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Ii

The Ii blood group system (ISBT 027) is unique as its antigens, i and I, represent different structural arrangements – linear versus branched – of the same repeating N-acetyllactosamine carbohydrate chains. This system is characterized by a significant developmental shift, with fetal/newborn red cells expressing predominantly linear i antigen, which transitions to the branched I antigen on adult red cells due to the increasing activity of a specific branching enzyme. These I/i structures also serve as the crucial carbohydrate backbone for the synthesis of other important blood group antigens like ABO and H

The Building Blocks: Linear vs. Branched Chains

Unlike systems defined by single amino acid changes (like MNS, Rh C/c) or single sugar additions (like ABO), the I and i antigens represent different arrangements of the same basic repeating sugar unit: N-acetyllactosamine (LacNAc), which is Galactose linked to N-acetylglucosamine (Galβ1→4GlcNAc)

  • i Antigen: Characterized by LINEAR, repeating chains of N-acetyllactosamine units (Galβ1→4GlcNAcβ1→3Galβ1→4GlcNAc…)
    • Think of it like a simple, straight chain of beads
    • This linear structure is the predominant form found on fetal and newborn red blood cells
  • I Antigen: Characterized by BRANCHED N-acetyllactosamine chains
    • The branching occurs when an additional N-acetyllactosamine unit is added via a β1→6 linkage to an internal galactose residue within the linear chain
    • Imagine branches coming off the main trunk of the chain
    • This branched structure becomes the predominant form on adult red blood cells

The Biochemistry: The Branching Enzyme

The transition from the linear ‘i’ structure to the branched ‘I’ structure is controlled by a specific enzyme:

  • Enzyme: β-1,6-N-acetylglucosaminyltransferase (I-branching enzyme)
  • Gene: GCNT2
  • Action: This enzyme creates the crucial β1→6 linkage that adds the “branch” onto the linear i-active chains
  • Developmental Control: The activity of this enzyme is very low in fetuses and newborns but increases significantly during the first 18-24 months of life. This enzymatic change drives the conversion of i antigen to I antigen on the red cell surface

Developmental Expression: The Big Switch

This change in antigen expression from birth to adulthood is a hallmark of the Ii system:

  • Newborn RBCs: Rich in i antigen (linear chains), poor in I antigen (few branched chains). Cord blood cells are an excellent source of i+ cells for testing
  • Adult RBCs: Rich in I antigen (branched chains), with only small amounts of residual i antigen
  • Transition Period: Takes place gradually over the first ~2 years of life as the branching enzyme activity ramps up

Foundation for Other Blood Groups

Crucially, the I and i carbohydrate structures are not just antigens in their own right; they form the backbone upon which other important carbohydrate blood group antigens are built:

  • ABO Antigens: The H antigen (precursor to A and B) is formed by adding fucose to the terminal galactose of these I/i chains (specifically Type 2 chains on RBCs). The A and B transferases then add their specific sugars onto the H structure
  • Lewis Antigens: Lewis antigens are built on Type 1 chains, which also have underlying i/I structures, primarily in secretions and plasma

So, the complexity of the I/i branching pattern underlies the structure where ABO/H antigens are added

Location of Ii Antigens

Ii antigens are widely distributed:

  • Red Blood Cells: As integral parts of glycoproteins and glycolipids
  • Other Cells: Leukocytes, platelets
  • Body Fluids: Present on soluble glycoproteins in plasma, saliva, milk, amniotic fluid, etc

Ii System Antibodies

Antibodies in this system are relatively common, particularly autoantibodies

  • Anti-I
    • Type: Often a naturally occurring autoantibody, usually IgM
    • Reactivity: Typically a cold agglutinin, reacting best at 4°C. Agglutination weakens or disappears as the temperature increases towards 37°C. Reactivity is often enhanced by enzyme treatment of test cells
    • Clinical Significance
      • Benign Autoanti-I: Very common. Can interfere with in vitro testing at room temperature (e.g., ABO reverse grouping, immediate spin crossmatch, antibody screening) but is usually harmless in vivo because it doesn’t react at body temperature. Prewarming techniques are used to bypass its interference
      • Pathologic Autoanti-I: Less common, but significant. These antibodies have a high thermal amplitude (reactivity extends to 30°C or higher) and/or high titer. They can cause Cold Agglutinin Syndrome (CAS), a type of autoimmune hemolytic anemia where the antibody binds in cooler extremities and activates complement, leading to hemolysis upon warming in the central circulation
    • Association: Potent, transient autoanti-I production is strongly associated with infections by Mycoplasma pneumoniae
    • Alloanti-I: Very rare, found only in individuals with the “adult i” phenotype (see below)
  • Anti-i
    • Type: Usually an autoantibody, typically IgM, cold-reacting
    • Reactivity: Reacts preferentially with cord blood cells (rich in i) and weakly or not at all with adult cells (rich in I)
    • Clinical Significance: Mostly benign, but potent examples with high thermal amplitude can occasionally cause hemolysis
    • Association: Strongly associated with Infectious Mononucleosis (IM) caused by Epstein-Barr virus (EBV). Also seen in some lymphoproliferative disorders
    • Alloanti-i: Extremely rare

The Adult i Phenotype

  • A rare phenotype where individuals fail to develop strong I antigen expression into adulthood. Their red cells remain rich in i antigen, similar to newborn cells (i+I-)
  • Cause: Usually due to inheriting two non-functional alleles of the GCNT2 gene (encoding the branching enzyme)
  • Antibodies: These individuals are capable of forming clinically significant alloanti-I if transfused with normal adult (I+) red blood cells. Finding compatible blood (other adult i donors) is difficult

Summary Table: I vs. i

Feature i Antigen I Antigen
Structure Linear LacNAc repeats Branched LacNAc chains
Predominant on Fetal/Newborn RBCs Adult RBCs
Branching Enzyme Low activity High activity
Common Auto-Ab Anti-i (assoc. with IM) Anti-I (assoc. with Mycoplasma)
Adult Phenotype Rare “Adult i” (i+I-) Common Adult (I+i-)

Key Terms

  • N-acetyllactosamine (LacNAc): The basic repeating disaccharide unit (Galβ1→4GlcNAc) of Ii antigens
  • Linear Chain: Characteristic structure of the i antigen
  • Branched Chain: Characteristic structure of the I antigen, formed by β1→6 linkages
  • Branching Enzyme: β-1,6-N-acetylglucosaminyltransferase (GCNT2 gene product) responsible for creating I from i
  • Developmental Antigen: An antigen whose expression level changes significantly from fetal life to adulthood (like i and I)
  • Cold Agglutinin: An antibody that reacts optimally at temperatures below 37°C, often IgM
  • Thermal Amplitude: The temperature range over which an antibody is reactive. Clinically significant cold antibodies have a wide thermal amplitude (react up to or near body temperature)
  • Cold Agglutinin Syndrome (CAS): Autoimmune hemolytic anemia caused by a pathologic cold agglutinin (often anti-I)
  • Adult i Phenotype: Rare condition where adult RBCs retain the fetal i-rich, I-poor phenotype