Immunology, Exam 2, 2023

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119 Terms

1

Haptens

  • Low molecular weight substances

  • Not immunogenic by itself

  • Couple to a larger carrier molecule to become immunogenic

  • The smallest part of an antigen that is recognized by B and T cell receptors

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Immunogen

  • An antigen that induces an immune response

  • Contain epitopes

  • All immunogens are antigens, but not all antigens are immunogens

  • Foreign, large, and chemically complex

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Epitope

  • Portion of an antigen that is recognized and bound by an antibody/T-cell receptor

  • Antigenic determinant

  • Immunologically active regions of an antigen that bind to receptors on lymphocytes/antibodies.

  • B cells and T cells recognize different types on the same antigenic molecule.

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Antigen

  • Any substance that binds to a B cell receptor, antibody or T cell receptor.

  • Combine specifically with antibodies produced by B-lymphocytes or sensitized T-lymphocytes

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Multivalent Antigen

Many epitopes of the same specificity

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Polyvalent Antigen

Many epitopes of different specificities

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Transplantation antigens

  • Poteins expressed on the donor tissue that have the capacity to initiate an immune reaction against the allograft.

  • Blood group antigens

  • Histocompatibility antigens

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Blood group antigens

  • A

  • B

  • Rh antigens

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9

Histocompatibility antigens

  • Glycoprotein molecules on all nucleotide cells

  • MHC and HLA

  • Most potent are class I and class II molecules of the MHC

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MHC

  • Cell surface proteins

  • Adaptive immune system

  • Recognition of foreign molecules

  • Determines histocompartibility

  • Helper T-cells recognize foreign antigens on surface of APCs when antigens are presented in the groove of MHC II

  • Cytotoxic T-cells recognize antigens, on the surfaces of cells when antigens are presented in the groove of MCH I

  • Poolymorphism

  • Capability to react with an antigen preexists

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Exogenous Antigens

  • Come from foreign substances that enter the body through cuts, nose, skin ,mouth etc

  • Bacterial antigens

  • Viral antigens

  • Superantigens

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Antigens related to bacterial cells

  • Somatic antigen: part of cell wall gm –ve bacter.

  • Capsular antigen: usually polysaccharide

  • Flagellar Ag: a protein made of flagellin

  • Fimbrial Ag: surface antigens in fimbriated bacilli

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Antigen secreted by bacteria

  • Exotoxins

  • Enzymes

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Viral antigens

  • protein coat viral antigens

  • Soluble antigens

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Superantigens

  • They activate multiple clones of T-lymphocytes

  • Bacterial toxins

  • They have the ability to bind both class II MHC molecules and TCR β chain

  • They act as a clamp providing a signal for T-cell activation

  • Active at low concentration and release of large amounts of cytokines

  • Not specific for the pathogen

  • No memory

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Autoantigens

  • Capable of immunizing the host from which they are obtained.

  • Self antigens are non-antigenic

  • Modifications of self-antigens are capable of eliciting an immune response

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Endogenous Antigens

  • Antigens found within the cytosol of cells

  • viral proteins

  • tumor proteins

  • Proteins from intracellular bacteria

  • They come from the body’s cell

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Immunogencity

is the ability to induce a humoral and/or cell-mediated immune response

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Factors influencing Immunogenicty

  • influence the potency and diversity of host immune responses to antigens

  • High molecular weight and complexity increase immunogenicty

  • Parenteral routes are more immunogenic to oral route

  • Substance when injected with an antigen enhance immunogenicty

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Alloantigen

Any antigen that stimulates the production of antibodies in those that lack it (an isoantigen)

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Zenoantigen

an antigen that occurs in organisms of more than one species

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Zenograft

a graft of tissue taken from a donor of one species and grafted into a recipient of another species

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23

How antigen degradability influences immunogenicity

  • T lymphocytes respond only to processed protein antigens

  • Antigen-presenting cells

  • Process and present antigenic peptides to T cells

  • Activate T cells

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Antigens are recognized by and bind to

  • BCR

  • TCR

  • MHC

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B-cell receptors (BCR)

  • These are membrane-bound immunoglobulins on B-cells

  • Can be secreted in plasma as antibodies

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T-cell receptors (TCR)

