Presentation on theme: "IMMUNOGLOBULINS STRUCTURE AND FUNCTION"— Presentation transcript:
1 IMMUNOGLOBULINS STRUCTURE AND FUNCTION BSc Public Health5th week, 2014
2 IMMUNOGLOBULINS Definition Glycoprotein molecules that are present on B cells (BCR) or produced by plasma cells (usually referred to as antibodies) in response to an immunogen (antigen that provokes immune response)
3 B CELL ACTIVATIONGene rearrangement in an immature B cell leads to the expression of membrane-bound IgM and IgD on the mature B cell surface. After encounter with an antigen this isotype is produced in a secreted form by the plasma cell (IgM largely while IgD only is small amounts). All isotypes (IgA, IgD, IgE, IgG and IgM) can be made in two forms: the bounded immunoglobulins serving as BCRs, and soluble secreted antibodies by the plasma cells. (The difference b/w membrane bound and secreted is a hydrophobic part and hydrophilic parts at the carboxy terminus, respectively).
4 Immunoglobulin STRUCTURE 2x Heavy chain (light blue)2x light chain (dark blue)Variable regions antigen bindingConstant regionsdisulfide bondcarbohydrateCLVLCH2CH3CH1hinge regionVH
5 mIg sIg BCR (B cell receptor) Antibody Transmembrane domainAssociated chains for signalingCytoplasmic domainSOLUBLE (freely circulating)MEMBRANE BOUND!Antigen binding effector functionsProduced by plasma cellsAntigen recognition B cell activation
6 ANTIBODY DOMAINS AND THEIR FUNCTIONS Antigen recognitionVariable domainAgAgConstant domainsEffector functions
7 B CELL ACTIVATIONB cellBCR oligomerization results in B cell activation, proliferation and differentiation
8 ANTIGEN BINDING Antigen Binding Fragment (Fab) Complement binding site Placental transferConstant fragment (Fc)Binding to Fc receptors on phagocytic cells
9 HYPERVARIABLE REGIONS B cell development in the red bone marrow DNA recombination (somatic gene rearrangement) of gene segments encoding variable domains of heavy and light polypeptide chains is responsible for generation of B cells with highly variable specificityEpitopeCDR1CDR2CDR3Light chainHeavy chainCDR = complementarity determining region = hypervariable region
10 DIFFERENT VARIABLE REGIONS DIFFERENT ANTIGEN-BINDING SITES DIFFERENT SPECIFICITIES the same applies to TCRs!
11 Sequence variability of H/L-chain constant regions ISOTYPE (CLASS)Sequence variability of H/L-chain constant regionsIgG - gamma (γ) heavy chainsIgM - mu (μ) heavy chainsIgA - alpha (α) heavy chainsIgD - delta (δ) heavy chainsIgE - epsilon (ε) heavy chains
12 PHASES OF B CELL RESPONSE Gene rearrangement in an immature B cell leads to the expression of membrane-bound IgM and IgD on the mature B cell surface. After encounter with an antigen this isotype is produced in a secreted form by the plasma cell (IgM largely while IgD only is small amounts). All isotypes (IgA, IgD, IgE, IgG and IgM) can be made in two forms: the bounded immunoglobulins serving as BCRs, and soluble secreted antibodies by the plasma cells. (The difference b/w membrane bound and secreted is a hydrophobic part and hydrophilic parts at the carboxy terminus, respectively).
13 ISOTYPE SWITCHINGIsotype Switching during B Cell Development During the initial stages of a B cell’s primary response to antigen, it produces and secretes IgM. Later in the primary response or during subsequent responses, different heavy chain isotypes may be expressed by the progeny of the original IgM-producing clone. Such “switching” occurs at the DNA level, resulting in the production of an Ig protein with the same V region but a different C region. Thus, over the lifetime of a B cell clone, it may produce antibodies of the same specificity but different isotypes.
