The protective association of HLA-C*12:02 and HLA-DQB1*06:01 with severe acute hepatitis of unknown origin in the Japanese population.

Global surveillance has been conducted to elucidate the pathogenesis of acute hepatitis of unknown origin (AHUO), However, the factors associated with the aggravation of this serious disease are unclear. Therefore, we conducted a HLA association study to identify HLA alleles or haplotypes predisposing or protective against Japanese AHUO. The HLA 5 locus (HLA-A, HLA-B, C, DRB1, and DQB1) 4-digit genotyping results of 72 AHUO patients who underwent liver transplantation at our institution between 2000 and 2021 were compared to those of 873 healthy Japanese controls. Protective associations of HLA-B*52:01 (p-corrected (pc) = 3.15 × 10-3 ), HLA-C*12:02 (pc = 1.66 ×10-3 ), HLA-DQB1*06:01 (pc = 1.42 × 10-2 ), and HLA-DRB1*15:02 (pc = 1.36 × 10-2 ) with severe AHUO in Japanese patients were observed. The amino acid residues of tryptophan at position 156, which are located in the antigen-binding grooves of the HLA-C protein, showed a protective association with AHUO, showing a significant difference from other amino acid variations (pc = 9.0 × 10-4 ). Furthermore, 5 amino acid residues of the HLA-DQB1 protein were also protectively associated with AHUO with a significant difference from other amino acid variations (pc = 1.42 × 10-2 to 2.89 × 10-2 ). These alleles have a protective association with the aggravation of AHUO in the Japanese population.

Impact of Spousal Donation on Postoperative Outcomes of Living-donor Lobar Lung Transplantation.

BACKGROUND: The effect of human leukocyte antigen mismatches between donors and recipients on postoperative outcomes of lung transplantation remains controversial. We retrospectively reviewed adult recipients receiving living-donor lobar lung transplantation (LDLLT) to examine the difference in de novo donor-specific antibody (dnDSA) development and clinically diagnosed unilateral chronic lung allograft dysfunction per graft (unilateral CLAD) between lung grafts donated by spouses (nonblood relatives) and nonspouses (relatives within the third degree). We also investigated the difference in prognoses between recipients undergoing LDLLTs including spouse donors (spousal LDLLTs) and not including spouse donors (nonspousal LDLLTs). METHODS: In this study, 63 adult recipients undergoing LDLLTs (61 bilateral and 2 unilateral LDLLTs from 124 living donors) between 2008 and 2020 were enrolled. The cumulative incidence of dnDSAs per lung graft was calculated, and prognoses were compared between recipients undergoing spousal and nonspousal LDLLTs. RESULTS: The cumulative incidence of both dnDSAs and unilateral CLAD in grafts donated by spouses was significantly higher than that in grafts donated by nonspouses (5-y incidence of dnDSAs: 18.7% versus 6.4%, P = 0.038; 5-y incidence of unilateral CLAD: 45.6% versus 19.4%, P = 0.011). However, there were no significant differences in the overall survival or chronic lung allograft dysfunction-free survival between recipients undergoing spousal and nonspousal LDLLTs ( P > 0.99 and P = 0.434, respectively). CONCLUSIONS: Although there were no significant differences in prognoses between spousal and nonspousal LDLLTs, more attention should be paid to spousal LDLLTs because of the higher development rate of dnDSAs and unilateral CLAD.

An adult case of refractory autoimmune neutropenia after liver transplantation.

Autoimmune neutropenia (AIN) is an exceptionally rare condition that occurs after liver transplantation. Here, we report an adult case of refractory AIN 3.5 years after liver transplantation. A 59-year-old man who underwent brain-dead donor liver transplantation in August 2018 developed rapid neutropenia (0.07 × 109/L) in December 2021. The patient was diagnosed with AIN based on positivity for anti-human neutrophil antigen-1a antibody. There was no response to granulocyte colony-stimulating factor (G-CSF), prednisolone, or rituximab, and intravenous immunoglobulin (IVIg) therapy induced only a temporary recovery in neutrophil count. The patient continued to have a low neutrophil count for several months. However, the response to IVIg and G-CSF improved after the post-transplant immunosuppressant was changed from tacrolimus to cyclosporine. Post-transplant AIN has many unknown aspects. Tacrolimus-induced immunomodulation and graft-associated alloimmunity may be involved in its pathogenesis. Further studies are needed to elucidate the underlying mechanisms and explore new treatment options.

