Microbiome & Vaccinology Past Paper PDF

Microbiome & Vaccinology [2 0 0 2] I2B 412/BIO418 V. Stalin Raj School of Biology Vaccinations prevent future infection  Vaccine prevent future infection Vaccines can be Prophylactic (to prevent the effects of a future infection). Most of the vaccines that we know of...

Microbiome & Vaccinology [2 0 0 2] I2B 412/BIO418 V. Stalin Raj School of Biology Vaccinations prevent future infection  Vaccine prevent future infection Vaccines can be Prophylactic (to prevent the effects of a future infection). Most of the vaccines that we know of, falls into this category The administration of vaccines is called vaccination. Vaccination is the most effective method of preventing the spread of infectious diseases. widespread immunity due to vaccination is largely responsible for the worldwide eradication of smallpox and the restriction of diseases such as polio, measles, and tetanus from much of the world. Vaccination strategies are highly effective against several potentially fatal diseases Avian influenza rinderpest virus- cattle polio Avian influenza  Vaccine Smallpox was a contagious and deadly disease, causing the deaths of 20–60% of infected adults and over 80% of infected children. When smallpox was nally eradicated in 1979, it had already killed an estimated 300–500 million people in the 20th century. The rst disease people tried to prevent by inoculation was most likely smallpox, with the rst recorded cases occurring in the 16th century in China. It was also the rst disease for which a vaccine was produced. The smallpox vaccine was invented in 1796 by English physician Edward Jenner. fi fi fi fi  Small pox vaccine The terms vaccine and vaccination are derived from Variolae vaccinae (smallpox of the cow), the term devised by Edward Jenner to denote cowpox. He used it in 1798 in the long title of his Inquiry into the Variolae vaccinae Known as the Cow Pox, in which he described the protective effect of cowpox against smallpox. Cholera Vaccine Rabies Vaccine  Rabies Vaccine Pasteur chose to conduct his experiments using rabbits and transmitted the infectious agent from animal to animal by intracerebral inoculations until he obtained a stable preparation. In order to attenuate the invisible agent, he desiccated the spinal cords of infected animals until the preparation became almost nonvirulent. He realized later that, instead of creating an attenuated form of the agent, his treatment had actually neutralized it. (Pasteur perceived the neutralizing effect as a killing effect on the agent, since he suspected that the agent was a living organism.) Thus, rather unknowingly, he had produced, instead of attenuated live microorganisms, a neutralized agent and opened the way for the development of a second class of vaccines, known as inactivated vaccines. On July 6, 1885, Pasteur vaccinated Joseph Meister, a nine-year-old boy who had been bitten by a rabid dog. The vaccine was so successful that it brought immediate glory and fame to Pasteur. Hundreds of other bite victims throughout the world were subsequently saved by Pasteur’s vaccine, and the era of preventive medicine had begun. An international fund-raising campaign was launched to build the Pasteur Institute in Paris, the inauguration of which took place on November 14, 1888.  Epitopes Epitope or Antigenic Determinant: That portion of an antigen that combines with the products of a speci c immune response. fi  Immunology of vaccines Epitope: the portion of an antigen that is recognized and bound by an Ab or TCR/MHC complex (aka antigenic determinant) Paratope: “The site in the variable (V) domain of an antibody or T-cell receptor that binds to an epitope on an antigen  Epitopes for B-cells vs T-cells By examining myoglobin one can see that the Ag’s seen by B-cells and T-cells are different. B-cells see a continuous or discontinuous series of amino acids; by some circumstance, amino acid residue 109 has never been a part of an epitope for any monoclonal antibody; yet residue 109 is always part of the processed antigen seen by a TCR.  Linear and conformational epitopes Linear epitopes are formed by linear stretch residues in the antigenic protein sequence and typically vary from 5 to 20 amino acids in length. conformational epitopes are formed by residues that are far apart in the antigen sequence, and these residues are brought together in space by their folding. Although the majority of epitopes are conformational, most of them are composed of 1-5 linear stretches epitopes and speci city fi Epitopes Epitopes Locks Key B and T cell maturation  B and T cell maturation Antigen-activated B cells and T cells migrate towards the borders of the B cell follicles and the T cell zones of secondary lymphoid organs, respectively, which leads to them establishing stable B cell–T cell interactions and enables B cells to receive helper signals from cognate CD4+ T cells. Activated B cells and T cells then migrate to the outer follicles, where B cells undergo proliferation (part a). Some of the proliferating B cells differentiate into short-lived plasma cells (part b), which give rise to the extrafollicular foci, and some develop into memory B