  • α and β chains anchored to T-cells

  • There is a groove which binds small peptides

  • presented by MHC on surface of APCs

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Cross-reacting Antigens

  • Antigens that share identical or very similar epitope

  • It is a measure of relatedness between two different antigens

  • Heterophile Antigens

  • Cross-Protection

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Antigen binding molecules

  • Immunoglobulin

  • T cell receptor

  • MHC molecules

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Carrier proteins produces

Anticarrier antibody

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Hapten-carrier conjugate produces

  • Anticarrier antibody

  • Antihapten antibody

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Autocoupling Haptens

  • Haptens that spontaneously form covalent bonds with host cell proteins or polysaccharides

  • Usually results in allergic phenomena

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Adjuvants

  • molecules which interact with the immune response to make a molecule that is not antigenic more antigenic

  • Adjuvants enhance the immune response

  • Commonly used in vaccines

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The Instructional Theory

This was the concept that a par-ticular antigen would serve as a template around which antibody would fold

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The Selective Theory

  • This was the concept that cells possessed antigen receptors that could react with specific infectious agents

  • The specificity of the receptor was determined prior to antigen exposure and that antigen selected the cell with the appropriate receptor

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Immunoglobulins

  • immunoglobulins are proteins that specifically react with the antigens that triggered their production.

  • They make up 20% of all proteins in the blood serum.

  • Antibody fractions are found in both serum and plasma.

  • Antibodies can exist either in a soluble form or attached to the surface of B cells.

  • Heavy and light chains chains linked by disulfide bonds

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B cell receptor

  • carry receptors on their surfaces called BCRs

  • Are membrane-bound immunoglobulin

  • May be monomeric IgM or IgD

  • Function to recognize and bind specific antigen

  • Are associated with accessory molecules that aid in signal transduction

  • Are sulphide-linked heterodimers

  • Contain ITAMs

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Fab fragment

  • Immunoglobulin subunits

  • Binds with antigen (variable)

  • Detects antigen

  • Precipitate antigen

  • Block the active sites of toxins or pathogen-associated molecules

  • Block interactions between host and pathogen-associated molecules

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Fc fragment

  • Immunologic trigger (non-variable)

  • Binds complement and receptors

  • Fc structure is common to all specificities of antibody within an ISOTYPE

  • The structure acts as a receptor for complement proteins and a ligand for cellular binding sites

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Hypervariable region

  • Found on both heavy and light chain of the immunoglobulin

  • Responsible for specific binding to antigen

  • Comprises one domain

  • Interaction of VH and VL

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Constant region

  • Responsible for triggering

  • Comprises three domains

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Antibody isotypes

  • IgM, IgG, IgA, IgE, IgD

  • Differences lie in heavy chain types

  • Kappa or Lambda light chains with any of the classes

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Allotypes

Genetically determined differences in antibodies between different animals

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Idiotypes

Antibodies that recognize different specific epitopes

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Heavy chain

  • Determines the immunoglobulin class the receptor becomes or the antibody the cell will secrete.

  • V, D, J segments

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Light chain

  • λ (lambda) or κ (kappa)

  • Each antibody molecule contains either λ or κ, but not both

  • V and J segments

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IgM

  • Present as surface B cell receptor or pentamer

  • Can fix / activate complement

  • Can cause agglutination of large particles

  • First ab secreted after activation little in quantity but with 10 ag.

  • Binding sites, good for agglutination and complement fixing

  • Cμ - constant portion

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pentamer

  • secreted IgM form in blood

  • secreted only during primary immune response to an antigen

  • 5 units joined by a J chain

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IgG

  • Most prevalent

  • Contains gamma heavy chain

  • Is a monomer

  • Four subclasses (IgG1-4)

  • Longest half-life

  • Activate complement

  • Can cross the placenta and confers immunity to developing fetus

  • Bind to & coat large antigens marking them for phagocytosis (opsonins)

  • Can bind to Fc receptors on macrophages & neutrophils and facilitate phagocytosis

  • Cγ- constant portion

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IgA

  • Monomeric is found in serum

  • Dimeric is found in secretions

  • Joined by a J chain

  • Accompanied by a secretory component which aids in transfer across epithelial cells

  • Four binding sites

  • Important in mucosal regions

  • Cα - constant portion

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IgE

  • The primary trigger of “allergic” reactions

  • A trigger for mast cells and basophils

  • Stimulates release of cytokines that mediate allergy

  • Is the primary defense against multicellular parasites (Bind to antigens on the surface of the worm then binds to eosinophils causing them to degranulate)

