write up vaccinology

8/8/2019 Write Up Vaccinology

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IMMUNE RESPONSE TO VACCINE ANTIGENS

Immunity :- The ability of the body to recognize the “self” cells, and to eliminate foreign

(“nonself”) materials.A vaccine is a biological preparation that improves immunity to a particular disease. It containsan agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins.The agent stimulates the body's immune system torecognize the agent as foreign, destroy it, and "recognize" it, so that the immune system canmore easily recognize and destroy any of these microorganisms that it later encounters.

Vaccine-induced immunity :- Vaccines trigger the body to think that it’s being invaded by aspecific organism. The immune system work to destroy the invader organism. If the body isexposed to a disease for which it had been vaccinated, the invading germs are met byantibodies( generated against vaccine) that will destroy them.

The immunity that develops after vaccination is similar to the immunity acquired from natural infection

Overview of the Immune Response :-

When a microbe enters the body the immune system responds in an attempt to eliminate theinfectious agent. There are two types immune systems which works to eliminate the infection.Innate immune system relies on immediate recognition of antigenic structures common to many

micro-organisms (pathogen associated molecular patterns /PAMPS)

Adaptive immune response made up of T & B lymphocytes that have unique receptors specificto microbial antigens, take time to respond



Adaptive immune response - review

Goal of Vaccination:-

Its main aim is to generate and sustain the number of antigen specific B & T cells against a particular pathogen / antigen sufficient to provide protection. Most of the successful vaccinesare against small organisms (viruses & bacteria). But there are some microorganisms that haveevolved complex defense mechanisms that interfere with the immune response. Some of theseare molecular mimicry, interference with antigen processing, prevention of apoptosis of infectedcells

Primary response to a vaccine:- Most of the current vaccines induce protective antibodies in primary immune response



Over view of primary immune response:-



Secondary immune response:- Secondary immune response to an infection primed by vaccine



Primary & secondary antibody responses vaccination & infection:-

Initiation of immune response- danger signal :-

For Initiation of immune response antigen must be recognised as foreign i.e. a danger signal.Initial recognition is likely by dendritic cells & tissue resident macrophages in non-

lymphoid tissue . Activation of dendritic cells is crucial in initiation of a primary immuneresponse

First their is a uptake of antigen which initiates antigen processing, migration of cells to lymphnodes, maturation of dendritic cells

Antigen processing:- it is of two types

endogenesis pathway:- in it, the exogenous antigens like extracellular proteins, are internalizedinto vesicular compartment of APCs (Dentritic, macrophages,B-cells. These are then degraded togenerate small peptide which bind into class II MHC molecules. Peptide-MHC II complex is

transported to surface of APCs to be presented to CD4 TH cells.



The Exogenous Pathway :-Antigens synthesised in the cell (such as viruses) are broken down to peptides

by proteasomes and transported to rough endoplasmic reticulum for loading intoMHC I molecules and transport to cell surface

Migration of cells to lymph nodes :- Antigen presenting dendritic cells migrate from the tissuesto the draining lymph nodes. The migration is controlled by chemokines & receptors.

Maturation of dendritic cells :- Dendritic cells mature to display more of the surface moleculesneeded for interaction with T cells (CD40, B7 deliver co-stimulatory signals to T cellactivation).Example of DC maturation in measles infection is shown below in diagrmaticform.



Thus mature dendritic cells activate T cells, activated TH lymphocytes becomes effectors cellsthat secrete cytokines. These cytokines stimulate other effectors cells of CMI and humoral

immune response and mediate many processes, for example : Attraction of monocytes,macrophages and lymphocytes to the site, Activation of macrophages to kill intracellular microbes, Promotion of activity of CD8 CTLs which directly kill virus infected cells,tumour cells. And cytokines also stimulate the B-cells to differentiate into memory Bcells and plasma cells that secret antibody.

• These Memory B cells converted into plasma B cells during infection with same antigenagainst which the body had been vaccinated.

Two aspects important for vaccine :-

First is the need for the “danger signal” to initiate immune response. It is done by whole micro-organism which may deliver the right signals or by some immonogenic components of wholemicro-organism. But sub-unit vaccines may be poorly immunogenic and we need adjuvant togenerate proper immune response. Adjuvants may be needed to increase “danger signal”.Secondone is the nature of the “danger signal” that has an important impact on the type of immune response generated.