14 MAIN CHARACTERISTICS OF ANTIBODY ISOTYPES IgG1-IgG4IgA1-IgA2
16 ANTIBODY PRODUCTION DURING THE PRIMARY AND THE SECONDARY IMMUNE RESPONSESLevel of antibodiessecondary response against antigen APrimary response against antigen Aprimary response against antigen BDaysnapokAntigen AAntigen A and B
20 Complement binding site Binding to Fc receptors Antigen bindingComplement binding sitePlacental transferBinding to Fc receptors
21 OPSONIZED PHAGOCYTOSIS Flagging a pathogenAntigen binding fragment (Fab) binds the pathogen the Fc region is accessible for Fc-receptors of phagocytic cells, facilitating (speeding up) the process of phagocytosis
22 Opsonization facilitate and accelerate the recognition of the pathogens by phagocytes Main opsonins:antibodiesComplement moleculesAcute-phase proteins (CRP, SAP)Phagocytes must express receptors for the opsonins:IgG FcγRIC3b CR1
24 MAST CELL DEGRANULATION FcεRI+IgEMast cells, basophils and activated eosinophils in mucosal surfaces play a role in the defense against parasites and express the FcεRI.FcεRI has such high affinity that the IgEs, specific for many different antigens- cannot dissociate.Upon antigen binding and FcεRI cross-linking the mast cell is activated (degranulation) inflammatory mediators released, acting on vessel permeability- swelling, pain etc, and acting on smooth muscle cells Sneezing, coughing, vomiting, diarrhea.Directly killing the parasite by toxic granule content or Indirectly flushing it.An unnecessary response to an innocuous substance (pollens etc.) are an unfortunate side effect of the highly specialized and powerful antibodies.(A) High-affinity FcRs on the surface of the cell bind antibodies before it binds to antigen. (mast cell)(B) Low-affinity FcRs bind multiple Igs that have already bound to a multivalent antigen. (macrophage, NK cell)
25 Complement binding site Binding to Fc receptors Antigen bindingComplement binding sitePlacental transferBinding to Fc receptors
26 Complement binding site Binding to Fc receptors Antigen bindingComplement binding sitePlacental transferBinding to Fc receptorsFcRn on the placenta facilitate the transfer of maternal IgG to the body of the fetus
27 PRODUCTION OF IMMUNOGLOBULINS IgG transport is so efficient that at birth babies have as high a level of IgG in their plasma as their mothersThese transfers are a form of passive immunization. The babies protection by IgG and IgA is against those pathogen that the mother has mountedThe children are most vulnerable during the first year of life (esp.3-12m) when maternal IgGs have disappeared but the de novo synthesis is at low level
28 Pathological consequences of placental transport of IgG (hemolytic disease of the newborn)Passive anti-D IgGanti-RhIgMRhesus incompatibility: In case a fetus is Rh+ (meaning he expresses the D antigen on his RBCs surface) and the mother is RH- (no D antigens and no anti-D antibodies) after the first delivery when some fetal RBCs mix with maternal circulation, the mother will initiate a primary immune response towards the D antigen. These antibodies as it is the first immune response will be of IgM isotype and therefore not able to pass the placenta. However, with time, isotype switching might take place that will result in the production of IgG antibodies against the D antigen. These are now able to pass through the placenta, thus, in the second pregnancy if the fetus is Rh+ his RBCs will be attacked by maternal anti-D IgG antibodies, causing the mild to severe ‘hemolytic disease of the newborn’ (destruction of red RBCs anemia)To avoid that, i.m. anti-D IgGs are administered to the mother. These will bind any D antigens on fetal RBCs that entered the mothers circulation and prevent her from developing anti-D antibodies. The IgGs eliminate the RBCs coated with D antigens through opsonisation and elimination by macrophages and granulocytes.… One might say, well IgGs pass the placenta, then these anti D antibodies can attack the fetus RBCs- true, but the clinical course of such an event is benign and requires no treatment.
29 SECRETORY IgA AND TRANSCYTOSIS JCSs‘Stalk’ of the pIgR is degraded to release IgA containing part of the pIgR (the secretory component)JCSsJCSsMUC USJCSsJCSsIgA and pIgR are transported to the apical surface in vesiclesJCSsEpithelialcellpIgR and IgA areinternalisedPolymeric Ig receptors are expressed on the basolateral surface of epithelial cells to capture IgA produced in the mucosaJCSsplasma cells located in the submucosaproduce dimeric IgA