FcyRIIB,the only inhibitory IgG Fc receptor,functions to suppress the hyper-activation of immune cells.Numerous studies have illustrated its inhibitory function through the ITIM motif in the cytoplasmic tail of FcyRIIB.However,later studies revealed that in addition to the ITIM,the transmembrane (TM) domain of FcyRIIB is also indispensable for its inhibitory function.Indeed,recent epidemiological studies revealed that a non-synonymous single nucleotide polymorphism (rs1050501)within the TM domain of FcyRIIB,responsible for the I232T substitution,is associated with the susceptibility to systemic lupus erythematosus (SLE).In this review,we will summarize these epidemiological and functional studies of FcyRIIB-I232T in the past few years,and will further discuss the mechanisms accounting for the functional loss of FcyRIIB-I232T.Our review will help the reader gain a deeper understanding of the importance of the TM domain in mediating the inhibitory function of FcyRIIB and may provide insights to a new therapeutic target for the associated diseases.