Age distribution and prevalence in different age groups of four myositis-specific autoantibodies, including anti-ARS, anti-MDA5, anti-Mi-2, and anti-TIF1γ antibodies.

We accumulated the demographic information and analyzed the prevalence of myositis-specific antibodies (MSAs) in a large cohort across Japan as standard testing for MSAs becomes more widely available. This retrospective, observational, cohort study analyzed the records of individuals aged 0-99 years who are tested for serum MSAs at SRL Incorporation from January 2014 to April 2020 across Japan. An enzyme-linked immunosorbent assay testing was applied to determine the presence of anti-aminoacyl tRNA synthetase (anti-ARS), anti-Mi-2, anti-melanoma differentiation-associated gene 5 (anti-MDA5), or anti-transcriptional intermediary factor 1-γ (anti-TIF1γ) (Medical and Biological Laboratories). Anti-TIF1γ antibody was detected more in male patients than female patients. In contrast, women were predominant in patients with other MSAs. More than half of the anti-ARS or anti-TIF1γ antibody-positive patients were over 60 years old, although anti-MDA5 or anti-Mi-2-positive patients were mostly under <60 years old. Anti-MDA5 antibody-positive patients were mostly aged 40-59 years, while other MSA groups were mostly 60-79 years. Anti-MDA5 antibody was detected most frequently in the age range of 0-29 years. Anti-TIF1γ antibody was the second most commonly detected autoantibody in the age range of 0-19 years. Anti-ARS antibody was the most frequently detected autoantibody after the age of 30 years, and the frequency of anti-ARS gradually increased at more advanced ages. The second and third most detected autoantibodies were anti-MDA5 and anti-TIF1γ, respectively, in ages 30-79 years. We performed a nationwide >3-year evaluation of MSA detection in a routine diagnostic setting. This paper provides clinical images concerning the relationship between four MSA types and the distribution of sex and age in a large population.

A case of palisaded neutrophilic and granulomatous dermatitis associated with systemic lupus erythematosus presenting with pustules.

Palisaded neutrophilic and granulomatous dermatitis (PNGD) is a relatively rare skin disease that is characterized by a reactive granulomatous histopathological pattern and is often associated with systemic autoimmune diseases. We encountered a case of PNGD that presented with pustules, although the prototypical clinical presentation of PNGD is mainly erythema and papules. Here, this rare case of PNGD with pustules is presented and discussed in relation to the relevant literature.

Cell surface-expressed Ro52/IgG/HLA-DR complex is targeted by autoantibodies in patients with inflammatory myopathies.

Intracellular proteins are often targeted by autoantibodies in autoimmune diseases; however, the mechanism through which intracellular molecules are targeted remains unknown. We previously found that several intracellular misfolded proteins are transported to the cell surface by HLA class II molecules and are recognized by autoantibodies in some autoimmune diseases, such as rheumatoid arthritis, antiphospholipid syndrome, and microscopic polyangiitis. Ro52 is an intracellular Fc receptor that is a target antigen for myositis-associated autoantibodies. We analyzed the role of HLA class II molecules in the autoantibody recognition of Ro52. Ro52 alone was not transported to the cell surface by HLA class II molecules; however, it was transported to the cell surface in the presence of both IgG heavy chain and HLA class II molecules to form a Ro52/IgG/HLA-DR complex. The Ro52/IgG/HLA-DR complex was specifically recognized by autoantibodies from some patients with inflammatory myopathies. We then evaluated 120 patients with inflammatory myopathies with four types of myositis-specific antibodies and analyzed the autoantibodies against the Ro52/IgG/HLA-DR complex. The specific antibodies against the Ro52/IgG/HLA-DR complex were detected in 90% and 93% of patients who were positive for anti-MDA5 and anti-ARS antibodies, respectively. In individual patients with these two inflammatory myopathies, changes in serum titers of anti-Ro52/IgG/HLA-DR-specific antibodies were correlated with the levels of KL-6 (R = 0.51 in anti-MDA5 antibody-positive DM patients, R = 0.67 in anti-ARS antibody-positive PM/DM patients with respiratory symptoms) and CK (R = 0.63 in anti-ARS antibody-positive PM/DM patients with muscle symptoms) over time. These results suggest that antibodies against Ro52/IgG/HLA-DR expressed on the cell surface could be involved in the pathogenesis of inflammatory myopathy subgroups.

Clinical and laboratory parameters predicting cancer in dermatomyositis patients with anti-TIF1γ antibodies.

BACKGROUND: Dermatomyositis (DM) is a chronic acquired autoimmune disorder strongly associated with cancer development. Until now, identifying predictive markers indicating a high risk of cancer has challenged clinicians. Although anti-TIF1γ antibody is a major serological indicator for cancer-associated DM, many anti-TIF1γ antibody-positive DM patients lack malignancy. OBJECTIVES: To determine clinical and laboratory parameters that support cancer prediction in anti-TIF1γ antibody-positive DM patients. METHODS: Clinical and laboratory data were collected from cancer-associated and unassociated DM patients with anti-TIF1γ antibodies. Serum cytokine concentrations were measured with a cytokine array assay. The values of inflammatory cytokines in cancer prognosis were determined with a receiver operating characteristic curve analysis. RESULTS: The cancer group had a significantly higher frequency of males, older mean age and higher anti-TIF1γ antibody levels. Some inflammatory cytokines, particularly tumour necrosis factor (TNF) and TNF receptor superfamilies, had increased levels in sera that were correlated with myositis markers, cutaneous severity and DM disease activity. Moreover, these cytokines had an area under the curve (AUC) ≥0.8 and high sensitivity and specificity at their specific cut-off, even higher than anti-TIF1γ levels in cancer prediction in our DM patients. CONCLUSIONS: Our results suggest a close pathophysiological relationship among myositis, cancer and skin involvements in DM patients with anti-TIF1γ antibodies and the potential clinical significance of anti-TIF1γ antibody levels in evaluating disease severity and prognosis in DM patients. Some inflammatory cytokines, particularly TNF and TNF receptor superfamilies including BAFF, sTNF-R1 and sTNF-R2, may support cancer prediction in DM patients with anti-TIF1γ antibodies.