Risk factors for antibody-mediated rejection in ABO blood-type incompatible and donor-specific antibody-positive liver transplantation.

Antibody-mediated rejection (AMR) is a refractory rejection after ABO blood-type incompatible (ABOi) or donor-specific antibody (DSA)-positive liver transplantation (LT). Pretransplant rituximab desensitization dramatically reduced posttransplant AMR development; however, risk factors for AMR in the rituximab era remain unclear in both ABOi living-donor LT (ABOi-LDLT) and preformed DSA-positive LT (pDSA-LT). Of our 596 adult LDLTs (≥18 y) after rituximab introduction (2004-2019), 136 were ABOi-LDLT (22.8%). After excluding retransplants (9), acute liver failure (7), and protocol deviations (16), 104 ABOi-LDLTs were finally enrolled. Of these, 19 recipients developed AMR, 18 of which occurred within 2 weeks after transplantation (95%). ABOi-AMR significantly worsened graft and recipient survival than those without ( p =0.02 and 0.04, respectively). Model for End-stage Liver Disease (MELD) ≤13 (OR: 5.15 [1.63-16.3], p =0.005) and pre-rituximab anti-ABO IgM-titer ≥128 (OR: 3.25 [1.05-10.0], p =0.03) were identified as independent risk factors for ABOi-AMR development. Recipients fulfilling both factors showed significantly worse survival rates than those who did not ( p =0.003). Of 352 adult LTs, after introducing the LABScreen Single Ag method (2009-2019), pDSA with mean fluorescence intensity (MFI) ≥500 was detected in 50 cases (14.2%). After excluding 10 ABOi-LDLTs, 40 pDSA-LTs were finally analyzed, of which 5 developed AMR. The combination of high-titer (sum-MFI ≥10,000) and multi-loci pDSAs was a significant risk factor for pDSA-AMR development ( p <0.001); however, it did not affect the 5-year recipient survival compared with those without ( p =0.56). In conclusion, preoperative MELD ≤13 and pre-rituximab anti-ABO IgM-titer ≥128 for ABOi-LDLT, and the combination of sum-MFI ≥10,000 and multi-loci pDSAs for pDSA-LT, are risk factors for AMR in the era of rituximab desensitization. Characteristically, ABOi-AMR significantly deteriorated graft and recipient survival, whereas pDSA-AMR did not.

Genetic architecture underlying IgG-RF production is distinct from that of IgM-RF.

OBJECTIVE: HLA-DRB1 alleles, particularly the shared epitope (SE) alleles, are strongly associated with RA. Different genetic structures underlie the production of the various autoantibodies in RA. While extensive genetic analyses have been conducted to generate a detailed profile of ACPA, a representative autoantibody in RA, the genetic architecture underlying subfractions of RF other than IgM-RF, namely IgG-RF, known to be associated with rheumatoid vasculitis, is not well understood. METHODS: We enrolled a total of 743 RA subjects whose detailed autoantibody (IgG-RF, IgM-RF, and ACPA) data were available. We evaluated co-presence and correlations of the levels of these autoantibodies. We analysed associations between the presence or levels of the autoantibodies and HLA-DRB1 alleles for the 743 RA patients and 2008 healthy controls. RESULTS: We found both IgG-RF(+) and IgG-RF(-) RA subjects showed comparable associations with SE alleles, which was not observed for the other autoantibodies. Furthermore, there was a clear difference in SE allele associations between IgG-RF(+) and (-) subsets: the association with the IgG-RF(+) subsets was solely driven by HLA-DRB1*04:05, the most frequent SE allele in the Japanese population, while not only HLA-DRB1*04:05 but also HLA-DRB1*04:01, less frequent in the Japanese population but the most frequent SE allele in Europeans, were main drivers of the association in the IgG-RF(-) subset. We confirmed that these associations were irrespective of ACPA presence. CONCLUSION: We found a unique genetic architecture for IgG-RF(-) RA, which showed a strong association with a SE allele not frequent in the Japanese population but the most frequent SE allele in Europeans. The findings could shed light on uncovered RA pathology.

Co-occurrence of relapsing polychondritis and autoimmune thyroid diseases.

