**Core Concept**
Hemolytic disease of the newborn (HDN) is an immune-mediated condition where maternal antibodies against fetal red blood cell antigens cause hemolysis. The antigens involved in HDN are usually those present on the RhD and Kell blood group systems.

**Why the Correct Answer is Right**
The RhD antigen is the most common cause of HDN due to its high prevalence in the population (approximately 85% of Caucasians are RhD positive). Maternal RhD antibodies can cross the placenta and bind to fetal RhD-positive red blood cells, leading to their destruction. The immune response is triggered when an RhD-negative mother is exposed to RhD-positive red blood cells, either during pregnancy or through transfusion. This exposure can be due to a small amount of RhD-positive blood from the fetus entering the maternal circulation.

**Why Each Wrong Option is Incorrect**
* **Option A:** The Kell antigen is another common cause of HDN, but it is less prevalent than the RhD antigen. The Kell antigen is more likely to cause severe HDN.
* **Option B:** The Duffy antigen is not typically associated with HDN. While it can be a cause of hemolytic anemia, it is not as common as the RhD or Kell antigens.
* **Option D:** The ABO blood group system is not typically associated with HDN. However, ABO incompatibility can cause hemolytic disease of the newborn, but it is usually less severe than that caused by RhD or Kell incompatibility.

**Clinical Pearl / High-Yield Fact**
RhD-negative mothers should receive RhD immunoglobulin (RhIg) at 28 weeks of gestation and within 72 hours of delivery if the fetus is RhD-positive to prevent the formation of anti-RhD antibodies.

**Correct Answer:** C.