Maheshwari Ashish, Killeen Robert B.
Institute of Liver and Biliary Sciences
University of Illinois
Blood group antigens are substances found on the surface of red blood cells (RBCs) that serve as markers, distinguishing different blood types. Common blood group antigens include the ABO system, the Rhesus (Rh) factor, Duffy, and Kell. The Duffy blood group system is determined by the gene (OMIM 613665), which is located on chromosome 1q23.2. The 2 main codominant alleles, and , produce the Fy and Fy antigens, which are expressed on the surface of RBCs, vasculature endothelial cells, alveolar epithelial cells, collecting tubules in the kidneys, and the surface of Purkinje cells in the brain. Duffy antigens are absent on platelets, lymphocytes, monocytes, and granulocytes. Single-nucleotide differences in the coding region result in a change in a single amino acid, which determines the presence of the Fy and Fy antigens. Fy contains a guanine at nucleotide 125 and a glycine at amino acid 42. Alternatively, Fyhas an adenine at nucleotide 125 and an aspartate at amino acid 42. Patients lacking Fy and Fy antigens are considered Duffy-null. These individuals are typically heterozygous for a genetic variation, rs2814778-C (c.-67T>C), in the promoter region, which results in the loss of Duffy antigens on the surface of RBCs without affecting their expression on other cells. In most Duffy-null individuals, a mutation in the allele, sometimes referred to as or the erythrocyte silent allele, specifically the 67T>C mutation (or position 46, depending on the numbering system) near the gene's transcription initiation site, causes this phenotype. This mutation disrupts a binding site for the erythroid transcription factor GATA1, which is crucial for expressing the gene in erythroid cells. This mutation prevents the expression of Duffy glycoproteins on erythrocytes while allowing the expression of Fy on nonerythroid cells. Rarely, the mutation may also involve the allele. The Duffy antigens, also known as the atypical chemokine receptor 1 (ACKR1), are glycoproteins that function as chemokine receptors. They bind to chemokines released during inflammation and attract immune system cells to areas of damage. These chemokines include acute inflammation (C-X-R) and chronic inflammation (C-C) chemokines, interleukin (IL)-8, and regulated on activation, normal T expressed and secreted (RANTES). The ACKR1, previously the Duffy antigen receptors for cytokines (DARC) or CD234, is the primary attachment site for the malarial parasite . Patients who are phenotypically Fy(a−b−) are resistant to infection. Although Fy and Fy are the main determinants of the Duffy system, a total of 5 antigens are present in the Duffy blood group system: Fy, Fy, Fy3, Fy5, and Fy6. Anti-Fy and anti-Fy are the most clinically significant antibodies. These antibodies are the leading causes of immediate or delayed hemolytic transfusion reactions (HTRs). Anti-Fy3 is a less common cause of delayed HTRs. Anti-Fy is the most common cause of hemolytic disease of the fetus and newborn (HDFN), whereas anti-Fy3 and anti-Fyare uncommon causes of HDFN. Antibodies against Duffy blood group antigens are primarily immunoglobulin G (IgG), and IgM type is uncommon. These antibodies typically develop following exposure to Duffy antigens during blood transfusions, pregnancy, or organ transplantation. Anti-Fy antibodies are the most common among Duffy antibodies. Most Duffy antibodies react at body temperature, which can cause hemolysis and make them clinically significant. These antibodies can lead to both acute and delayed types of HTRs and HDFN. The Duffy blood group system demonstrates a dosage phenomenon, where individuals with a homozygous phenotype have more antigens per RBC than those with a heterozygous phenotype. As a result, Duffy antibodies react more strongly in patients with homozygous phenotypes, Fy(a−b+) or Fy(a+b−), than in those with the heterozygous phenotype Fy(a+b+). The predominant Duffy phenotypes are Fy(a+b−), Fy(a+b+), Fy(a−b+), and Fy(a−b−). The Fy and Fy antigens are most commonly found in White patients and patients of Asian descent, and least commonly in Black patients. Additionally, 67% of Black individuals have the Duffy-null phenotype, which is rare in White patients (see the below). An additional minor Duffy phenotype, the Fy or [Fy(b+x)], is a variant caused by a missense mutation in . The allele encodes the Fy antigen and weakly expresses Fy, which may not be detected by anti-Fy.
