bioinformática inmunológica grupo 5. the mammalian immune system a complex and adaptive learning...
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Bioinformática Inmunológica
Grupo 5
The Mammalian Immune System
• A complex and adaptive learning system• Evolved to defend an individual against
foreign invaders• Operates at multiple levels: from molecule to
cell, organ, organism and community
ANTIGENO
• Sustancia genética y estructuralmente extraña para el organismo receptor
• Molécula que genera una respuesta inmune: Inmunógeno (contraparte Tolerógeno)
• Molécula que reacciona con receptores específicos de células T o B (anticuerpos libres)
INMUNÒGENO
• Molécula que desencadena una respuesta inmune con producción de anticuerpos.
• Ej: Microorganismos enteros, aislados, productos metabólicos; otras sustancias
Características• Alto PM• Químicamente compleja
Moléculas complejas y mucho más inmunogénicos que los polisacáridosFormado por cientos de AaTienen muchos epítopes de diferente especificidad. Proteínas conjugadas: glicoproteinas, lipoproteínas, nucleoproteínas
PROTEINAS
RECEPTOR DE CELULA B - RECEPTOR DE CELULAS T
What Are Epitopes
• Antigenic determinants or Epitopes are the portions of the antigen molecules which are responsible for specificity of the antigens in antigen-antibody (Ag-Ab) reactions and that combine with the antigen binding site of Ab, to which they are complementary.
Properties of Epitopes
• They occur on the surface of the protein and are more flexible than the rest of the protein.
• They have high degree of exposure to the solvent.
• The amino acids making the epitope are usually charged and hydrophilic.
Epitopes • In protein antigens epitopes can be defined in terms of:
– Amino acid composition– Protein location– Length (5-15 amino acids)
• Immunodominant epitopes:– Epitopes bound by a greater proportion
of antibodies than others in a normal
in vivo immune response. – Also known as Major Antigenic Sites.
• Epitopes can be divided into 2 classes:– Discontinuous epitopes– Continuous (linear) epitopes
Epitopes could be -
contiguous (when Ab binds to a contiguous sequence of amino acids)
non-contiguous (when Ab binds to non-contiguous residues, brought together by folding).
Sequential epitopes are contiguous epitopes.
Conformational epitopes are non-contiguous antigenic determinants.
Discontinuous Epitopes
• Constitutive residues are non-sequential in the primary sequence.
• Highly conformational dependant.
• Account for approx. 90% of epitopes on a given antigenic (globular) protein.
Linear (continuous) Epitopes
• Constitutive residues are sequential in the primary sequence of the protein.
• Fewer conformational constraints on Ab recognition.
• Often contain residues that are not implicated in antibody interaction.
Epitopes
Sequential Conformational
Ab-binding sites
Types of Epitopes• Conformational / Discontinuous epitopes:
• recognized by B cells
• non-linear discrete amino acid sequences, come together due to folding.
• Sequential / Continuous epitopes:
• recognized by T cells & B cells• linear peptide fragments
•
Types of Peptide Epitope
LinearB cell
Epitope
T cell Epitope
Antibody or “B cell”
EpitopeConformational
Non-Conformational
Class II MHCs
Professional Antigen Presenting cells
Foreign proteins
8-20 amino acids
Class I MHCs
all cells
Foreign and self proteins
8-10 amino acids
B cells can recognize linear or conformational epitopes on cell surfaces, of proteins, of carbohydrates or of lipids. The B cell antigen receptor is a form of membrane Ig.
T cells recognize linear peptide fragments bound to MHC class I or class II molecules.
T cells and B cells use Distinct Antigen Receptorsto Recognize Fundamentally Different Forms of Antigen
Sperm whale myoglobin (1vxg) contains five sequential epitopes (red, green, magenta, blue, orange) and two
conformational epitopes (yellow, pink).).
T cell epitope
Denatured antigen
Linear peptide 8-30 ac
Internal (often)
Binding to T cell receptor:
Kd 10-5 – 10-7 M (low affinity)
Slow on-rate, slow off-rate (once bound, peptide may stay associated for hours to many days)
B cell epitope
Native or denatured (rare) antigen
Sequential or conformationalSequential or conformational
Accessible, hydrophilic, mobile, usually on the surface or could be exposed as a result of physicochemical change
Binding to antibody:
Kd 10-7 – 10-11 M (high affinity)
Rapid on-rate, variable off-rate
B cells and T cells recognize different epitopes of the same protein antigen
Why is the knowledge of antibody epitopes is so important?
