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Blood Bank

Classes & Subclasses

Think of immunoglobulins, or antibodies, as the specialized tools your immune system creates to target specific threats. While they all share a basic structure, they come in different “models” – called classes and subclasses – each designed for slightly different jobs and locations in the body. Understanding these is super important in blood banking because different antibody classes have vastly different clinical significance!

The class (and subclass) of an immunoglobulin is determined by its heavy chain – the larger protein chains in its structure. There are five main types of heavy chains, corresponding to the five main Ig classes:

  • Gamma (γ): heavy chains define IgG
  • Mu (μ): heavy chains define IgM
  • Alpha (α): heavy chains define IgA
  • Epsilon (ε): heavy chains define IgE
  • Delta (δ): heavy chains define IgD

(Remember the mnemonic GAMED for the five classes!)

Now, let’s look at each class and its subclasses (where applicable):

Immunoglobulin G (IgG)

The workhorse of the adaptive immune response, especially in the blood!

  • Heavy Chain: Gamma (γ)
  • Structure: Monomer (a single Y-shaped unit)
  • Concentration: Highest concentration in serum (~75-80% of total serum Ig). Found in blood, lymph, and tissue fluids
  • Key Functions
    • Major player in secondary immune responses: Produced in large amounts upon re-exposure to an antigen
    • Neutralizes toxins and viruses.
    • Opsonization: Coats pathogens, making them easier for phagocytes (like macrophages) to engulf (binds via its Fc region to Fc receptors on phagocytes)
    • Activates the classical complement pathway: But requires two IgG molecules close together
    • Crosses the placenta: Provides passive immunity to the fetus and newborn. Crucial point!
    • Long half-life: Persists in circulation for weeks (around 23 days)
  • Blood Bank Relevance
    • Most clinically significant alloantibodies: (antibodies against foreign red cell antigens like Rh, Kell, Duffy, Kidd) that cause hemolytic transfusion reactions (HTRs) and Hemolytic Disease of the Fetus and Newborn (HDFN) are IgG
    • Many warm autoantibodies (reacting with self-antigens at 37°C) are IgG
    • Detected best by the Indirect Antiglobulin Test (IAT) or Direct Antiglobulin Test (DAT) because they are often non-agglutinating on their own (“incomplete” antibodies)

IgG Subclasses

There are four subclasses of IgG (IgG1, IgG2, IgG3, IgG4), determined by slight variations in their gamma heavy chains. They differ primarily in their abundance and functional capabilities:

  • IgG1: Most abundant (~65% of total IgG). Good all-around performer: crosses placenta well, activates complement, binds Fc receptors. Many Rh antibodies (like anti-D) are IgG1
  • IgG2: Second most abundant (~23%). Primarily responds to polysaccharide antigens (like bacterial capsules). Poor complement activator and crosses the placenta less efficiently than IgG1 and IgG3
  • IgG3: Less abundant (~8%). Most effective complement activator among IgG subclasses! Crosses the placenta well and binds Fc receptors effectively. Has a shorter half-life than other subclasses. Some potent alloantibodies (like certain anti-Jka) can be IgG3
  • IgG4: Least abundant (~4%). Does not activate the classical complement pathway. Can cross the placenta. Its role is complex, sometimes associated with allergy responses or immune tolerance. Rarely implicated alone in significant red cell hemolysis, but can be present in some autoimmune conditions

Key Subclass Takeaway Differences in complement activation (IgG3 > IgG1 >> IgG2, None for IgG4) and placental transfer (all cross, IgG2 less so) are the most clinically relevant distinctions for blood bankers!

Immunoglobulin M (IgM)

The “first responder” antibody!

  • Heavy Chain: Mu (μ)
  • Structure: Pentamer (five Y-shaped units joined together by a J-chain) in its secreted form. Looks like a snowflake! It also exists as a monomer on the surface of naive B cells as the B cell receptor (BCR)
  • Concentration: About 5-10% of total serum Ig. Mostly confined to the bloodstream due to its large size
  • Key Functions
    • Predominant antibody in the primary immune response.
    • Excellent activator of the classical complement pathway: Its pentameric structure provides multiple binding sites for C1q, making it very efficient
    • Efficient agglutinator: Its large size and multiple binding arms (10 potential binding sites, though usually only 5 are functional due to steric hindrance) make it great at clumping cells (like red blood cells)
    • Does NOT cross the placenta: (generally too large)
    • Shorter half-life than IgG (~5 days)
  • Blood Bank Relevance
    • Naturally occurring ABO antibodies (anti-A, anti-B): are primarily IgM. This is why ABO incompatibility can cause rapid intravascular hemolysis (due to potent complement activation)
    • Many cold-reactive antibodies (reacting best below 37°C), both alloantibodies (like anti-M, -N, -P1) and autoantibodies (like anti-I, anti-i associated with Cold Agglutinin Disease), are IgM
    • Often detected by immediate spin or room temperature phases of testing due to their agglutinating ability (“complete” antibodies)

Immunoglobulin A (IgA)

The guardian of mucosal surfaces!

