Immature T cells fail to recognize and bind self peptide : self MHC molecule. - Non-functional TCRs. - Lack receptors recognizing MHC molecules.  Immunobiology Immature T cells successfully recognize and bind self peptide : self MHC molecule. - Binding is not too strong nor too weak (moderate binding strength). - T cells migrate to peripheral lymphoid organs.  Immunobiology Immature T cells recognize and bind self peptide : self MHC molecule with very strong affinity. - Dead cells are phagocytosed by macrophages in the thymus.  Immunobiology - Not all self antigens are expressed in the thymus. - Some self antigens appear in other tissues or at other stages in the development of cells. - What is the source of self antigens? - Healthy tissues and organs shed low levels of component proteins - Cells undergo apoptosis (normal turnover process)  Immunobiology Peripheral tolerance activation Prevent T - Clonal deletion cell - Anergy - responses Immune deviation immune Control - Immune previlege - Immunosuppressive cytokines - Regulatory T cells  Immunobiology Infection  Generation of signals (PAMPs)  Signals are recognized by PRRs of innate cells  Innate cells release cytokines  Induce the maturation of dendritic cells Immunobiology  Immunobiology Clonal deletion - In case of self antigens co-stimulatory molecules are not expressed by dendritic cells. - T cells receive first signal for its activation. - No second signals are received - Auto-reactive T cells are eliminated by programmed cell death or apoptosis.  Immunobiology Anergy: some auto-reactive T cells survive but remain inactivated. Binding of CD 28 cell Absence of costimulatory surface receptor on T molecule (B7) presents cells is required for on the surface of APCs  presentation of non-self clonal anergy antigens to T  Immunobiology Peripheral tolerance uses several other control mechanisms: - Immune deviation: potentially harmful immune response is converted to a less harmful immune response by skewing of Th differentiation toward particular antigen. - Immune privilege: anatomical regions that are less subject to immune responses (CNS, brain, eyes and testes). - Immunosuppressive cytokines: IL-10 and  Immunobiology Central B cell tolerance - Receptor editing - Clonal deletion - Anergy  Immunobiology Origin and maturation of B cells occur in the bone marrow  Migrate to the peripheral lymphoid organs  Encounter specific antigens  Activation  Proliferation and differentiation into  Immunobiology - Vast repertoire of BCRs having different antigen specificities. - Some of these B cells can be auto-reactive. - Auto-reactive B cells produce auto- antibodies and cause autoimmune diseases. - Immature B cells undergo screening process in the bone marrow.  Immunobiology - What is the source of self antigens in bone marrow? - Cell surface molecules expressed by stromal cells, hematopoietic cells and molecules circulating in blood. - How auto-reactive B cells are distinguished from other cells? - The strength with which BCRs of immature B cell bind to antigens in the bone marrow.  Immunobiology - Most of the antigens encountered by immature B cells in the bone marrow are multivalent. - Multivalent antigens are effective at cross- linking BCRs.  Immunobiology No interaction/weak Very strong interaction interaction   B cell development is Successfully leave bone arrested. marrow and migrate to These B cells are retained peripheral lymphoid in the bone marrow. organs. Immunobiology Immunobiology  Immunobiology Central B cell tolerance uses 3 mechanisms to induce tolerance: - Receptor editing: - antigen receptor of auto-reactive immature B cell is modified. - Immature B cells have the ability to rearrange their immunoglobulin genes of the light chain loci. - Clonal deletion: - If B cells failed to rearrange their immunoglobulin genes of the light chain loci they undergo apoptosis. - Anergy: - B cells become unresponsive and enter peripheral Immunobiology Immunobiology  Immunobiology Peripheral B cell tolerance - B cells do not encounter all the self antigens in the bone marrow. - Circulating B cells come in contact with tissue specific cell surface proteins and secreted proteins.  Immunobiology Anergy: - B cells require T helper cells for activation. - Auto-reactive T cells are eliminated by central tolerance. - Without T helper cells there is no signal 2 and eventually signal 3. - B cells become unresponsive.  Immunobiology Activation of B and T cells  Immunobiology Activation of B cells B cell activation Based on the type of antigen encountered by the B cells T cell T cell independent dependent activation activation  Immunobiology - The antigens which can trigger B cell activation without T helper cell are called T independent or thymus independent (Ti) antigens. - B cell activation without T helper cell is known as T independent B cell activation. - Antigens that trigger B cell activation with the help of T helper cells are called T dependent or thymus dependent (Td) antigens. - B cell activation which requires T helper cell is known as T dependent B cell activation.  Immunobiology B cells activation without T helper cell - Polysaccharides, glycolipids, and nucleic acids Signal 1: clustering of BCRs with multiple repetitive identical epitopes of the multivalent antigen Signal 2: TLRs on B cell recognize various Immunobiology Immunobiology  Immunobiology B cells activation with T helper cell - Most antigens are proteins but not present as multiple repeating epitopes that cannot crosslink multiple BCRs. - Thus, clustering of B cell receptors is difficult. - B cell activation requires T helper cell. - Three signals process occurs.  Immunobiology Signal 1: antigen recognition and binding by B cell.  Immunobiology The same antigen is also recognized by mature naïve CD4+ T helper cell.  Immunobiology Signal 2: is derived from B and T cell interaction.  Immunobiology Signal 3: Cytokines released by the T helper cell stimulate B cell. Immunobiology Immunobiology Immunobiology