At the earliest developmental stage, pro-B cells require direct contact with stromal cells in the bone marrow. This interaction is mediated by several cell-adhesion molecules, including VLA-4on the pro-B cell and its ligand, VCAM-1, on the stromal cell . After initial contact is made, areceptor on the pro-B cell called c-Kit interacts with a stromal-cell surface molecule known asstem-cell factor (SCF). This interaction activates c-Kit, which is a tyrosine kinase, and the pro-Bcell begins to divide and differentiate into a pre-B cell and begins expressing a receptor for IL-7.The IL-7 secreted by the stromal cells drives the maturation process, eventually inducing down-regulation of the adhesion molecules on the pre-B cells, so that the proliferating cells can detachfrom the stromal cells. At this stage, pre-B cells no longer require direct contact with stromalcells but continue to require IL-7 for growth and maturation.

Ig-Gene Rearrangment Produces Immature B Cells

B-cell maturation depends on rearrangement of the immunoglobulin DNA in the lymphoid stemcells. First to occur in the pro-B cell stage is a heavy-chain DH-to-JH gene rearrangement; this isfollowed by a VH-to-DHJH rearrangement .



If the first heavy-chain rearrangement is not productive, then VH-DH-JH rearrangementcontinues on the other chromosome. Upon completion of heavy-chain rearrangement, the cell isclassified as a pre-B cell. Continued development of a pre-B cell into an immature B cellrequires a productive light-chain gene rearrangement. Because of allelic exclusion, only onelight-chain isotype is expressed on the membrane of a B cell. Completion of a productive light-chain rearrangement commits the now immature B cell to a particular antigenic specificitydetermined by the cell’s heavy-chain VDJ sequence and light-chain VJ sequence. Immature Bcells express mIgM (membrane IgM) on the cell surface.The recombinase enzymes RAG-1 and RAG-2, which are required for both heavy-chain andlight-chain gene rearrangements, are expressed during the pro-B and pre-B cell stages . Theenzyme terminal deoxyribonucleotidyl transferase (TdT), which catalyzes insertion of N-nucleotides at the DH-JH and VH-DHJH coding joints, is active during the pro-B cell stage andceases to be active early in the pre–B-cell stage. Because TdT expression is turned off during the

part of the pre–B-cell stage when light-chain rearrangement occurs,N-nucleotides

B-Cell Activation and Proliferation:-

Thymus-Dependent and Thymus- Independent Antigen Have DifferentRequirements for Response.

Depending on the nature of the antigen, B-cell activation proceeds by two different routes, onedependent upon TH cells, the other not. The B-cell response to thymus-dependent (TD)antigens requires direct contact with TH cells, not simply exposure to TH-derivedcytokines.Antigens that can activate B cells in the absence of this kind of direct participation byTH cells are known as thymus-independent (TI) antigens. TI antigens are divided into types 1and 2, and they activate B cells by different mechanisms. Some bacterial cell-wall components,including lipopolysaccharide (LPS), function as type 1 thymus-independent (TI-1) antigens. Type 2 thymus-independent (TI-2) antigens are highly repetitious molecules suchas polymeric proteins (e.g., bacterial flagellin) or bacterial cell-wall polysaccharides withrepeating polysaccharide units.Most TI-1 antigens are polyclonal B-cell activators (mitogens); that is, they are able to activateB cells regardless of their antigenic specificity. At high concentrations, some TI-1 antigens willstimulate proliferation and antibody secretion by as many as one third of all B cells. The



mechanism by which TI-1 antigens activate B cells is not well understood. When B cells areexposed to lower concentrations of TI-1 antigens, only those B cells specific for epitopes of theantigen will be activated. These antigens can stimulate antibody production in nude mice (whichlack a thymus and thus are greatly deficient in T cells), and the response is not greatly augmented

by transferring T cells into these athymic mice, indicating that TI-1 antigens are truly T-cell

independent. The prototypic TI-1 antigen is lipopolysaccharide (LPS), a major component of the cell walls of gram-negative bacteria. At low concentrations, LPS stimulates the production of antibodies specific for LPS. At high concentrations, it is a polyclonal B-cell activator.TI-2 antigens activate B cells by extensively crosslinking the mIg receptor. However, TI-2antigens differ from TI-1 antigens in three important respects. First, they are not B-cell mitogensand so do not act as polyclonal activators. Second, TI-1 antigens will activate both mature andimmature B cells, but TI-2 antigens activate mature B cells and inactivate immature B cells.Third, although the B-cell response to TI-2 antigens does not require direct involvement of THcells, cytokines derived from TH cells are required for efficient B-cell proliferation and for classswitching to isotypes other than IgM.

