Molecular nature of antigens implicated in immune neutropenias

Granulocyte (neutrophil) antibodies can cause autoimmune neutropenia, drug-induced neutropenia, immune neutropenia after bone marrow transplantation, neonatal immune neutropenia, refractoriness to granulocyte transfusions as well as febrile and pulmonary transfusion reactions. In the last decade, considerable progress has been made in the characterization of the implicated antigens. In 1998, the Granulocyte Antigen Working Party of the ISBT introduced a new nomenclature for human neutrophil alloantigens (HNA), which is based on the antigens' glycoprotein location. In the HNA nomenclature the immunogenic (glyco-) proteins are indicated by arabic numbers followed by a letter of the alphabet which identify the (glyco-) proteins' polymorphisms, i.e. the specific antigens. Currently, seven HNA antigens are assigned to five systems. The HNA-1a, HNA-lb and HNA-1c antigens, the former NA1, NA2, and SH antigens, have been identified as polymorphic forms of the neutrophil Fc gamma receptor IIIb (CD16b) encoded by three alleles. Recently, we could elucidate the primary structure of the HNA-2a antigen, the former NB1. We could identify the HNA-2a-bearing glycoprotein as a novel member of the Ly-6/uPAR superfamily which has been clustered meanwhile as CD177. The HNA-3a antigen, the former 5b, is located on a 70-95 kDa glycoprotein. However, its molecular basis is still unknown. Finally, the HNA-4a and HNA-5a antigens, the former MART and OND, were found to be caused by single nucleotide mutations in the alphaM (CD11b) and alphaL (CD11a) subunits of the leucocyte adhesion molecules (beta2 integrins). The glycoproteins CD11b, CD16b, and CD177 have been found to be also frequent targets of autoantibodies - approximately 30% of neutrophil autoantibodies are directed against CD16b. Characterization of granulocyte antigens have expanded our diagnostic tools by the introduction of genotyping techniques and immunoassays for antibody identification. In addition, it allowed new insights in the pathophysiology of immune neutropenias and transfusion reactions. Ongoing studies will further improve the prevention and management of granulocyte antibody-mediated diseases.