Antibodies
Immunoglobulins are soluble BCRs synthesized by plasma cells, at the end of the maturation and activation of B cells (see B cell ontogeny / B cell activation). Just like the BCR, immunoglobulins recognise native antigens, necessarily extracellular. The association of an immunoglobulin with its specific antigen forms the immune complex, involved in several crucial immunological mechanisms. There are several classes of immunoglobulins (called isotypes), which each have their own specificities.
Tertiary structure of immunoglobulin
Immunoglobulin is a heterotetramer formed of two light chains (κ or λ) and two heavy chains (µ or δ or α or δ or γ) identical in pairs. Each of these chains is the product of the V(D)J rearrangement, whose polymorphism is concentrated in the V regions (VL and VH respectively) to offer maximum diversity at the level of the paratope (Fab) which recognizes the antigen, particularly at the level of the hypervariable regions (CDR Complementary Determining Region) of the variable region of light chains (CDR1, CDR2 and CDR3). The function of the immunoglobulin is carried by the Fc fragment, which determines the isotype of the immunoglobulin.
L = Light (light chain), C = Constant
Functions
Opsonization
Immunoglobulins recognise antigens present on the surface of a target cell. Fc fragments are recognised by Fc receptors found on the surface of phagocytic cells, which facilitates the internalisation and then destruction of the antigen involved.
ADCC (Antibody-Dependent Cell-mediated Cytotoxicity)
In the same way as opsonization, immunoglobulins attached to membrane antigens (located on foreign cells for example) can bind the Fc receptor to the surface of phagocytic cells or NK cells to initiate their activation against the foreign cell.
Complement activation
The C1 complex can bind to the Fc fragments of IgM and certain IgG subtypes (IgG1 and IgG3) to activate the classical complement cascade pathway.
It is important to note that the effectiveness of an immunoglobulin in engaging the functions mentioned above depends on its isotype, with each isotype being more or less specialised for each of the functions. The ability to diffuse across the placental barrier or into mucous membranes also depends on the isotype of the immunoglobulin.
Specificity of the different classes of immunoglobulins
| Isotype | IgM | IgD | IgG | IgA | IgE |
|---|---|---|---|---|---|
| Heavy chain | μ | δ | γ | α | ε |
| Structure |  |  |  |  |  |
| Subclass | / | / | IgG1 to IgG4 | IgA1 and IgA2 | / |
| Affinity | +/- because produced by B cells, which have not undergone affinity maturation BUT counterbalanced by pentamerisation | +/- | +++ | +++ | +++ |
| Passage through mucous membranes | - | - | - | + | - |
| Passage through the placenta | - | - | + | - | - |
| Complement activation | ++ | - | Depending on the subclass, especially IgG3 ++ | - | - |
| Opsonization | ++ | ++ especially IgG1 and IgG3 | |||
| ADCC | ? | ++ | + |
It should be noted that the IgG and IgM isotypes are fundamentally pro-inflammatory because they activate complement, increase phagocytosis (for opsonization), which in turn potentiates antigen presentation, and activate ADCC, a vector of cytotoxicity.
Antibodies in organ transplantation
Antibodies directed against the graft are the absolute enemies of grafts! In fact, if recipient antibodies recognise the donor cells as foreign, they can induce an inflammatory cascade leading to rejection.
In practice, when a graft is proposed for a recipient, it is necessary to check that the recipient does not have preformed antibodies directed against the graft. To date, we mainly check the absence of anti-HLA antibodies directed against the graft , which could have been synthesised following an immunizing event (possible transfusions, first transplant or pregnancy). Following a transplant, potential rejection is monitored by looking for these same antibodies directed against the graft, also called DSA (Donor Specific Antibody).
In practice, it is difficult to determine a priori the alloreactive potential of an antibody directed against the graft. We can also question the participation of antibodies directed against graft antigens which are not HLA molecules (“non-anti-HLA antibodies”).
It should be noted that natural ABO type antibodies are present even in the absence of an immunising (an individual with blood group A naturally has anti-B antibodies and vice versa). This is why transplants are most often carried out in isogroup or ABO-compatible as part of an organ transplant from a cadaveric donor.
What needs to be remembered
Immunoglobulins are synthesized by plasma cells, that is to say B cells having evolved through the entire process of ontogeny and activation secondary to antigenic encounter (affinity maturation and class switching in particular). The main functions of immunoglobulins are complement activation, opsonization, and ADCC. Depending on the heavy chains constituting this heterotetramer, there are five isotypes - IgA, IgD, IgE, IgG and IgM - each with its own specificities. The study of immunoglobulins directed against the graft (DSA) is an essential part of the acceptance of a graft for a given recipient, then of the monitoring of the graft if necessary.