Two Types of Signals Drive B Cells into and Through the Cell Cycle Naive, or resting, B cells are nondividing cells in the G0 stage of the cell cycle. Activation drivesthe resting cell into the cell cycle, progressing through G1 into the S phase, in which DNA isreplicated. The transition from G1 to S is a critical restriction point in the cell cycle. Once a cellhas reached S, it completes the cell cycle, moving through G2 and into mitosis (M).

Analysis of the progression of lymphocytes from G0 to the S phase revealed similarities with the parallel sequence in fibroblast cells. These events could be grouped into two categories,competence signals and progression signals. Competence signals drive the B cell from G0 intoearly G1, rendering the cell competent to receive the next level of signals. Progression



signals then drive the cell from G1 into S and ultimately to cell division and differentiation.Competence is achieved by not one but two distinct signaling events, which are designated

signal 1 and signal 2. These signaling events are generated by different pathways with thymus-independent and thymus-dependent antigens, but both pathways include signals generated whenmultivalent antigen binds and crosslinks mIg. Once the B cell has acquired an effective

competence signal in early activation, the interaction of cytokines and possibly other ligandswith the B-cell membrane receptors provides progression signals.

CLASS SWITCHING:-



Antibodies perform two important activities: the specific binding to an antigen, which isdetermined by the VH and VL domains; and participation in various biological effector functions, which is determined by the isotype of the heavychain constant domain. Classswitching allows any given VH domain to associate with the constant region of any isotype. Thisenables antibody specificity to remain constant while the biological effector activities of themolecule vary. A number of cytokines affect the decision of what Ig class is chosen when anIgM-bearing cell undergoes the class switch .



The humoral response to thymus dependent antigens is marked by extensive class switching toisotypes other than IgM, whereas the antibody response to thymus- independent antigens isdominated by IgM. In the case of thymus-dependent antigens, membrane interaction betweenCD40 on the B cell and CD40L on the TH cell is essential for the induction of class switching.

The importance of the CD40/ CD40L interaction is illustrated by the X-linked hyper-IgMsyndrome, an immunodeficiency disorder in which TH cells fail to express CD40L. Patientswith this disorder produce IgM but not other isotypes. Such patients fail to generate memorycell

populations, fail to form germinal centers, and their antibodies fail to undergo somatichypermutation.

T-Cell Maturation and the Thymus:-

Progenitor T cells from the early sites of hematopoiesis begin to migrate to the thymus at aboutday 11 of gestation in mice and in the eighth or ninth week of gestation in humans. In a manner

similar to B-cell maturation in the bone marrow, Tcell maturation involves rearrangements of thegerm-line TCR genes and the expression of various membrane markers. In the thymus,developing T cells, known as thymocytes, proliferate and differentiate along developmental

pathways that generate functionally distinct subpopulations of mature T cells.



T-cell precursors arrive at the thymus from bone marrow via the bloodstream, undergodevelopment to mature T cells, and are exported to the periphery where they can undergoantigen-induced activation and differentiation into effector cells and memory cells. Each stage of development is characterized by stage-specificintracellular events and the display of distinctive cell-surface markers.

TH-Cell Activation:-

TH cell activation is initiated by interaction of the TCR-CD3 complex with a processed antigenic peptide bound to a class II MHC molecule on the surface of an antigen-presenting cell. Thisinteraction and the resulting activating signals also involve various accessory membrane

molecules on the TH cell and the antigen-presenting cell. Interaction of a TH cell with antigeninitiates a cascade of biochemical events that induces the resting TH cell to enter the cell cycle,

proliferating and differentiating into memory cells or effector cells

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