P2-028 MECHANISMS OF BLISTER INDUCTION BY AUTOANTIBODIES AGAINST THE EPIDERMAL BASEMENT MEMBRANE

Collagens, laminins and other constituents of the epidermal basement membrane mediate a broad range of functions, including tissue scaffolding, cell adhesion, cell migration, cancer, angiogenesis, tissue morphogenesis and tissue repair. In addition to these roles, these components of the dermal-epidermal junction may also function as targets of autoreactive T and B cells in autoimmune skin diseases. In a group of organ-specific autoimmune blistering diseases the main autoantigens include collagen VII, the main constituent of the anchoring fibrils, the transmembrane hemidesomosomal protein collagen XVII/BP180 and laminin 332. Autoimmunity to collagen XVII and laminin 332 is associated with pemphigoid diseases, while collagen VII is the main autoantigen of epidermolysis bullosa acquisita. Whereas autoreactive T cells are required for the initiation and modulation of the autoimmune response, tissue damage resulting in subepidermal blistering is essentially mediated by autoantibodies. The mechanisms of blister formation are multiple and include direct effects by steric hindrance and/or by triggering the transduction of a signal to the cell. However, in addition to the binding to their target antigen, autoantibodies need to interact with factors of the innate immune system, including the complement system and inflammatory cells, in order to induce full-blown disease. Understanding the mechanisms by which autoantibodies specific to collagens and laminins disrupt the cell-matrix adhesion should facilitate the development of more specific therapeutic strategies of autoimmune blistering diseases.

Hyper-immunoglobulin E syndromes (HIES) are very rare primary immunodeficiency which is characterized by clinical triad of high serum level of Immunoglobulin E/IgE (>2000 IU/mL) and eosinophilia, recurring staphylococcal skin abscess, and pneumonia with pneumatocele formation. GrimbacherÕs scoring system (NIH-HIES scoring system) is used to diagnose HIES. Scores greater than 40% of the maximal score, based on age group, has a high significance of HIES. The maximal NIH-HIES score for 3-6 year age group is 60 points. We reported a 5 year old girl who had elevating total IgE serum level >2500 IU/mL, more than four lesions of skin abscess, pneumonia, which is proven by 3 times X-ray examination, serious skin infections (staphylococcal scaled skin syndrome), total eosinophil serum 1760 cells/µL, severe eczema and oral candidiasis. She had 41 points for total score, which was 60% of the total score based on group of age, and we diagnosed HIES in our case based on this scoring systems. We used intravenous immunoglobulin (IVIG), which may influence the IgE levels due to an increased immunoglobulin catabolism or IgE neutralization via an anti-idiotype network. The patient was discharged with better clinical presentation and laboratory findings two days after had IVIG therapy.

Formation of antibodies to biologics has been regarded as main cause of treatment failure in rheumatoid arthritis and ankylosing spondylitis (AS). However, assessment of anti-drug antibodies (ADA) is not available in routine practice till now. Here, to find clinical markers predicting ADA formation in AS, we analyzed disease-associated parameters and ADA presence.

In 20 AS patients initiating anti-TNFα therapy, blood was collected serially at baseline and 3-month after therapy and serum-ADA levels were measured using ELISA. Disease-associated parameters including Ankylosing Spondylitis Disease Activity Score (ASDAS), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI) and laboratory data including ESR/CRP were assessed.

Among 20 patients (Adalimumab n=16, Infliximab n=4), ADA were detected in 4 (20%) patients (Adalimumab n=2, Infliximab n=2). At baseline, there was no significant difference in laboratory data and clinical activity scores between patients with and without ADA. After 3-month, only 1 of the 4 ADA-positive patients fulfilled clinically important improvement (CII) criteria using ASDAS-CRP score (CII defined decrease ≥ 1.1 from baseline). However, all ADA-negative patients (n=16) achieved CII. (1/4 vs. 16/16, p=0.004). When assessed by ASDAS-ESR, CII achievement was similar to that of ASDAS-CRP between ADA-positive and ADA-negative group. (1/4 vs. 15/16, p=0.013). However, changes of BASDAI and BASFI score and number of patients who treated concomitantly with anti-rheumatic drugs or NSAIDs was not different in both groups.

In AS patients with anti-TNFα therapy, failure achieving CII using ASDAS at 3-month could suggest developing drug immunogenicity.

Methodology: Plasma concentrations of IL-35 and soluble gp130 were measured using ELISA. Expression of IL-35 receptor components IL-12Rβ2 and gp130 on the CD4⁺ helper (Th) cells and CD19⁺ B cells, and the number of CD4⁺CD25⁺CD127^- Treg cells were quantitated by flow cytometry.

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease that affects multiple organ systems with immune complexes and a large array of autoantibodies. Thrombosis has been reported in about 10%-26% of SLE patients and antiphospholipid antibodies(aPL) are important risk factors for thrombosis. Renal artery thrombosis has rarely been reported in young patients, and no pediatric cases about aPL-negative SLE patients with renal artery thrombosis have been reported in Korea.

Case : A 12-year-old female patient presented to the hospital with a 3-day history of nausea, vomiting, and right flank pain. She was diagnosed with SLE with lupus nephritis two years ago and she has been treated with a corticosteroid, mycophenolate mofetil and hydroxychloroquine. Right costovertebral angle tenderness was revealed on physical examination. Initial laboratory investigations revealed that lupus anticoagulant antibody, anti-beta2 glycoprotein-I antibody, anti-cardiolipin Ab lgG and IgM were negative. Abdominal computed tomography showed renal artery thrombosis and renal infarction. Subcutaneous low molecular weighted heparin was started and concurrently, warfarin was started and has been continued for 3 months. After 3 months, 2.2cm sized heterogenous hypodense lesion at the upper pole of right kidney was not seen and it lefted small atrophic changes in the abdominal computed tomography. She is doing well by maintaining oral anticoagulant and followed up regularly through outpatient clinic visits.

Conclusion : Renal infarction should be suspected in cases of unexplained sudden flank or upper abdominal pain, with or without fever, nausea, and vomiting even if antiphospholipid antibody is negative.

Animal models demonstrate two independent mechanisms leading to systemic lupus erythematosus (SLE): overexpression of B-Cell-Activating-Factor (BAFF) in a T-independent manner, and abnormal activation of follicular-T-helper (Tfh) cells with normal BAFF levels. In SLE patients, it has been reported that disease severity correlates with increased serum BAFF levels, increased circulating Tfh cells and several B cell abnormalities. Monocyte involvement in the pathogenesis of SLE has been proposed to act through enhanced recognition of immune complexes containing TLR-binding self-antigens. Total numbers of NK cells are decreased in SLE patients, but NK subset distribution is similar to healthy controls. It remains unclear whether these abnormalities co-exist within patients, or if human SLE can be divided into subcategories depending on the immune process driving the disease.

Flow cytometric analysis of PBMCs in 30 SLE samples indicated that frequency of CD27^-IgD^- memory B cells was increased in SLE patients and inversely correlated with disease severity. While some SLE patients had a greatly increased population of transitional B cells, other SLE and control samples had almost none. Neither patients nor controls had clearly identifiable populations of circulating Tfh cells. Frequency of CD56^briCD16^- NK cells was significantly higher in SLE patients than controls, while frequency of CD56^dimCD16⁺ NK cells was significantly decreased in SLE patients compared with healthy controls.

Measurement of BAFF levels is currently being performed. This study will be extended to a larger cohort of patients. Our results will indicate the relative contributions of T-dependent and T-independent mechanisms, monocytes and NK cells in human SLE.