  • Heavy Chain: Alpha (α)
  • Structure
    • Serum IgA: Primarily a monomer
    • Secretory IgA (sIgA): Dimer (two units) joined by a J-chain and complexed with a Secretory Component. This component protects it from enzymatic digestion in harsh mucosal environments
  • Concentration: About 10-15% of total serum Ig, but it’s the most abundant Ig overall in the body due to its high concentration in secretions. Found in tears, saliva, mucus (respiratory, GI, GU tracts), sweat, and breast milk
  • Key Functions
    • Mucosal Immunity: Prevents attachment of bacteria and viruses to mucous membranes (immune exclusion). Neutralizes toxins locally
    • Does NOT typically activate the classical complement pathway
    • Passed to newborns via breast milk, providing passive mucosal immunity
  • Blood Bank Relevance
    • Usually not directly involved in red cell destruction
    • Clinically Significant: Patients who are IgA deficient (the most common primary immunodeficiency) can produce anti-IgA antibodies if exposed to IgA through plasma-containing blood products. Re-exposure can lead to severe anaphylactic transfusion reactions. These patients require IgA-deficient blood products (e.g., washed red cells/platelets or products from IgA-deficient donors)

IgA Subclasses

  • IgA1: Predominant in serum and produced by bone marrow plasma cells
  • IgA2: Predominant in secretions, especially in the colon. More resistant to bacterial proteases than IgA1

Immunoglobulin E (IgE)

The allergy and parasite defender!

  • Heavy Chain: Epsilon (ε)
  • Structure: Monomer
  • Concentration: Lowest concentration in serum. Most IgE is bound to the surface of mast cells and basophils via high-affinity Fc receptors (FcεRI)
  • Key Functions
    • Allergic Reactions: When antigen (allergen) binds to IgE on mast cells/basophils, it triggers degranulation – the release of histamine, leukotrienes, and other inflammatory mediators, causing allergic symptoms (hives, asthma, anaphylaxis)
    • Defense against parasitic worms (helminths).
  • Blood Bank Relevance
    • Responsible for allergic transfusion reactions, ranging from mild urticaria (hives) to potentially severe anaphylaxis (though anaphylaxis in transfusion is more commonly associated with anti-IgA)

Immunoglobulin D (IgD)

The mysterious one, mostly found on B cells

  • Heavy Chain: Delta (δ)
  • Structure: Monomer
  • Concentration: Very low concentration in serum. Primarily found on the surface of naive B lymphocytes, often co-expressed with IgM, acting as a B cell receptor (BCR)
  • Key Functions
    • Involved in B cell activation and differentiation. Signals when the naive B cell encounters its specific antigen
    • Serum function is largely unknown
  • Blood Bank Relevance
    • No known direct role in transfusion reactions or routine blood bank testing

Summary Table

Feature IgG IgM IgA (Secretory) IgE IgD
Heavy Chain Gamma (γ) Mu (μ) Alpha (α) Epsilon (ε) Delta (δ)
Structure Monomer Pentamer (+ J chain) Dimer (+ J chain, Secretory Comp.) Monomer Monomer
Serum Conc. Highest (~75%) Moderate (~10%) Lower (~15% serum, HIGH in secretions) Lowest Very Low
Location Blood, Tissues Blood Secretions, Mucosa Bound to Mast Cells/Basophils B cell surface, Low serum
Placental Transfer YES (esp. IgG1, IgG3) NO NO NO NO
Complement (Classic) YES (IgG3>IgG1>>IgG2, No IgG4) YES (Very Effective) NO NO NO
Key Function Secondary Response, Opsonization, HDFN Primary Response, Agglutination, ABO Abs Mucosal Immunity Allergy, Anti-Parasite B cell Receptor/Activation
BB Significance HTR, HDFN, Warm AutoAbs ABO Abs, Cold Agglutinins, Early AlloAbs Anti-IgA -> Anaphylaxis (if deficient) Allergic Reactions (Urticaria) Minimal

Key Terms

  • Immunoglobulin (Ig) / Antibody: Glycoproteins produced by plasma cells (differentiated B lymphocytes) that specifically bind to antigens. They are key components of the humoral immune response
  • Class (Isotype): The major categories of immunoglobulins (IgG, IgM, IgA, IgE, IgD) determined by the type of heavy chain (gamma, mu, alpha, epsilon, delta, respectively) present in the molecule. Each class has distinct structural characteristics and effector functions
  • Subclass: Further divisions within certain immunoglobulin classes (specifically IgG and IgA), based on minor variations in their heavy chains (e.g., IgG1, IgG2, IgG3, IgG4; IgA1, IgA2). Subclasses can differ in their functional properties, such as complement activation or placental transfer efficiency
  • Heavy Chain: The larger of the two types of polypeptide chains that make up an immunoglobulin molecule. The amino acid sequence of the constant region of the heavy chain determines the immunoglobulin’s class and subclass
  • IgG (Immunoglobulin G): The most abundant immunoglobulin class in serum, existing as a monomer. It dominates secondary immune responses, readily crosses the placenta, and includes most clinically significant red blood cell alloantibodies responsible for HTR and HDFN
  • IgM (Immunoglobulin M)
    • Definition: An immunoglobulin class existing as a large pentamer (in serum) joined by a J-chain. It is the first antibody produced in a primary immune response, is very efficient at activating complement, and includes naturally occurring ABO antibodies. It does not cross the placenta
  • IgA (Immunoglobulin A): An immunoglobulin class found as a monomer in serum but primarily as a dimer (secretory IgA) in mucosal secretions. Its main role is mucosal immunity. Clinically relevant in blood banking due to potential anti-IgA antibodies in IgA-deficient individuals causing anaphylactic reactions
  • Placental Transfer: The ability of an immunoglobulin class, specifically IgG, to pass across the placental barrier from mother to fetus via active transport involving Fc receptors on placental cells. This provides passive immunity to the newborn but is also the mechanism by which maternal IgG antibodies cause HDFN
  • Complement Activation (Classical Pathway): The ability of certain immunoglobulin classes (primarily IgM and some IgG subclasses, notably IgG3 and IgG1) to initiate the classical complement cascade upon binding to an antigen. This leads to inflammation, opsonization, and potentially cell lysis (e.g., intravascular hemolysis)
  • J-Chain (Joining Chain): A small polypeptide chain that links immunoglobulin monomers together to form the polymeric structures of IgM (pentamer) and secretory IgA (dimer)