Takaya Fukumoto

Polymorphisms of HLA class II genes and autoimmune responses to Ro/SS-A-La/SS-B among Japanese subjects

OBJECTIVE To investigate HLA class II allele associations with autoantibody responses to Ro/SS-A and La/SS-B among Japanese subjects. METHODS Haplotype and allele distributions, along with molecular polymorphisms, of HLA class II genes were analyzed by polymerase chain reaction-restriction fragment length polymorphism in 41 Japanese women with precipitating autoantibodies to Ro/SS-A and/or La/SS-B. RESULTS Among women with both Ro/SS-A and La/SS-B antibodies, the HLA class II haplotype DRB1*08032/DQA1*0103/DQB1*0601 and DRB1*08032 allele showed significantly increased frequencies compared with patients with anti-Ro/SS-A alone or with normal controls. All women with both anti-Ro/SS-A and anti-La/SS-B, but not those with anti-Ro/SS-A alone, carried DRB1 alleles that shared the same amino acid residues at positions 14-31 and 71 of the hypervariable regions of the DRB1 chain. All anti-Ro/SS-A positive women carried 1 or 2 alleles of DQB1*06 and DQB1*03 subtypes that shared the same amino acid residues at positions 71-77 of the DQB1 chain. HLA class II allele distributions did not differ among 3 anti-Ro/SS-A positive groups with different disease expressions, i.e., patients with systemic lupus erythematosus, patients with primary Sjögrens syndrome, and women with no apparent symptoms of rheumatic disease. CONCLUSION HLA class II allele distributions differ among anti-Ro/SS-A positive subjects according to the presence or absence of coexisting anti-La/SS-B antibodies, but not according to disease expression. Our findings suggest that different HLA class II molecules might control the development of anti-Ro/SS-A and/or anti-La/SS-B antibodies in the autoimmune response to the Ro/SS-A-La/SS-B complex.

Identification of thymus and activation-regulated chemokine (TARC/CCL17) as a potential marker for early indication of disease and prediction of disease activity in drug-induced hypersensitivity syndrome (DIHS)/drug rash with eosinophilia and systemic symptoms (DRESS).

BACKGROUND Drug-induced hypersensitivity syndrome (DIHS)/drug rash with eosinophilia and systemic symptoms (DRESS) is a serious acute drug reaction with fever, cutaneous eruption, lymphadenopathy, and several visceral dysfunctions. Eosinophilia is a common hematological abnormality in DIHS/DRESS suggesting that the Th2-type immune response is involved. Thymus and activation-regulated chemokine (TARC/CCL17) is a family of CC chemokines known to play an important role in Th2-mediated immune-inflammatory processes. OBJECTIVE We investigated the pathogenic role of TARC in patients with DIHS. METHODS Sera were obtained from 8 patients with DIHS, 7 patients with Stevens-Johnson syndrome/Toxic epidermal necrolysis (SJS/TEN), and 14 patients with drug-induced maculopapular exanthema (MPE). Serum TARC levels were measured by ELISA. TARC levels were then compared with clinical symptoms and various hematological parameters. In addition, a biopsy was taken from the lesional skin of patients with DIHS and stained with anti-TARC Ab and anti-CD11c Ab. RESULTS Serum TARC levels in patients with DIHS were significantly higher than those in patients with SJS/TEN and MPE during the acute phase. Serum TARC levels in DIHS patients correlated with skin eruptions, serum sIL-2R levels, eosinophil counts, and serum IL-5 levels. Immunohistochemical staining revealed that TARC was mainly expressed on CD11c+ dermal dendritic cells in patients with DIHS. CONCLUSION Serum TARC levels may be associated with the initial presentation of DIHS as well as disease activity during the course. Thus, they could be useful as an indicator for early diagnosis and assessment of disease activity in DIHS. CD11c+ dendritic cells may be the main source of TARC in patients with DIHS.

