Although our observations stem from a single sample of immature B cells derived from the pooling of three HuMs, the reduction in the usage of the inherently autoreactive IGHV4-34 gene and the SLE-associated IGKV4-1 gene in the periphery compared to the newly formed immature B cells presents compelling evidence that such a checkpoint in the regulation of the repertoire is operational in humanized mice. Here, IGHV4-34 is linked to systemic lupus erythematosus.