BACKGROUND: Relapsing polychondritis (RP) is a rare inflammatory disease characterized by recurrent inflammation and destruction of cartilaginous tissues. RP has characteristics of autoimmune disease and some reports have noted co-occurrence with autoimmune thyroid disease (AITD), consisting of Graves' disease (GD) and Hashimoto thyroiditis (HT). However, there have been no detailed studies on the co-occurrence of RP and AITD. In this study, we aimed to determine whether patients with RP tend to be complicated with AITD. We also analyzed the clinical and genetic profiles of patients in whom these diseases co-occur. METHODS: We recruited 117 patients with RP and reviewed their medical records. Furthermore, we genotyped Human Leucocyte Antigen (HLA)-A, B Cw, DRB1, DQB1, and DPB1 alleles for 93 of the 117 patients. The prevalence of AITD among the patients with RP was compared with that among the general Japanese population. We also analyzed the clinical and genetic features of the patients with both RP and AITD. RESULTS: The prevalence of GD among the patients with RP was 4.3% (5 among 117 patients), significantly higher than that among Japanese (0.11%) (p = 2.44 × 10-7, binomial test). RP patients with GD tended to have nasal involvement (p = 0.023) (odds ratio (OR) 2.58) and HLA-DPB1*02:02 (p = 0.035, OR 10.41). We did not find significant enrichment of HT in patients with RP. CONCLUSIONS: Patients with RP appear to be at elevated risk of GD. Nasal involvement and HLA-DPB1*02:02 characterize the subset of RP patients with GD, which may guide attempts to characterize a distinct subtype of RP for precision medicine.

The impact of human leukocyte antigen mismatch on recipient outcomes in living-donor liver transplantation.

Donor-recipient human leukocyte antigen (HLA) compatibility has not been considered to significantly affect liver transplantation (LT) outcomes; however, its significance in living-donor LT (LDLT), which is mostly performed between blood relatives, remains unclear. This retrospective cohort study included 1954 LDLTs at our institution (1990-2020). The primary and secondary endpoints were recipient survival and the incidence of T cell-mediated rejection (TCMR) after LDLT, respectively, according to the number of HLA mismatches at all five loci: HLA-A, HLA-B, HLA-C, HLA-DR, and HLA-DQ. Subgroup analyses were also performed in between-siblings that characteristically have widely distributed 0-10 HLA mismatches. A total of 1304 cases of primary LDLTs were finally enrolled, including 631 adults (recipient age at LT ≥18 years) and 673 children (<18 years). In adult-to-adult LDLT, the more HLA mismatches at each locus, the significantly worse the recipient survival was (p = 0.03, 0.01, 0.03, 0.001, and <0.001 for HLA-A, HLA-B, HLA-C, HLA-DR, and HLA-DQ, respectively). This trend was more pronounced when multiple loci were combined (all p < 0.001 for A + B + DR, A + B + C, DR + DQ, and A + B + C + DR + DQ). Notably, a total of three or more HLA-B + DR mismatches was an independent risk factor for both TCMR (hazard ratio [HR] 2.66, 95% confidence interval [CI] 1.21-5.87; p = 0.02) and recipient survival (HR 2.44, 95% CI 1.11-5.35; p = 0.03) in between-siblings. By contrast, HLA mismatch did not affect pediatric LDLT outcomes at any locus or in any combinations; however, it should be noted that all donor-recipient relationships are parent-to-child that characteristically possesses one or less HLA mismatch at each locus and maximally five or less mismatches in total. In conclusion, HLA mismatch significantly affects not only TCMR development but also recipient survival in adult LDLT, but not in children.

Comparison of de novo donor-specific antibodies between living and cadaveric lung transplantation.