Relationship among human herpesvirus 6 reactivation, serum interleukin 10 levels, and rash/graft-versus-host disease after allogeneic stem cell transplantation

BACKGROUND The relationship between herpesvirus reactivation and graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (allo-SCT) is unclear. OBJECTIVE We sought to examine the relationship between human herpesvirus (HHV) reactivation and rash/GVHD after allo-SCT by prospective evaluation. METHODS Fifteen patients who had received allo-SCT underwent prospective serial examinations for human herpesvirus 6 (HHV-6), HHV-7, cytomegalovirus, and Epstein-Barr virus DNA in the blood by polymerase chain reaction and real-time polymerase chain reaction. Serum interferon gamma, interleukins 4 and 10, tumor necrosis factor alpha, and soluble interleukin 2 receptor (sIL-2R) were also measured. RESULTS In 10 of 15 patients, macular/papular eruptions were seen after allo-SCT and GVHD was diagnosed. In 8 patients with rash, HHV-6 DNA levels correlated with the cutaneous manifestation. Interleukin 10 and sIL-2R also increased in association with rash. LIMITATIONS The number of patients in our study was relatively small. Not all patients were examined for cytokines and sIL-2R. CONCLUSIONS HHV-6 reactivation may be involved in the pathogenesis of rash/GVHD after allo-SCT.

Anti-Ro/SSA-associated annular erythema in childhood

Summary We report lour children with anti‐Ro/SSA positive who presented with an annular erythema as a manifestation of Sjögrens syndrome. One patient had an aseptic meningoencephalitis as well as cutaneous lesions. Children with annular erythema should he carefully followed for features of Sjögrens syndrome, which is believed to be a rare condition in children.

Neonatal lupus erythematosus: Analysis of HLA class II alleles in mothers and siblings from seven Japanese families

BACKGROUND Neonatal lupus erythematosus (NLE) is a syndrome characterized by dermatitis and congenital heart block. The disease is mostly associated with transplacental passage of maternal anti-Ro(SS-A) or anti-La(SS-B) antibodies. Maternal HLA-DR3 and DQ2 alleles are associated with NLE in white and North American black populations. OBJECTIVE We sought evidence of a potential genetic disposition to NLE in mothers with a relatively homogeneous ethnic background. METHODS Class II human major histocompatibility complex HLA-DRB1, DQA1, DQB1, and DPB1 alleles were determined by polymerase chain reaction-restriction fragment length polymorphism in anti-Ro(SS-A)-positive mothers as well as in infants from seven Japanese families with siblings concordant or discordant for disease expression of NLE. RESULTS All seven mothers had two or three DQ alleles of DQA1 and DQB1 possessing specific amino acid residues, which are reportedly associated with anti-Ro(SS-A) autoantibody response in white and black populations. There was no class II HLA profile that distinguished disease manifestations of NLE in infants. CONCLUSION The HLA class II allele associations with anti-Ro(SS-A) autoantibodies that have been noted in other ethnic groups were also found in Japanese anti-Ro(SS-A)-positive mothers whose infants had NLE, suggesting shared susceptibility factors across racial barriers in maternal predisposition to Ro(SS-A) autoimmune response.

Neonatal lupus erythematosus: studies on HLA class II genes and autoantibody profiles in Japanese mothers.

Neonatal lupus erythematosus (NLE) is a rare disorder of neonates characterized by two major clinical manifestations: congenital heart block and cutaneous lupus lesions. The disease is associated with placentally transferred maternal anti-Ro/SSA and/or La/SSB antibodies. To clarify possible class II HLA associations with maternal autoantibody responses, haplotypic and allelic distributions, along with the polymorphism of the MHC class II HLA alleles, were analyzed based on PCR-RFLP results in 25 Japanese mothers of two groups defined by precipitating autoantibody profiles. Among mothers with both anti-Ro/SSA and anti-La/SSB antibodies, but not those with anti-Ro/SSA alone, the class II haplotypes DRB1*1101-DQA1*0501-DQB1*0301 and DRB1*08032-DQA1*0103-DQB1*0601 as well as individual class II alleles DRB1*1101, DRB1*08032 and DQB1*0301 showed significantly increased frequencies compared to those in normal controls. All anti-Ro/SSA and anti-La/SSB positive mothers carried DRB1 alleles that shared the same amino acid residues at positions 14-31 and 71 of the DRB1 chain. These mothers also carried homozygous or heterozygous DQ6 and DQ3 alleles that shared the same amino acid residues at positions 27-36 and 71-77 of hypervariable regions of the DQB1 chain. Furthermore, all mothers with both anti-Ro/SSA and anti-La/SSB were homozygous for DPB1*0501. Nine of 10 anti-Ro/SSA and anti-La/SSB-positive mothers, but only 6 of 15 mothers with anti-Ro/SSA alone, had affected infants. Thus, our findings suggest that there may be immunogenetic differences among mothers according to their autoantibody profiles, and that mothers with both anti-Ro/SSA and anti-La/SSB are more likely to have infants with NLE than mothers with anti-Ro/SSA alone.