血型抗原是存在于红细胞（RBC）表面的物质，作为标志物区分不同血型。常见的血型抗原包括ABO系统、恒河猴（Rh）因子、达菲和凯尔。达菲血型系统由位于1号染色体1q23.2的基因（OMIM 613665）决定。两个主要的共显性等位基因和产生Fy和Fy抗原，它们表达于红细胞、血管内皮细胞、肺泡上皮细胞、肾集合小管以及脑内浦肯野细胞的表面。血小板、淋巴细胞、单核细胞和粒细胞上不存在达菲抗原。编码区的单核苷酸差异导致单个氨基酸的改变，从而决定Fy和Fy抗原的存在。Fy在核苷酸125处含有鸟嘌呤，在氨基酸42处含有甘氨酸。或者，Fy在核苷酸125处含有腺嘌呤，在氨基酸42处含有天冬氨酸。缺乏Fy和Fy抗原的患者被认为是达菲阴性。这些个体通常在启动子区域存在遗传变异rs2814778-C（c.-67T>C）的杂合子，这导致红细胞表面达菲抗原缺失，而不影响其在其他细胞上的表达。在大多数达菲阴性个体中，等位基因的突变，有时称为或红细胞沉默等位基因，特别是基因转录起始位点附近的67T>C突变（或根据编号系统为位置46）导致了这种表型。这种突变破坏了红系转录因子GATA1的结合位点，而GATA1对于在红系细胞中表达基因至关重要。这种突变阻止了达菲糖蛋白在红细胞上的表达，同时允许Fy在非红系细胞上表达。很少情况下，突变也可能涉及等位基因。达菲抗原，也称为非典型趋化因子受体1（ACKR1），是作为趋化因子受体起作用的糖蛋白。它们与炎症期间释放的趋化因子结合，并将免疫系统细胞吸引到损伤部位。这些趋化因子包括急性炎症（C-X-R）和慢性炎症（C-C）趋化因子、白细胞介素（IL）-8以及活化调节正常T细胞表达和分泌因子（RANTES）。ACKR1，以前称为细胞因子的达菲抗原受体（DARC）或CD234，是疟原虫的主要附着位点。表型为Fy(a−b−)的患者对感染具有抗性。虽然Fy和Fy是达菲系统的主要决定因素，但达菲血型系统中总共存在5种抗原：Fy、Fy、Fy3、Fy5和Fy6。抗Fy和抗Fy是临床上最重要的抗体。这些抗体是立即或延迟溶血性输血反应（HTR）的主要原因。抗Fy3是延迟HTR的较不常见原因。抗Fy是胎儿和新生儿溶血病（HDFN）最常见的原因，而抗Fy3和抗Fy是HDFN的不常见原因。针对达菲血型抗原的抗体主要是免疫球蛋白G（IgG），IgM型不常见。这些抗体通常在输血、妊娠或器官移植过程中接触到达菲抗原后产生。抗Fy抗体在达菲抗体中最为常见。大多数达菲抗体在体温下发生反应，可导致溶血，使其具有临床意义。这些抗体可导致急性和延迟型HTR以及HDFN。达菲血型系统表现出剂量现象，即纯合表型的个体每个红细胞上的抗原比杂合表型的个体更多。因此，达菲抗体在纯合表型Fy(a−b+)或Fy(a+b−)的患者中比在杂合表型Fy(a+b+)的患者中反应更强。主要的达菲表型是Fy(a+b−)、Fy(a+b+)、Fy(a−b+)和Fy(a−b−)。Fy和Fy抗原最常见于白人患者和亚裔患者，最不常见于黑人患者。此外，67%的黑人个体具有达菲阴性表型，这在白人患者中很少见（见下文）。另一种次要的达菲表型，Fy或[Fy(b+x)]，是由中的错义突变引起的变异。等位基因编码Fy抗原并弱表达Fy，抗Fy可能检测不到。