BACKGROUND: Despite growing interest in donor-specific antibodies (DSAs) and antibody-mediated rejection (AMR) in lung transplantation (LTx), no study evaluating the outcomes in recipients with de novo DSAs (dnDSAs) in living-donor lobar LTx (LDLLT) exists. We compared various characteristics of DSAs in LDLLT with those in cadaveric LTx (CLT) based on prospectively collected data. METHODS: Between October 2009 and September 2019, 211 recipients underwent LTx (128 CLTs and 83 LDLLTs). We reviewed 108 CLTs and 74 LDLLTs to determine the characteristics and clinical impact of dnDSAs. Eighteen data-deficient cases, 7 cases with preformed DSAs, and 4 re-transplants were excluded. RESULTS: There were significant differences between CLT and LDLLT patients in age, primary disease, ischemic time, and number of human leukocyte antigen mismatches per donor. The dnDSA incidence in LDLLT (6.8%) was significantly lower than that in CLT (19.4%, p = 0.02). The dnDSAs appeared later in LDLLT (mean 1,256 days) than in CLT (mean 196 days, p = 0.003). According to Cox models analyzed using dnDSA as a time-dependent covariate, dnDSA positivity was significantly associated with a poor overall survival (OS; hazard ratio [HR] 3.46, 95% confidence interval [CI] 1.59-7.57, p = 0.002) and poor CLAD-free survival in case of CLT (HR: 2.23, 95% CI: 1.08-4.63, p = 0.003). However, no such significant associations were noted in case of LDLLT. CONCLUSIONS: The dnDSA occurrence was significantly lower and later in LDLLT than in CLT. Furthermore, dnDSA-positivity was significantly associated with worse OS and CLAD-free survival after CLT but not after LDLLT.

Postoperative outcomes of lung transplant recipients with preformed donor-specific antibodies.

OBJECTIVES: Few studies have evaluated the outcomes of lung transplantation (LTx) in recipients with preformed donor-specific antibodies (DSAs). This study investigated the postoperative changes in preformed DSAs based on prospectively collected data of DSAs, and the influences of preformed DSAs on postoperative outcomes among LTx recipients. METHODS: Between July 2010 and December 2019, 216 recipients underwent LTx (81 living-donor lobar lung transplants and 135 deceased-donor lung transplants). We reviewed 8 cases with preformed DSAs to determine postoperative changes in DSAs and compared postoperative outcomes between recipients with and without DSAs. RESULTS: The preoperative mean fluorescence intensity of preformed DSAs ranged from 1141 to 14 695. Two recipients experienced antibody-mediated rejection within 2 weeks after LTx. DSAs disappeared in 7 recipients; however, 1 recipient experienced the relapse of DSAs and died from chronic lung allograft syndrome (CLAD), whereas 1 recipient had persisting DSAs within the study period and died from CLAD. Neither overall survival (OS) nor CLAD-free survival was significantly different between recipients with and without DSAs (P = 0.26 and P = 0.17, respectively). However, both OS and CLAD-free survival were significantly lower in recipients with DSAs against HLA class II than in those without these antibodies {5-year OS: 25.0% [95% confidence interval (CI): 0.9-66.5%] vs 72.1% (95% CI: 63.8-78.9%), P = 0.030 and 5-year CLAD-free survival: 26.7% (95% CI: 1.0-68.6%) vs 73.7% (95% CI: 66.5-79.5%), P = 0.002}. CONCLUSIONS: Prognosis in recipients experiencing the relapse of preformed DSAs and those with persisting DSAs may be poor. The recipients with anti-HLA class II preformed DSAs had a significantly worse prognosis.

[Small B-cell neoplasm responding to ibrutinib after 17 years of cold agglutinin disease symptom].

In this study, we report a case of a 77-year-old woman who was presented with anemia in the winter of 2002. She was diagnosed with cold agglutinin disease (CAD) and treated with corticosteroids. Further, her hemoglobin levels were maintained between 7.0 g/dl and 8.0 g/dl. In May 2019, mature peripheral blood lymphocytes increased with exacerbation of hemolytic anemia. The lymphocytes were positive for CD19 and CD20, but negative for CD5, CD10, and CD23. Additionally, they were positive for cell surface IgM-κ. The B-cell neoplasm could not be further subclassified due to the lack of BCL2-IgH and BCL1-IgH rearrangement and morphology. The IgM-κ-type M-protein was found in serum, and the direct Coombs test was negative for IgG but positive for C3b/C3d. These findings suggested that small B-cell neoplasm-associated M-protein was involved in the development of CAD through complement activation. Based on the presence of TP53 deletion, the patient was treated with ibrutinib monotherapy. Although hemolysis rapidly improved with a dramatic decrease in lymphocytes, she died from a cerebral hemorrhage. It is assumed that ibrutinib improved CAD through suppression of small B-cell neoplasm-related M-protein. CAD can precede lymphoproliferative disorders; however, the risk of ibrutinib-associated hemorrhage should be noted.