Erythema induratum of Bazin in an infant after Bacille Calmette‐Guerin vaccination

We report the first case of erythema induratum of Bazin (EIB) after Bacille Calmette‐Guerin (BCG) vaccination in an infant. The patient developed recurrent multiple erythematous and subcutaneous nodules on his legs 2 months after a BCG vaccination. He had no other symptoms or family history of tuberculosis (TB). Histopathological findings revealed a granulomatous lobular panniculitis. EIB often appears as a chronic, nodular eruptions that frequently occur on the lower legs of females with tuberculin hypersensitivity. To date, only a few cases of infants with EIB have been reported. There have been no clinical reports of EIB after BCG vaccination. Our case suggests that Mycobacterium bovis in the BCG vaccination may have caused EIB.

Increased ratio of FoxP3+ regulatory T cells/CD3+ T cells in skin lesions in drug-induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms.

Drug‐induced hypersensitivity syndrome/drug rash with eosinophilia with systemic symptoms (DIHS/DRESS) is a severe drug eruption accompanied by multiorgan disorders. Several unique aspects of DIHS/DRESS, including herpesvirus reactivation, liver dysfunction and hypogammaglobulinaemia, have similarities to graft‐versus‐host disease (GVHD).

Recombinant granulocyte colony-stimulating factor for dapsone-induced agranulocytosis in leukocytoclastic vasculitis

A 16-year-old girlhadan 8-weekhistoryofnodules and ulcerson both legs. Examination revealed manynodules with ulceration, mainlyonthe flexor aspect ofher leftleg (Fig. I). Other lesions werepurpura, blisters, and livedo reticularis bilaterally. The patient had nosystemic manifestations. Laboratory data indicating abnormality included an erythrocyte sedimentation rate of 44 mm/hr, hypergammaglobulinemia of 29.4% with a serum IgG of 2804 mg/dl (normal 780 to 1450 mg/dl). The rheumatoid factorwas42UIml (normal<15UIml), and C-reactive proteinwas2.9mg/dl (normal<0.7 mg/dl). Fluorescent antinuclear antibodies andanti-UIRNP antibodies were positive in titers of 1:2560 and 1:20, respectively.

Maternal Autoimmune Response to Recombinant RO/SSA and LA/SSB Proteins in Japanese Neonatal Lupus Erythem Atosus

BACKGROUND Neonatal lupus erythematosus (NLE) is a syndrome characterized by dermatitis and congenital heart block (CHB). The disease is mostly associated with transplacental passage of maternal anti-Ro/SSA and/or La/SSB antibodies. OBJECTIVE To examine maternal autoimmune response to recombinant Ro/SSA and La/SSB proteins in NLE with a single ethnic background. METHODS This study examined 12 NLE infants and their mothers. Serum samples were tested by enzyme-linked immunosorbent assay for reactivity with full-length recombinant human 60-kd Ro/SSA, 52-kd Ro/SSA, and 48-kd La/SSB proteins. RESULTS All 10 infants with skin lesions and/or CHB had maternal antibodies reactive to both the 60- and 52-kd Ro/SSA polypeptide components of the Ro/SSA particle. Anti-60-kd Ro/SSA without anti-52-kd Ro/SSA, or vice versa, was found in mothers of infants who had only hepatic manifestation of NLE. Nine of 12 NLE infants had anti-48-kd La/SSB. CONCLUSION In the majority of Japanese infants with NLE, maternal anti-Ro/SSA autoimmune response was directed against both of 60-kd and 52-kd recombinant Ro/SSA proteins. There was no profile of anti-Ro/SSA and La/SSB response unique to mothers of children with CHB or cutaneous manifestations of NLE.