An HLA-linked immune suppression gene in man.

Genetic control of immune response in man was investigated with the system of antigen-specific T cell proliferation in vitro against streptococcal cell wall (SCW) antigen. Family analysis by Morton's maximum likelihood scoring method revealed that the low response to SCW antigen was controlled by a single dominant gene. Furthermore, this gene was shown to be closely linked to HLA (lod score was 3,209 at theta = 0). This is the first description of the HLA-linked immune suppression gene in man. The possible mechanism for this gene action was discussed.

Mutations of carnitine palmitoyltransferase II (CPT II) in Japanese patients with CPT II deficiency.

Carnitine palmitoyltransferase II (CPT II) deficiency is an inherited disorder involving beta-oxidation of long-chain fatty acids. CPT II deficiency is a wide-spectrum disorder that includes a lethal neonatal form, an infantile form, and an adult-onset form. However, the ethnic characteristics and the relationship between genotype and clinical manifestation are not well understood. We investigated three non-consanguineous Japanese patients with CPT II deficiency and examined cell lines from 4 unrelated patients and 50 healthy donors. The CPT 2 gene was typed by direct DNA sequencing of polymerase chain reaction-amplified gene products. Case 1 (infantile form) was heterozygous for a phenylalanine to tyrosine substitution at position 383 (p.F383Y) and a novel valine to leucine substitution at 605 (p.V605L). Cases 2, 4, and 5 (infantile form) and case 3 (adult-onset form) were heterozygous for a single mutation at F383Y. Case 6 (adult-onset form) was compound heterozygous at the CPT 2 locus, with deletion of cytosine and thymine at residue 408, resulting in a stop signal at 420 (p.Y408fsX420), and an arginine to cysteine substitution at position 631 (p.R631C). Case 7 (adult-onset form) was homozygous for the p.F383Y mutation. In conclusion, we identified p.F383Y mutations in six of seven patients with CPT II deficiency and two novel variants of the coding gene: p.Y408fsX420 and p.V605L. These mutations differ from those in Caucasian patients, who commonly harbor p.S113L, p.P50H, and p.Q413fsX449 mutations; therefore, our data and those of other Japanese groups suggest that the p.F383Y mutation is significant in Japanese patients with CPT II deficiency.

Solid-phase direct DNA sequencing of allele-specific polymerase chain reaction-amplified HLA-DR genes.

We describe in this report a new strategy to directly sequence polymerase chain reaction-amplified human leucocyte antigen DRB genes using biotinylated allele-specific synthetic oligonucleotide primers coupled to streptavidin-coated magnetic beads. The use of allele-specific primers in the polymerase chain reaction allows for selective amplification of DNA from one haplotype, which when combined with the direct sequencing technique circumvents the need for DNA cloning prior to sequencing. We demonstrate here that this method can be used to characterize human leucocyte antigen DRB genes among heterozygous individuals. This method can be used for the rapid analysis of highly polymorphic genes among individuals heterozygous at the gene of interest.

Proximal symphalangism with "coarse" facial appearance, mixed hearing loss, and chronic renal failure: new malformation syndrome?

A 25-year-old man is described with short stature, moderate mental retardation, an abnormal facial appearance, a webbed neck, skeletal abnormalities including proximal symphalangism of bilateral second through fifth fingers, mixed hearing loss, and slowly progressive, sclerosing nephropathy. He was large at birth with generalized edema, more pronounced around the jaw, neck and the upper part of the body, but became short with increasing age, and currently measures 143 cm (-4.9 SD). He had intermittent proteinuria and slowly progressive deterioration of the renal function. A biopsy of the left kidney showed global glomerular sclerosis with interstitial fibrosis. He was placed on maintenance peritoneal dialysis at age 17 years, and now on hemodialysis. His skeletal abnormalities included, in addition to proximal symphalangism, stenosis of the cervical canal, scoliosis, brachydactyly of the hands, hypoplastic hip joints, and pes valgus. Other abnormalities noted were a communicating defects of the diaphragm (surgically corrected), bilateral inguinal hernia and cryptorchidism. These clinical manifestations indicate a hitherto undescribed combination of manifestations and nephropathy.

Disseminated strongyloidiasis in nephrotic syndrome.

Strongyloides stercoralis is endemic in the southwestern islands Amami and Ryukyu in Japan. Systemic strongyloidiasis occurs in immunocompromised hosts. We report here on a 60-year-old patient with minimal-change nephrotic syndrome (MCNS) without eosinophilia or HTLV-I infection. She was treated with corticosteroid for MCNS and died of disseminated strongyloidiasis. The patient developed systemic purpura, ileus, respiratory distress, malabsorption, pancytopenia, pulmonary hemorrhage and sepsis due to Escherichia coli before death. Massive infestation with Strongyloides stercoralis was disclosed by autopsy, and the larvae was considered as a pathomechanism or exacerbating agent of nephrotic syndrome in endemic areas.

[Superantigens and autoimmune diseases].

Superantigens are potent immunomodulators derived from microorganisms such as bacteria, viruses and mycoplasmas. Their effects on immune systems are obtained through their binding both to outer portion of binding grooves of an MHC on antigen presenting cells and to non-recognizing structure of hypervariable region of T cell antigen receptors. X-ray crystallography revealed precise structures of some superantigens, a beta barrel domain as a ligand to MHC class II alpha chain and a beta grasp domain to TCRV beta chain. Superantigens induce not only T/B cell activation but also immunological tolerance through oligoclonal deletion and/or anergy. Contribution of superantigens to the pathogenesis of autoimmune diseases has been discussed since a superantigen, mycoplasma arthritis T cell mitogen revealed to be arthritogenic to mice, and the murine arthritis resembled human rheumatoid arthritis in the pathological findings. Rheumatoid arthritis as well as Kawasaki Disease, Sjögren syndrome, and multiple sclerosis is now well studied through the oligoclonal expression of TCR beta specificities on infiltrating T cells. Application of superantigens to the treatment of autoimmune diseases is also discussed.