Amyloidosis cutis dyschromica (ACD) is a distinct form of primary cutaneous amyloidosis characterized by generalized hyperpigmentation mottled with small hypopigmented macules on the trunks and limbs. Affected families and sporadic case subjects have been reported predominantly in East and Southeast Asian ethnicities; however, the genetic cause has not been elucidated. We report here that the compound heterozygosity or homozygosity of GPNMB truncating alleles is the cause of autosomal-recessive ACD. Six nonsense or frameshift mutations were identified in nine individuals diagnosed with ACD. Immunofluorescence analysis of skin biopsies showed that GPNMB is expressed in all epidermal cells, with the highest staining observed in melanocytes. GPNMB staining is significantly reduced in the lesional skin of affected individuals. Hyperpigmented lesions exhibited significantly increased amounts of DNA/keratin-positive amyloid deposits in the papillary dermis and infiltrating macrophages compared with hypo- or depigmented macules. Depigmentation of the lesions was attributable to loss of melanocytes. Intracytoplasmic fibrillary aggregates were observed in keratinocytes scattered in the lesional epidermis. Thus, our analysis indicates that loss of GPNMB, which has been implicated in melanosome formation, autophagy, phagocytosis, tissue repair, and negative regulation of inflammation, underlies autosomal-recessive ACD and provides insights into the etiology of amyloidosis and pigment dyschromia.

Spondylocarpotarsal synostosis syndrome (SCT) is a distinct group of disorders characterized by short stature, disrupted vertebral segmentation with vertebral fusion, scoliosis, lordosis, carpal/tarsal synostosis, and lack of rib anomalies. Mutations in filamin B (FLNB) and MYH3 have been reported for autosomal-recessive and autosomal-dominant SCT, respectively. We present a family with two patients suffering from autosomal-recessive SCT with rib anomalies, including malalignment, crowding, and uneven size and shape of ribs. Whole-exome sequencing revealed a novel p.S2542Lfs 82 (c.7621dup) frameshift mutation in FLNB. This frameshift mutation lies in the C-terminal-most domain involved in FLNB dimerization and resulted in a 20-residue elongation, with complete familial segregation and absence in 376 normal controls. The mutant p.S2542Lfs 82 FLNB demonstrated a complete loss of ability to form a functional dimer in transiently transfected HEK293T cells. The p.S2542Lfs 82 mutation also led to significantly reduced protein levels and accumulation of the mutant protein in the Golgi apparatus. This is the first identified mutation in the dimerization domain of FLNB. This loss-of-function frameshift mutation in FLNB causes autosomal-recessive SCT with rarely reported rib anomalies. This report demonstrates the involvement of rib anomaly in SCT and its causative mutation in the dimerization domain of FLNB.

Here, we reevaluate the effects of early termination of infection on primary T cell expansion, subsequent memory cell development, and protective immunity. Using a murine Listeria monocytogenes (LM) infection model, we found the primary expansions of both CD4+ and CD8+ T cells were affected even when ampicillin was given as late as 60 h postinfection (p.i.). Subsequent development of CD8+ memory T cells was also impaired, although to a lesser extent, and only mice that received ampicillin at 24 h p.i. revealed a significant decrease in memory CD8+ T cells. Upon rechallenge with 1 × 105 CFU of LM, all ampicillin-treated mice cleared LM as effectively, and they generated similar amounts of Ag-specific CD8+ T cells as with untreated mice. However, mice that received ampicillin at 24 h p.i. lost their protective abilities when rechallenged with 7.5 × 105 CFU of LM. Ampicillin treatment also revealed early down-regulation of B7.1 and B7.2, but not CD40, on dendritic cells 72 h p.i. Our results have several important implications: 1) they argue against the hypothesis that brief exposure of T cells to an Ag is sufficient for full-fledged primary T cell responses and subsequent memory T cell development in vivo; 2) they suggest the existence of a reservoir of memory T cells, more than the immune system can possibly expand during secondary infection; and 3) they suggest that protective capacity is correlated with the number of preexisting memory T cells and that secondary expanding T cells play a limited role, at least in murine LM infection.