Agent 006001 is promiscuous? (anti-K is so common!)

The blog title is a take-off on James Bond, Agent 007.

As a long-time blood bank instructor, I was fascinated by this paper by French authors in the August 2006 issue of Transfusion:

Noizat-Pirenne F, Tournamille C, Bierling P, Roudot-Thoraval F, Le Pennec P-Y, Rouger P, Ansart-Pirenne H. Relative immunogenicity of Fya and K antigens in a Caucasian population, based on HLA class II restriction analysis. Transfusion 2006 Aug;46 (8):1328-33.

THE MYSTERY
One of the many mysteries in transfusion medicine is why some red cell antigens are more immunogenic than others. Reasons for the relative immunogenicity was thought to relate to the nature of the antigen, including the number and affinity of potential derived peptides once the antigen is recognized as foreign and processed by antigen presenting cells. This papers adds one more piece to the puzzle.

WHAT WE KNOW

The D antigen in the Rh system is known to be the most immunogenic. In the Kell blood group system the K antigen (ISBT #006001) is known to be considerably more immunogenic that antigens in the Duffy and Kidd blood group systems. The immunogenicity of an antigen is assessed by comparing the observed frequency of alloantibodies with the calculated frequency of the opportunity for alloimmunization. For example, the K antigen has been shown to be 9 times as immunogenic as Fy^a.

A brief review of how antibodies are produced:

We have long known how important MHC is to the immune response. Red cell antigens, like other protein antigens, elicit an immune response as follows:

• They are processed and displayed in conjunction with HLA molecules on antigen-presenting cells (APC) such as macrophages,
• and presented to T-cell receptors on T lymphocytes.
• Recognition of RBC-derived peptide displayed by HLA class II molecules activates a specific CD4+ T cell (see diagram of an APC activating a CD4+ T cell)
• The T cell divides and produces a clone of CD4+ T cells,
• which in turn activates a specific B cell that produces a clone of antibody-producing cells.

HLA-DR molecules account for more than 90 percent of the HLA class II isotypes expressed on APCs, the HLA-DRB1* locus being highly polymorphic.

RESULTS
The authors found that for people who made anti-Fy^a (n=29) the DRB1*04 phenotypic frequency was 100%, indicating that the DRB1*04 molecule is the restriction molecule for Fy^a. For those who made anti-K (n=30) many DRB1* molecules were identified, demonstrating that the K antigen has a high degree of histocompatibility promiscuity.

This suggests that

• only people with the DRB1*04 phenotype can produce anti-Fy^a
• all or nearly all individuals in the Caucasian population are able to bind K-derived peptides and therefore could produce anti-K when stimulated.

Assuming that this finding is confirmed by future studies, it turns out that the immunogenicity of a given red cell antigen is related both to the nature of the antigen and to the distribution within the population of HLA-DRB1* molecules on antigen-presenting cells.

Why anti-K is so common may be mainly because the K antigen is promiscuous when it comes to which HLA-DRB1* molecules it binds with. Now is that cool or what?

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