  • Cε - constant portion

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IgD

  • The mystery immunoglobulin

  • Exists on the surface of B cells as a receptor

  • Small amount of IgD is found free in the serum

  • Cδ - constant portion

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Agglutination

  • IgM, IgG, IgA

  • Enhances phagocytosis and reduces number of infectious units

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Opsonization

  • IgG

  • Coating antigen with antibody to enhance phagocytosis

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Toxin Neutralization

  • IgG, IgA, IgM

  • Antibody blocks binding of toxin

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Complement Activation

  • IgM, IgG

  • Cell lysis

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Antigen-Antibody Interaction

  • Electrostatic interactions

  • Hydrogen bonds

  • Van der Waals forces

  • Hydrophobic interactions

  • Similar to enzyme-substrate, receptor-ligand

  • Antigen-antibody interaction is extremely specific

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Antigen-Antibody Good Fit Interactions

high attraction and low repulsion

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Antigen-Antibody Poor Fit Interactions

high repulsion and low attraction

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Cross-reactivity and antigen binding

  • if the antibody can bind similar, but different antigens

  • Avidity will always be higher for the original antigen

  • If there is competition, the original antigen will win

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During B cell development

  • L, J, D segments are rearranged and assembled into functional genes

  • functional genes are then transcribed and translated into the peptide chains of the immunoglobulin/surface B cell receptor

  • this step does NOT require the presence of antigen

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Somatic Hypermutation

  • Occurs in stimulated proliferating B cells

  • Point mutations in genes encoding the Variable region

  • Results in progeny B cells producing BCRs/antibodies with different affinities for the same antigen

  • Responsible for Affinity maturation

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Affinity maturation

B cells with receptors having better affinitiy for antigen are more likely to proliferate, since they bind to antigen more competitively

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Class Switching

  • A plasma cell may switch/change the heavy chain of the antibody it secretes

  • The effector-end of the antibody molecule is different

  • The specificity for antigen is unaltered

  • Occurs In Memory B Cells

  • The light chains do not change, just the constant heavy chain

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Polyclonal antibodies

Refers to the different antibodies produced against various antigens of a single infectious agent

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Monoclonal antibodies

  • Refers to antibodies derived from a single clone of B cells

  • All the antibodies derived will have specificity for a single antigen

  • Used in many tests

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Membrane-bound antibody

  • Serve as receptors on B cells – can detect presence of antigen and generate signals

  • Membrane bound antibodies have an additional anchoring segment

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Secreted antibodies

  • Serve to execute certain functions

  • Initiation of the complement cascade

  • Signal certain cells to kill

  • Directly kill/neutralize

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B cell recognition

  • Directly recognize and bind antigen

  • Can recognize diverse antigens

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T cell recognition

  • Can ONLY recognize antigens when presented by MHC molecules

  • Recognize only peptide antigens

  • Heterodimer (2 αβ chains embedded in the T cell membrane)

  • Has C and V domains

  • No class switching

  • No somatic hypermutation

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TCR Accessory molecules

  • Associated closely with TCR

  • Needed for signal transduction

  • CD4 (helper T) or CD8 (cytotoxic T)

  • CD3 complex

  • Zeta-zeta dimer

  • LFA-1 (CD11)

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TCR C domains

close to the membrane

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V domains

  • Distant from the membrane

  • Have 3 hypervariable regions arranged in a flat surface

  • Are specific for a single sequence of amino acids AND the amino acids present on an MHC molecule

  • Has a peptige (antigen) binding groove

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CD4 (helper T) or CD8 (cytotoxic T)

Co-receptor, senses MHC molecule attached to antigen

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CD3 complex

Four peptide chains which transduce signals

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Zeta-zeta dimer

Have ITAMS for conveying signals to the interior of the T cell to the nucleus so transcription and translation can occur

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LFA-1 (CD11)

is an integrin that docks the T cell to the APC

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ITAMs

  • Immunoreceptor tyrosine-based activating motifs

  • Activated by phosphorylation

  • Are BCR & TCR accessory proteins, and several other receptor proteins

  • Essential for signal transduction

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γδ T Cells

  • Mysterious

  • Derived from a separate cell lineage

  • May be 1st line defense at epithelial tissues

  • NOT MHC restricted

  • May recognize carbohydrate antigens presented by a CD1 molecule (similar to an MHC)