Donor-dominant one-way matching of human leukocyte antigen-A/B/DR alleles predicts graft-versus-host disease following living donor liver transplantation.

AIM: Graft-versus-host disease (GVHD) following liver transplantation is rare but fatal. Therefore, it is important to identify possible risk factors before transplantation. Although it has been suggested that donor-dominant one-way human leukocyte antigen (HLA) matching of three loci (HLA-A/B/DR) is associated with the occurrence of GVHD, the precise significance of HLA matching including HLA-C/DQ/DP remains unclear. METHODS: We retrospectively analyzed the impact of donor-dominant one-way HLA matching at six HLA loci at the allele level on GVHD using clinical registry data from 1759 cases who underwent living donor liver transplantation between June 1990 and June 2019. We extracted cases with donor-dominant one-way HLA matching at the antigen level and reconfirmed them at the allele level using preserved DNA samples. RESULTS: Three of four cases (75%) who developed GVHD showed donor-dominant one-way HLA matching at three HLA-A/B/DR loci. These cases also showed donor-dominant one-way HLA matching at HLA-C/DQ/DP. Three of six cases (50%) with donor-dominant one-way HLA matching at three loci of HLA-A/B/DR developed GVHD. Notably, none of the cases with donor-dominant one-way HLA matching at one or two HLA-A/B/DR loci developed GVHD, irrespective of matching status at HLA-C/DQ/DP. The HLA matching status at the antigen level was revised in 22 of 56 cases, following reconfirmation at the allele level. CONCLUSIONS: Pairing of donors and recipients with donor-dominant one-way HLA matching at three HLA-A/B/DR loci should be avoided to prevent GVHD. No impact of HLA-C/DQ/DP on GVHD was identified. For liver transplantation, HLA genotypes should be determined at the allele level.

Erythrocyte Alloimmunity and Genetic Variance: Results from the Collaborative Study of Alloimmunity to Antigen Diversity in Asian Populations (All ADP).

As an East-Asian international study, we evaluated erythrocyte alloimmunity by gender and history of transfusion or pregnancy. In total, data from more than 1,826,000 patients were analyzed, from whom 26,170 irregular erythrocyte antibodies were detected in 22,653 cases. Antibody frequencies in these cases were as follows: anti-E, 26.8%; anti-Lea, 20.0%; anti-P1, 7.1%; anti-M, 6.4%; anti-Mia, 5.6%; anti-c + E, 5.6%; anti-Leb, 4.6%; anti-D, 2.8%; anti-Fyb, 2.6%; anti-Lea+Leb, 2.5%; anti-Dia, 2.0%; and others. For pregnant patients, anti-D (12.7%) was statistically more frequent. For transfused patients, anti-E (37.3%), anti-c + E (9.5%), anti-C + e (3.3%) and anti-Jka (3.1%) were significantly more frequent.

Long-term follow-up of patients with anti-cyclic citrullinated peptide antibody-positive connective tissue disease: a retrospective observational study including information on the HLA-DRB1 allele and citrullination dependency.

BACKGROUND: The anti-cyclic citrullinated peptide (CCP) antibody is a diagnostic biomarker of rheumatoid arthritis (RA). However, some non-RA connective tissue disease (CTD) patients also test positive for the anti-CCP antibody and, thus, may ultimately develop RA. We retrospectively investigated whether anti-CCP-positive non-RA CTD patients developed RA and attempted to identify factors that may differentiate RA-overlapping CTD from pure CTD. METHODS: In total, 842 CTD patients with a primary diagnosis that was not RA were selected from our CTD database as of December 2012. Anti-CCP antibody titers were obtained from a retrospective chart review or measured using stored sera. RA was diagnosed according to the 1987 revised American College of Rheumatology classification criteria. Thirty-three anti-CCP-positive non-RA CTD patients were retrospectively followed up for the development of RA. Bone erosions on the hands and feet were assessed by X-ray. Citrullination dependency was evaluated by an in-house ELISA, the HLA-DRB1 allele was typed, and the results obtained were then compared between RA-overlapping and non-RA anti-CCP-positive CTD patients. RESULTS: Two out of 33 anti-CCP-positive CTD patients (6.1%) developed RA during a mean follow-up period of 8.9 years. X-rays were examined in 27 out of the 33 patients, and only one (3.7%) showed bone erosions. The frequency of the HLA-DRB1 shared epitope (SE) and anti-CCP antibody titers were both significantly higher in anti-CCP-positive RA-overlapping CTD patients than in anti-CCP-positive non-RA CTD patients, while no significant differences were observed in citrullination dependency. CONCLUSIONS: Anti-CCP-positive non-RA CTD patients rarely developed RA. HLA-DRB1 SE and anti-CCP antibody titers may facilitate the differentiation of RA-overlapping CTD from anti-CCP-positive non-RA CTD.

