Introduction to Immunology PDF

Introduction to Immunology Padmini Salgame, PhD Department of Medicine Centre for Emerging Pathogens [email protected] The eradication of smallpox by vaccination After a period of 3 years in which no cases of smallpox were recorded, the World Health Organization was able to announce in 197...

Introduction to Immunology Padmini Salgame, PhD Department of Medicine Centre for Emerging Pathogens [email protected] The eradication of smallpox by vaccination After a period of 3 years in which no cases of smallpox were recorded, the World Health Organization was able to announce in 1979 that smallpox had been eradicated, and vaccination stopped (upper panel). This individual (lower panel) contracted and survived the last case of smallpox in Somalia in 1977. Photograph courtesy of Dr. Jason Cells of the Immune System TB Aspergillus Plasmodium MRSA Anthrax H5N1 Flu HIV The response to an initial infection occurs in distinct phases The first two phases rely on the recognition of pathogens by germline-encoded receptors of the innate immune system, whereas adaptive immunity uses variable antigen-specific receptors that are produced as a result of gene segment rearrangements. Adaptive immunity occurs late, because the rare B cells and T cells specific for the invading pathogen must first undergo clonal expansion before they differentiate into effector cells that migrate to the site of infection and clear the infection. The effector mechanisms that remove the infectious agent are similar or identical in each phase Physical Barriers Many barriers prevent pathogens from crossing epithelia and colonizing tissues Surface epithelia provide Recognition by preformed non-specific and broadly specific effectors Complement Macrophages express receptors that enable them to take up microbes by phagocytosis CTLD- C-type lectin-like domain. SR- collagen-like domains and form trimers. Bacteria binding to neutrophil receptors induce phagocytosis and microbial killing Neutrophil extracellular traps (NETs) can trap bacteria and fungi Recruitment of effectors cells & the Inflammatory response Phagocytosis of infecting bacteria triggers an inflammatory response -Cells can traverse from one part of the body to another -Vascular endothelium serves as gatekeeper -Increase permeability of blood vessels allowing fluid and protein to pass into tissues The four sequential steps in lymphocyte extravasation Infection stimulates macrophages to release cytokines and chemokines that initiate an inflammatory response Cytokines produced by tissue macrophages at the site of infection cause the dilation of local small blood vessels and changes in the endothelial cells of their walls. These changes lead to the movement of leukocytes, such as neutrophils and monocytes, out of the blood vessel (extravasation) and into the infected tissue; this movement is guided by chemokines produced by the activated macrophages. The blood vessels also become more permeable, allowing plasma proteins and fluid to leak into the tissues. Together, these changes cause the characteristic inflammatory signs of heat, pain, redness, and swelling at the site of infection. Recognition of pathogen by PAMPs Activation of effector cells The cellular locations of the mammalian Toll-like receptors TLR signaling can activate the transcription factor NFκB, which induces the expression of pro-inflammatory cytokines Expression of antiviral interferons in response to viral nucleic acids can be stimulated by TLR signaling pathways. The release of TNF-α by macrophages induces local protective effects, but TNF-α can be damaging when released systemically When there is a systemic infection, or sepsis, with bacteria that elicit TNF-α production, TNF-α is released into the blood by macrophages in the liver and spleen and acts in a similar way on all small blood vessels in the body. The result is shock, disseminated intravascular coagulation with depletion of clotting factors, and consequent bleeding, multiple organ failure, and frequently death. Transport of antigen to lymphoid organs Dendritic cellsKey to initiating adaptive immune response Activation of the Adaptive Immune response Two main arms of the adaptive immune response Adaptive Immunity Cellmediated immunity T helper cells T cytotoxic cells Humoral Immunity B cells Structure of an Antibody and T-cell receptor Antigens are the molecules recognized by the immune response, while epitopes are sites within antigens to which antigen receptors bind Antigens can be complex macromolecules such as proteins, as shown in yellow. Most antigens are larger than the sites on the antibody or antigen receptor to which they bind, and the actual portion of the antigen that is bound is known as the antigenic determinant, or epitope, for that receptor. Large antigens such as proteins can contain more than one epitope (indicated in red and blue) and thus may bind different antibodies (shown here in the same color as the epitopes they bind). Antibodies generally recognize epitopes on the surface of the antigen. T-cell receptors bind a complex of an antigen fragment and a self molecule General structures of the five major antibody isotypes Can cross placenta basophils and mast cells in saliva and nasal secretions defends against parasitic invasion responsible for allergic reactions Abundant in mucosal secretions prevents passage of foreign substances into the circulatory system Efficient complement fixing Expressed on the surface of B cells Clonal expansion and differentiation to effector cells Clonal Selection of B lymphocytes Thymic education of T cells Mechanisms by which antibodies combat infection ADCC Successful vaccination -Diphtheria, polio, and measles have been virtually eliminated in the United States SSPE stands for subacute sclerosing panencephalitis, a brain disease that is a late consequence of measles infection in a few patients. MHC class I and class II molecules Classical routes of antigen presentation by MHC class I and II molecules Cytotoxic CD8 T cells recognize antigen presented by MHC class I molecules and kill the cell. CD4 T cells recognize antigen presented by MHC class II molecules Mechanism of host defense against intracellular infection by mycobacteria. Granulomas form when an intracellular pathogen or its constituents cannot be completely eliminated Within the immune synapse formed between Antigen Presenting Cells (APCs) and T cells, three signals are required for antigenspecific T cell activation J Clin Invest. 2007;117(5):1119-1127. Differentiation of naive CD4+ T cells into different T-helper-cell subsets is dependent on factors present in the local environment, most prominently cytokines Nature Reviews Rheumatology 8, 337-347 (June 2012) JAK/STAT signaling pathway Cytokines are regulatory molecules that coordinate immune responses. Cytokine receptors are transmembrane proteins that transmit a signal into the cell upon ligand binding. The systemic and mucosal immune systems use different strategies for coping with infections Five ways in which the commensal gut microbiota benefit their human hosts -The microbiota tune local and systemic immune responses. -The microbiota has local and distant effects on immune function, although only a few individual organisms and mechanisms have been identified. Memory immunity The course of a typical acute infection that is cleared by an adaptive immune response Comparison of a primary and secondary immune responseImmunological memory and Specificity Both the affinity and the amount of antibody increase with repeated immunization Somatic hypermutation Generation of memory T cells after an infection primary response of CD4 T cells that are LLO-specific the contraction and memory phase of LLO-specific CD4 T cells T cells differentiate into central memory and effector memory subsets Tissue resident memory T cells Immune responses can be beneficial or harmful, depending on the nature of the antigen Recap The components of the three phases of the immune response against different classes of microorganisms. Infections and the responses to them can be divided into a series of stages Adaptive immune response-Humoral & Cell-mediated Kuby Immunology, W.H. Freeman and Company, New York. The time course of infection in normal and immunodeficient mice and humans Immune surveillance Immune System