The Lutheran blood group was initially described in 1945 when the first example of anti-Lu^a was discovered in the serum of a patient following transfusion of a unit of blood carrying the corresponding low frequency antigen. The new antibody was named Lutheran, a misinterpretation of the patient's name, Luteran. In 1956, Cutbush and Chanarin described anti-Lu^b, which defined the high frequency antithetical partner. The Lutheran blood group system, now consists of 18 antigens, including four allelic pairs: Lu^a (Lu1) and Lu^b (Lu2); Lu6 and Lu9; Lu8 and Lu14; Au^a (Lu18) and Au^b (Lu19).

The Lu(a-b-) phenotype or Lu_null is very rare and may rise from one of the three distinct genetic circumstances. These individuals have mild acanthocytosis and poikilocytosis of their red cells. A dominant inhibitor gene, In(Lu), which is independent of the Lutheran locus, is responsible for the most common form of the Lu(a-b-) phenotype. The red cells appear to lack all Lutheran antigens using hemagglutination techniques; however, their presence can be demonstrated by absorption/elution methods. A second Lu_null type is due to the homozygous inheritance of an amorph at the Lutheran locus. This is probably the true Lu_null as no Lu antigens have been detected on the red cells even using absorption/elution techniques. Less than a half dozen individuals with this type are known. The final Lu(a-b-) type, due to an X-linked suppresser gene (XS2), also presents with weakened Lu antigens similar to the inhibitor type, however, only one such family has been found to date. The In(Lu) gene not only suppresses Lutheran but also the i, P₁, Au^a, Anton (An/Wj) and several other antigens defined by monoclonal antibodies.

The Lu protein has a molecular weight of 85 kD and is composed of 5 extracellular Ig- like domains. Lu and B-CAM (basel cell adhesion molecule) are different forms of the same protein/gene whose function is to bind/aminin.