Immunoglobulins

The section covers the key aspects of immunoglobulins (antibodies) – their different types (classes/subclasses), how they’re built (structure), and what they actually do based on that structure (biologic/physical properties)

Think of immunoglobulins as the highly specialized security force of your adaptive immune system. They are proteins made by plasma cells (mature B cells) designed to recognize and neutralize specific foreign targets (antigens). Their brilliance lies in their structure, which perfectly equips them for this dual role

The Basic Design (Structure): The “Y” Shape

• At its core, an immunoglobulin is a Y-shaped molecule built from four protein chains: two identical Heavy (H) chains forming the stem and inner arms, and two identical Light (L) chains forming the outer arms. These are held together by disulfide bonds
• Each arm tip contains the Variable (V) region, which is unique to that antibody and forms the antigen-binding site (Fab fragment). This is where the antibody specifically latches onto its target (like the D antigen on a red cell). The incredible diversity here comes from gene rearrangement (V(D)J)
• The stem and lower arms make up the Constant (C) region (Fc fragment). This part is more consistent within an antibody class and determines the antibody’s effector functions – how it interacts with other parts of the immune system (like complement or phagocytic cells) and its general physical properties

The Different Models (Classes & Subclasses): Variations on the Theme

• The type of Heavy chain constant region dictates the antibody’s class (isotype). There are five main classes (Remember GAMED):
  • IgG (Gamma heavy chain): The most abundant Ig in serum. A monomer. The workhorse for fighting infections in blood/tissues and the star of the secondary immune response. Crucially, it crosses the placenta. Comes in 4 subclasses (IgG1, IgG2, IgG3, IgG4) with differing abilities (esp. complement activation: IgG3 > IgG1 >> IgG2)
  • IgM (Mu heavy chain): Usually a large pentamer (5 Y-units joined by a J-chain). The first responder in a primary immune response. Excellent at activating complement and agglutinating cells due to its size and multiple binding sites. Stays mainly in the bloodstream and does NOT cross the placenta
  • IgA (Alpha heavy chain): A monomer in serum, but a dimer (with J-chain and Secretory Component) in mucosal secretions (gut, lungs, tears, saliva). The guardian of body surfaces. Does NOT typically activate complement or cross the placenta
  • IgE (Epsilon heavy chain): A monomer found in very low serum levels, mostly bound to mast cells/basophils. Triggers allergic reactions
  • IgD (Delta heavy chain): A monomer primarily found on the surface of naive B cells as a receptor

Form Dictates Function (Biologic & Physical Properties)

• Size & Structure: Monomeric IgG is small enough to move into tissues and cross the placenta. Pentameric IgM is large, stays in the blood, and is great at clumping things together (agglutination)
• Antigen Binding (Fab): Specificity determined by Variable regions. IgM has high avidity (overall binding strength) due to multiple sites; IgG often develops high affinity (single site strength) during immune responses
• Effector Functions (Fc)
  • Complement Activation: IgM is the champ. IgG (esp. IgG3/IgG1) can also do it. Leads to potential cell lysis (intravascular hemolysis)
  • Opsonization: IgG’s Fc region binds well to macrophage receptors, tagging cells for destruction (extravascular hemolysis)
  • Placental Transfer: Only IgG has the Fc structure recognized for active transport across the placenta
• Location: IgG is systemic (blood/tissues); IgM is mainly blood; IgA is mucosal; IgE is on mast cells
• Half-life: IgG lasts longest (~3 weeks), IgM much shorter (~5 days)

Blood Bank Relevance - Why We Care

• HDFN: Caused by maternal IgG crossing the placenta and attacking fetal red cells. IgM cannot do this
• HTRs
  • IgM: (like ABO antibodies) often causes rapid intravascular hemolysis due to potent complement activation. Usually detected by immediate spin/RT agglutination
  • IgG: (like Rh, Kell, Duffy antibodies) often causes extravascular hemolysis via macrophage uptake in spleen/liver (opsonization). Complement activation can contribute. Usually requires the Antiglobulin Test (IAT/DAT) for detection as they are poor agglutinators (“incomplete”). Often react best at 37°C
• Antibody Identification: Knowing the likely class helps interpret reaction phases (e.g., cold reaction likely IgM, AHG reaction likely IgG). Treating plasma with DTT can destroy IgM activity, helping differentiate
• Anaphylactic Reactions: Usually due to anti-IgA (often IgG class) in IgA-deficient patients reacting with IgA in transfused products
• Allergic Reactions: Mediated by IgE causing histamine release from mast cells (hives)