بسم الله الرحمن الرحيم. Antigen Samira Rajaei, MD, PhD. Assistant professor...
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Transcript of بسم الله الرحمن الرحيم. Antigen Samira Rajaei, MD, PhD. Assistant professor...
بسم الله الرحمن الرحيم
Antigen
Samira Rajaei, MD, PhD.Assistant professor
Department of ImmunologyTehran University of Medical Sciences
Antigen definition
Antigen Anti(body)+ generator
• Antigen
• Immunogen
• Tolerogen
Which cells are the main players of adaptive immunity?
Any substance that may be specifically recognized by an antibody molecule (BCR) or T cell receptor
(TCR)
Antigen
Antibodies can recognize as antigens almost every kind of biologic molecule: Lipids Carbohydrates Proteins Nucleic acids
TCRs mainly recognize peptides
Difference between Ag recognition
Immunogen
Antigens are capable of activating lymphocyte
All antigens are recognized by specific lymphocytes ① true ②falseAll antigens are capable of activating lymphocyte① true ②false
True/False
Foreign antigens may be administered in ways that preferentially induce tolerance rather than immune responses.
These antigens are tolerogen.
Tolerogen
Small chemicals (dinitrophenol) may bind to antibodies, and are therefore antigens, but cannot activate B cells on their own (they are not immunogenic)
Hapten
Immunogenicity
Foreignness Molecular sizeChemical structure
complexityDosage, Route, individual difference, timing of
administration
Foreignness is essential to immunogenicity
Self-responsive cells are eliminated during lymphocyte ontogeny
More Foreignness; more immunogenicity
Foreignness
>100000 Dalton <10000 Dalton
Molecular size
Composition Proteins (most potent) Polysaccharides (second potent) Nucleic acids and lipids (are not immunogenic
unless …) Chemical complexity
Homopolymrs of amino acids? Which one of protein structures are more
immunogen? More complex molecules are more immunogen
Chemical structure complexity
High doses of immunogen may cause a lack of responsiveness (tolerance)
Intermediate doses of immunogen are generally the best immune response inducers
Low doses of immunogen may not induce immune responses
Dosage
Route of administration influences which cells (and how many of them) are stimulated s.c. (subcutaneous) i.d. (intradermal) i.m. (intramuscular) i.v. (intravenous) Oral administration i.n. (intranasal)
Route of immunogen administration
How to generate antibody against
haptens?
attach them to a protein before immunization which is called carrier.
attaching a number of hapten molecules to a single molecule of a polysaccharide (render it multivalent)
Hapten+Carrier
An adjuvant is any substance that enhances the immunogenicity of substances mixed with it
Many adjuvants in experimental use are microbial products, such as killed mycobacteria and LPS, that engage TLRs
What are the differences between Adjuvant and carrier? do not form stable linkages with the immunogen adjuvants are needed primarily for initial immunizations,
whereas carriers are required to elicit not only primary but also subsequent responses to haptens.
Adjuvant
Soluble : (proteins , polysaccharides) + Adjuvants
Particulate: bacteria, virus and RBCs (Adjuvants are not necessary)
Colloidal (non robust immunogens)
Physicochemical structure of Antigens
Delayed release of antigens Adjuvants convert soluble protein antigens into
particulate material, which is more readily ingested by antigen-presenting cells such as macrophages
adjuvants activate dendritic cells to express more MHC, increase the expression of costimulators, and cytokines needed for T cell activation, stimulate migration of the dendritic cells to lymph nodes .
How adjuvants enhance immunogenicity of proteins?
Freund’s adjuvant Incomplete (oil in water emulsion) Complete (oil in water emulsion and dead
mycobacteria)
Alum (aluminum hydroxide or aluminum phosphate)
Types of adjuvants
Epitope/Determinant
Macromolecules (proteins, polysaccharides, and nucleic acids) are usually much bigger than the antigen-binding region of an antibody molecule
Any antibody binds to only a portion of the
macromolecule, which is called
a determinant or an epitope
Most of the macromolecules have multiple determinants.
Polyvalency/multivalency
The presence of multiple identical determinants in an antigen is referred to as polyvalency or multivalency. Polysaccharides nucleic acids
Surface of microbs Polyvalent antigens can induce
clustering of the B cell receptors and initiate the process of B cell activation
Globular proteins
Most globular proteins do not contain multiple identical epitopes and are not polyvalent
Proteins could not cross link the B cell receptors.
They need the help of T lymphocytes. Proteins are T-dependent antigens.
Nonoverlapping determinants 2 or more antibody bind to a protein antigen No steric interference
Overlapping determinants Steric interference
Spatial arrangement of epitopes
Allosteric effects (conformational changes positively or negatively effects another antibody binding without Steric interference)
Allosteric Effects
Epitopes formed by several adjacent amino acid residues are called linear determinants.
The antigen-binding site of an antibody can usually accommodate a linear determinant made up of about 6 amino acids.
If linear determinants appear on the external surface or in a region of extended conformation in the native folded protein, they may be accessible to antibodies
More often, linear determinants may be inaccessible in the native conformation and appear only when the protein is denatured.
Linear determinants
Conformational determinants are formed by amino acid residues that are not in a sequence but become spatially juxtaposed in the folded protein.
Conformational determinants
Proteins may be subjected to modifications such as glycosylation, phosphorylation, ubiquitination, acetylation, and proteolysis.
Modifications produce new epitopes.
Neoantigenic determinants
T lymphocytes recognize linear peptide determinants in combination with MHC residues.
Epitopes determined by T cells
These molecules are able to bind to TCR complex and CD2, causing them to cluster on the cell surface, thereby mimicking the clustering caused by antigen presentation.
They activate the T cells regardless of their antigen specificity. Phytohemagglutinin (PHA), a lectin Concanavalin-A
Mitogens
Molecules that can activate T cells non-specifically
Superantigens bind to MHC class II molecules on APCs and are recognized by TCRs, but not in the same way as an MHC molecule-peptide complex.
Binding is to the Vβ chain of the TCR Staphylococcal enterotoxins Toxic shock syndrome toxin
Superantigens