• Vaccine design (immunogenicity, i.e. ability of vaccine to elicit in the naïve individual the production of pathogen neutralizing antibodies, is required): Purified antigen (subunit) vaccines:
• Inactivated toxins “toxoids”: tetanus toxoid, diphteria toxoid• Vaccines composed of bacterial polysaccharide antigens: flu,
pneumococcus Synthetic antigen vaccines:
• hepatitus B (recombinant protein), herpes simplex virus
• Diagnostic design (antigenicity, i.e. ability of synthetic antigen to be recognized by the original antibody, is required):
• Autoimmune diseases: lupus, rheumatoid arthritis• Allergic reactions
• Basic knowledge of antigenicity.
Respuesta Inmune
The humoral response involves interaction of B cells with antigen (Ag) and their differentiation into antibody-secreting plasma cells. The secreted antibody (Ab) binds to the antigen and facilitates its clearance from the body.
The cell-mediated responses involve various subpopulations of T cells that recognize antigen presented on self-cells. Helper T cells respond to antigen by producing cytokines. Cytotoxic T cells respond to antigen by developing into cytotoxic T lymphocytes (CTLs), which mediate killing of altered self-cells (e.g., virus-infected cells).
The Immune Response
Complejo Mayor Histocompatibilidad I
MHC
• Molécula de reconocimiento de lo propio y extraño.
• Involucrada en la respuesta inmune adquirida.
• Importante en la presentación de antígenos.
• No es exclusiva de humanos.
The genetic organization of the major histocompatibility complex (MHC) in human
Característica MHC I MHC II
Cadenas peptídicas α (44-47 kD)
β2-microglobulina(12kD)
α (32-34kD)
β (29-32kD)
Localización de residuos polimorfos
Dominio α1 y α2 Dominio α1 y β1
Punto de unión al receptor de linfocito T
Región α3 se une al CD8 Región β2
se une al CD4
Tamaño de la hendidura de unión a peptidos
8-11 a.a 10-30 a.a
Genes que codf. HLA A, HLA B, HLA C HLA DR HLA DP, HLA DQ
Carracteristícas de las moleculas de las MHC clase I y II
The structure of an MHC class I molecule determined by X-ray crystallography
The MHC class I pathway
Antigen Presenting Cell
Proteasome
Antigen
Peptides
ER
MHC I TCD8+
T-cell epitope
MHC class I molecules present antigen derived from proteins in the cytosol
MHC class I molecules do not leave the endoplasmic reticulum unless they bind peptides
Reconocimiento del linfocito T de un complejo péptido -MHC
TCR-Class I MHC peptide complex
Complejo Mayor de Histocompatibilidad II
MHC II• La generación de péptidos antigénicos y su asociación con las MHC
requiere acción concertada de moléculas accesorias como chaperonas, transportadores de péptidos y proteasas encargadas de degradar los Ags.
• Los péptidos se originan por vía endógena o exógena.
• Las MHCI, presentan péptidos de vía endógena, degradados por el proteasoma y presentados al LTCD8+.
• Las MHCII, presentan péptidos de vía exógena fagocitadas por una APC, son presentados al LTCD4+.
• En circunstancias especiales péptidos de la vía endógena son presentados por MHCII y viceversa.
•
MHCclass I
MHCclass II
Peptide binding to MHC class I -8 to 10 amino acids long -importance of N and C term -two or more anchor residues
Peptide binding to MHC class II -up to 20 amino acids long -importance of backbone contacts -two or more anchor residues
Peptide recognition by MHC molecules
MHC molecules present antigen from 3 main sources
The immunoglobulin fold
Common Structures - Both the antibodies of the humoral response and the molecules involved in the cellular response (antibody, TCR, most CD [cell surface molecules expressed on various cell types in the immune system]) contain elements of common structure.
The domains in these molecules are built on a common motif, called the immunoglobulin fold, in which two anti-parallel sheets lie face to face. This structure probably represents the primitive structural element in the evolution of the immune response. The immunoglobulin fold is also found in a number of other proteins.