Outcomes of combination therapy including rituximab for antibody-mediated rejection after lung transplantation.

OBJECTIVES: This study assessed the outcomes of combination therapy including rituximab for antibody-mediated rejection after lung transplantation. METHODS: Retrospective chart reviews were performed for all patients who received combination therapy including rituximab for post-lung transplantation antibody-mediated rejection between June 2008 and October 2018. RESULTS: Among the 196 consecutive patients undergoing lung transplantation during the study period, eight (4.1%) were eligible for this study. Two patients (25.0%) were classified as having clinically definite antibody-mediated rejection and six (75.0%) as having possible antibody-mediated rejection. Prior to treatment, four patients (50.0%) met the definition of chronic lung allograft dysfunction; seven of the eight patients (87.5%) remained alive at 6 months and four (50.0%) at 12 months after antibody-mediated rejection. All patients identified as having chronic lung allograft dysfunction, prior to the treatment, died of allograft failure, or underwent re-transplantation. Decreases in the mean fluorescence intensities of the major donor-specific antibodies were observed in three patients. One patient, diagnosed with clinical antibody-mediated rejection but without pre-treatment chronic lung allograft dysfunction, began treatment relatively soon after lung transplantation, and demonstrated improved respiratory function at the 3-year follow-up. CONCLUSIONS: Our experience suggests that multimodality therapy that includes rituximab is feasible and may prevent progression of antibody-mediated rejection after lung transplantation in selected patients.

Successful granulocyte apheresis using medium molecular weight hydroxyethyl starch.

Granulocyte transfusion (GTX) is a therapeutic option for severe bacterial or fungal infection in patients with sustained neutropenia after chemotherapy or stem cell transplantation. However, high molecular weight hydroxyethyl starch (HES), which has been used for selective sedimentation of red blood cells during apheresis, is not easily available in many countries including Japan. In this study, we evaluated the efficiency of granulocyte collection using medium molecular weight HES (130 kDa) in combination with the Spectra Optia apheresis system. Apheresis was performed for 2 consecutive days from seven donors and the mean total neutrophil yield from the first and second apheresis was 5.27 ± 3.10 × 1010 and 2.91 ± 2.92 × 1010, respectively. Infusion of concentrates from the first apheresis resulted in a significant neutrophil count increase and concentrates from the second apheresis were enough for maintenance of the neutrophil counts in all the recipients. Although the number of cases is limited, our results clearly show that sufficient number of granulocytes can be harvested by using medium molecular weight HES and this strategy is a safe and effective clinical practice in countries where high molecular weight HES is not available.

HLA-DRB1 Analysis Identified a Genetically Unique Subset within Rheumatoid Arthritis and Distinct Genetic Background of Rheumatoid Factor Levels from Anticyclic Citrullinated Peptide Antibodies.

OBJECTIVE: HLA-DRB1 is the most important locus associated with rheumatoid arthritis (RA) and anticitrullinated protein antibodies (ACPA). However, fluctuations of rheumatoid factor (RF) over the disease course have made it difficult to define fine subgroups according to consistent RF positivity for the analyses of genetic background and the levels of RF. METHODS: A total of 2873 patients with RA and 2008 healthy controls were recruited. We genotyped HLA-DRB1 alleles for the participants and collected consecutive data of RF in the case subjects. In addition to RF+ and RF- subsets, we classified the RF+ subjects into group 1 (constant RF+) and group 2 (seroconversion). We compared HLA-DRB1 alleles between the RA subsets and controls and performed linear regression analysis to identify HLA-DRB1 alleles associated with maximal RF levels. Omnibus tests were conducted to assess important amino acid positions. RESULTS: RF positivity was 88%, and 1372 and 970 RF+ subjects were classified into groups 1 and 2, respectively. RF+ and RF- showed similar genetic associations to ACPA+ and ACPA- RA, respectively. We found that shared epitope (SE) was more enriched in group 2 than 1, p = 2.0 × 10-5, and that amino acid position 11 showed a significant association between 1 and 2, p = 2.7 × 10-5. These associations were independent of ACPA positivity. SE showed a tendency to be negatively correlated with RF titer (p = 0.012). HLA-DRB1*09:01, which reduces ACPA titer, was not associated with RF levels (p = 0.70). CONCLUSION: The seroconversion group was shown to have distinct genetic characteristics. The genetic architecture of RF levels is different from that of ACPA.