Imbalance toward TFH 1 cells playing a role in aberrant B cell differentiation in systemic sclerosis.

OBJECTIVE: SSc is a connective tissue disease with multisystem disorder induced by the inflammation and fibrosis following T and B cell abnormalities. Follicular helper CD4+ T (TFH) cells play a crucial role in the formation of germinal centres and specialize in interacting to aid B cell differentiation. We aimed to investigate TFH cells and their subsets to evaluate their involvement with B cell alteration in SSc. METHOD: Circulating TFH cells (cTFH), B cells and their subsets were assessed by flow cytometry. The concentration of serum cytokines was measured by cytokine array assay. Immunohistochemistry and IF were performed to evaluate the migration of TFH cells in SSc skin lesions. RESULTS: The proportion of cTFH cells did not differ from controls, but their subsets were imbalanced in SSc patients. The frequency of TFH 1 was increased and correlated with ACA titre, serum IgM or CRP levels of patients, and cytokine concentrations of IL-21 and IL-6 that induce B cell differentiation in SSc. cTFH cells from SSc showed activated phenotype with expressing higher cytokine levels compared with controls. The frequency of TFH 17 was also increased, but was not correlated with a high level of Th17 cytokines in patients' sera. Furthermore, infiltration of TFH cells was found in skin lesion of SSc patients. CONCLUSION: We here describe an imbalance of cTFH toward TFH 1 that may induce B cell alteration through IL-21 and IL-6 pathways and promote inflammation, contributing to the pathogenesis of SSc disease.

Exploring the imbalance of circulating follicular helper CD4+ T cells in sarcoidosis patients.

BACKGROUND: Sarcoidosis is a systemic granulomatous disease characterized by the combination of Th1 and Th17 responses. Recently, several arguments have suggested a potential involvement of B cells as well as T cells in the pathogenesis of sarcoidosis. Follicular helper CD4+ T (TFH) cells are specialized in interacting with and helping B cells, and play a crucial role in the formation of germinal centers. OBJECTIVE: We sought to explore the status of TFH cells and investigate their possible pathogenic role in sarcoidosis. METHODS: TFH cells and B cells in peripheral blood were examined by flow cytometry, and serum samples were studied by cytokine arrays. Immunohistochemistry was performed to check for the presence of TFH cells in sarcoidosis skin lesions. Gene expression in isolated TFH cells was analyzed by quantitative RT-PCR. RESULTS: The proportion of circulating TFH cells was decreased. CD4+CXCR5+ TFH cells were observed in cutaneous lesions in sarcoidosis. Gene expression in circulating TFH cells and serum cytokine concentrations related to Th17 were increased in sarcoidosis patients. Gene expressions of B cell differentiation cytokines in TFH cells were not altered in sarcoidosis patients. CONCLUSION: We herein describe a decrease of circulating TFH cells and their migration to affected tissues. Circulating TFH cells are one of the potential cell types capable of producing IL-17 and enhancing Th17 responses, and may promote the chronic inflammation. We could not demonstrate a direct linkage between the imbalance of TFH cells and abnormal B cell differentiation in sarcoidosis.

Clinical characteristics of sarcoidosis patients with systemic sclerosis-specific autoantibody: Possible involvement of thymus and activation-regulated chemokine and a review of the published works.

Sarcoidosis and systemic sclerosis (SSc) are both multisystem disorders of unknown etiology. Some cases having both sarcoidosis and SSc have been reported previously. The present study was to investigate clinical features in sarcoidosis patients who possessed SSc-specific autoantibody. The pathophysiology of each disease, including shared pathways leading to the development of both conditions, is reviewed in addition to previous reports of patients with concomitant SSc and sarcoidosis. SSc-specific autoantibodies including anticentromere antibody (ACA), anti-topoisomerase I antibody, anti-RNA polymerase III antibody and anti-U1RNP antibody were examined in sarcoidosis patients. Complete medical histories, clinical examinations and laboratory tests were conducted for all patients. For reviewing previously published reports, all cases were retrieved through a PubMed search. ACA was most frequently observed in sarcoidosis patients. Plaques and papules were the most frequent as the cutaneous sarcoidosis lesions. Soluble interleukin-2 receptor was elevated in most of the cases (6/8, 75%), and thymus and activation-regulated chemokine (TARC) was elevated in all cases (6/6, 100%). Together with our two cases (cases 1 and 3), a review of previously reported cases of sarcoidosis patients concomitant with SSc showed high frequency of ACA and plaques as cutaneous lesions. We suppose that TARC may play some roles in the production of SSc-specific autoantibodies and development of concomitance with SSc in sarcoidosis, although the mechanisms remain unknown.