Is There Also Antigens Other Than HLA Antigens in the Body?

While HLA antigens are the “main event” in transplant immunology, nonHLA antigens are the hidden players. These are other proteins found on the surface of cells—especially on the lining of blood vessels (endothelium) or inside kidney cells—that can also trigger an immune response.

If HLA molecules are the “barcode,” nonHLA antigens are the “security tags” hidden inside the garment. Even if the barcode matches, the security tag can still set off the alarm.

Sometimes a patient rejects an organ despite having a perfect HLA match and a negative virtual crossmatch. In these “unexplained” cases, the cause is often a nonHLA antibody.

Common Types of Non HLA Antigens

Medical research has identified several important nonHLA targets that the immune system may attack:

1. MICA and MICB (Major Histocompatibility Complex Class I–related Chain A and B)
   These are stress induced proteins. They may not always be visible, but if the donor organ experiences stress or injury (for example, during organ recovery), these proteins can appear on the cell surface. The recipient’s immune system may interpret them as a danger signal and initiate an attack.

2. Angiotensin II Type 1 Receptor (AT1R)
   This is one of the most common nonHLA targets.

   • The problem: If the recipient has antibodies against AT1R, the blood vessels in the transplanted kidney may constrict and become inflamed.

   • The result: This can mimic severe hypertension or sudden graft dysfunction, but the underlying cause is an immune attack on the receptor.

3. Endothelial Cell Antigens
   The endothelium forms the inner lining of all blood vessels. Because the recipient’s blood is the first thing to contact the donor organ, any antibodies against the donor’s endothelial cells can cause immediate clotting, inflammation, or early graft injury.