A Rare Case of Adult Autoimmune Neutropenia Successfully Treated with Prednisolone.

Autoimmune neutropenia (AIN) is a rare disorder that may cause life-threatening infections. In adults, most cases are secondary to other pathological conditions, and primary AIN is extremely rare. We herein report a case involving a 57-year-old woman diagnosed with AIN. A granulocyte immunofluorescence test detected autoantibodies against human neutrophil antigens in her serum, while various examinations revealed no other causes of neutropenia, suggesting her AIN was primary. She was refractory to granulocyte-colony-stimulating factor but responded to prednisolone. Her neutrophil count remained normal after gradual discontinuation of prednisolone. Diagnostic procedures and optimal treatments for this disorder need to be established.

Impact of Antibodies That React With Liver Tissue and Donor-Specific Anti-HLA Antibodies in Pediatric Idiopathic Posttransplantation Hepatitis.

BACKGROUND: The cause of late graft dysfunction has not been elucidated. Although an antibody-mediated reaction is suspected as a potential mechanism, the target antigens have not been clarified. METHODS: To clarify the etiology of idiopathic posttransplantation hepatitis (IPTH), we simultaneously examined the presence of antibodies that react with liver tissue (ARLT) by means of indirect immunofluorescence staining, as well as the presence of donor-specific anti-human leukocyte antigen antibodies (HLA-DSA). A subanalysis of the IPTH group was also performed. Within the IPTH group, the correlation between ARLT titer and clinical data were analyzed. RESULTS: In the sera of patients with IPTH (30 patients), ARLT were found at a significantly higher frequency than in patients without IPTH (42 patients; P < 0.001). Moreover, the ARLT titer appeared to be correlated with the severity of hepatitis or hepatic injury. In contrast, the frequency of HLA-DSA was significantly lower in patients with IPTH than in patients without IPTH (P = 0.001). CONCLUSION: Our findings indicate that ARLT, and not HLA-DSA, profoundly influence the etiology of IPTH.

Genotyping of relapsing polychondritis identified novel susceptibility HLA alleles and distinct genetic characteristics from other rheumatic diseases.

OBJECTIVE: To uncover the genetic background of relapsing polychondritis (RPC), a rare autoimmune disease with unknown mechanisms characterized by systemic inflammation of the cartilage, to deepen our understanding of the pathophysiology of RPC and show its distinct genetic characteristics from other rheumatic diseases. METHODS: A total of 102 patients with RPC and 1000 healthy subjects were recruited for a two-staged genetic association study and genotyped for six HLA classical loci. Haplotype association tests were also performed. The associations of amino acid (AA) residues and positions with susceptibility to RPC were analysed. Frequencies of representative susceptibility HLA alleles to other rheumatic diseases in RPC were also analysed. RESULTS: HLA-DRB1*16:02, HLA-DQB1*05:02 and HLA-B*67:01, which are in linkage disequilibrium with each other, were associated with RPC (P = 1.9 × 10(-6), 1.4 × 10(-5) and 0.00024, respectively). AA residue at position 57 in HLA-DQB1, the most significant position in type I diabetes mellitus, showed the strongest association among AA residues. HLA-DR4, a known susceptibility allele in Germans, showed a trend of susceptibility association without significance (P = 0.067). No associations were observed between the three alleles and clinical phenotypes. Representative susceptibility HLA alleles to RA, SLE, Behçet disease and Takayasu arteritis did not show enrichment in RPC in spite of sufficient statistical power. CONCLUSIONS: HLA-DRB1*16:02, HLA-DQB1*05:02 and HLA-B*67:01, in linkage disequilibrium with each other, are associated with susceptibility to RPC Importance of HLA-class II loci in RPC susceptibility is suggested. RPC is considered a genetically distinct disease from other rheumatic diseases.