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MHC Class I

  • Found on all nucleated cells

  • heterodimers – α chain (contains groove) and β chain (does not insert inro cell membrane)

  • presents endogenous (intracellular) peptides

  • Presents antigen to cytotoxic T cells

  • Bind to CD8

  • The presence of foreign material targets cell for destruction

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MHC Class II

  • heterodimers – α chain and β chain that insert into the membrane

  • peptide binding groove is located in the α chain AND the β chain

  • groove is longer

  • found on B cells, macrophages, and dendritic cells

  • present exogenous peptides to T helper cells

  • Presents antigen to helper T cells

  • Bind to CD4

  • The presence of foreign antigens induces antibody production and attracts immune cells

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MHC Restriction

  • T cells are specific for both antigen and MHC molecule

  • The T cell can only react with its specific antigen if it is presented by a “self” MHC molecule

  • TCR interaction with self MHC is learned in the thymus during development

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Antibody diversity

  • Gene rearrangement

  • Somatic hypermutation (affinity maturation)

  • Class switching

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TCR / BCR diversity

gene rearrangement

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Bone Marrow

  • Primary and secondary lymphoid organ

  • Site of early events in B cell development

  • Site of long-lived plasma cells

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RAG-1/RAG-2

Operate during gene rearrangement in BOTH T and B cells

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Primary lymphoid organs

  • Location where lymphocytes develop and mature to a stage where they can interact with antigen

  • Thymus, Bursa of Fabricius, Bone marrow, and Peyer’s patches

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Secondary lymphoid organs

  • They are a site of further lymphocyte maturation,

  • Trap antigens for exposure to T and B cells.

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Functions of the Lymphoid tissues and organs

  • the concentration of foreign antigen from all parts of the body into the lymphoid organs and tissues

  • lymphocyte circulation to facilitate interaction between antigen and antigen-sensitive lym-phocytes

  • carry products of the adaptive immune res-ponse [antibodies and effector cells] to the bloodstream and various organs and tissues

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Lymphopoiesis

  • To generate a diverse set of lymphocytes  each with a unique receptor.

  • To get rid of lymphocytes that have receptors that react against self antigen

  • To allow non-self reactive lymphocytes to continue  to mature and move to the peripheral lymphoid organs for activation

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Hematopoietetic stem cell in the bone marrow

  • matures to a common lymphocyte progenitor cell

  • Can become either a B or T cell.

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Common lymphocyte  progenitor

  • To become a B cell, develops to immature B cell in the bone marrow

  • Completes it maturation to antibody secreting B cell or plasma cell in lymph nodes and the spleen

  • To become a T cell migrates to the thymus gland to become a thymocyte and completes its maturation to a T cell

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IL-7

Stimulates growth and proliferation

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Stromal cells provide developing B cells

  • Constant interaction

  • Adhesion molecules for attachment

  • Growth factors like IL 7 for growth and proliferation

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B cell development

  • six stages

    • common lymphoid progenitor

    • Early pro-B

    • Late pro-B

    • Large B

    • Small B

    • Immature B

  • permanent changes in its DNA

  • receptor that binds to a specific foreign antigen but not self.

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The B cell receptor Antigen biding site

  • The specificity to a receptor is determined  by the shape of the variable region of the receptor

  • made of 3 protein segments: Variable- V,  Diversity-D and Joining –J

  • The region where the H and L chains come together

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Deficiency of RAG genes causes

Severe Combined immunodeficiency or Omenn syndrome.

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genetic defect in the recombinase complex

  • Severe Combined Immunodeficiency (SCID).

  • These animals are unable to make functional B cell and T cell receptors because they cannot successfully rearrange their DNA.

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Autoimmune  Regulator gene (AIRE)

  • Expressed by the primary lymphoid organ

  • Allows them to express antigens normally expressed in other body tissues-liver brain, spleen etc. Hence serving as microcosm of the entire body

  • B cell receptors are tested in the safe bone marrow environment

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Negative selection

  • Small Pre-B cell binds strongly to a self antigen

  • APOPTOSIS

  • Thymocytes whose TCRs react strongly with self antigen-MHC complexes; or cannot react with antigen-MHC complexes

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Positive selection

Only Small Pre-B cells that do not recognize self antigens at all develop to immature B cells

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