cells (part c; germinal centre-independent memory B cells). Alternatively, the activated B cells can return to the follicle and can undergo rapid proliferation to form the germinal centre (part d). In the dark zone of the germinal centre, the clonal expansion of antigen-speci c B cells is accompanied by B cell receptor (BCR) diversi cation through somatic hypermutation. The B cells that exit the cell cycle relocate to the light zone, where af nity selection takes place through interaction with immune complex-coated follicular dendritic cells (FDCs) and antigen-speci c T follicular helper cells (TFH cells). The af nity-matured germinal centre B cells can re-enter the germinal centre cycle. Alternatively, these germinal centre B cells exit the germinal centre, either as memory B cells (part e; germinal centre-dependent memory B cells) or as long-lived plasma cells (part f) that contribute to serological memory. The strength of signals that B cells receive is likely to determine their fate; stronger signals (indicated by bold arrows) favour development into plasma cells or germinal centre B cells, whereas weaker signals (indicated by narrow arrows) determine memory B cell differentiation. TCR, T cell receptor. fi fi fi fi fi Follicular dendritic cells: beyond the necessity of T-cell help 1. Model illustrating the important receptors and ligands used by T cells and follicular dendritic cells (FDCs) in signaling to B cells. The requirement for B-cell MHC class II to present antigen (Ag)-derived peptides as ligands for the T-cell receptor (TCR) is well known, as is the involvement of CD40 on the B cell interacting with T cell CD40 ligand (CD40L). The FDC–B cell interaction delivers a primary signal through FDC Ag–B-cell receptor (BCR) interaction and a cosignal through B cell CD21 interacting with FDC CD21 ligand (CD21L). The events of a recall response are summarized as follows. (1) FDCs trap Ag–antibody (Ab) complexes and provide intact Ag for interaction with BCRs on germinal center (GC) B cells; this Ag–BCR interaction provides a positive signal for B-cell activation and differentiation. (2) FDCs provide a complement-derived CD21L for B cell CD21; its interaction with the CD21–CD19–CD81 complex delivers a positive cosignal for B-cell activation and differentiation. Coligation of BCR and CD21 (as illustrated here with a single molecule of Ag) facilitates association of the two receptors, and the cytoplasmic tail of CD19 is phosphorylated by a tyrosine kinase associated with the BCR complex51. The arrow pointing from the BCR to CD19 indicates this known interaction. (3) A high density of Fc γ receptor IIB (FcγRIIB) on FDCs binds Ig Fc in the Ag–Ab complex and consequently the signal delivered by the immunoreceptor tyrosine-based inhibition motif (ITIM) in the B cells might be blocked. This inhibitory signal is initiated by Ag–Ab complexes crosslinking BCR and FcγRIIB on B cells. Note that BCR is not crosslinked with B cell FcγRIIB in the model and thus a high concentration of FcγRIIB on FDCs minimizes a negative signal to the B cell. (4) In addition, FDCs provide immune complex-coated bodies (iccosomes), which are readily taken up by B cells52. The iccosome membrane is derived from FDC membranes that have Ag, CD21L and Ig Fc attached. Iccosomes bind tightly to B cells and are rapidly endocytosed11. We reason that binding of BCR, complement receptor 2 (CR2) and possibly B cell Fc receptor (FcR) to the iccosomal Ag–CD21L–Ig Fc complex is crucial to the process of endocytosis. The B cells process this FDC-derived Ag, present it and thus obtain T-cell help. Follicular dendritic cells: beyond the necessity of T-cell help  FDC INFLUENCE ON B CELLS Recruitment FDC INFLUENCE ON B CELLS. Recruitment: FDCs secret the B cell attracting chemokine CXCL13 (1). GC B cells express the CXCL13-binding chemokine receptor CXCR5 and are thereby attracted towards the B cell follicle (2). Survival: FDCs produce B-cell activating factor [BAFF, (1)], which is involved in regulating GC B cell survival (2). IC presentation: Via their CR1s FDCs present naive antigen to GC B cells (1). Antigen-speci c GC B cells, recognizing the antigen via their BCR, endocytose, and process it into peptides (2), and subsequently present it to T follicular helper cells (TFH cells) in form of peptide- MHCII (3). TFH cells then supply cognate B cells with survival signals. It is assumed that after each round of somatic hypermutation, B cells with high- af nity BCRs are able to access antigen presented by FDCs and, thus are able to interact with TFH cells. This leads to the positive selection of such B cells, while others bearing lower af nity receptors are unable to compete for binding to limiting amounts of antigen and undergo apoptosis. Removal: the large number of GC B cells that fail to bind antigen presented by FDCs and do not receive TFH help die by apoptosis. To prevent autoimmunity, these cells have to be cleared ef ciently. FDCs secrete the apoptotic cell binding protein Mfge8 (1). Mfge8-opsonized apoptotic cells (2) are then recognized and removed by tingible body macrophages (TBMϕs, 3, 4). fi fi fi fi Polyclonal and Monoclonal Polyclonal Monoclonal